U.S. BRAND NAMES — Norvasc®
PHARMACOLOGIC CATEGORY
Calcium Channel Blocker
DOSING: ADULTS
Hypertension: Oral: Initial dose: 5 mg once daily; maximum dose: 10 mg once daily. In general, titrate in 2.5 mg increments over 7-14 days. Usual dosage range (JNC 7): 2.5-10 mg once daily.
Angina: Oral: Usual dose: 5-10 mg; lower dose suggested in elderly or hepatic impairment; most patients require 10 mg for adequate effect.
DOSING: PEDIATRIC — Hypertension: Oral: Children 6-17 years: 2.5-5 mg once daily
(For additional information see "Amlodipine: Pediatric drug information")
DOSING: ELDERLY — Dosing should start at the lower end of dosing range due to possible increased incidence of hepatic, renal, or cardiac impairment. Elderly patients also show decreased clearance of amlodipine.
Hypertension: Oral: 2.5 mg once daily
Angina: Oral: 5 mg once daily
DOSING: HEPATIC IMPAIRMENT
Hypertension: Administer 2.5 mg once daily
Angina: Administer 5 mg once daily
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Norvasc®: 2.5 mg, 5 mg, 10 mg
DOSAGE FORMS: CONCISE
Tablet:
Norvasc®: 2.5 mg, 5 mg, 10 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — May be administered without regard to meals.
USE — Treatment of hypertension; treatment of symptomatic chronic stable angina, vasospastic (Prinzmetal's) angina (confirmed or suspected); prevention of hospitalization due to angina with documented CAD (limited to patients without heart failure or ejection fraction <40%)>10%: Cardiovascular: Peripheral edema (2% to 15% dose related)
1% to 10%:
Cardiovascular: Flushing (1% to 3%), palpitation (1% to 4%)
Central nervous system: Headache (7%; similar to placebo 8%), dizziness (1% to 3%), fatigue (4%), somnolence (1% to 2%)
Dermatologic: Rash (1% to 2%), pruritus (1% to 2%)
Endocrine & metabolic: Male sexual dysfunction (1% to 2%)
Gastrointestinal: Nausea (3%), abdominal pain (1% to 2%), dyspepsia (1% to 2%), gingival hyperplasia
Neuromuscular & skeletal: Muscle cramps (1% to 2%), weakness (1% to 2%)
Respiratory: Dyspnea (1% to 2%), pulmonary edema (15% from PRAISE trial, CHF population)
<1%>90%) to inactive metabolite
Bioavailability: 64% to 90%
Half-life elimination: 30-50 hours; increased with hepatic dysfunction
Time to peak, plasma: 6-12 hours
Excretion: Urine (10% as parent, 60% as metabolite)
PATIENT INFORMATION — Take as prescribed; do not stop abruptly without consulting prescriber. You may experience headache (if unrelieved, consult prescriber), nausea or vomiting (frequent small meals may help), or constipation (increased dietary bulk and fluids may help). May cause drowsiness; use caution when driving or engaging in tasks that require alertness until response to drug is known. Report unrelieved headache, vomiting, constipation, palpitations, peripheral or facial swelling, weight gain >5 lb/week, or respiratory changes.
Amlexanox
U.S. BRAND NAMES — Aphthasol®
PHARMACOLOGIC CATEGORY
Anti-inflammatory, Locally Applied
DOSING: ADULTS — Aphthous ulcers: Topical: Administer (0.5 cm - 1/4") directly on ulcers 4 times/day following oral hygiene, after meals, and at bedtime.
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Paste: 5% (5 g) [contains benzyl alcohol]
DOSAGE FORMS: CONCISE
Paste:
Aphthasol®: 5% (5 g)
GENERIC EQUIVALENT AVAILABLE — No
USE — Treatment of aphthous ulcers (ie, canker sores)
USE - UNLABELED / INVESTIGATIONAL — Allergic disorders
ADVERSE REACTIONS SIGNIFICANT
1% to 2%:
Dermatologic: Allergic contact dermatitis
Gastrointestinal: Oral irritation
<1% (Limited to important or life-threatening): Contact mucositis
CONTRAINDICATIONS — Hypersensitivity to amlexanox or any component of the formulation
WARNINGS / PRECAUTIONS — Discontinue therapy if rash or contact mucositis develops.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Due to lack of data, avoid use in pregnancy, if possible.
LACTATION — Excretion in breast milk unknown/use caution
PRICING — (data from drugstore.com)
Paste (Aphthasol)
5% (5): $23.20
MECHANISM OF ACTION — As a benzopyrano-bipyridine carboxylic acid derivative, amlexanox has anti-inflammatory and antiallergic properties; it inhibits chemical mediatory release of the slow-reacting substance of anaphylaxis (SRS-A) and may have antagonistic effects on interleukin-3
PHARMACODYNAMICS / KINETICS
Absorption: Some from swallowed paste
Metabolism: Hydroxylated and conjugated metabolites
Half-life elimination: 3.5 hours
Time to peak, serum: 2 hours
Excretion: Urine (17% as unchanged drug)
PHARMACOLOGIC CATEGORY
Anti-inflammatory, Locally Applied
DOSING: ADULTS — Aphthous ulcers: Topical: Administer (0.5 cm - 1/4") directly on ulcers 4 times/day following oral hygiene, after meals, and at bedtime.
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Paste: 5% (5 g) [contains benzyl alcohol]
DOSAGE FORMS: CONCISE
Paste:
Aphthasol®: 5% (5 g)
GENERIC EQUIVALENT AVAILABLE — No
USE — Treatment of aphthous ulcers (ie, canker sores)
USE - UNLABELED / INVESTIGATIONAL — Allergic disorders
ADVERSE REACTIONS SIGNIFICANT
1% to 2%:
Dermatologic: Allergic contact dermatitis
Gastrointestinal: Oral irritation
<1% (Limited to important or life-threatening): Contact mucositis
CONTRAINDICATIONS — Hypersensitivity to amlexanox or any component of the formulation
WARNINGS / PRECAUTIONS — Discontinue therapy if rash or contact mucositis develops.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Due to lack of data, avoid use in pregnancy, if possible.
LACTATION — Excretion in breast milk unknown/use caution
PRICING — (data from drugstore.com)
Paste (Aphthasol)
5% (5): $23.20
MECHANISM OF ACTION — As a benzopyrano-bipyridine carboxylic acid derivative, amlexanox has anti-inflammatory and antiallergic properties; it inhibits chemical mediatory release of the slow-reacting substance of anaphylaxis (SRS-A) and may have antagonistic effects on interleukin-3
PHARMACODYNAMICS / KINETICS
Absorption: Some from swallowed paste
Metabolism: Hydroxylated and conjugated metabolites
Half-life elimination: 3.5 hours
Time to peak, serum: 2 hours
Excretion: Urine (17% as unchanged drug)
Amitriptyline and perphenazine
PHARMACOLOGIC CATEGORY
Antidepressant, Tricyclic (Tertiary Amine)
Antipsychotic Agent, Typical, Phenothiazine
DOSING: ADULTS — Depression and anxiety: Oral: 1 tablet 2-4 times/day
DOSING: ELDERLY — Refer to adult dosing.
DOSING: HEPATIC IMPAIRMENT — Avoid use in severe hepatic failure.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
2-10: Amitriptyline hydrochloride 10 mg and perphenazine 2 mg
2-25: Amitriptyline hydrochloride 25 mg and perphenazine 2 mg
4-10: Amitriptyline hydrochloride 10 mg and perphenazine 4 mg
4-25: Amitriptyline hydrochloride 25 mg and perphenazine 4 mg
4-50: Amitriptyline hydrochloride 50 mg and perphenazine 4 mg
DOSAGE FORMS: CONCISE
Tablet:
Generics:
2-10: Amitriptyline 10 mg and perphenazine 2 mg
2-25: Amitriptyline 25 mg and perphenazine 2 mg
4-10: Amitriptyline 10 mg and perphenazine 4 mg
4-25: Amitriptyline 25 mg and perphenazine 4 mg
4-50: Amitriptyline 50 mg and perphenazine 4 mg
GENERIC EQUIVALENT AVAILABLE — Yes
USE — Treatment of patients with moderate to severe anxiety and depression
USE - UNLABELED / INVESTIGATIONAL — Depression with psychotic features
ADVERSE REACTIONS SIGNIFICANT — See individual agents.
CONTRAINDICATIONS — Hypersensitivity to amitriptyline, perphenazine, or any component of the formulation (cross-sensitivity with other phenothiazines may exist); angle-closure glaucoma; bone marrow depression; severe liver or cardiac disease; pregnancy
WARNINGS / PRECAUTIONS
Based on the amitriptyline component:
Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with major depressive disorder (MDD) and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. A medication guide should be dispensed with each prescription.
The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Monitor for worsening of depression or suicidality, especially during initiation of therapy or with dose increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression occur.
May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder.
Often causes drowsiness/sedation, resulting in impaired performance of tasks requiring alertness (eg, operating machinery or driving). Sedative effects may be additive with other CNS depressants and/or ethanol. The degree of sedation is very high relative to other antidepressants. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disease. May cause hyponatremia/SIADH. May increase the risks associated with electroconvulsive therapy. Consider discontinuing, when possible, prior to elective surgery.. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.
May cause orthostatic hypotension; the risk of this problem is very high relative to other antidepressants. Use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). The degree of anticholinergic blockade produced by this agent is very high relative to other cyclic antidepressants; use with caution in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or a history of bowel obstruction. May alter glucose control - use with caution in patients with diabetes.
Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities). The risk of conduction abnormalities with this agent is high relative to other antidepressants. May lower seizure threshold - use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold. Use with caution in hyperthyroid patients or those receiving thyroid supplementation. Use with caution in patients with hepatic or renal dysfunction and in elderly patients.
Based on the perphenazine component:
May cause hypotension. May be sedating; use with caution in disorders where CNS depression is a feature. Use with caution in Parkinson's disease. Caution in patients with hemodynamic instability; predisposition to seizures; severe cardiac, hepatic, renal, or respiratory disease. Esophageal dysmotility and aspiration have been associated with antipsychotic use - use with caution in patients at risk of pneumonia (eg, Alzheimer's disease). Caution in breast cancer or other prolactin-dependent tumors (may elevate prolactin levels). May alter temperature regulation or mask toxicity of other drugs due to antiemetic effects. May alter cardiac conduction - life-threatening arrhythmias have occurred with therapeutic doses of phenothiazines. May cause orthostatic hypotension - use with caution in patients at risk of this effect or those who would tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, or other medications which may predispose).
Phenothiazines may cause anticholinergic effects (confusion, agitation, constipation, xerostomia, blurred vision, urinary retention); therefore, they should be used with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems. Conditions which also may be exacerbated by cholinergic blockade include narrow-angle glaucoma (screening is recommended) and worsening of myasthenia gravis. Relative to other neuroleptics, perphenazine has a low potency of cholinergic blockade.
May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is moderate-high relative to other neuroleptics). Older patients are at increased risk for developing tardive dyskinesia. May be associated with neuroleptic malignant syndrome (NMS) or pigmentary retinopathy.
This combination is not FDA approved for use in children or for the treatment of bipolar depression.
RESTRICTIONS — An FDA-approved medication guide concerning the use of antidepressants in children and teenagers must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm. Dispense to parents or guardians of children and teenagers receiving this medication.
DRUG INTERACTIONS
Amitriptyline: Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak)
Perphenazine: Substrate of CYP1A2 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2D6 (weak)
Also see individual agents.
ETHANOL / NUTRITION / HERB INTERACTIONS — Ethanol: Avoid ethanol (due to increased sedation).
PREGNANCY RISK FACTOR — D (show table)
LACTATION — Enters breast milk/contraindicated
PRICING — (data from drugstore.com)
Tablets (Perphenazine-Amitriptyline)
2-10 mg (60): $8.99
2-25 mg (30): $7.99
4-25 mg (60): $11.99
4-50 mg (60): $27.99
MONITORING PARAMETERS — Vital signs; lipid profile, fasting blood glucose/Hb A1c; BMI, weight; mental status, abnormal involuntary movement scale (AIMS), extrapyramidal symptoms (EPS)
CANADIAN BRAND NAMES — Etrafon®
INTERNATIONAL BRAND NAMES — Etrafon (CA); Mutabase (ES); Mutabon A (AE, BH, CY, EG, IL, IQ, IR, JO, LY, OM, QA, SA, SY); Mutabon D (AE, AR, BH, CL, CY, EG, ID, IL, IQ, IR, JO, LY, OM, PY, QA, SA, SY); Mutabon F (AE, BH, CY, EG, IL, IQ, IR, JO, LY, OM, QA, SA, SY); Mutabon M (AE, BH, CY, EG, ID, IL, IQ, IR, JO, LY, OM, QA, SA, SY); Mutabon-A (AN, BB, BM, BS, BZ, GY, JM, SR, TT); Mutabon-D (AN, BB, BM, BS, BZ, GY, JM, SR, TT); Mutabon-F (AN, BB, BM, BS, BZ, GY, JM, SR, TT); Mutabon-M (AN, BB, BM, BS, BZ, GY, JM, SR, TT); Neuragon-A (TH); Neuragon-B (TH); Polybon (TH); Triptafen (GB); Triptafen M (GB)
MECHANISM OF ACTION
Amitriptyline increases the synaptic concentration of serotonin and/or norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane.
Perphenazine is a piperazine phenothiazine antipsychotic which blocks postsynaptic mesolimbic dopaminergic receptors in the brain; exhibits alpha-adrenergic blocking effect and depresses the release of hypothalamic and hypophyseal hormones.
PHARMACODYNAMICS / KINETICS — See individual agents.
Antidepressant, Tricyclic (Tertiary Amine)
Antipsychotic Agent, Typical, Phenothiazine
DOSING: ADULTS — Depression and anxiety: Oral: 1 tablet 2-4 times/day
DOSING: ELDERLY — Refer to adult dosing.
DOSING: HEPATIC IMPAIRMENT — Avoid use in severe hepatic failure.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
2-10: Amitriptyline hydrochloride 10 mg and perphenazine 2 mg
2-25: Amitriptyline hydrochloride 25 mg and perphenazine 2 mg
4-10: Amitriptyline hydrochloride 10 mg and perphenazine 4 mg
4-25: Amitriptyline hydrochloride 25 mg and perphenazine 4 mg
4-50: Amitriptyline hydrochloride 50 mg and perphenazine 4 mg
DOSAGE FORMS: CONCISE
Tablet:
Generics:
2-10: Amitriptyline 10 mg and perphenazine 2 mg
2-25: Amitriptyline 25 mg and perphenazine 2 mg
4-10: Amitriptyline 10 mg and perphenazine 4 mg
4-25: Amitriptyline 25 mg and perphenazine 4 mg
4-50: Amitriptyline 50 mg and perphenazine 4 mg
GENERIC EQUIVALENT AVAILABLE — Yes
USE — Treatment of patients with moderate to severe anxiety and depression
USE - UNLABELED / INVESTIGATIONAL — Depression with psychotic features
ADVERSE REACTIONS SIGNIFICANT — See individual agents.
CONTRAINDICATIONS — Hypersensitivity to amitriptyline, perphenazine, or any component of the formulation (cross-sensitivity with other phenothiazines may exist); angle-closure glaucoma; bone marrow depression; severe liver or cardiac disease; pregnancy
WARNINGS / PRECAUTIONS
Based on the amitriptyline component:
Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with major depressive disorder (MDD) and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. A medication guide should be dispensed with each prescription.
The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Monitor for worsening of depression or suicidality, especially during initiation of therapy or with dose increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression occur.
May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder.
Often causes drowsiness/sedation, resulting in impaired performance of tasks requiring alertness (eg, operating machinery or driving). Sedative effects may be additive with other CNS depressants and/or ethanol. The degree of sedation is very high relative to other antidepressants. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disease. May cause hyponatremia/SIADH. May increase the risks associated with electroconvulsive therapy. Consider discontinuing, when possible, prior to elective surgery.. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.
May cause orthostatic hypotension; the risk of this problem is very high relative to other antidepressants. Use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). The degree of anticholinergic blockade produced by this agent is very high relative to other cyclic antidepressants; use with caution in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or a history of bowel obstruction. May alter glucose control - use with caution in patients with diabetes.
Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities). The risk of conduction abnormalities with this agent is high relative to other antidepressants. May lower seizure threshold - use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold. Use with caution in hyperthyroid patients or those receiving thyroid supplementation. Use with caution in patients with hepatic or renal dysfunction and in elderly patients.
Based on the perphenazine component:
May cause hypotension. May be sedating; use with caution in disorders where CNS depression is a feature. Use with caution in Parkinson's disease. Caution in patients with hemodynamic instability; predisposition to seizures; severe cardiac, hepatic, renal, or respiratory disease. Esophageal dysmotility and aspiration have been associated with antipsychotic use - use with caution in patients at risk of pneumonia (eg, Alzheimer's disease). Caution in breast cancer or other prolactin-dependent tumors (may elevate prolactin levels). May alter temperature regulation or mask toxicity of other drugs due to antiemetic effects. May alter cardiac conduction - life-threatening arrhythmias have occurred with therapeutic doses of phenothiazines. May cause orthostatic hypotension - use with caution in patients at risk of this effect or those who would tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, or other medications which may predispose).
Phenothiazines may cause anticholinergic effects (confusion, agitation, constipation, xerostomia, blurred vision, urinary retention); therefore, they should be used with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems. Conditions which also may be exacerbated by cholinergic blockade include narrow-angle glaucoma (screening is recommended) and worsening of myasthenia gravis. Relative to other neuroleptics, perphenazine has a low potency of cholinergic blockade.
May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is moderate-high relative to other neuroleptics). Older patients are at increased risk for developing tardive dyskinesia. May be associated with neuroleptic malignant syndrome (NMS) or pigmentary retinopathy.
This combination is not FDA approved for use in children or for the treatment of bipolar depression.
RESTRICTIONS — An FDA-approved medication guide concerning the use of antidepressants in children and teenagers must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm. Dispense to parents or guardians of children and teenagers receiving this medication.
DRUG INTERACTIONS
Amitriptyline: Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak)
Perphenazine: Substrate of CYP1A2 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2D6 (weak)
Also see individual agents.
ETHANOL / NUTRITION / HERB INTERACTIONS — Ethanol: Avoid ethanol (due to increased sedation).
PREGNANCY RISK FACTOR — D (show table)
LACTATION — Enters breast milk/contraindicated
PRICING — (data from drugstore.com)
Tablets (Perphenazine-Amitriptyline)
2-10 mg (60): $8.99
2-25 mg (30): $7.99
4-25 mg (60): $11.99
4-50 mg (60): $27.99
MONITORING PARAMETERS — Vital signs; lipid profile, fasting blood glucose/Hb A1c; BMI, weight; mental status, abnormal involuntary movement scale (AIMS), extrapyramidal symptoms (EPS)
CANADIAN BRAND NAMES — Etrafon®
INTERNATIONAL BRAND NAMES — Etrafon (CA); Mutabase (ES); Mutabon A (AE, BH, CY, EG, IL, IQ, IR, JO, LY, OM, QA, SA, SY); Mutabon D (AE, AR, BH, CL, CY, EG, ID, IL, IQ, IR, JO, LY, OM, PY, QA, SA, SY); Mutabon F (AE, BH, CY, EG, IL, IQ, IR, JO, LY, OM, QA, SA, SY); Mutabon M (AE, BH, CY, EG, ID, IL, IQ, IR, JO, LY, OM, QA, SA, SY); Mutabon-A (AN, BB, BM, BS, BZ, GY, JM, SR, TT); Mutabon-D (AN, BB, BM, BS, BZ, GY, JM, SR, TT); Mutabon-F (AN, BB, BM, BS, BZ, GY, JM, SR, TT); Mutabon-M (AN, BB, BM, BS, BZ, GY, JM, SR, TT); Neuragon-A (TH); Neuragon-B (TH); Polybon (TH); Triptafen (GB); Triptafen M (GB)
MECHANISM OF ACTION
Amitriptyline increases the synaptic concentration of serotonin and/or norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane.
Perphenazine is a piperazine phenothiazine antipsychotic which blocks postsynaptic mesolimbic dopaminergic receptors in the brain; exhibits alpha-adrenergic blocking effect and depresses the release of hypothalamic and hypophyseal hormones.
PHARMACODYNAMICS / KINETICS — See individual agents.
Amitriptyline and chlordiazepoxide
U.S. BRAND NAMES — Limbitrol® DS; Limbitrol®
PHARMACOLOGIC CATEGORY
Antidepressant, Tricyclic (Tertiary Amine)
Benzodiazepine
DOSING: ADULTS — Depression and anxiety: Oral: Initial: 3-4 tablets in divided doses; this may be increased to 6 tablets/day as required. Some patients respond to smaller doses and can be maintained on 2 tablets.
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 12.5/5: Amitriptyline hydrochloride 12.5 mg and chlordiazepoxide 5 mg; 25/10: Amitriptyline hydrochloride 25 mg and chlordiazepoxide 10 mg
Limbitrol®: 12.5/5: Amitriptyline hydrochloride 12.5 mg and chlordiazepoxide 5 mg
Limbitrol® DS: 25/10: Amitriptyline hydrochloride 25 mg and chlordiazepoxide 10 mg
DOSAGE FORMS: CONCISE
Tablet: 12.5/5: Amitriptyline 12.5 mg and chlordiazepoxide 5 mg; 25/10: Amitriptyline 25 mg and chlordiazepoxide 10 mg
Limbitrol®: 12.5/5: Amitriptyline 12.5 mg and chlordiazepoxide 5 mg
Limbitrol® DS: 25/10: Amitriptyline 25 mg and chlordiazepoxide 10 mg
GENERIC EQUIVALENT AVAILABLE — Yes
USE — Treatment of moderate to severe anxiety and/or agitation and depression
ADVERSE REACTIONS SIGNIFICANT — See individual agents.
CONTRAINDICATIONS — Hypersensitivity to benzodiazepines, tricyclic antidepressants, or any component of the formulation; depression of CNS; MAO inhibitors; acute recovery phase following MI; angle-closure glaucoma; pregnancy
WARNINGS / PRECAUTIONS
Based on amitriptyline component:
Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with major depressive disorder (MDD) and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. A medication guide should be dispensed with each prescription.
The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Monitor for worsening of depression or suicidality, especially during initiation of therapy or with dose increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression occur.
May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder.
Often causes drowsiness/sedation, resulting in impaired performance of tasks requiring alertness (eg, operating machinery or driving). Sedative effects may be additive with other CNS depressants and/or ethanol. The degree of sedation is very high relative to other antidepressants. May cause hyponatremia/SIADH. May increase the risks associated with electroconvulsive therapy. Consider discontinuing, when possible, prior to elective surgery. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.
May cause orthostatic hypotension; the risk of this problem is very high relative to other antidepressants. Use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). The degree of anticholinergic blockade produced by this agent is very high relative to other cyclic antidepressants; use with caution in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or a history of bowel obstruction. May alter glucose control - use with caution in patients with diabetes.
Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities). The risk of conduction abnormalities with this agent is high relative to other antidepressants. May lower seizure threshold - use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold. Use with caution in hyperthyroid patients or those receiving thyroid supplementation. Use with caution in patients with hepatic or renal dysfunction and in elderly patients.
Based on chlordiazepoxide component:
Active metabolites with extended half-lives may lead to delayed accumulation and adverse effects. Use with caution in elderly or debilitated patients, pediatric patients, patients with hepatic disease (including alcoholics) or renal impairment. Use with caution in patients with respiratory disease or impaired gag reflex. Use with caution in patients with porphyria.
Parenteral administration should be avoided in comatose patients or shock. Adequate resuscitative equipment/personnel should be available, and appropriate monitoring should be conducted at the time of injection and for several hours following administration. The parenteral formulation should be diluted for I.M. administration with the supplied diluent only. This diluent should not be used when preparing the drug for intravenous administration.
Causes CNS depression (dose related) resulting in sedation, dizziness, confusion, or ataxia which may impair physical and mental capabilities. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Use with caution in patients receiving other CNS depressants or psychoactive agents (lithium, phenothiazines). Effects with other sedative drugs or ethanol may be potentiated. Benzodiazepines have been associated with falls and traumatic injury and should be used with extreme caution in patients who are at risk of these events (especially the elderly).
Use caution in patients with depression, particularly if suicidal risk may be present. Use with caution in patients with a history of drug dependence. Benzodiazepines have been associated with dependence and acute withdrawal symptoms on discontinuation or reduction in dose. Acute withdrawal, including seizures, may be precipitated after administration of flumazenil to patients receiving long-term benzodiazepine therapy.
Benzodiazepines have been associated with anterograde amnesia. Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients. Does not have analgesic, antidepressant, or antipsychotic properties.
Amitriptyline and chlordiazepoxide combination is FDA approved for depression associated with anxiety in children 12 years of age. This combination is not FDA approved for the treatment of bipolar depression.
RESTRICTIONS — C-IV
An FDA-approved medication guide concerning the use of antidepressants in children and teenagers must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm. Dispense to parents or guardians of children and teenagers receiving this medication.
DRUG INTERACTIONS
Amitriptyline: Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak)
Chlordiazepoxide: Substrate of CYP3A4 (major)
Also see individual agents.
PREGNANCY RISK FACTOR — D (show table)
LACTATION — Excretion in breast milk unknown/contraindicated
PRICING — (data from drugstore.com)
Tablets (Chlordiazepoxide-Amitriptyline)
5-12.5 mg (60): $38.12
Tablets (Limbitrol DS)
10-25 mg (60): $109.99
CANADIAN BRAND NAMES — Limbitrol®
INTERNATIONAL BRAND NAMES — Limbatril (DE); Limbatrilin (CL); Limbitrol (AE, AT, BH, BR, CA, CY, EG, FI, FR, GB, GH, GR, ID, IE, IQ, IR, JO, KE, KW, LB, LY, NL, OM, QA, SA, SY, TW, TZ, UG, YE, ZA, ZM); Limbitrol F (ZA); Limbitryl (IT)
MECHANISM OF ACTION — See individual agents.
PHARMACODYNAMICS / KINETICS — See individual agents.
PHARMACOLOGIC CATEGORY
Antidepressant, Tricyclic (Tertiary Amine)
Benzodiazepine
DOSING: ADULTS — Depression and anxiety: Oral: Initial: 3-4 tablets in divided doses; this may be increased to 6 tablets/day as required. Some patients respond to smaller doses and can be maintained on 2 tablets.
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 12.5/5: Amitriptyline hydrochloride 12.5 mg and chlordiazepoxide 5 mg; 25/10: Amitriptyline hydrochloride 25 mg and chlordiazepoxide 10 mg
Limbitrol®: 12.5/5: Amitriptyline hydrochloride 12.5 mg and chlordiazepoxide 5 mg
Limbitrol® DS: 25/10: Amitriptyline hydrochloride 25 mg and chlordiazepoxide 10 mg
DOSAGE FORMS: CONCISE
Tablet: 12.5/5: Amitriptyline 12.5 mg and chlordiazepoxide 5 mg; 25/10: Amitriptyline 25 mg and chlordiazepoxide 10 mg
Limbitrol®: 12.5/5: Amitriptyline 12.5 mg and chlordiazepoxide 5 mg
Limbitrol® DS: 25/10: Amitriptyline 25 mg and chlordiazepoxide 10 mg
GENERIC EQUIVALENT AVAILABLE — Yes
USE — Treatment of moderate to severe anxiety and/or agitation and depression
ADVERSE REACTIONS SIGNIFICANT — See individual agents.
CONTRAINDICATIONS — Hypersensitivity to benzodiazepines, tricyclic antidepressants, or any component of the formulation; depression of CNS; MAO inhibitors; acute recovery phase following MI; angle-closure glaucoma; pregnancy
WARNINGS / PRECAUTIONS
Based on amitriptyline component:
Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with major depressive disorder (MDD) and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. A medication guide should be dispensed with each prescription.
The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Monitor for worsening of depression or suicidality, especially during initiation of therapy or with dose increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression occur.
May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder.
Often causes drowsiness/sedation, resulting in impaired performance of tasks requiring alertness (eg, operating machinery or driving). Sedative effects may be additive with other CNS depressants and/or ethanol. The degree of sedation is very high relative to other antidepressants. May cause hyponatremia/SIADH. May increase the risks associated with electroconvulsive therapy. Consider discontinuing, when possible, prior to elective surgery. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.
May cause orthostatic hypotension; the risk of this problem is very high relative to other antidepressants. Use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). The degree of anticholinergic blockade produced by this agent is very high relative to other cyclic antidepressants; use with caution in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or a history of bowel obstruction. May alter glucose control - use with caution in patients with diabetes.
Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities). The risk of conduction abnormalities with this agent is high relative to other antidepressants. May lower seizure threshold - use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold. Use with caution in hyperthyroid patients or those receiving thyroid supplementation. Use with caution in patients with hepatic or renal dysfunction and in elderly patients.
Based on chlordiazepoxide component:
Active metabolites with extended half-lives may lead to delayed accumulation and adverse effects. Use with caution in elderly or debilitated patients, pediatric patients, patients with hepatic disease (including alcoholics) or renal impairment. Use with caution in patients with respiratory disease or impaired gag reflex. Use with caution in patients with porphyria.
Parenteral administration should be avoided in comatose patients or shock. Adequate resuscitative equipment/personnel should be available, and appropriate monitoring should be conducted at the time of injection and for several hours following administration. The parenteral formulation should be diluted for I.M. administration with the supplied diluent only. This diluent should not be used when preparing the drug for intravenous administration.
Causes CNS depression (dose related) resulting in sedation, dizziness, confusion, or ataxia which may impair physical and mental capabilities. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Use with caution in patients receiving other CNS depressants or psychoactive agents (lithium, phenothiazines). Effects with other sedative drugs or ethanol may be potentiated. Benzodiazepines have been associated with falls and traumatic injury and should be used with extreme caution in patients who are at risk of these events (especially the elderly).
Use caution in patients with depression, particularly if suicidal risk may be present. Use with caution in patients with a history of drug dependence. Benzodiazepines have been associated with dependence and acute withdrawal symptoms on discontinuation or reduction in dose. Acute withdrawal, including seizures, may be precipitated after administration of flumazenil to patients receiving long-term benzodiazepine therapy.
Benzodiazepines have been associated with anterograde amnesia. Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients. Does not have analgesic, antidepressant, or antipsychotic properties.
Amitriptyline and chlordiazepoxide combination is FDA approved for depression associated with anxiety in children 12 years of age. This combination is not FDA approved for the treatment of bipolar depression.
RESTRICTIONS — C-IV
An FDA-approved medication guide concerning the use of antidepressants in children and teenagers must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm. Dispense to parents or guardians of children and teenagers receiving this medication.
DRUG INTERACTIONS
Amitriptyline: Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak)
Chlordiazepoxide: Substrate of CYP3A4 (major)
Also see individual agents.
PREGNANCY RISK FACTOR — D (show table)
LACTATION — Excretion in breast milk unknown/contraindicated
PRICING — (data from drugstore.com)
Tablets (Chlordiazepoxide-Amitriptyline)
5-12.5 mg (60): $38.12
Tablets (Limbitrol DS)
10-25 mg (60): $109.99
CANADIAN BRAND NAMES — Limbitrol®
INTERNATIONAL BRAND NAMES — Limbatril (DE); Limbatrilin (CL); Limbitrol (AE, AT, BH, BR, CA, CY, EG, FI, FR, GB, GH, GR, ID, IE, IQ, IR, JO, KE, KW, LB, LY, NL, OM, QA, SA, SY, TW, TZ, UG, YE, ZA, ZM); Limbitrol F (ZA); Limbitryl (IT)
MECHANISM OF ACTION — See individual agents.
PHARMACODYNAMICS / KINETICS — See individual agents.
Amitriptyline
PHARMACOLOGIC CATEGORY
Antidepressant, Tricyclic (Tertiary Amine)
DOSING: ADULTS
Depression: Oral: 50-150 mg/day single dose at bedtime or in divided doses; dose may be gradually increased up to 300 mg/day.
Chronic pain management (unlabeled use): Oral: Initial: 25 mg at bedtime; may increase as tolerated to 100 mg/day.
Migraine prophylaxis (unlabeled use): Oral: Initial: 10-25 mg at bedtime; usual dose: 150 mg; reported dosing ranges: 10-400 mg/day
DOSING: PEDIATRIC
(For additional information see "Amitriptyline: Pediatric drug information")
Chronic pain management (unlabeled use): Oral: Initial: 0.1 mg/kg at bedtime, may advance as tolerated over 2-3 weeks to 0.5-2 mg/kg at bedtime
Depressive disorders:
Children (unlabeled use): Oral: Initial doses of 1 mg/kg/day given in 3 divided doses with increases to 1.5 mg/kg/day have been reported in a small number of children (n=9) 9-12 years of age; clinically, doses up to 3 mg/kg/day (5 mg/kg/day if monitored closely) have been proposed
Adolescents: Initial: 25-50 mg/day; may administer in divided doses; increase gradually to 100 mg/day in divided doses.
Migraine prophylaxis (unlabeled use): Oral: Initial: 0.25 mg/kg/day, given at bedtime; increase dose by 0.25 mg/kg/day to maximum 1 mg/kg/day. Reported dosing ranges: 0.1-2 mg/kg/day; maximum suggested dose: 10 mg.
DOSING: ELDERLY — Depression: Oral: Initial: 10-25 mg at bedtime; dose should be increased in 10-25 mg increments every week if tolerated; dose range: 25-150 mg/day. See Renal/Hepatic Impairment.
DOSING: RENAL IMPAIRMENT — Nondialyzable
DOSING: HEPATIC IMPAIRMENT — Use with caution and monitor plasma levels and patient response.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, as hydrochloride: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg
DOSAGE FORMS: CONCISE
Tablet: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg
GENERIC EQUIVALENT AVAILABLE — Yes
USE — Relief of symptoms of depression
USE - UNLABELED / INVESTIGATIONAL — Analgesic for certain chronic and neuropathic pain; prophylaxis against migraine headaches; treatment of depressive disorders in children
ADVERSE REACTIONS SIGNIFICANT — Anticholinergic effects may be pronounced; moderate to marked sedation can occur (tolerance to these effects usually occurs).
Frequency not defined.
Cardiovascular: Orthostatic hypotension, tachycardia, ECG changes (nonspecific), AV conduction changes, cardiomyopathy (rare), MI, stroke, heart block, arrhythmia, syncope, hypertension, palpitation
Central nervous system: Restlessness, dizziness, insomnia, sedation, fatigue, anxiety, cognitive function impaired, seizure, extrapyramidal symptoms, coma, hallucinations, confusion, disorientation, coordination impaired, ataxia, headache, nightmares, hyperpyrexia
Dermatologic: Allergic rash, urticaria, photosensitivity, alopecia
Endocrine & metabolic: Syndrome of inappropriate ADH secretion
Gastrointestinal: Weight gain, xerostomia, constipation, paralytic ileus, nausea, vomiting, anorexia, stomatitis, peculiar taste, diarrhea, black tongue
Genitourinary: Urinary retention
Hematologic: Bone marrow depression, purpura, eosinophilia
Neuromuscular & skeletal: Numbness, paresthesia, peripheral neuropathy, tremor, weakness
Ocular: Blurred vision, mydriasis, ocular pressure increased
Otic: Tinnitus
Miscellaneous: Diaphoresis, withdrawal reactions (nausea, headache, malaise)
Postmarketing and/or case reports: Neuroleptic malignant syndrome (rare), serotonin syndrome (rare)
CONTRAINDICATIONS — Hypersensitivity to amitriptyline or any component of the formulation (cross-sensitivity with other tricyclics may occur); use of MAO inhibitors within past 14 days; acute recovery phase following myocardial infarction; concurrent use of cisapride
WARNINGS / PRECAUTIONS — [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with major depressive disorder (MDD) and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. A medication guide should be dispensed with each prescription. Amitriptyline is not FDA-approved for use in children <12>0.5 mcg/mL; plasma levels do not always correlate with clinical effectiveness
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Symptoms include agitation, confusion, hallucinations, urinary retention, hypothermia, hypotension, ventricular tachycardia, and seizures. Following initiation of essential overdose management, toxic symptoms should be treated. Sodium bicarbonate is indicated when the QRS interval is >0.10 seconds or the QTc is >0.42 seconds. Ventricular arrhythmias often respond to phenytoin 15-20 mg/kg (adults) with concurrent systemic alkalinization (sodium bicarbonate 0.5-2 mEq/kg I.V.). Arrhythmias unresponsive to this therapy may respond to lidocaine 1 mg/kg I.V. followed by a titrated infusion. Physostigmine (1-2 mg slow I.V. for adults or 0.5 mg slow I.V. for children) may be indicated in reversing cardiac arrhythmias that are due to vagal blockade, or for anticholinergic effects, but should only be used as a last measure in life-threatening situations. Seizures usually respond to diazepam I.V. boluses (5-10 mg for adults up to 30 mg or 0.25-0.4 mg/kg/dose for children up to 10 mg/dose). If seizures are unresponsive or recur, phenytoin or phenobarbital may be required.
CANADIAN BRAND NAMES — Apo-Amitriptyline®; Levate®; Novo-Triptyn; PMS-Amitriptyline
INTERNATIONAL BRAND NAMES — Adepril (IT); Amilit (IT); Amineurin (DE); Amiplin (TW); Amiprin (JP); Amitrip (NZ); Amitriptylinum (PL); Amytril (BR); Anapsique (MX); Antalin (CL); Apo-Amitriptyline (CA); Domical (GB); Elatrol (IL); Elatrolet (IL); Elavil (FR); Enafon (KR); Endep (AU); Lantron (JP); Laroxyl (BF, BJ, CI, ET, FR, GH, GM, GN, IT, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TZ, UG, ZM, ZW); Levate (CA); Miketorin (JP); Neurotol (PY); Novo-Triptyn (CA); Novoprotect (DE); Pinsaun (TW); PMS-Amitriptyline (CA); Protanol (BR); Qualitriptine (HK); Redomex (BE); Sarotard (KR); Saroten (BF, BJ, CH, CI, CY, DE, DK, EE, ET, FI, GH, GM, GN, GR, IR, KE, LR, MA, ML, MR, MU, MW, NE, NG, PT, SC, SD, SE, SL, SN, TZ, UG, ZA, ZM, ZW); Saroten Retard (MY); Sarotena (IN); Sarotex (NL, NO, UY); Syneudon (DE); Teperin (HU, IQ, JO); Trepiline (ZA); Tridep (BG); Tripta (MY, TH); Triptizol (IT); Trynol (TW); Tryptal (IL); Tryptanol (AR, BR, EC, JP, MX, PE, TH, ZA); Tryptizol (AT, BE, CH, DK, EG, ES, GB, NL, NO, PT, SE); Trytomer (IN); Uxen (AR)
MECHANISM OF ACTION — Increases the synaptic concentration of serotonin and/or norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane
PHARMACODYNAMICS / KINETICS
Onset of action: Migraine prophylaxis: 6 weeks, higher dosage may be required in heavy smokers because of increased metabolism; Depression: 4-6 weeks, reduce dosage to lowest effective level
Distribution: Crosses placenta; enters breast milk
Metabolism: Hepatic to nortriptyline (active), hydroxy and conjugated derivatives; may be impaired in the elderly
Half-life elimination: Adults: 9-27 hours (average: 15 hours)
Time to peak, serum: ~4 hours
Excretion: Urine (18% as unchanged drug); feces (small amounts)
PATIENT INFORMATION — Do not discontinue medication abruptly. Full effect may not occur for 3-6 weeks. Avoid alcohol. May cause urine to turn blue-green. May cause drowsiness. Dry mouth may be helped by sips of water, sugarless gum, or hard candy.
Antidepressant, Tricyclic (Tertiary Amine)
DOSING: ADULTS
Depression: Oral: 50-150 mg/day single dose at bedtime or in divided doses; dose may be gradually increased up to 300 mg/day.
Chronic pain management (unlabeled use): Oral: Initial: 25 mg at bedtime; may increase as tolerated to 100 mg/day.
Migraine prophylaxis (unlabeled use): Oral: Initial: 10-25 mg at bedtime; usual dose: 150 mg; reported dosing ranges: 10-400 mg/day
DOSING: PEDIATRIC
(For additional information see "Amitriptyline: Pediatric drug information")
Chronic pain management (unlabeled use): Oral: Initial: 0.1 mg/kg at bedtime, may advance as tolerated over 2-3 weeks to 0.5-2 mg/kg at bedtime
Depressive disorders:
Children (unlabeled use): Oral: Initial doses of 1 mg/kg/day given in 3 divided doses with increases to 1.5 mg/kg/day have been reported in a small number of children (n=9) 9-12 years of age; clinically, doses up to 3 mg/kg/day (5 mg/kg/day if monitored closely) have been proposed
Adolescents: Initial: 25-50 mg/day; may administer in divided doses; increase gradually to 100 mg/day in divided doses.
Migraine prophylaxis (unlabeled use): Oral: Initial: 0.25 mg/kg/day, given at bedtime; increase dose by 0.25 mg/kg/day to maximum 1 mg/kg/day. Reported dosing ranges: 0.1-2 mg/kg/day; maximum suggested dose: 10 mg.
DOSING: ELDERLY — Depression: Oral: Initial: 10-25 mg at bedtime; dose should be increased in 10-25 mg increments every week if tolerated; dose range: 25-150 mg/day. See Renal/Hepatic Impairment.
DOSING: RENAL IMPAIRMENT — Nondialyzable
DOSING: HEPATIC IMPAIRMENT — Use with caution and monitor plasma levels and patient response.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, as hydrochloride: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg
DOSAGE FORMS: CONCISE
Tablet: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg
GENERIC EQUIVALENT AVAILABLE — Yes
USE — Relief of symptoms of depression
USE - UNLABELED / INVESTIGATIONAL — Analgesic for certain chronic and neuropathic pain; prophylaxis against migraine headaches; treatment of depressive disorders in children
ADVERSE REACTIONS SIGNIFICANT — Anticholinergic effects may be pronounced; moderate to marked sedation can occur (tolerance to these effects usually occurs).
Frequency not defined.
Cardiovascular: Orthostatic hypotension, tachycardia, ECG changes (nonspecific), AV conduction changes, cardiomyopathy (rare), MI, stroke, heart block, arrhythmia, syncope, hypertension, palpitation
Central nervous system: Restlessness, dizziness, insomnia, sedation, fatigue, anxiety, cognitive function impaired, seizure, extrapyramidal symptoms, coma, hallucinations, confusion, disorientation, coordination impaired, ataxia, headache, nightmares, hyperpyrexia
Dermatologic: Allergic rash, urticaria, photosensitivity, alopecia
Endocrine & metabolic: Syndrome of inappropriate ADH secretion
Gastrointestinal: Weight gain, xerostomia, constipation, paralytic ileus, nausea, vomiting, anorexia, stomatitis, peculiar taste, diarrhea, black tongue
Genitourinary: Urinary retention
Hematologic: Bone marrow depression, purpura, eosinophilia
Neuromuscular & skeletal: Numbness, paresthesia, peripheral neuropathy, tremor, weakness
Ocular: Blurred vision, mydriasis, ocular pressure increased
Otic: Tinnitus
Miscellaneous: Diaphoresis, withdrawal reactions (nausea, headache, malaise)
Postmarketing and/or case reports: Neuroleptic malignant syndrome (rare), serotonin syndrome (rare)
CONTRAINDICATIONS — Hypersensitivity to amitriptyline or any component of the formulation (cross-sensitivity with other tricyclics may occur); use of MAO inhibitors within past 14 days; acute recovery phase following myocardial infarction; concurrent use of cisapride
WARNINGS / PRECAUTIONS — [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with major depressive disorder (MDD) and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. A medication guide should be dispensed with each prescription. Amitriptyline is not FDA-approved for use in children <12>0.5 mcg/mL; plasma levels do not always correlate with clinical effectiveness
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Symptoms include agitation, confusion, hallucinations, urinary retention, hypothermia, hypotension, ventricular tachycardia, and seizures. Following initiation of essential overdose management, toxic symptoms should be treated. Sodium bicarbonate is indicated when the QRS interval is >0.10 seconds or the QTc is >0.42 seconds. Ventricular arrhythmias often respond to phenytoin 15-20 mg/kg (adults) with concurrent systemic alkalinization (sodium bicarbonate 0.5-2 mEq/kg I.V.). Arrhythmias unresponsive to this therapy may respond to lidocaine 1 mg/kg I.V. followed by a titrated infusion. Physostigmine (1-2 mg slow I.V. for adults or 0.5 mg slow I.V. for children) may be indicated in reversing cardiac arrhythmias that are due to vagal blockade, or for anticholinergic effects, but should only be used as a last measure in life-threatening situations. Seizures usually respond to diazepam I.V. boluses (5-10 mg for adults up to 30 mg or 0.25-0.4 mg/kg/dose for children up to 10 mg/dose). If seizures are unresponsive or recur, phenytoin or phenobarbital may be required.
CANADIAN BRAND NAMES — Apo-Amitriptyline®; Levate®; Novo-Triptyn; PMS-Amitriptyline
INTERNATIONAL BRAND NAMES — Adepril (IT); Amilit (IT); Amineurin (DE); Amiplin (TW); Amiprin (JP); Amitrip (NZ); Amitriptylinum (PL); Amytril (BR); Anapsique (MX); Antalin (CL); Apo-Amitriptyline (CA); Domical (GB); Elatrol (IL); Elatrolet (IL); Elavil (FR); Enafon (KR); Endep (AU); Lantron (JP); Laroxyl (BF, BJ, CI, ET, FR, GH, GM, GN, IT, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TZ, UG, ZM, ZW); Levate (CA); Miketorin (JP); Neurotol (PY); Novo-Triptyn (CA); Novoprotect (DE); Pinsaun (TW); PMS-Amitriptyline (CA); Protanol (BR); Qualitriptine (HK); Redomex (BE); Sarotard (KR); Saroten (BF, BJ, CH, CI, CY, DE, DK, EE, ET, FI, GH, GM, GN, GR, IR, KE, LR, MA, ML, MR, MU, MW, NE, NG, PT, SC, SD, SE, SL, SN, TZ, UG, ZA, ZM, ZW); Saroten Retard (MY); Sarotena (IN); Sarotex (NL, NO, UY); Syneudon (DE); Teperin (HU, IQ, JO); Trepiline (ZA); Tridep (BG); Tripta (MY, TH); Triptizol (IT); Trynol (TW); Tryptal (IL); Tryptanol (AR, BR, EC, JP, MX, PE, TH, ZA); Tryptizol (AT, BE, CH, DK, EG, ES, GB, NL, NO, PT, SE); Trytomer (IN); Uxen (AR)
MECHANISM OF ACTION — Increases the synaptic concentration of serotonin and/or norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane
PHARMACODYNAMICS / KINETICS
Onset of action: Migraine prophylaxis: 6 weeks, higher dosage may be required in heavy smokers because of increased metabolism; Depression: 4-6 weeks, reduce dosage to lowest effective level
Distribution: Crosses placenta; enters breast milk
Metabolism: Hepatic to nortriptyline (active), hydroxy and conjugated derivatives; may be impaired in the elderly
Half-life elimination: Adults: 9-27 hours (average: 15 hours)
Time to peak, serum: ~4 hours
Excretion: Urine (18% as unchanged drug); feces (small amounts)
PATIENT INFORMATION — Do not discontinue medication abruptly. Full effect may not occur for 3-6 weeks. Avoid alcohol. May cause urine to turn blue-green. May cause drowsiness. Dry mouth may be helped by sips of water, sugarless gum, or hard candy.
Amiodarone
U.S. BRAND NAMES — Cordarone®; Pacerone®
PHARMACOLOGIC CATEGORY
Antiarrhythmic Agent, Class III
DOSING: ADULTS — Note: Lower loading and maintenance doses are preferable in women and all patients with low body weight.
Ventricular arrhythmias: Oral: 800-1600 mg/day in 1-2 doses for 1-3 weeks, then 600-800 mg/day in 1-2 doses for 1 month; maintenance: 400 mg/day; lower doses are recommended for supraventricular arrhythmias.
Breakthrough VF or VT: I.V.: 150 mg supplemental doses in 100 mL D5W over 10 minutes
Pulseless VF or VT: I.V. push: Initial: 300 mg in 20-30 mL NS or D5W; if VF or VT recurs, supplemental dose of 150 mg followed by infusion of 1 mg/minute for 6 hours, then 0.5 mg/minute (maximum daily dose: 2.1 g)
I.V. to oral therapy conversion: Use the following as a guide:
<1>3 week I.V. infusion: 400 mg
Recommendations for conversion to intravenous amiodarone after oral administration: During long-term amiodarone therapy (ie, 4 months), the mean plasma-elimination half-life of the active metabolite of amiodarone is 61 days. Replacement therapy may not be necessary in such patients if oral therapy is discontinued for a period <2>1 hour, use concentrations 2 mg/mL unless a central venous catheter is used. Use only volumetric infusion pump; use of drop counting may lead to underdosing. Administer through I.V. line with in-line filter.
Adjust administration rate to urgency (give more slowly when perfusing arrhythmia present). Slow the infusion rate if hypotension or bradycardia develops. Infusions >2 hours must be administered in glass or polyolefin bottles. Note: I.V. administration at lower flow rates (potentially associated with use in pediatrics) and higher concentrations than recommended may result in leaching of plasticizers (DEHP) from intravenous tubing. DEHP may adversely affect male reproductive tract development. Alternative means of dosing and administration (1 mg/kg aliquots) may need to be considered.
COMPATIBILITY — Variable stability (consult detailed reference): D5W, NS.
Y-site administration: Compatible: Amikacin, bretylium, clarithromycin, clindamycin, dobutamine, dopamine, doxycycline, erythromycin lactobionate, esmolol, gentamicin, insulin (regular), isoproterenol, labetalol, lidocaine, metaraminol, metronidazole, midazolam, morphine, nitroglycerin, norepinephrine, penicillin G potassium, phentolamine, phenylephrine, potassium chloride, procainamide, tobramycin, vancomycin. Incompatible: Aminophylline, cefamandole, heparin, sodium bicarbonate. Variable (consult detailed reference): Cefazolin.
Compatibility in syringe: Incompatible: Heparin.
Compatibility when admixed: Compatible: Dobutamine, lidocaine, potassium chloride, procainamide, propafenone, verapamil. Incompatible: Floxacillin. Variable (consult detailed reference): Furosemide, quinidine.
USE — Management of life-threatening recurrent ventricular fibrillation (VF) or hemodynamically-unstable ventricular tachycardia (VT) refractory to other antiarrhythmic agents or in patients intolerant of other agents used for these conditions
USE - UNLABELED/INVESTIGATIONAL
Cardiac arrest with persistent ventricular tachycardia (VT) or ventricular fibrillation (VF) if defibrillation, CPR, and vasopressor administration have failed (ACLS/PALS guidelines)
Control of hemodynamically-stable VT, polymorphic VT with a normal QT interval, or wide-complex tachycardia of uncertain origin (ACLS/PALS guidelines)
Control of rapid ventricular rate due to accessory pathway conduction in pre-excited atrial arrhythmias (ACLS guidelines)
Heart rate control in patients with atrial fibrillation and heart failure [no accessory pathway] (ACC/AHA/ESC Practice Guidelines)
Paroxysmal supraventricular tachycardia (SVT)
Prevention of postoperative atrial fibrillation during cardiothoracic surgery
Pharmacologic adjunct to ICD therapy to suppress symptomatic ventricular tachyarrhythmias in otherwise optimally-treated patients with heart failure (ACC/AHA/ESC Practice Guidelines)
Pharmacologic conversion of atrial fibrillation to normal sinus rhythm; maintenance of normal sinus rhythm
ADVERSE REACTIONS SIGNIFICANT — In a recent meta-analysis, patients taking lower doses of amiodarone (152-330 mg daily for at least 12 months) were more likely to develop thyroid, neurologic, skin, ocular, and bradycardic abnormalities than those taking placebo (Vorperian, 1997). Pulmonary toxicity was similar in both the low dose amiodarone group and in the placebo group but there was a trend towards increased toxicity in the amiodarone group. Gastrointestinal and hepatic events were seen to a similar extent in both the low dose amiodarone group and placebo group. As the frequency of adverse events varies considerably across studies as a function of route and dose, a consolidation of adverse event rates is provided by Goldschlager, 2000.
Cardiovascular: Hypotension (I.V. 16%, refractory in rare cases)
Central nervous system (3% to 40%): Abnormal gait/ataxia, dizziness, fatigue, headache, malaise, impaired memory, involuntary movement, insomnia, poor coordination, peripheral neuropathy, sleep disturbances, tremor
Dermatologic: Photosensitivity (10% to 75%)
Endocrine & Metabolic: Hypothyroidism (1% to 22%)
Gastrointestinal: Nausea, vomiting, anorexia, and constipation (10% to 33%)
Hepatic: AST or ALT level >2x normal (15% to 50%)
Ocular: Corneal microdeposits (>90%; causes visual disturbance in <10%)>3 mg/mL)
Ocular: Visual disturbances (2% to 9%), halo vision (<5%>6 days but <2 years ago) myocardial infarction patients with asymptomatic, nonlife-threatening ventricular arrhythmias did not benefit and may have been harmed by attempts to suppress the arrhythmia with flecainide or encainide. An increased mortality or nonfatal cardiac arrest rate (7.7%) was seen in the active treatment group compared with patients in the placebo group (3%). The applicability of the CAST results to other populations is unknown. Antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias. Discontinuation of therapy: Due to complex pharmacokinetics, when discontinued there is still an increased risk of drug interactions and it may be difficult to predict when an arrhythmia may occur.
RESTRICTIONS — An FDA-approved medication guide must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm.
DRUG INTERACTIONS — Substrate of CYP1A2 (minor), 2C8 (major at low concentrations), 2C19 (minor), 2D6 (minor), 3A4 (major); Inhibits CYP1A2 (weak), 2A6 (moderate), 2B6 (weak), 2C9 (moderate), 2C19 (weak), 2D6 (moderate), 3A4 (moderate)
Anesthetics (halogenated, inhaled): Amiodarone enhances the myocardial depressant and conduction effects of inhalation anesthetics; monitor.
Azole antifungals: May prolong QTc, potentially leading to malignant arrhythmias; use caution.
Beta-blockers may cause excessive AV block; monitor response.
Calcium channel blockers (diltiazem, verapamil): May cause excessive AV block; monitor.
Cimetidine: May increase amiodarone blood levels.
Cholestyramine: May decrease amiodarone blood levels.
Cisapride: May prolong QTc interval potentially leading to malignant arrhythmias.
Cyclosporine: Serum levels may be increased by amiodarone; monitor.
CYP2A6 substrates: Amiodarone may increase the levels/effects of CYP2A6 substrates. Example substrates include dexmedetomidine and ifosfamide.
CYP2C8 inducers: May decrease the levels/effects of amiodarone. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.
CYP2C8 inhibitors: May increase the levels/effects of amiodarone. Example inhibitors include atazanavir, gemfibrozil, and ritonavir.
CYP2C9 substrates: Amiodarone may increase the levels/effects of CYP2C9 substrates. Example substrates include bosentan, dapsone, fluoxetine, glimepiride, glipizide, losartan, montelukast, nateglinide, paclitaxel, phenytoin, warfarin, and zafirlukast.
CYP2D6 substrates: Amiodarone may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.
CYP2D6 prodrug substrates: Amiodarone may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.
CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of amiodarone. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.
CYP3A4 inhibitors: May increase the levels/effects of amiodarone. Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil.
CYP3A4 substrates: Amiodarone may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, ergot derivatives, mirtazapine, nateglinide, nefazodone, tacrolimus, and venlafaxine.
Digoxin levels may be increased by amiodarone; consider reducing digoxin dose by 50% and monitor digoxin blood levels closely.
Fentanyl: Concurrent use may lead to bradycardia, sinus arrest, and hypotension.
Flecainide blood levels may be increased; consider reducing flecainide dose by 25% to 33% with concurrent use.
Fluoroquinolones (sparfloxacin, gatifloxacin, moxifloxacin): May result in additional prolongation of the QT interval; concurrent use of sparfloxacin is contraindicated.
HMG-CoA reductase inhibitors (lovastatin, simvastatin, and others dependent on CYP3A4 metabolism): Amiodarone inhibits metabolism of lovastatin and/or simvastatin and may increase the risk of myopathy and rhabdomyolysis. Concurrent use of lovastatin or simvastatin is not recommended, but if unavoidable, dose of lovastatin should not exceed 40 mg/day. The dose of simvastatin should not exceed 20 mg/day; consider alternative HMG-CoA reductase inhibitor.
Lidocaine: Amiodarone may increase serum levels/toxicity of lidocaine. Sinus bradycardia may occur with concurrent use.
Macrolide antibiotics: May prolong QTc, potentially leading to malignant arrhythmias. Use caution and evaluate risk:benefit.
Metoprolol blood levels may be increased; monitor response.
Phenytoin blood levels may be increased by amiodarone; amiodarone blood levels may be decreased by phenytoin.
Procainamide and NAPA plasma levels may be increased; consider reducing procainamide dosage by 25% with concurrent use.
Propranolol blood levels may be increased.
Protease inhibitors (amprenavir, indinavir, ritonavir): May increase amiodarone blood levels and toxicity; concurrent use is contraindicated.
QTc interval prolonging agents (including but may not be limited to amitriptyline, bepridil, disopyramide, erythromycin, haloperidol, imipramine, quinidine, pimozide, procainamide, sotalol, and thioridazine): Effect/toxicity increased; use with caution.
Quinidine blood levels may be increased; monitor quinidine trough concentration.
Rifampin may decrease amiodarone blood levels.
Theophylline blood levels may be increased.
Thioridazine: Amiodarone may enhance the QTc-prolonging effect of thioridazine.
Thyroid supplements: Amiodarone may alter thyroid function; monitor closely.
Trazodone: Amiodarone may increase levels/effects of trazodone. QTC prolongation and torsade de pointes have been reported with concurrent use.
Warfarin: Hypoprothrombinemic response increased. Monitor INR closely when amiodarone is initiated or discontinued. Reduce warfarin's dose by 1/3 to 1/2 when amiodarone is started.
ETHANOL/NUTRITION/HERB INTERACTIONS
Food: Increases the rate and extent of absorption of amiodarone. Grapefruit juice increases bioavailability of oral amiodarone by 50% and decreases the conversion of amiodarone to N-DEA (active metabolite); altered effects are possible; use should be avoided during therapy.
Herb/Nutraceutical: St John's wort may decrease amiodarone levels or enhance photosensitization. Avoid ephedra (may worsen arrhythmia). Avoid dong quai.
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — May cause fetal harm when administered to a pregnant woman, leading to congenital goiter and hypo- or hyperthyroidism.
LACTATION — Enters breast milk/not recommended (AAP rates "of concern")
BREAST-FEEDING CONSIDERATIONS — Hypothyroidism may occur in nursing infants. Both amiodarone and its active metabolite are excreted in human milk. Breast-feeding may lead to significant infant exposure and potential toxicity.
DIETARY CONSIDERATIONS — Administer consistently with regard to meals. Amiodarone is a potential source of large amounts of inorganic iodine; ~3 mg of inorganic iodine per 100 mg of amiodarone is released into the systemic circulation. Recommended daily allowance for iodine in adults is 150 mcg.
Grapefruit juice is not recommended.
PRICING — (data from drugstore.com)
Tablets (Amiodarone HCl)
200 mg (30): $28.99
Tablets (Cordarone)
200 mg (60): $242.47
Tablets (Pacerone)
100 mg (30): $139.99
MONITORING PARAMETERS — Blood pressure, heart rate (ECG) and rhythm throughout therapy; assess patient for signs of lethargy, edema of the hands or feet, weight loss, and pulmonary toxicity (baseline pulmonary function tests); liver function tests; monitor serum electrolytes, especially potassium and magnesium. Assess thyroid function tests before initiation of treatment and then periodically thereafter (some experts suggest every 3-6 months). If signs or symptoms of thyroid disease or arrhythmia breakthrough/exacerbation occur then immediate re-evaluation is necessary. Amiodarone partially inhibits the peripheral conversion of thyroxine (T4) to triiodothyronine (T3); serum T4 and reverse triiodothyronine (rT3) concentrations may be increased and serum T3 may be decreased; most patients remain clinically euthyroid, however, clinical hypothyroidism or hyperthyroidism may occur.
Perform regular ophthalmic exams.
REFERENCE RANGE — Therapeutic: 0.5-2.5 mg/L (SI: 1-4 µmol/L) (parent); desethyl metabolite is active and is present in equal concentration to parent drug
TOXICOLOGY/OVERDOSE COMPREHENSIVE — Symptoms include extensions of pharmacologic effect, sinus bradycardia and/or heart block, hypotension and QT prolongation. Patients should be monitored for several days following ingestion. Intoxication with amiodarone necessitates ECG monitoring. Bradycardia may be atropine resistant. Injectable isoproterenol or a temporary pacemaker may be required. Dialysis is not beneficial.
CANADIAN BRAND NAMES — Alti-Amiodarone; Amiodarone Hydrochloride for Injection®; Apo-Amiodarone®; Cordarone®; Gen-Amiodarone; Novo-Amiodarone; Rhoxal-amiodarone; Sandoz-Amiodarone
(For additional information see "Amiodarone: Patient drug information" and see "Amiodarone: Pediatric drug information")
INTERNATIONAL BRAND NAMES — Aldarin (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TZ, UG, ZM, ZW); Alti-Amiodarone (CA); Amdarone (TH); Amicordin (PL); Amiocar (AR); Amiodacore (IL); Amiodarex (DE); Amiodarona (CL); Amiodarone Hydrochloride for Injection (CA); Amiohexal (DE); Amiokordin (PL); Ancaron (JP); Angiodarona (BR); Angoron (GR); Apo-Amiodarone (CA); Aratac (AU, MY, NZ, SG, TH, TW); Arycor (CO); Atlansil (AR, BR, CL, EC, PE, UY); Braxan (MX); Cardinorm (AU); Corbionax (FR); Cordarex (DE); Cordaron (BG); Cordarone (AE, AN, BB, BE, BF, BG, BH, BJ, CA, CH, CI, CN, CO, CR, CY, CZ, DO, EC, EE, EG, ET, FI, FR, GH, GM, GN, GT, HK, HN, HU, ID, IQ, IR, IT, JO, KE, KR, KW, LB, LR, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NI, NL, NO, OM, PA, PE, PH, PK, PL, PT, PY, QA, SA, SC, SD, SE, SL, SN, SV, SY, TH, TT, TW, TZ, UG, YE, ZA, ZM, ZW); Cordarone X (AU, GB, IE, IN, NZ, ZA); Coronovo (AR); Diarona (UY); Eurythmic (IN); Forken (MX); Gen-Amiodarone (CA); Hexarone (ZA); Kendaron (ID); Miodar (DO); Novo-Amiodarone (CA); Opacorden (PL); Procor (IL); Rhoxal-amiodarone (CA); Rithmik (AU); Sandoz-Amiodarone (CA); Sedacoron (AT, HK, PL, TW); Tachydaron (DE); Tiaryt (ID); Trangorex (ES, VE)
MECHANISM OF ACTION — Class III antiarrhythmic agent which inhibits adrenergic stimulation (alpha- and beta-blocking properties), affects sodium, potassium, and calcium channels, prolongs the action potential and refractory period in myocardial tissue; decreases AV conduction and sinus node function
PHARMACODYNAMICS/KINETICS
Onset of action: Oral: 2 days to 3 weeks; I.V.: May be more rapid
Peak effect: 1 week to 5 months
Duration after discontinuing therapy: 7-50 days
Note: Mean onset of effect and duration after discontinuation may be shorter in children than adults
Distribution: Vd: 66 L/kg (range: 18-148 L/kg); crosses placenta; enters breast milk in concentrations higher than maternal plasma concentrations
Protein binding: 96%
Metabolism: Hepatic via CYP2C8 and 3A4 to active N-desethylamiodarone metabolite; possible enterohepatic recirculation
Bioavailability: Oral: ~50%
Half-life elimination: Terminal: 40-55 days (range: 26-107 days); shorter in children than adults
Excretion: Feces; urine (<1% as unchanged drug)
PATIENT INFORMATION — Take with food; use sunscreen or stay out of sun to prevent burns; skin discoloration is reversible; photophobia may make sunglasses necessary; do not discontinue abruptly; regular blood work for thyroid functions tests and ophthalmologic exams are necessary; notify prescriber if persistent dry cough or shortness of breath occurs
PHARMACOLOGIC CATEGORY
Antiarrhythmic Agent, Class III
DOSING: ADULTS — Note: Lower loading and maintenance doses are preferable in women and all patients with low body weight.
Ventricular arrhythmias: Oral: 800-1600 mg/day in 1-2 doses for 1-3 weeks, then 600-800 mg/day in 1-2 doses for 1 month; maintenance: 400 mg/day; lower doses are recommended for supraventricular arrhythmias.
Breakthrough VF or VT: I.V.: 150 mg supplemental doses in 100 mL D5W over 10 minutes
Pulseless VF or VT: I.V. push: Initial: 300 mg in 20-30 mL NS or D5W; if VF or VT recurs, supplemental dose of 150 mg followed by infusion of 1 mg/minute for 6 hours, then 0.5 mg/minute (maximum daily dose: 2.1 g)
I.V. to oral therapy conversion: Use the following as a guide:
<1>3 week I.V. infusion: 400 mg
Recommendations for conversion to intravenous amiodarone after oral administration: During long-term amiodarone therapy (ie, 4 months), the mean plasma-elimination half-life of the active metabolite of amiodarone is 61 days. Replacement therapy may not be necessary in such patients if oral therapy is discontinued for a period <2>1 hour, use concentrations 2 mg/mL unless a central venous catheter is used. Use only volumetric infusion pump; use of drop counting may lead to underdosing. Administer through I.V. line with in-line filter.
Adjust administration rate to urgency (give more slowly when perfusing arrhythmia present). Slow the infusion rate if hypotension or bradycardia develops. Infusions >2 hours must be administered in glass or polyolefin bottles. Note: I.V. administration at lower flow rates (potentially associated with use in pediatrics) and higher concentrations than recommended may result in leaching of plasticizers (DEHP) from intravenous tubing. DEHP may adversely affect male reproductive tract development. Alternative means of dosing and administration (1 mg/kg aliquots) may need to be considered.
COMPATIBILITY — Variable stability (consult detailed reference): D5W, NS.
Y-site administration: Compatible: Amikacin, bretylium, clarithromycin, clindamycin, dobutamine, dopamine, doxycycline, erythromycin lactobionate, esmolol, gentamicin, insulin (regular), isoproterenol, labetalol, lidocaine, metaraminol, metronidazole, midazolam, morphine, nitroglycerin, norepinephrine, penicillin G potassium, phentolamine, phenylephrine, potassium chloride, procainamide, tobramycin, vancomycin. Incompatible: Aminophylline, cefamandole, heparin, sodium bicarbonate. Variable (consult detailed reference): Cefazolin.
Compatibility in syringe: Incompatible: Heparin.
Compatibility when admixed: Compatible: Dobutamine, lidocaine, potassium chloride, procainamide, propafenone, verapamil. Incompatible: Floxacillin. Variable (consult detailed reference): Furosemide, quinidine.
USE — Management of life-threatening recurrent ventricular fibrillation (VF) or hemodynamically-unstable ventricular tachycardia (VT) refractory to other antiarrhythmic agents or in patients intolerant of other agents used for these conditions
USE - UNLABELED/INVESTIGATIONAL
Cardiac arrest with persistent ventricular tachycardia (VT) or ventricular fibrillation (VF) if defibrillation, CPR, and vasopressor administration have failed (ACLS/PALS guidelines)
Control of hemodynamically-stable VT, polymorphic VT with a normal QT interval, or wide-complex tachycardia of uncertain origin (ACLS/PALS guidelines)
Control of rapid ventricular rate due to accessory pathway conduction in pre-excited atrial arrhythmias (ACLS guidelines)
Heart rate control in patients with atrial fibrillation and heart failure [no accessory pathway] (ACC/AHA/ESC Practice Guidelines)
Paroxysmal supraventricular tachycardia (SVT)
Prevention of postoperative atrial fibrillation during cardiothoracic surgery
Pharmacologic adjunct to ICD therapy to suppress symptomatic ventricular tachyarrhythmias in otherwise optimally-treated patients with heart failure (ACC/AHA/ESC Practice Guidelines)
Pharmacologic conversion of atrial fibrillation to normal sinus rhythm; maintenance of normal sinus rhythm
ADVERSE REACTIONS SIGNIFICANT — In a recent meta-analysis, patients taking lower doses of amiodarone (152-330 mg daily for at least 12 months) were more likely to develop thyroid, neurologic, skin, ocular, and bradycardic abnormalities than those taking placebo (Vorperian, 1997). Pulmonary toxicity was similar in both the low dose amiodarone group and in the placebo group but there was a trend towards increased toxicity in the amiodarone group. Gastrointestinal and hepatic events were seen to a similar extent in both the low dose amiodarone group and placebo group. As the frequency of adverse events varies considerably across studies as a function of route and dose, a consolidation of adverse event rates is provided by Goldschlager, 2000.
Cardiovascular: Hypotension (I.V. 16%, refractory in rare cases)
Central nervous system (3% to 40%): Abnormal gait/ataxia, dizziness, fatigue, headache, malaise, impaired memory, involuntary movement, insomnia, poor coordination, peripheral neuropathy, sleep disturbances, tremor
Dermatologic: Photosensitivity (10% to 75%)
Endocrine & Metabolic: Hypothyroidism (1% to 22%)
Gastrointestinal: Nausea, vomiting, anorexia, and constipation (10% to 33%)
Hepatic: AST or ALT level >2x normal (15% to 50%)
Ocular: Corneal microdeposits (>90%; causes visual disturbance in <10%)>3 mg/mL)
Ocular: Visual disturbances (2% to 9%), halo vision (<5%>6 days but <2 years ago) myocardial infarction patients with asymptomatic, nonlife-threatening ventricular arrhythmias did not benefit and may have been harmed by attempts to suppress the arrhythmia with flecainide or encainide. An increased mortality or nonfatal cardiac arrest rate (7.7%) was seen in the active treatment group compared with patients in the placebo group (3%). The applicability of the CAST results to other populations is unknown. Antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias. Discontinuation of therapy: Due to complex pharmacokinetics, when discontinued there is still an increased risk of drug interactions and it may be difficult to predict when an arrhythmia may occur.
RESTRICTIONS — An FDA-approved medication guide must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm.
DRUG INTERACTIONS — Substrate of CYP1A2 (minor), 2C8 (major at low concentrations), 2C19 (minor), 2D6 (minor), 3A4 (major); Inhibits CYP1A2 (weak), 2A6 (moderate), 2B6 (weak), 2C9 (moderate), 2C19 (weak), 2D6 (moderate), 3A4 (moderate)
Anesthetics (halogenated, inhaled): Amiodarone enhances the myocardial depressant and conduction effects of inhalation anesthetics; monitor.
Azole antifungals: May prolong QTc, potentially leading to malignant arrhythmias; use caution.
Beta-blockers may cause excessive AV block; monitor response.
Calcium channel blockers (diltiazem, verapamil): May cause excessive AV block; monitor.
Cimetidine: May increase amiodarone blood levels.
Cholestyramine: May decrease amiodarone blood levels.
Cisapride: May prolong QTc interval potentially leading to malignant arrhythmias.
Cyclosporine: Serum levels may be increased by amiodarone; monitor.
CYP2A6 substrates: Amiodarone may increase the levels/effects of CYP2A6 substrates. Example substrates include dexmedetomidine and ifosfamide.
CYP2C8 inducers: May decrease the levels/effects of amiodarone. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.
CYP2C8 inhibitors: May increase the levels/effects of amiodarone. Example inhibitors include atazanavir, gemfibrozil, and ritonavir.
CYP2C9 substrates: Amiodarone may increase the levels/effects of CYP2C9 substrates. Example substrates include bosentan, dapsone, fluoxetine, glimepiride, glipizide, losartan, montelukast, nateglinide, paclitaxel, phenytoin, warfarin, and zafirlukast.
CYP2D6 substrates: Amiodarone may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.
CYP2D6 prodrug substrates: Amiodarone may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.
CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of amiodarone. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.
CYP3A4 inhibitors: May increase the levels/effects of amiodarone. Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil.
CYP3A4 substrates: Amiodarone may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, ergot derivatives, mirtazapine, nateglinide, nefazodone, tacrolimus, and venlafaxine.
Digoxin levels may be increased by amiodarone; consider reducing digoxin dose by 50% and monitor digoxin blood levels closely.
Fentanyl: Concurrent use may lead to bradycardia, sinus arrest, and hypotension.
Flecainide blood levels may be increased; consider reducing flecainide dose by 25% to 33% with concurrent use.
Fluoroquinolones (sparfloxacin, gatifloxacin, moxifloxacin): May result in additional prolongation of the QT interval; concurrent use of sparfloxacin is contraindicated.
HMG-CoA reductase inhibitors (lovastatin, simvastatin, and others dependent on CYP3A4 metabolism): Amiodarone inhibits metabolism of lovastatin and/or simvastatin and may increase the risk of myopathy and rhabdomyolysis. Concurrent use of lovastatin or simvastatin is not recommended, but if unavoidable, dose of lovastatin should not exceed 40 mg/day. The dose of simvastatin should not exceed 20 mg/day; consider alternative HMG-CoA reductase inhibitor.
Lidocaine: Amiodarone may increase serum levels/toxicity of lidocaine. Sinus bradycardia may occur with concurrent use.
Macrolide antibiotics: May prolong QTc, potentially leading to malignant arrhythmias. Use caution and evaluate risk:benefit.
Metoprolol blood levels may be increased; monitor response.
Phenytoin blood levels may be increased by amiodarone; amiodarone blood levels may be decreased by phenytoin.
Procainamide and NAPA plasma levels may be increased; consider reducing procainamide dosage by 25% with concurrent use.
Propranolol blood levels may be increased.
Protease inhibitors (amprenavir, indinavir, ritonavir): May increase amiodarone blood levels and toxicity; concurrent use is contraindicated.
QTc interval prolonging agents (including but may not be limited to amitriptyline, bepridil, disopyramide, erythromycin, haloperidol, imipramine, quinidine, pimozide, procainamide, sotalol, and thioridazine): Effect/toxicity increased; use with caution.
Quinidine blood levels may be increased; monitor quinidine trough concentration.
Rifampin may decrease amiodarone blood levels.
Theophylline blood levels may be increased.
Thioridazine: Amiodarone may enhance the QTc-prolonging effect of thioridazine.
Thyroid supplements: Amiodarone may alter thyroid function; monitor closely.
Trazodone: Amiodarone may increase levels/effects of trazodone. QTC prolongation and torsade de pointes have been reported with concurrent use.
Warfarin: Hypoprothrombinemic response increased. Monitor INR closely when amiodarone is initiated or discontinued. Reduce warfarin's dose by 1/3 to 1/2 when amiodarone is started.
ETHANOL/NUTRITION/HERB INTERACTIONS
Food: Increases the rate and extent of absorption of amiodarone. Grapefruit juice increases bioavailability of oral amiodarone by 50% and decreases the conversion of amiodarone to N-DEA (active metabolite); altered effects are possible; use should be avoided during therapy.
Herb/Nutraceutical: St John's wort may decrease amiodarone levels or enhance photosensitization. Avoid ephedra (may worsen arrhythmia). Avoid dong quai.
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — May cause fetal harm when administered to a pregnant woman, leading to congenital goiter and hypo- or hyperthyroidism.
LACTATION — Enters breast milk/not recommended (AAP rates "of concern")
BREAST-FEEDING CONSIDERATIONS — Hypothyroidism may occur in nursing infants. Both amiodarone and its active metabolite are excreted in human milk. Breast-feeding may lead to significant infant exposure and potential toxicity.
DIETARY CONSIDERATIONS — Administer consistently with regard to meals. Amiodarone is a potential source of large amounts of inorganic iodine; ~3 mg of inorganic iodine per 100 mg of amiodarone is released into the systemic circulation. Recommended daily allowance for iodine in adults is 150 mcg.
Grapefruit juice is not recommended.
PRICING — (data from drugstore.com)
Tablets (Amiodarone HCl)
200 mg (30): $28.99
Tablets (Cordarone)
200 mg (60): $242.47
Tablets (Pacerone)
100 mg (30): $139.99
MONITORING PARAMETERS — Blood pressure, heart rate (ECG) and rhythm throughout therapy; assess patient for signs of lethargy, edema of the hands or feet, weight loss, and pulmonary toxicity (baseline pulmonary function tests); liver function tests; monitor serum electrolytes, especially potassium and magnesium. Assess thyroid function tests before initiation of treatment and then periodically thereafter (some experts suggest every 3-6 months). If signs or symptoms of thyroid disease or arrhythmia breakthrough/exacerbation occur then immediate re-evaluation is necessary. Amiodarone partially inhibits the peripheral conversion of thyroxine (T4) to triiodothyronine (T3); serum T4 and reverse triiodothyronine (rT3) concentrations may be increased and serum T3 may be decreased; most patients remain clinically euthyroid, however, clinical hypothyroidism or hyperthyroidism may occur.
Perform regular ophthalmic exams.
REFERENCE RANGE — Therapeutic: 0.5-2.5 mg/L (SI: 1-4 µmol/L) (parent); desethyl metabolite is active and is present in equal concentration to parent drug
TOXICOLOGY/OVERDOSE COMPREHENSIVE — Symptoms include extensions of pharmacologic effect, sinus bradycardia and/or heart block, hypotension and QT prolongation. Patients should be monitored for several days following ingestion. Intoxication with amiodarone necessitates ECG monitoring. Bradycardia may be atropine resistant. Injectable isoproterenol or a temporary pacemaker may be required. Dialysis is not beneficial.
CANADIAN BRAND NAMES — Alti-Amiodarone; Amiodarone Hydrochloride for Injection®; Apo-Amiodarone®; Cordarone®; Gen-Amiodarone; Novo-Amiodarone; Rhoxal-amiodarone; Sandoz-Amiodarone
(For additional information see "Amiodarone: Patient drug information" and see "Amiodarone: Pediatric drug information")
INTERNATIONAL BRAND NAMES — Aldarin (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TZ, UG, ZM, ZW); Alti-Amiodarone (CA); Amdarone (TH); Amicordin (PL); Amiocar (AR); Amiodacore (IL); Amiodarex (DE); Amiodarona (CL); Amiodarone Hydrochloride for Injection (CA); Amiohexal (DE); Amiokordin (PL); Ancaron (JP); Angiodarona (BR); Angoron (GR); Apo-Amiodarone (CA); Aratac (AU, MY, NZ, SG, TH, TW); Arycor (CO); Atlansil (AR, BR, CL, EC, PE, UY); Braxan (MX); Cardinorm (AU); Corbionax (FR); Cordarex (DE); Cordaron (BG); Cordarone (AE, AN, BB, BE, BF, BG, BH, BJ, CA, CH, CI, CN, CO, CR, CY, CZ, DO, EC, EE, EG, ET, FI, FR, GH, GM, GN, GT, HK, HN, HU, ID, IQ, IR, IT, JO, KE, KR, KW, LB, LR, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NI, NL, NO, OM, PA, PE, PH, PK, PL, PT, PY, QA, SA, SC, SD, SE, SL, SN, SV, SY, TH, TT, TW, TZ, UG, YE, ZA, ZM, ZW); Cordarone X (AU, GB, IE, IN, NZ, ZA); Coronovo (AR); Diarona (UY); Eurythmic (IN); Forken (MX); Gen-Amiodarone (CA); Hexarone (ZA); Kendaron (ID); Miodar (DO); Novo-Amiodarone (CA); Opacorden (PL); Procor (IL); Rhoxal-amiodarone (CA); Rithmik (AU); Sandoz-Amiodarone (CA); Sedacoron (AT, HK, PL, TW); Tachydaron (DE); Tiaryt (ID); Trangorex (ES, VE)
MECHANISM OF ACTION — Class III antiarrhythmic agent which inhibits adrenergic stimulation (alpha- and beta-blocking properties), affects sodium, potassium, and calcium channels, prolongs the action potential and refractory period in myocardial tissue; decreases AV conduction and sinus node function
PHARMACODYNAMICS/KINETICS
Onset of action: Oral: 2 days to 3 weeks; I.V.: May be more rapid
Peak effect: 1 week to 5 months
Duration after discontinuing therapy: 7-50 days
Note: Mean onset of effect and duration after discontinuation may be shorter in children than adults
Distribution: Vd: 66 L/kg (range: 18-148 L/kg); crosses placenta; enters breast milk in concentrations higher than maternal plasma concentrations
Protein binding: 96%
Metabolism: Hepatic via CYP2C8 and 3A4 to active N-desethylamiodarone metabolite; possible enterohepatic recirculation
Bioavailability: Oral: ~50%
Half-life elimination: Terminal: 40-55 days (range: 26-107 days); shorter in children than adults
Excretion: Feces; urine (<1% as unchanged drug)
PATIENT INFORMATION — Take with food; use sunscreen or stay out of sun to prevent burns; skin discoloration is reversible; photophobia may make sunglasses necessary; do not discontinue abruptly; regular blood work for thyroid functions tests and ophthalmologic exams are necessary; notify prescriber if persistent dry cough or shortness of breath occurs
Aminophylline
PHARMACOLOGIC CATEGORY
Theophylline Derivative
DOSING: ADULTS
Treatment of acute bronchospasm: I.V.:
Loading dose (in patients not currently receiving aminophylline or theophylline): 6 mg/kg (based on aminophylline) administered I.V. over 20-30 minutes; administration rate should not exceed 25 mg/minute (aminophylline)
Approximate I.V. maintenance dosages: Based upon continuous infusions; bolus dosing may be determined by multiplying the hourly infusion rate by 24 hours and dividing by the desired number of doses/day
Smoker: 0.8 mg/kg/hour
Nonsmoker: 0.5 mg/kg/hour
Older patients and patients with cor pulmonale: 0.3 mg/kg/hour
Patients with congestive heart failure: 0.1-0.2 mg/kg/hour
Dosage should be adjusted according to serum level measurements during the first 12- to 24-hour period.
Bronchodilator: Oral: Initial: 380 mg/day (equivalent to theophylline 300 mg/day) in divided doses every 6-8 hours; may increase dose after 3 days; maximum dose: 928 mg/day (equivalent to theophylline 800 mg/day)
DOSING: PEDIATRIC
(For additional information see "Aminophylline: Pediatric drug information")
Treatment of acute bronchospasm: I.V.:
Loading dose: Patients not currently receiving aminophylline or theophylline: 6 mg/kg (based on aminophylline) administered I.V. over 20-30 minutes; administration rate should not exceed 25 mg/minute (aminophylline)
Approximate I.V. maintenance dosages: Based upon continuous infusions; bolus dosing (often used in children <6>1 year and Adults: Hepatic; involves CYP1A2, 2E1, and 3A4; forms active metabolites (caffeine and 3-methylxanthine)
Half-life elimination: Highly variable and dependent upon age, liver function, cardiac function, lung disease, and smoking history
Time to peak, serum:
Oral: Immediate release: 1-2 hours
I.V.: Within 30 minutes
Excretion: Children >3 months and Adults: Urine (10% as unchanged drug)
PATIENT INFORMATION — Do not drink or eat large quantities of caffeine-containing beverages or food (colas, coffee, chocolate).
Theophylline Derivative
DOSING: ADULTS
Treatment of acute bronchospasm: I.V.:
Loading dose (in patients not currently receiving aminophylline or theophylline): 6 mg/kg (based on aminophylline) administered I.V. over 20-30 minutes; administration rate should not exceed 25 mg/minute (aminophylline)
Approximate I.V. maintenance dosages: Based upon continuous infusions; bolus dosing may be determined by multiplying the hourly infusion rate by 24 hours and dividing by the desired number of doses/day
Smoker: 0.8 mg/kg/hour
Nonsmoker: 0.5 mg/kg/hour
Older patients and patients with cor pulmonale: 0.3 mg/kg/hour
Patients with congestive heart failure: 0.1-0.2 mg/kg/hour
Dosage should be adjusted according to serum level measurements during the first 12- to 24-hour period.
Bronchodilator: Oral: Initial: 380 mg/day (equivalent to theophylline 300 mg/day) in divided doses every 6-8 hours; may increase dose after 3 days; maximum dose: 928 mg/day (equivalent to theophylline 800 mg/day)
DOSING: PEDIATRIC
(For additional information see "Aminophylline: Pediatric drug information")
Treatment of acute bronchospasm: I.V.:
Loading dose: Patients not currently receiving aminophylline or theophylline: 6 mg/kg (based on aminophylline) administered I.V. over 20-30 minutes; administration rate should not exceed 25 mg/minute (aminophylline)
Approximate I.V. maintenance dosages: Based upon continuous infusions; bolus dosing (often used in children <6>1 year and Adults: Hepatic; involves CYP1A2, 2E1, and 3A4; forms active metabolites (caffeine and 3-methylxanthine)
Half-life elimination: Highly variable and dependent upon age, liver function, cardiac function, lung disease, and smoking history
Time to peak, serum:
Oral: Immediate release: 1-2 hours
I.V.: Within 30 minutes
Excretion: Children >3 months and Adults: Urine (10% as unchanged drug)
PATIENT INFORMATION — Do not drink or eat large quantities of caffeine-containing beverages or food (colas, coffee, chocolate).
Aminolevulinic acid
U.S. BRAND NAMES — Levulan® Kerastick®
PHARMACOLOGIC CATEGORY
Photosensitizing Agent, Topical
Topical Skin Product
DOSING: ADULTS — Actinic keratoses: Topical: Apply to actinic keratoses (not perilesional skin) followed 14-18 hours later by blue light illumination. Application/treatment may be repeated at a treatment site after 8 weeks.
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Powder for topical solution:
Levulan® Kerastick®: 20% (6s) [2-component system containing aminolevulinic acid hydrochloride 354 mg (powder) and diluent containing ethanol 48% (1.5 mL) packaged together in an applicator tube]
DOSAGE FORMS: CONCISE
Powder for topical solution:
Levulan® Kerastick®: 20% (6s)
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Dab lesion gently with wet applicator tip. Do not apply to periorbital area, ocular tissue, or mucosal surfaces. Allow to dry, then reapply to same lesion. Apply to either scalp or facial lesions, but not to both simultaneously. Follow application with blue light exposure in 14-18 hours.
USE — Treatment of minimally to moderately thick actinic keratoses (grade 1 or 2) of the face or scalp; to be used in conjunction with blue light illumination
ADVERSE REACTIONS SIGNIFICANT — Transient stinging, burning, itching, erythema, and edema result from the photosensitizing properties of this agent. Symptoms subside between 1 minute and 24 hours after turning off the blue light illuminator. Severe stinging or burning was reported in at least 50% of patients from at least 1 lesional site treatment.
>10%: Dermatologic: Severe stinging or burning (50%), scaling of the skin/crusted skin (64% to 71%), hyper-/hypopigmentation (22% to 36%), itching (14% to 25%), erosion (2% to 14%)
1% to 10%:
Central nervous system: Dysesthesia (up to 2%)
Dermatologic: Skin ulceration (2% to 4%), vesiculation (4% to 5%), pustular drug eruption (up to 4%), skin disorder (5% to 12%)
Hematologic: Bleeding/hemorrhage (2% to 4%)
Local: Wheal/flare (2% to 7%), local pain (1%), tenderness (1% to 2%), edema (1%), scabbing (up to 2%), ulceration (2% to 4%), excoriation (1%)
CONTRAINDICATIONS — Hypersensitivity to aminolevulinic acid or any component of the formulation; individuals with cutaneous photosensitivity at wavelengths of 400-450 nm; porphyria; allergy to porphyrins
WARNINGS / PRECAUTIONS — For external use only. Do not apply to eyes or mucous membranes. Treatment site will become photosensitive following application. Patients should be instructed to avoid exposure to sunlight, bright indoor lights, or tanning beds during the period prior to blue light treatment. Should be applied by a qualified health professional to avoid application to perilesional skin. Has not been tested in individuals with coagulation defects (acquired or inherited).
DRUG INTERACTIONS — Photosensitizing agents including griseofulvin, thiazide diuretics, sulfonamides, sulfonylureas, phenothiazines, and tetracyclines theoretically may increase the photosensitizing potential of aminolevulinic acid.
PREGNANCY RISK FACTOR — C (show table)
PREGNANCY IMPLICATIONS — Animal reproduction studies have not been conducted, and there are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if clearly needed.
LACTATION — Excretion in breast milk unknown/use caution
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Monitoring and supportive care are recommended. Patients should be advised to avoid incidental exposure to intense light sources for at least 40 hours. Consequences of exceeding the recommended topical dosage are not known.
CANADIAN BRAND NAMES — Levulan®
INTERNATIONAL BRAND NAMES — Levulan (CA)
MECHANISM OF ACTION — Aminolevulinic acid is a metabolic precursor of protoporphyrin IX (PpIX), which is a photosensitizer. Photosensitization following application of aminolevulinic acid topical solution occurs through the metabolic conversion to PpIX. When exposed to light of appropriate wavelength and energy, accumulated PpIX produces a photodynamic reaction.
PHARMACODYNAMICS / KINETICS
PpIX:
Peak fluorescence intensity: 11 hours +/- 1 hour
Half-life, mean clearance for lesions: 30 +/- 10 hours
PATIENT INFORMATION — Solution will be applied by prescriber. Once solution is applied, affected skin will be sensitive to light. Wear protective clothing when exposed to light and avoid bright lights (including tanning beds) and sunlight. Sunscreens will not prevent phototoxic reactions. Solution will be applied directly to lesions; blue light exposure should follow 14-18 hours later. Do not wash solution off skin during this time. If you are not able to return for blue light therapy, avoid sunlight and other bright light for at least 40 hours following application of solution.
PHARMACOLOGIC CATEGORY
Photosensitizing Agent, Topical
Topical Skin Product
DOSING: ADULTS — Actinic keratoses: Topical: Apply to actinic keratoses (not perilesional skin) followed 14-18 hours later by blue light illumination. Application/treatment may be repeated at a treatment site after 8 weeks.
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Powder for topical solution:
Levulan® Kerastick®: 20% (6s) [2-component system containing aminolevulinic acid hydrochloride 354 mg (powder) and diluent containing ethanol 48% (1.5 mL) packaged together in an applicator tube]
DOSAGE FORMS: CONCISE
Powder for topical solution:
Levulan® Kerastick®: 20% (6s)
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Dab lesion gently with wet applicator tip. Do not apply to periorbital area, ocular tissue, or mucosal surfaces. Allow to dry, then reapply to same lesion. Apply to either scalp or facial lesions, but not to both simultaneously. Follow application with blue light exposure in 14-18 hours.
USE — Treatment of minimally to moderately thick actinic keratoses (grade 1 or 2) of the face or scalp; to be used in conjunction with blue light illumination
ADVERSE REACTIONS SIGNIFICANT — Transient stinging, burning, itching, erythema, and edema result from the photosensitizing properties of this agent. Symptoms subside between 1 minute and 24 hours after turning off the blue light illuminator. Severe stinging or burning was reported in at least 50% of patients from at least 1 lesional site treatment.
>10%: Dermatologic: Severe stinging or burning (50%), scaling of the skin/crusted skin (64% to 71%), hyper-/hypopigmentation (22% to 36%), itching (14% to 25%), erosion (2% to 14%)
1% to 10%:
Central nervous system: Dysesthesia (up to 2%)
Dermatologic: Skin ulceration (2% to 4%), vesiculation (4% to 5%), pustular drug eruption (up to 4%), skin disorder (5% to 12%)
Hematologic: Bleeding/hemorrhage (2% to 4%)
Local: Wheal/flare (2% to 7%), local pain (1%), tenderness (1% to 2%), edema (1%), scabbing (up to 2%), ulceration (2% to 4%), excoriation (1%)
CONTRAINDICATIONS — Hypersensitivity to aminolevulinic acid or any component of the formulation; individuals with cutaneous photosensitivity at wavelengths of 400-450 nm; porphyria; allergy to porphyrins
WARNINGS / PRECAUTIONS — For external use only. Do not apply to eyes or mucous membranes. Treatment site will become photosensitive following application. Patients should be instructed to avoid exposure to sunlight, bright indoor lights, or tanning beds during the period prior to blue light treatment. Should be applied by a qualified health professional to avoid application to perilesional skin. Has not been tested in individuals with coagulation defects (acquired or inherited).
DRUG INTERACTIONS — Photosensitizing agents including griseofulvin, thiazide diuretics, sulfonamides, sulfonylureas, phenothiazines, and tetracyclines theoretically may increase the photosensitizing potential of aminolevulinic acid.
PREGNANCY RISK FACTOR — C (show table)
PREGNANCY IMPLICATIONS — Animal reproduction studies have not been conducted, and there are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if clearly needed.
LACTATION — Excretion in breast milk unknown/use caution
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Monitoring and supportive care are recommended. Patients should be advised to avoid incidental exposure to intense light sources for at least 40 hours. Consequences of exceeding the recommended topical dosage are not known.
CANADIAN BRAND NAMES — Levulan®
INTERNATIONAL BRAND NAMES — Levulan (CA)
MECHANISM OF ACTION — Aminolevulinic acid is a metabolic precursor of protoporphyrin IX (PpIX), which is a photosensitizer. Photosensitization following application of aminolevulinic acid topical solution occurs through the metabolic conversion to PpIX. When exposed to light of appropriate wavelength and energy, accumulated PpIX produces a photodynamic reaction.
PHARMACODYNAMICS / KINETICS
PpIX:
Peak fluorescence intensity: 11 hours +/- 1 hour
Half-life, mean clearance for lesions: 30 +/- 10 hours
PATIENT INFORMATION — Solution will be applied by prescriber. Once solution is applied, affected skin will be sensitive to light. Wear protective clothing when exposed to light and avoid bright lights (including tanning beds) and sunlight. Sunscreens will not prevent phototoxic reactions. Solution will be applied directly to lesions; blue light exposure should follow 14-18 hours later. Do not wash solution off skin during this time. If you are not able to return for blue light therapy, avoid sunlight and other bright light for at least 40 hours following application of solution.
Aminoglutethimide
U.S. BRAND NAMES — Cytadren®
PHARMACOLOGIC CATEGORY
Antineoplastic Agent, Aromatase Inhibitor
Enzyme Inhibitor
Hormonal Antagonist, Anti-Adrenal
Nonsteroidal Aromatase Inhibitor
DOSING: ADULTS
Cushing disease: Oral: 250 mg every 6 hours may be increased at 1- to 2-week intervals to a total of 2 g/day
Breast cancer, prostate cancer (unlabeled use): Oral: 250 mg 4 times/day
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — Dose reduction may be necessary.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet [scored]: 250 mg
DOSAGE FORMS: CONCISE
Tablet [scored]:
Cytadren®: 250 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer every 6 hours to reduce incidence of nausea and vomiting.
USE — Suppression of adrenal function in selected patients with Cushing's syndrome
USE - UNLABELED / INVESTIGATIONAL — Treatment of breast and prostate cancer (androgen synthesis inhibitor)
ADVERSE REACTIONS SIGNIFICANT — Most adverse effects will diminish in incidence and severity after the first 2-6 weeks
>10%:
Central nervous system: Headache, dizziness, drowsiness, lethargy, clumsiness
Dermatologic: Skin rash
Gastrointestinal: Nausea, anorexia
Hepatic: Cholestatic jaundice
Neuromuscular & skeletal: Myalgia
Renal: Nephrotoxicity
Respiratory: Pulmonary alveolar damage
1% to 10%:
Cardiovascular: Hypotension, tachycardia, orthostasis
Dermatologic: Hirsutism, pruritus
Endocrine & metabolic: Adrenocortical insufficiency
Gastrointestinal: Vomiting
<1% (Limited to important or life-threatening): Adrenal suppression, hepatotoxicity, hypercholesterolemia, hyperkalemia, hypothyroidism, goiter, masculinization of females, pulmonary hypersensitivity, urticaria; rare cases of neutropenia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis have been reported
CONTRAINDICATIONS — Hypersensitivity to aminoglutethimide, glutethimide, or any component of the formulation; pregnancy
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Hypothyroidism: With use, hypothyroidism may occur.
Other warnings/precautions: Blood pressure monitoring: In all patients, monitor blood pressure at appropriate intervals. Mineralocorticoid/glucocorticoid replacement: Mineralocorticoid replacement is necessary in up to 50% of patients. Glucocorticoid replacement is necessary in most patients.
DRUG INTERACTIONS — Induces CYP1A2 (strong), 2C19 (strong), 3A4 (strong)
CYP1A2 substrates: Aminoglutethimide may decrease the levels/effects of CYP1A2 substrates. Example substrates include aminophylline, estrogens, fluvoxamine, mirtazapine, ropinirole, and theophylline.
CYP2C19 substrates: Aminoglutethimide may decrease the levels/effects of CYP2C19 substrates. Example substrates include citalopram, diazepam, methsuximide, phenytoin, propranolol, proton pump inhibitors, sertraline, and voriconazole.
CYP3A4 substrates: Aminoglutethimide may decrease the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, clarithromycin, cyclosporine, erythromycin, estrogens, mirtazapine, nateglinide, nefazodone, nevirapine, protease inhibitors, tacrolimus, and venlafaxine.
Dexamethasone: Aminoglutethimide increases metabolism of dexamethasone; hydrocortisone is preferred if glucocorticoid treatment is needed.
Medroxyprogesterone: Aminoglutethimide increases medroxyprogesterone clearance.
Megestrol: Aminoglutethimide increases megestrol clearance.
Tamoxifen: Aminoglutethimide increases tamoxifen clearance.
Theophylline: Aminoglutethimide increases metabolism of theophylline.
Warfarin: Aminoglutethimide increases warfarin clearance.
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — Suspected of causing virilization when given throughout pregnancy
LACTATION — Excretion in breast milk unknown/contraindicated
PRICING — (data from drugstore.com)
Tablets (Cytadren)
250 mg (30): $47.99
MONITORING PARAMETERS — Follow adrenal cortical response by careful monitoring of plasma cortisol until the desired level of suppression is achieved. Mineralocorticoid (fludrocortisone) replacement therapy may be necessary in up to 50% of patients. If glucocorticoid replacement therapy is necessary, 20-30 mg hydrocortisone orally in the morning will replace endogenous secretion.
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Symptoms include ataxia, somnolence, lethargy, dizziness, distress, fatigue, coma, hyperventilation, respiratory depression, hypovolemia, and shock. Treatment is supportive.
INTERNATIONAL BRAND NAMES — Aminoglutetimid (PL); Cytadren (AU, NZ); Mamomit (HR); Orimeten (AR, AT, BE, BF, BG, BJ, BR, CH, CI, CL, CN, CZ, DE, EG, ES, ET, FI, GH, GM, GN, HU, IT, KE, LR, MA, ML, MR, MU, MW, NE, NG, NL, NO, PL, PT, SC, SD, SE, SL, SN, TZ, UG, ZA, ZM, ZW); Orimetene (GR, HK, TW)
MECHANISM OF ACTION — Blocks the enzymatic conversion of cholesterol to delta-5-pregnenolone, thereby reducing the synthesis of adrenal glucocorticoids, mineralocorticoids, estrogens, aldosterone, and androgens
PHARMACODYNAMICS / KINETICS
Onset of action: Adrenal suppression: 3-5 days; following withdrawal of therapy, adrenal function returns within 72 hours
Absorption: 90%
Protein binding, plasma: 20% to 25%
Metabolism: Major metabolite is N-acetylaminoglutethimide; induces its own metabolism
Half-life elimination: 7-15 hours; shorter following multiple doses
Excretion: Urine (34% to 50% as unchanged drug, 25% as metabolites)
PHARMACOLOGIC CATEGORY
Antineoplastic Agent, Aromatase Inhibitor
Enzyme Inhibitor
Hormonal Antagonist, Anti-Adrenal
Nonsteroidal Aromatase Inhibitor
DOSING: ADULTS
Cushing disease: Oral: 250 mg every 6 hours may be increased at 1- to 2-week intervals to a total of 2 g/day
Breast cancer, prostate cancer (unlabeled use): Oral: 250 mg 4 times/day
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — Dose reduction may be necessary.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet [scored]: 250 mg
DOSAGE FORMS: CONCISE
Tablet [scored]:
Cytadren®: 250 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer every 6 hours to reduce incidence of nausea and vomiting.
USE — Suppression of adrenal function in selected patients with Cushing's syndrome
USE - UNLABELED / INVESTIGATIONAL — Treatment of breast and prostate cancer (androgen synthesis inhibitor)
ADVERSE REACTIONS SIGNIFICANT — Most adverse effects will diminish in incidence and severity after the first 2-6 weeks
>10%:
Central nervous system: Headache, dizziness, drowsiness, lethargy, clumsiness
Dermatologic: Skin rash
Gastrointestinal: Nausea, anorexia
Hepatic: Cholestatic jaundice
Neuromuscular & skeletal: Myalgia
Renal: Nephrotoxicity
Respiratory: Pulmonary alveolar damage
1% to 10%:
Cardiovascular: Hypotension, tachycardia, orthostasis
Dermatologic: Hirsutism, pruritus
Endocrine & metabolic: Adrenocortical insufficiency
Gastrointestinal: Vomiting
<1% (Limited to important or life-threatening): Adrenal suppression, hepatotoxicity, hypercholesterolemia, hyperkalemia, hypothyroidism, goiter, masculinization of females, pulmonary hypersensitivity, urticaria; rare cases of neutropenia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis have been reported
CONTRAINDICATIONS — Hypersensitivity to aminoglutethimide, glutethimide, or any component of the formulation; pregnancy
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Hypothyroidism: With use, hypothyroidism may occur.
Other warnings/precautions: Blood pressure monitoring: In all patients, monitor blood pressure at appropriate intervals. Mineralocorticoid/glucocorticoid replacement: Mineralocorticoid replacement is necessary in up to 50% of patients. Glucocorticoid replacement is necessary in most patients.
DRUG INTERACTIONS — Induces CYP1A2 (strong), 2C19 (strong), 3A4 (strong)
CYP1A2 substrates: Aminoglutethimide may decrease the levels/effects of CYP1A2 substrates. Example substrates include aminophylline, estrogens, fluvoxamine, mirtazapine, ropinirole, and theophylline.
CYP2C19 substrates: Aminoglutethimide may decrease the levels/effects of CYP2C19 substrates. Example substrates include citalopram, diazepam, methsuximide, phenytoin, propranolol, proton pump inhibitors, sertraline, and voriconazole.
CYP3A4 substrates: Aminoglutethimide may decrease the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, clarithromycin, cyclosporine, erythromycin, estrogens, mirtazapine, nateglinide, nefazodone, nevirapine, protease inhibitors, tacrolimus, and venlafaxine.
Dexamethasone: Aminoglutethimide increases metabolism of dexamethasone; hydrocortisone is preferred if glucocorticoid treatment is needed.
Medroxyprogesterone: Aminoglutethimide increases medroxyprogesterone clearance.
Megestrol: Aminoglutethimide increases megestrol clearance.
Tamoxifen: Aminoglutethimide increases tamoxifen clearance.
Theophylline: Aminoglutethimide increases metabolism of theophylline.
Warfarin: Aminoglutethimide increases warfarin clearance.
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — Suspected of causing virilization when given throughout pregnancy
LACTATION — Excretion in breast milk unknown/contraindicated
PRICING — (data from drugstore.com)
Tablets (Cytadren)
250 mg (30): $47.99
MONITORING PARAMETERS — Follow adrenal cortical response by careful monitoring of plasma cortisol until the desired level of suppression is achieved. Mineralocorticoid (fludrocortisone) replacement therapy may be necessary in up to 50% of patients. If glucocorticoid replacement therapy is necessary, 20-30 mg hydrocortisone orally in the morning will replace endogenous secretion.
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Symptoms include ataxia, somnolence, lethargy, dizziness, distress, fatigue, coma, hyperventilation, respiratory depression, hypovolemia, and shock. Treatment is supportive.
INTERNATIONAL BRAND NAMES — Aminoglutetimid (PL); Cytadren (AU, NZ); Mamomit (HR); Orimeten (AR, AT, BE, BF, BG, BJ, BR, CH, CI, CL, CN, CZ, DE, EG, ES, ET, FI, GH, GM, GN, HU, IT, KE, LR, MA, ML, MR, MU, MW, NE, NG, NL, NO, PL, PT, SC, SD, SE, SL, SN, TZ, UG, ZA, ZM, ZW); Orimetene (GR, HK, TW)
MECHANISM OF ACTION — Blocks the enzymatic conversion of cholesterol to delta-5-pregnenolone, thereby reducing the synthesis of adrenal glucocorticoids, mineralocorticoids, estrogens, aldosterone, and androgens
PHARMACODYNAMICS / KINETICS
Onset of action: Adrenal suppression: 3-5 days; following withdrawal of therapy, adrenal function returns within 72 hours
Absorption: 90%
Protein binding, plasma: 20% to 25%
Metabolism: Major metabolite is N-acetylaminoglutethimide; induces its own metabolism
Half-life elimination: 7-15 hours; shorter following multiple doses
Excretion: Urine (34% to 50% as unchanged drug, 25% as metabolites)
Aminocaproic acid
U.S. BRAND NAMES — Amicar®
PHARMACOLOGIC CATEGORY
Hemostatic Agent
DOSING: ADULTS
Acute bleeding syndrome: Oral, I.V.: 4-5 g during the first hour, followed by 1 g/hour for 8 hours or until bleeding controlled (maximum daily dose: 30 g)
Control bleeding in thrombocytopenia (unlabeled use):
Initial: I.V.: 0.1 g/kg over 30-60 minutes
Maintenance: Oral: 1-3 g every 6 hours
Control oral bleeding in congenital and acquired coagulation disorder (unlabeled use): Oral: 50-60 mg/kg every 4 hours
Traumatic hyphema (unlabeled use): Oral: 100 mg/kg/dose every 4 hours (maximum daily dose: 30 g)
DOSING: PEDIATRIC
(For additional information see "Aminocaproic acid: Pediatric drug information")
Acute bleeding syndrome (unlabeled use): Oral, I.V.: 100-200 mg/kg during the first hour, followed by continuous infusion at 33.3 mg/kg/hour or 100 mg/kg (oral or I.V.) every 6 hours
Traumatic hyphema (unlabeled use): Oral: Refer to adult dosing.
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — May accumulate in patients with decreased renal function.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution: 250 mg/mL (20 mL)
Amicar®: 250 mg/mL (20 mL) [contains benzyl alcohol]
Solution, oral: 1.25 g/5 mL (240 mL, 480 mL)
Syrup:
Amicar®: 1.25 g/5 mL (480 mL) [raspberry flavor]
Tablet [scored]: 500 mg, 1000 mg
Amicar®: 500 mg, 1000 mg
DOSAGE FORMS: CONCISE
Injection, solution: 250 mg/mL (20 mL)
Amicar®: 250 mg/mL (20 mL)
Solution, oral: 1.25 g/5 mL (480 mL)
Syrup:
Amicar®: 1.25 g/5 mL
Tablet [scored]: 500 mg, 1000 mg
Amicar®: 500 mg, 1000 mg
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — I.V.: May be administered over 30-60 minutes or by continuous infusion; rapid I.V. injection (IVP) should be avoided due to possible hypotension, bradycardia, and arrhythmia.
COMPATIBILITY — Stable in D5W, NS.
Compatibility when admixed: Compatible: Netilmicin.
USE — Treatment of excessive bleeding from fibrinolysis
USE - UNLABELED / INVESTIGATIONAL — Treatment of traumatic hyphema; control bleeding in thrombocytopenia; control oral bleeding in congenital and acquired coagulation disorders
ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.
Cardiovascular: Arrhythmia, bradycardia, hypotension, peripheral ischemia, syncope, thrombosis
Central nervous system: Confusion, delirium, dizziness, fatigue, hallucinations, headache, intracranial hypertension, malaise, seizure, stroke
Dermatologic: Rash, pruritus
Gastrointestinal: Abdominal pain, anorexia, cramps, diarrhea, GI irritation, nausea
Genitourinary: Dry ejaculation
Hematologic: Agranulocytosis, bleeding time increased, leukopenia, thrombocytopenia
Neuromuscular & skeletal: CPK increased, myalgia, myositis, myopathy, rhabdomyolysis (rare), weakness
Ophthalmic: Watery eyes, vision decreased
Otic: Tinnitus
Renal: Failure (rare), myoglobinuria (rare)
Respiratory: Dyspnea, nasal congestion, pulmonary embolism
CONTRAINDICATIONS — Hypersensitivity to aminocaproic acid or any component of the formulation; disseminated intravascular coagulation (without heparin); evidence of an intravascular clotting process
WARNINGS / PRECAUTIONS — Avoid rapid I.V. administration; may induce hypotension, bradycardia, or arrhythmia. Aminocaproic acid may accumulate in patients with decreased renal function. Intrarenal obstruction may occur secondary to glomerular capillary thrombosis or clots in the renal pelvis and ureters. Do not use in hematuria of upper urinary tract origin unless possible benefits outweigh risks. Use with caution in patients with cardiac, renal, or hepatic disease. Do not administer without a definite diagnosis of laboratory findings indicative of hyperfibrinolysis. Inhibition of fibrinolysis may promote clotting or thrombosis; more likely due to the presence of DIC. Subsequently, use with great caution in patients with, or at risk for, veno-occlusive disease of the liver. Benzyl alcohol is used as a preservative in the injection, therefore, these products should not be used in the neonate. Do not administer with factor IX complex concentrates or anti-inhibitor coagulant complexes.
DRUG INTERACTIONS — Increased toxic effect with oral contraceptives, estrogens.
PREGNANCY RISK FACTOR — C (show table)
PREGNANCY IMPLICATIONS — Reproductive studies have not been conducted.
LACTATION — Excretion in breast milk unknown/use caution
PRICING — (data from drugstore.com)
Tablets (Amicar)
500 mg (30): $78.37
MONITORING PARAMETERS — Fibrinogen, fibrin split products, creatine phosphokinase (with long-term therapy)
REFERENCE RANGE — Therapeutic concentration: >130 mcg/mL (concentration necessary for inhibition of fibrinolysis)
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Symptoms include acute renal failure, delirium, diarrhea, hepatic necrosis, nausea, seizures, transient hypotension, and thromboembolism. Aminocaproic acid may be removed by hemodialysis.
INTERNATIONAL BRAND NAMES — Acidum e-aminocapronicum (PL); Amicar (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE, ZA); Caproamin (VE); Caprolisin (IT); Hamostat (IN); Ipsilon (AR, BR, JP, PY, UY); Resplamin (JP); Syrop acidi e-aminocapronici (PL)
MECHANISM OF ACTION — Competitively inhibits activation of plasminogen to plasmin, also, a lesser antiplasmin effect
PHARMACODYNAMICS / KINETICS
Onset of action: ~1-72 hours
Distribution: Widely through intravascular and extravascular compartments
Vd: Oral: 23 L, I.V.: 30 L
Metabolism: Minimally hepatic
Half-life elimination: 2 hours
Time to peak: Oral: Within 2 hours
Excretion: Urine (65% as unchanged drug, 11% as metabolite)
PATIENT INFORMATION — Report any signs of bleeding; change positions slowly to minimize dizziness
PHARMACOLOGIC CATEGORY
Hemostatic Agent
DOSING: ADULTS
Acute bleeding syndrome: Oral, I.V.: 4-5 g during the first hour, followed by 1 g/hour for 8 hours or until bleeding controlled (maximum daily dose: 30 g)
Control bleeding in thrombocytopenia (unlabeled use):
Initial: I.V.: 0.1 g/kg over 30-60 minutes
Maintenance: Oral: 1-3 g every 6 hours
Control oral bleeding in congenital and acquired coagulation disorder (unlabeled use): Oral: 50-60 mg/kg every 4 hours
Traumatic hyphema (unlabeled use): Oral: 100 mg/kg/dose every 4 hours (maximum daily dose: 30 g)
DOSING: PEDIATRIC
(For additional information see "Aminocaproic acid: Pediatric drug information")
Acute bleeding syndrome (unlabeled use): Oral, I.V.: 100-200 mg/kg during the first hour, followed by continuous infusion at 33.3 mg/kg/hour or 100 mg/kg (oral or I.V.) every 6 hours
Traumatic hyphema (unlabeled use): Oral: Refer to adult dosing.
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — May accumulate in patients with decreased renal function.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution: 250 mg/mL (20 mL)
Amicar®: 250 mg/mL (20 mL) [contains benzyl alcohol]
Solution, oral: 1.25 g/5 mL (240 mL, 480 mL)
Syrup:
Amicar®: 1.25 g/5 mL (480 mL) [raspberry flavor]
Tablet [scored]: 500 mg, 1000 mg
Amicar®: 500 mg, 1000 mg
DOSAGE FORMS: CONCISE
Injection, solution: 250 mg/mL (20 mL)
Amicar®: 250 mg/mL (20 mL)
Solution, oral: 1.25 g/5 mL (480 mL)
Syrup:
Amicar®: 1.25 g/5 mL
Tablet [scored]: 500 mg, 1000 mg
Amicar®: 500 mg, 1000 mg
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — I.V.: May be administered over 30-60 minutes or by continuous infusion; rapid I.V. injection (IVP) should be avoided due to possible hypotension, bradycardia, and arrhythmia.
COMPATIBILITY — Stable in D5W, NS.
Compatibility when admixed: Compatible: Netilmicin.
USE — Treatment of excessive bleeding from fibrinolysis
USE - UNLABELED / INVESTIGATIONAL — Treatment of traumatic hyphema; control bleeding in thrombocytopenia; control oral bleeding in congenital and acquired coagulation disorders
ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.
Cardiovascular: Arrhythmia, bradycardia, hypotension, peripheral ischemia, syncope, thrombosis
Central nervous system: Confusion, delirium, dizziness, fatigue, hallucinations, headache, intracranial hypertension, malaise, seizure, stroke
Dermatologic: Rash, pruritus
Gastrointestinal: Abdominal pain, anorexia, cramps, diarrhea, GI irritation, nausea
Genitourinary: Dry ejaculation
Hematologic: Agranulocytosis, bleeding time increased, leukopenia, thrombocytopenia
Neuromuscular & skeletal: CPK increased, myalgia, myositis, myopathy, rhabdomyolysis (rare), weakness
Ophthalmic: Watery eyes, vision decreased
Otic: Tinnitus
Renal: Failure (rare), myoglobinuria (rare)
Respiratory: Dyspnea, nasal congestion, pulmonary embolism
CONTRAINDICATIONS — Hypersensitivity to aminocaproic acid or any component of the formulation; disseminated intravascular coagulation (without heparin); evidence of an intravascular clotting process
WARNINGS / PRECAUTIONS — Avoid rapid I.V. administration; may induce hypotension, bradycardia, or arrhythmia. Aminocaproic acid may accumulate in patients with decreased renal function. Intrarenal obstruction may occur secondary to glomerular capillary thrombosis or clots in the renal pelvis and ureters. Do not use in hematuria of upper urinary tract origin unless possible benefits outweigh risks. Use with caution in patients with cardiac, renal, or hepatic disease. Do not administer without a definite diagnosis of laboratory findings indicative of hyperfibrinolysis. Inhibition of fibrinolysis may promote clotting or thrombosis; more likely due to the presence of DIC. Subsequently, use with great caution in patients with, or at risk for, veno-occlusive disease of the liver. Benzyl alcohol is used as a preservative in the injection, therefore, these products should not be used in the neonate. Do not administer with factor IX complex concentrates or anti-inhibitor coagulant complexes.
DRUG INTERACTIONS — Increased toxic effect with oral contraceptives, estrogens.
PREGNANCY RISK FACTOR — C (show table)
PREGNANCY IMPLICATIONS — Reproductive studies have not been conducted.
LACTATION — Excretion in breast milk unknown/use caution
PRICING — (data from drugstore.com)
Tablets (Amicar)
500 mg (30): $78.37
MONITORING PARAMETERS — Fibrinogen, fibrin split products, creatine phosphokinase (with long-term therapy)
REFERENCE RANGE — Therapeutic concentration: >130 mcg/mL (concentration necessary for inhibition of fibrinolysis)
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Symptoms include acute renal failure, delirium, diarrhea, hepatic necrosis, nausea, seizures, transient hypotension, and thromboembolism. Aminocaproic acid may be removed by hemodialysis.
INTERNATIONAL BRAND NAMES — Acidum e-aminocapronicum (PL); Amicar (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE, ZA); Caproamin (VE); Caprolisin (IT); Hamostat (IN); Ipsilon (AR, BR, JP, PY, UY); Resplamin (JP); Syrop acidi e-aminocapronici (PL)
MECHANISM OF ACTION — Competitively inhibits activation of plasminogen to plasmin, also, a lesser antiplasmin effect
PHARMACODYNAMICS / KINETICS
Onset of action: ~1-72 hours
Distribution: Widely through intravascular and extravascular compartments
Vd: Oral: 23 L, I.V.: 30 L
Metabolism: Minimally hepatic
Half-life elimination: 2 hours
Time to peak: Oral: Within 2 hours
Excretion: Urine (65% as unchanged drug, 11% as metabolite)
PATIENT INFORMATION — Report any signs of bleeding; change positions slowly to minimize dizziness
Aminocamptothecin
PHARMACOLOGIC CATEGORY Antineoplastic Agent, DNA Binding AgentEnzyme Inhibitor, Topoisomerase I Inhibitor
DOSING: ADULTS — I.V.: 45-59 mcg/m2/hour for 72 hours as a continuous infusion; repeat every 2 weeks or 35 mcg/m2/hour as a 72-hour continuous infusion
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection: 5 mg ampul
DOSAGE FORMS: CONCISE Injection: 5 mg ampul [not available in the U.S.; investigational]
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer by continuous I.V. infusion.
USE - UNLABELED / INVESTIGATIONAL — Phase II trials: Relapsed lymphoma, refractory breast cancer, nonsmall cell lung cancer, untreated colorectal carcinoma
ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.
Central nervous system: Fatigue
Dermatologic: Alopecia
Gastrointestinal: Nausea, vomiting, diarrhea, mucositis, anorexia
Hematologic: Neutropenia (may be dose limiting), thrombocytopenia (reversible, but may be dose limiting), anemia
CONTRAINDICATIONS — Hypersensitivity to aminocamptothecin or any component of the formulation
WARNINGS / PRECAUTIONS Special handling: Hazardous agent: Use appropriate precautions for handling and disposal.
RESTRICTIONS — Not available in U.S./Investigational
DRUG INTERACTIONS — Patients taking anticonvulsants that induce hepatic enzymes have less toxicity and can tolerate higher doses of aminocamptothecin.
MONITORING PARAMETERS — WBC with differential, platelet count
MECHANISM OF ACTION — Aminocamptothecin binds to topoisomerase I, stabilizing the cleavable DNA-topoisomerase I complex, resulting in arrest of the replication fork and inhibition of DNA synthesis.
PHARMACODYNAMICS / KINETICS — Ratio of lactone to total drug is 8.7% +/- 4.7% because of instability of aminocamptothecin lactone in plasma.
Distribution: Vd: 46-92 L
Metabolism: None identified
Half-life elimination: Terminal: 8-17 hours for total aminocamptothecin
Excretion: Urine (32% of total drug delivered)
DOSING: ADULTS — I.V.: 45-59 mcg/m2/hour for 72 hours as a continuous infusion; repeat every 2 weeks or 35 mcg/m2/hour as a 72-hour continuous infusion
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection: 5 mg ampul
DOSAGE FORMS: CONCISE Injection: 5 mg ampul [not available in the U.S.; investigational]
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer by continuous I.V. infusion.
USE - UNLABELED / INVESTIGATIONAL — Phase II trials: Relapsed lymphoma, refractory breast cancer, nonsmall cell lung cancer, untreated colorectal carcinoma
ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.
Central nervous system: Fatigue
Dermatologic: Alopecia
Gastrointestinal: Nausea, vomiting, diarrhea, mucositis, anorexia
Hematologic: Neutropenia (may be dose limiting), thrombocytopenia (reversible, but may be dose limiting), anemia
CONTRAINDICATIONS — Hypersensitivity to aminocamptothecin or any component of the formulation
WARNINGS / PRECAUTIONS Special handling: Hazardous agent: Use appropriate precautions for handling and disposal.
RESTRICTIONS — Not available in U.S./Investigational
DRUG INTERACTIONS — Patients taking anticonvulsants that induce hepatic enzymes have less toxicity and can tolerate higher doses of aminocamptothecin.
MONITORING PARAMETERS — WBC with differential, platelet count
MECHANISM OF ACTION — Aminocamptothecin binds to topoisomerase I, stabilizing the cleavable DNA-topoisomerase I complex, resulting in arrest of the replication fork and inhibition of DNA synthesis.
PHARMACODYNAMICS / KINETICS — Ratio of lactone to total drug is 8.7% +/- 4.7% because of instability of aminocamptothecin lactone in plasma.
Distribution: Vd: 46-92 L
Metabolism: None identified
Half-life elimination: Terminal: 8-17 hours for total aminocamptothecin
Excretion: Urine (32% of total drug delivered)
Amiloride and hydrochlorothiazide
PHARMACOLOGIC CATEGORY Diuretic, Combination
DOSING: ADULTS — Hypertension, edema: Oral: Initial: 1 tablet/day; may be increased to 2 tablets/day if needed; usually given in a single dose
DOSING: ELDERLY — Oral: Initial: 1/2 to 1 tablet/day
DOSING: RENAL IMPAIRMENT — See individual agents.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 5/50: Amiloride hydrochloride 5 mg and hydrochlorothiazide 50 mg
DOSAGE FORMS: CONCISE Tablet: 5/50: Amiloride 5 mg and hydrochlorothiazide 50 mg
GENERIC EQUIVALENT AVAILABLE — Yes
USE — Potassium-sparing diuretic; antihypertensive
ADVERSE REACTIONS SIGNIFICANT — See individual agents.
WARNINGS / PRECAUTIONS Box warnings: Hyperkalemia: See "Concerns related to adverse effects" below.
Concerns related to adverse effects: Electrolyte disturbances: Hypochloremic alkalosis and hyponatremia can occur. Hyperkalemia: [U.S. Boxed Warning]: Hyperkalemia can occur; patients at risk include those with renal impairment, diabetes, the elderly, and the severely ill. Serum potassium levels must be monitored at frequent intervals especially when dosages are changed or with any illness that may cause renal dysfunction. Photosensitivity: Photosensitization may occur with hydrochlorothiazide. Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonamide allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe. Discontinue if signs of hypersensitivity are noted.
Disease-related concerns: Diabetes: Use with extreme caution in patients with diabetes mellitus; may see a change in glucose control. Monitor closely; discontinue amiloride 3 days prior to glucose tolerance testing. Gout: In certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure, gout can be precipitated with hydrochlorothiazide. Hepatic impairment: Use hydrochlorothiazide with caution in patients with severe hepatic dysfunction; in cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. Hypercholesterolemia: Use hydrochlorothiazide with caution in patients with moderate or high cholesterol concentrations. Metabolic/respiratory acidosis: Use with caution in patients who are at risk for metabolic or respiratory acidosis (eg, cardiopulmonary disease, uncontrolled diabetes). Renal impairment: Avoid use of hydrochlorothiazide in severe renal disease (ineffective). Systemic lupus erythematosus (SLE): Hydrochlorothiazide can cause SLE exacerbation or activation.
DRUG INTERACTIONS — See individual agents.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Refer to Hydrochlorothiazide.
LACTATION — Excretion in breast milk unknown/contraindicated
DIETARY CONSIDERATIONS — May be taken with food.
PRICING — (data from drugstore.com)Tablets (Amiloride-Hydrochlorothiazide) 5-50 mg (100): $27.99
CANADIAN BRAND NAMES — Apo-Amilzide®; Gen-Amilazide; Moduret; Novamilor; Nu-Amilzide
INTERNATIONAL BRAND NAMES — Adco-Retic (ZA); Add-Acten (AE, BF, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, QA, SA, SC, SD, SL, SN, SY, TZ, UG, YE, ZM, ZW); Ameride (ES); Amil-Co (GB); Amilco (DK); Amilco Mite (DK); Amilocomp beta (DE); Amiloretic (ZA); Amizide (AU, MY, NZ, TW, ZA); Amuretic (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Apo-Amilzide (CA, MY); Betaretic (ZA); Biduret (IN); Bildiuretic (TH); Gen-Amilazide (CA); Hyperetic (TH); Kaluril (IL); Lorinid (ID); Lorinid Mite (ID); Moduret (CA); Moduretic (AU, BE, BF, BJ, BR, CH, CI, CO, CZ, DE, DK, EC, ET, FI, GB, GH, GM, GN, GR, HK, IE, IT, KE, LR, MA, ML, MR, MU, MW, MX, MY, NE, NG, NL, PK, PT, PY, SC, SD, SE, SL, SN, TH, TW, TZ, UG, UY, VE, ZA, ZM, ZW); Moduretic Mite (NO); Moure-M (TH); Novamilor (CA); Nu-Amilzide (CA); Sefaretic (HK); Tiaden (TW); Uniretic (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Yostiretic (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE)
PHARMACODYNAMICS / KINETICS —
DOSING: ADULTS — Hypertension, edema: Oral: Initial: 1 tablet/day; may be increased to 2 tablets/day if needed; usually given in a single dose
DOSING: ELDERLY — Oral: Initial: 1/2 to 1 tablet/day
DOSING: RENAL IMPAIRMENT — See individual agents.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 5/50: Amiloride hydrochloride 5 mg and hydrochlorothiazide 50 mg
DOSAGE FORMS: CONCISE Tablet: 5/50: Amiloride 5 mg and hydrochlorothiazide 50 mg
GENERIC EQUIVALENT AVAILABLE — Yes
USE — Potassium-sparing diuretic; antihypertensive
ADVERSE REACTIONS SIGNIFICANT — See individual agents.
WARNINGS / PRECAUTIONS Box warnings: Hyperkalemia: See "Concerns related to adverse effects" below.
Concerns related to adverse effects: Electrolyte disturbances: Hypochloremic alkalosis and hyponatremia can occur. Hyperkalemia: [U.S. Boxed Warning]: Hyperkalemia can occur; patients at risk include those with renal impairment, diabetes, the elderly, and the severely ill. Serum potassium levels must be monitored at frequent intervals especially when dosages are changed or with any illness that may cause renal dysfunction. Photosensitivity: Photosensitization may occur with hydrochlorothiazide. Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonamide allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe. Discontinue if signs of hypersensitivity are noted.
Disease-related concerns: Diabetes: Use with extreme caution in patients with diabetes mellitus; may see a change in glucose control. Monitor closely; discontinue amiloride 3 days prior to glucose tolerance testing. Gout: In certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure, gout can be precipitated with hydrochlorothiazide. Hepatic impairment: Use hydrochlorothiazide with caution in patients with severe hepatic dysfunction; in cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. Hypercholesterolemia: Use hydrochlorothiazide with caution in patients with moderate or high cholesterol concentrations. Metabolic/respiratory acidosis: Use with caution in patients who are at risk for metabolic or respiratory acidosis (eg, cardiopulmonary disease, uncontrolled diabetes). Renal impairment: Avoid use of hydrochlorothiazide in severe renal disease (ineffective). Systemic lupus erythematosus (SLE): Hydrochlorothiazide can cause SLE exacerbation or activation.
DRUG INTERACTIONS — See individual agents.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Refer to Hydrochlorothiazide.
LACTATION — Excretion in breast milk unknown/contraindicated
DIETARY CONSIDERATIONS — May be taken with food.
PRICING — (data from drugstore.com)Tablets (Amiloride-Hydrochlorothiazide) 5-50 mg (100): $27.99
CANADIAN BRAND NAMES — Apo-Amilzide®; Gen-Amilazide; Moduret; Novamilor; Nu-Amilzide
INTERNATIONAL BRAND NAMES — Adco-Retic (ZA); Add-Acten (AE, BF, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, QA, SA, SC, SD, SL, SN, SY, TZ, UG, YE, ZM, ZW); Ameride (ES); Amil-Co (GB); Amilco (DK); Amilco Mite (DK); Amilocomp beta (DE); Amiloretic (ZA); Amizide (AU, MY, NZ, TW, ZA); Amuretic (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Apo-Amilzide (CA, MY); Betaretic (ZA); Biduret (IN); Bildiuretic (TH); Gen-Amilazide (CA); Hyperetic (TH); Kaluril (IL); Lorinid (ID); Lorinid Mite (ID); Moduret (CA); Moduretic (AU, BE, BF, BJ, BR, CH, CI, CO, CZ, DE, DK, EC, ET, FI, GB, GH, GM, GN, GR, HK, IE, IT, KE, LR, MA, ML, MR, MU, MW, MX, MY, NE, NG, NL, PK, PT, PY, SC, SD, SE, SL, SN, TH, TW, TZ, UG, UY, VE, ZA, ZM, ZW); Moduretic Mite (NO); Moure-M (TH); Novamilor (CA); Nu-Amilzide (CA); Sefaretic (HK); Tiaden (TW); Uniretic (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Yostiretic (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE)
PHARMACODYNAMICS / KINETICS —
Amiloride
U.S. BRAND NAMES — Midamor® [DSC]
PHARMACOLOGIC CATEGORY Diuretic, Potassium Sparing
DOSING: ADULTS — Hypertension, edema (to limit potassium loss): Oral: Initial: 5-10 mg/day (up to 20 mg) Hypertension (JNC 7): 5-10 mg/day in 1-2 divided doses
DOSING: PEDIATRIC — Edema, hypertension: Oral: Although safety and efficacy in children have not been established by the FDA, a dosage range of 0.4-0.625 mg/kg/day (maximum: 20 mg/day) has been used in children weighing 6-20 kg.
(For additional information see "Amiloride: Pediatric drug information")
DOSING: ELDERLY — Oral: Initial: 5 mg once daily or every other day
DOSING: RENAL IMPAIRMENT — Oral:
Clcr 10-50 mL/minute: Administer 50% of normal dose.
Clcr <10 mL/minute: Avoid use.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, as hydrochloride: 5 mg
DOSAGE FORMS: CONCISE Tablet: 5 mg
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — Administer with food or meals to avoid GI upset.
USE — Counteracts potassium loss induced by other diuretics in the treatment of hypertension or edematous conditions including CHF, hepatic cirrhosis, and hypoaldosteronism; usually used in conjunction with more potent diuretics such as thiazides or loop diuretics
USE - UNLABELED / INVESTIGATIONAL — Investigational: Cystic fibrosis; reduction of lithium-induced polyuria
ADVERSE REACTIONS SIGNIFICANT 1% to 10%: Central nervous system: Headache, fatigue, dizziness Endocrine & metabolic: Hyperkalemia (up to 10%; risk reduced in patients receiving kaliuretic diuretics), hyperchloremic metabolic acidosis, dehydration, hyponatremia, gynecomastia Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain, gas pain, appetite changes, constipation Genitourinary: Impotence Neuromuscular & skeletal: Muscle cramps, weakness Respiratory: Cough, dyspnea
<1% (Limited to important or life-threatening): Alopecia, arrhythmia, bladder spasms, chest pain, dyspnea, dysuria, GI bleeding, intraocular pressure increased, jaundice, orthostatic hypotension, palpitation, polyuria
CONTRAINDICATIONS — Hypersensitivity to amiloride or any component of the formulation; presence of elevated serum potassium levels (>5.5 mEq/L); if patient is receiving other potassium-conserving agents (eg, spironolactone, triamterene) or potassium supplementation (medicine, potassium-containing salt substitutes, potassium-rich diet); anuria; acute or chronic renal insufficiency; evidence of diabetic nephropathy. Patients with evidence of renal impairment or diabetes mellitus should not receive this medicine without close, frequent monitoring of serum electrolytes and renal function.
WARNINGS / PRECAUTIONS Box warnings: Hyperkalemia: See "Concerns related to adverse effects" below.
Concerns related to adverse effects: Fluid/electrolyte loss: Excess amounts can lead to profound diuresis with fluid and electrolyte loss; close medical supervision and dose evaluation are required. Watch for and correct electrolyte disturbances; adjust dose to avoid dehydration. Hyperkalemia: [U.S. Boxed Warning]: Hyperkalemia can occur; patients at risk include those with renal impairment, diabetes, the elderly, and the severely ill. Serum potassium levels must be monitored at frequent intervals especially when dosages are changed or with any illness that may cause renal dysfunction.
Disease-related concerns: Cirrhosis: In cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. Diabetes: Use with extreme caution in patients with diabetes mellitus; monitor closely. Discontinue amiloride 3 days prior to glucose tolerance testing. Metabolic/respiratory acidosis: Use with caution in patients who are at risk for metabolic or respiratory acidosis (eg, cardiopulmonary disease, uncontrolled diabetes).
DRUG INTERACTIONS Amoxicillin's absorption may be reduced; avoid concurrent use or observe for clinical response.
ACE inhibitors or angiotensin receptor antagonists can cause hyperkalemia, especially in patients with renal impairment, potassium-rich diets, or on other drugs causing hyperkalemia; avoid concurrent use or monitor closely.
Cyclosporine or tacrolimus: Risk of hyperkalemia may be increased by concurrent therapy.
NSAIDs: May decrease the effect of diuretics.
Potassium supplements may further increase potassium retention and cause hyperkalemia; avoid concurrent use.
Quinidine and amiloride together may increase risk of malignant arrhythmias; avoid concurrent use.
ETHANOL / NUTRITION / HERB INTERACTIONS — Food: Hyperkalemia may result if amiloride is taken with potassium-containing foods.
PREGNANCY RISK FACTOR — B (show table)
LACTATION — Excretion in breast milk unknown/contraindicated
DIETARY CONSIDERATIONS — Take with food or meals to avoid GI upset. Do not use salt substitutes or low salt milk without checking with your healthcare provider; too much potassium can be as harmful as too little.
PRICING — (data from drugstore.com)Tablets (Amiloride HCl) 5 mg (30): $22.41
Tablets (Midamor) 5 mg (30): $18.99
MONITORING PARAMETERS — I & O, daily weights, blood pressure, serum electrolytes, renal function
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Clinical signs are consistent with dehydration and electrolyte disturbance. Large amounts may result in life-threatening hyperkalemia (>6.5 mEq/L). This can be treated with I.V. glucose (dextrose 25% in water), with rapid-acting insulin, with concurrent I.V. sodium bicarbonate and, if needed, Kayexalate® oral or rectal solutions in sorbitol. Persistent hyperkalemia may require dialysis.
CANADIAN BRAND NAMES — Apo-Amiloride®
INTERNATIONAL BRAND NAMES — Amiclaran (CZ); Amikal (SE); Amilo 5 (KR); Amilozid (HU); Apo-Amiloride (CA); Kaluril (AU, TW); Medamor (FI); Midamor (NZ)
MECHANISM OF ACTION — Interferes with potassium/sodium exchange (active transport) in the distal tubule, cortical collecting tubule, and collecting duct by inhibiting sodium, potassium-ATPase; decreases calcium excretion; increases magnesium loss
PHARMACODYNAMICS / KINETICS Onset of action: 2 hours
Duration: 24 hours
Absorption: ~15% to 25%
Distribution: Vd: 350-380 L
Protein binding: 23%
Metabolism: No active metabolites
Half-life elimination: Normal renal function: 6-9 hours; End-stage renal disease: 8-144 hours
Time to peak, serum: 6-10 hours
Excretion: Urine and feces (equal amounts as unchanged drug)
PATIENT INFORMATION — Report any muscle cramps, weakness, nausea, or dizziness. Use caution operating machinery or performing other tasks requiring alertness.
PHARMACOLOGIC CATEGORY Diuretic, Potassium Sparing
DOSING: ADULTS — Hypertension, edema (to limit potassium loss): Oral: Initial: 5-10 mg/day (up to 20 mg) Hypertension (JNC 7): 5-10 mg/day in 1-2 divided doses
DOSING: PEDIATRIC — Edema, hypertension: Oral: Although safety and efficacy in children have not been established by the FDA, a dosage range of 0.4-0.625 mg/kg/day (maximum: 20 mg/day) has been used in children weighing 6-20 kg.
(For additional information see "Amiloride: Pediatric drug information")
DOSING: ELDERLY — Oral: Initial: 5 mg once daily or every other day
DOSING: RENAL IMPAIRMENT — Oral:
Clcr 10-50 mL/minute: Administer 50% of normal dose.
Clcr <10 mL/minute: Avoid use.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, as hydrochloride: 5 mg
DOSAGE FORMS: CONCISE Tablet: 5 mg
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — Administer with food or meals to avoid GI upset.
USE — Counteracts potassium loss induced by other diuretics in the treatment of hypertension or edematous conditions including CHF, hepatic cirrhosis, and hypoaldosteronism; usually used in conjunction with more potent diuretics such as thiazides or loop diuretics
USE - UNLABELED / INVESTIGATIONAL — Investigational: Cystic fibrosis; reduction of lithium-induced polyuria
ADVERSE REACTIONS SIGNIFICANT 1% to 10%: Central nervous system: Headache, fatigue, dizziness Endocrine & metabolic: Hyperkalemia (up to 10%; risk reduced in patients receiving kaliuretic diuretics), hyperchloremic metabolic acidosis, dehydration, hyponatremia, gynecomastia Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain, gas pain, appetite changes, constipation Genitourinary: Impotence Neuromuscular & skeletal: Muscle cramps, weakness Respiratory: Cough, dyspnea
<1% (Limited to important or life-threatening): Alopecia, arrhythmia, bladder spasms, chest pain, dyspnea, dysuria, GI bleeding, intraocular pressure increased, jaundice, orthostatic hypotension, palpitation, polyuria
CONTRAINDICATIONS — Hypersensitivity to amiloride or any component of the formulation; presence of elevated serum potassium levels (>5.5 mEq/L); if patient is receiving other potassium-conserving agents (eg, spironolactone, triamterene) or potassium supplementation (medicine, potassium-containing salt substitutes, potassium-rich diet); anuria; acute or chronic renal insufficiency; evidence of diabetic nephropathy. Patients with evidence of renal impairment or diabetes mellitus should not receive this medicine without close, frequent monitoring of serum electrolytes and renal function.
WARNINGS / PRECAUTIONS Box warnings: Hyperkalemia: See "Concerns related to adverse effects" below.
Concerns related to adverse effects: Fluid/electrolyte loss: Excess amounts can lead to profound diuresis with fluid and electrolyte loss; close medical supervision and dose evaluation are required. Watch for and correct electrolyte disturbances; adjust dose to avoid dehydration. Hyperkalemia: [U.S. Boxed Warning]: Hyperkalemia can occur; patients at risk include those with renal impairment, diabetes, the elderly, and the severely ill. Serum potassium levels must be monitored at frequent intervals especially when dosages are changed or with any illness that may cause renal dysfunction.
Disease-related concerns: Cirrhosis: In cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. Diabetes: Use with extreme caution in patients with diabetes mellitus; monitor closely. Discontinue amiloride 3 days prior to glucose tolerance testing. Metabolic/respiratory acidosis: Use with caution in patients who are at risk for metabolic or respiratory acidosis (eg, cardiopulmonary disease, uncontrolled diabetes).
DRUG INTERACTIONS Amoxicillin's absorption may be reduced; avoid concurrent use or observe for clinical response.
ACE inhibitors or angiotensin receptor antagonists can cause hyperkalemia, especially in patients with renal impairment, potassium-rich diets, or on other drugs causing hyperkalemia; avoid concurrent use or monitor closely.
Cyclosporine or tacrolimus: Risk of hyperkalemia may be increased by concurrent therapy.
NSAIDs: May decrease the effect of diuretics.
Potassium supplements may further increase potassium retention and cause hyperkalemia; avoid concurrent use.
Quinidine and amiloride together may increase risk of malignant arrhythmias; avoid concurrent use.
ETHANOL / NUTRITION / HERB INTERACTIONS — Food: Hyperkalemia may result if amiloride is taken with potassium-containing foods.
PREGNANCY RISK FACTOR — B (show table)
LACTATION — Excretion in breast milk unknown/contraindicated
DIETARY CONSIDERATIONS — Take with food or meals to avoid GI upset. Do not use salt substitutes or low salt milk without checking with your healthcare provider; too much potassium can be as harmful as too little.
PRICING — (data from drugstore.com)Tablets (Amiloride HCl) 5 mg (30): $22.41
Tablets (Midamor) 5 mg (30): $18.99
MONITORING PARAMETERS — I & O, daily weights, blood pressure, serum electrolytes, renal function
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Clinical signs are consistent with dehydration and electrolyte disturbance. Large amounts may result in life-threatening hyperkalemia (>6.5 mEq/L). This can be treated with I.V. glucose (dextrose 25% in water), with rapid-acting insulin, with concurrent I.V. sodium bicarbonate and, if needed, Kayexalate® oral or rectal solutions in sorbitol. Persistent hyperkalemia may require dialysis.
CANADIAN BRAND NAMES — Apo-Amiloride®
INTERNATIONAL BRAND NAMES — Amiclaran (CZ); Amikal (SE); Amilo 5 (KR); Amilozid (HU); Apo-Amiloride (CA); Kaluril (AU, TW); Medamor (FI); Midamor (NZ)
MECHANISM OF ACTION — Interferes with potassium/sodium exchange (active transport) in the distal tubule, cortical collecting tubule, and collecting duct by inhibiting sodium, potassium-ATPase; decreases calcium excretion; increases magnesium loss
PHARMACODYNAMICS / KINETICS Onset of action: 2 hours
Duration: 24 hours
Absorption: ~15% to 25%
Distribution: Vd: 350-380 L
Protein binding: 23%
Metabolism: No active metabolites
Half-life elimination: Normal renal function: 6-9 hours; End-stage renal disease: 8-144 hours
Time to peak, serum: 6-10 hours
Excretion: Urine and feces (equal amounts as unchanged drug)
PATIENT INFORMATION — Report any muscle cramps, weakness, nausea, or dizziness. Use caution operating machinery or performing other tasks requiring alertness.
Amikacin
U.S. BRAND NAMES — Amikin®
PHARMACOLOGIC CATEGORY Antibiotic, Aminoglycoside
DOSING: ADULTS — Individualization is critical because of the low therapeutic index
Note: Use of ideal body weight (IBW) for determining the mg/kg/dose appears to be more accurate than dosing on the basis of total body weight (TBW) In morbid obesity, dosage requirement may best be estimated using a dosing weight of IBW + 0.4 (TBW - IBW) Initial and periodic peak and trough plasma drug levels should be determined, particularly in critically-ill patients with serious infections or in disease states known to significantly alter aminoglycoside pharmacokinetics (eg, cystic fibrosis, burns, or major surgery)
Usual dosage range: I.M., I.V.: 5-7.5 mg/kg/dose every 8 hours Note: Some clinicians suggest a daily dose of 15-20 mg/kg for all patients with normal renal function. This dose is at least as efficacious with similar, if not less, toxicity than conventional dosing.
Hospital-acquired pneumonia (HAP): 20 mg/kg/day with antipseudomonal beta-lactam or carbapenem (American Thoracic Society/ATS guidelines)
Meningitis(Pseudomonas aeruginosa): 5 mg/kg every 8 hours (administered with another bacteriocidal drug)
Mycobacterium fortuitum, M. chelonae, or M. abscessus: 10-15 mg/kg daily for at least 2 weeks with high dose cefoxitin
DOSING: PEDIATRIC — Usual dosage range: Infants and Children: I.M., I.V.: 5-7.5 mg/kg/dose every 8 hours
(For additional information see "Amikacin: Pediatric drug information")
Note: Individualization is critical because of the low therapeutic index
Use of ideal body weight (IBW) for determining the mg/kg/dose appears to be more accurate than dosing on the basis of total body weight (TBW) In morbid obesity, dosage requirement may best be estimated using a dosing weight of IBW + 0.4 (TBW - IBW) Initial and periodic peak and trough plasma drug levels should be determined, particularly in critically-ill patients with serious infections or in disease states known to significantly alter aminoglycoside pharmacokinetics (eg, cystic fibrosis, burns, or major surgery)
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — Individualization is critical because of the low therapeutic index. Some patients may require larger or more frequent doses if serum levels document the need (ie, cystic fibrosis or febrile granulocytopenic patients). Clcr 60 mL/minute: Administer every 8 hours Clcr 40-60 mL/minute: Administer every 12 hours Clcr 20-40 mL/minute: Administer every 24 hours Clcr <20 mL/minute: Loading dose, then monitor levels
Dialyzable (50% to 100%)
Administer dose postdialysis or administer 2/3 normal dose as a supplemental dose postdialysis and follow levels.
Peritoneal dialysis effects: Dose as for Clcr <20 mL/minute: Follow levels.
Continuous arteriovenous or venovenous hemodiafiltration effects: Dose as for Clcr 10-40 mL/minute: Follow levels.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Injection, solution, as sulfate: 50 mg/mL (2 mL, 4 mL); 62.5 mg/mL (8 mL) [DSC]; 250 mg/mL (2 mL, 4 mL) Amikin®: 50 mg/mL (2 mL); 250 mg/mL (2 mL, 4 mL) [contains metabisulfite]
DOSAGE FORMS: CONCISE Injection, solution: 50 mg/mL (2 mL, 4 mL); 250 mg/mL (2 mL, 4 mL) Amikin®: 50 mg/mL (2 mL); 250 mg/mL (2 mL, 4 mL)
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — Administer around-the-clock to promote less variation in peak and trough serum levels. Do not mix with other drugs, administer separately.
I.M.: Administer I.M. injection in large muscle mass.
I.V.: Infuse over 30-60 minutes.
Some penicillins (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate in vitro. This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in vivo, particularly in the setting of profound renal impairment. However, definitive clinical evidence is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.
COMPATIBILITY — Stable in dextran 75 6% in NS, D5LR, D51/4NS, D51/3NS, D51/2NS, D5NS, D10NS, D5W, D10W, D20W, mannitol 20%, 1/4NS, 1/2NS, NS; variable stability (consult detailed reference) in peritoneal dialysis solutions.
Y-site administration: Compatible: Acyclovir, alatrofloxacin, amifostine, amiodarone, amsacrine, aztreonam, cefpirome, cisatracurium, cyclophosphamide, dexamethasone sodium phosphate, diltiazem, docetaxel, enalaprilat, esmolol, etoposide, filgrastim, fluconazole, fludarabine, foscarnet, furosemide, gatifloxacin, gemcitabine, granisetron, idarubicin, IL-2, labetalol, levofloxacin, linezolid, lorazepam, magnesium sulfate, melphalan, midazolam, morphine, ondansetron, paclitaxel, perphenazine, remifentanil, sargramostim, teniposide, thiotepa, vinorelbine, warfarin, zidovudine. Incompatible: Allopurinol, amphotericin B cholesteryl sulfate complex, hetastarch, propofol.
Compatibility in syringe: Compatible: Clindamycin, doxapram. Incompatible: Heparin.
Compatibility when admixed: Compatible: Amobarbital, ascorbic acid injection, bleomycin, calcium chloride, calcium gluconate, cefepime, cefoxitin, chloramphenicol, chlorpheniramine, cimetidine, ciprofloxacin, clindamycin, colistimethate, dimenhydrinate, diphenhydramine, epinephrine, ergonovine, fluconazole, furosemide, hyaluronidase, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, lincomycin, metaraminol, metronidazole, metronidazole with sodium bicarbonate, norepinephrine, pentobarbital, phenobarbital, phytonadione, polymyxin B sulfate, prochlorperazine edisylate, promethazine, ranitidine, sodium bicarbonate, succinylcholine, vancomycin, verapamil. Incompatible: Amphotericin B, ampicillin, cefazolin, chlorothiazide, heparin, phenytoin, thiopental, vitamin B complex with C. Variable (consult detailed reference): Aminophylline, dexamethasone sodium phosphate, oxacillin, penicillin G potassium, potassium chloride.
USE — Treatment of serious infections (bone infections, respiratory tract infections, endocarditis, and septicemia) due to organisms resistant to gentamicin and tobramycin, including Pseudomonas, Proteus, Serratia, and other gram-negative bacilli; documented infection of mycobacterial organisms susceptible to amikacin
ADVERSE REACTIONS SIGNIFICANT 1% to 10%: Central nervous system: Neurotoxicity Otic: Ototoxicity (auditory), ototoxicity (vestibular) Renal: Nephrotoxicity
<1% (Limited to important or life-threatening): Allergic reaction, dyspnea, eosinophilia
CONTRAINDICATIONS — Hypersensitivity to amikacin sulfate or any component of the formulation; cross-sensitivity may exist with other aminoglycosides
WARNINGS / PRECAUTIONS Box Warnings: Nephrotoxicity: See "Concerns related to adverse effects" below. Neuromuscular blockade and respiratory paralysis: See "Concerns related to adverse effects" below. Neurotoxicity: See "Concerns related to adverse effects" below.
Concerns related to adverse effects: Nephrotoxicity: [U.S. Boxed Warning]: May cause nephrotoxicity; usual risk factors include pre-existing renal impairment, concomitant nephrotoxic medications, advanced age and dehydration. Discontinue treatment if signs of nephrotoxicity occur; renal damage is usually reversible. Neuromuscular blockade and respiratory paralysis: [U.S. Boxed Warning]: May cause neuromuscular blockade and respiratory paralysis; especially when given soon after anesthesia or muscle relaxants. Neurotoxicity: [U.S. Boxed Warning]: May cause neurotoxicity; usual risk factors include pre-existing renal impairment, concomitant neuro-/nephrotoxic medications, advanced age and dehydration. Ototoxicity is proportional to the amount of drug given and the duration of treatment. Tinnitus or vertigo may be indications of vestibular injury and impending bilateral irreversible damage. Discontinue treatment if signs of ototoxicity occur. Superinfection: Prolonged use may result in superinfection, including pseudomembranous colitis.
Disease-related concerns: Hearing impairment: Use with caution in patients with pre-existing vertigo, tinnitus, or hearing loss. Hypocalcemia: Use with caution in patients with hypocalcemia. Neuromuscular disorders: Use with caution in patients with neuromuscular disorders, including myasthenia gravis. Renal impairment: Use with caution in patients with pre-existing renal insufficiency; dosage modification required.
Dosage form specific issues: Sulfite: Solution contains sodium metabisulfate; use caution in patients with sulfite allergy.
DRUG INTERACTIONS Decreased effect of aminoglycoside: High concentrations of penicillins and/or cephalosporins (in vitro data)
Increased toxicity of aminoglycoside: Indomethacin I.V., amphotericin, loop diuretics, vancomycin, enflurane, methoxyflurane; increased effect of neuromuscular-blocking agents and polypeptide antibiotics with administration of aminoglycosides
PREGNANCY RISK FACTOR — D (show table)
LACTATION — Enters breast milk/compatible
BREAST-FEEDING CONSIDERATIONS — Amikacin is excreted into breast milk in trace amounts; however, it is not absorbed when taken orally. This limited oral absorption may minimize exposure to the nursing infant. Nondose-related effects could include modification of bowel flora.
Although breast-feeding is not recommended by the manufacturer, based on available data, amikacin is generally considered compatible (low risk to infant) while breast-feeding [human data].
DIETARY CONSIDERATIONS — Sodium content of 1 g: 29.9 mg (1.3 mEq)
MONITORING PARAMETERS — Urinalysis, BUN, serum creatinine, appropriately timed peak and trough concentrations, vital signs, temperature, weight, I & O, hearing parameters
Some penicillin derivatives may accelerate the degradation of aminoglycosidesin vitro. This may be clinically-significant for certain penicillin (ticarcillin, piperacillin, carbenicillin) and aminoglycoside (gentamicin, tobramycin) combination therapy in patients with significant renal impairment. Close monitoring of aminoglycoside levels is warranted.
REFERENCE RANGE Sample size: 0.5-2 mL blood (red top tube) or 0.1-1 mL serum (separated)
Therapeutic levels: Peak: Life-threatening infections: 25-40 mcg/mL Serious infections: 20-25 mcg/mL Urinary tract infections: 15-20 mcg/mL Trough: Serious infections: <8 mcg/mL Life-threatening infections: <8 mcg/mL The American Thoracic Society (ATS) recommends trough levels of <4-5 mcg/mL for patients with hospital-acquired pneumonia.
Toxic concentration: Peak: >40 mcg/mL; Trough: >10 mcg/mL
Timing of serum samples: Draw peak 30 minutes after completion of 30-minute infusion or at 1 hour following initiation of infusion or I.M. injection; draw trough within 30 minutes prior to next dose
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Symptoms include ototoxicity, nephrotoxicity, and neuromuscular toxicity. Treatment of choice, following a single acute overdose, appears to be the maintenance of good urine output of at least 3 mL/kg/hour. Dialysis is of questionable value in the enhancement of aminoglycoside elimination. If required, hemodialysis is preferred over peritoneal dialysis in patients with normal renal function.
CANADIAN BRAND NAMES — Amikacin Sulfate Injection, USP; Amikin®
INTERNATIONAL BRAND NAMES — Akacin (TH); Akicin (TH); Akim (EC); Alostil (ID); Amicacina (ES); Amicasil (IT); Amicin (IN); Amikacin Sulfate Injection, USP (CA); Amikacina (CL); Amikafur (MX); Amikan (IT); Amikayect (MX); Amikin (AU, BF, BG, BJ, BR, CA, CH, CI, CO, CZ, EC, EE, ET, GB, GH, GM, GN, HK, HU, ID, IE, KE, KR, LR, MA, ML, MR, MU, MW, MX, MY, NE, NG, PE, PH, PK, PL, SC, SD, SG, SL, SN, TH, TW, TZ, UG, ZA, ZM, ZW); Amiklin (FR); Amikozit (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Amiktam (KR); Amukin (BE, NL); Biklin (AR, AT, DE, DK, FI, PH, SE, VE); Biodacyna (PL); Biokacin (PY); Briclin (UY); Briklin (GR); Chemacin (IT); Cidacid (PH); Cinmik (PH); Gamikal (MX); Glukamin (EC); Kacinth-A (ZA); Kamin (PH); Kanbine (ES); Kormakin (PH); Lanomycin (GR); Likacin (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Lukadin (IT); Miacin (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Nica (PH); Novamin (BR); Orlobin (GR); Pierami (TW); Riklinak (AR); Savox (TW); Selaxa (GR); Selemycin (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, MY, OM, QA, SA, SY, YE); Sikacin (TW); Tybikin (TH); Yectamid (MX)
MECHANISM OF ACTION — Inhibits protein synthesis in susceptible bacteria by binding to 30S ribosomal subunits
PHARMACODYNAMICS / KINETICS Absorption: I.M.: Rapid Oral: Poorly absorbed
Distribution: Primarily into extracellular fluid (highly hydrophilic); penetrates blood-brain barrier when meninges inflamed Relative diffusion of antimicrobial agents from blood into CSF: Good only with inflammation (exceeds usual MICs) CSF:blood level ratio: Normal meninges: 10% to 20%; Inflamed meninges: 15% to 24%
Protein-binding: 0% to 11%
Half-life elimination (renal function and age dependent): Infants: Low birth weight (1-3 days): 7-9 hours; Full-term >7 days: 4-5 hours Children: 1.6-2.5 hours Adults: Normal renal function: 1.4-2.3 hours; Anuria/end-stage renal disease: 28-86 hours
Time to peak, serum: I.M.: 45-120 minutes
Excretion: Urine (94% to 98%)
PATIENT INFORMATION — Report loss of hearing, ringing or roaring in the ears, or feeling of fullness in head.
PHARMACOLOGIC CATEGORY Antibiotic, Aminoglycoside
DOSING: ADULTS — Individualization is critical because of the low therapeutic index
Note: Use of ideal body weight (IBW) for determining the mg/kg/dose appears to be more accurate than dosing on the basis of total body weight (TBW) In morbid obesity, dosage requirement may best be estimated using a dosing weight of IBW + 0.4 (TBW - IBW) Initial and periodic peak and trough plasma drug levels should be determined, particularly in critically-ill patients with serious infections or in disease states known to significantly alter aminoglycoside pharmacokinetics (eg, cystic fibrosis, burns, or major surgery)
Usual dosage range: I.M., I.V.: 5-7.5 mg/kg/dose every 8 hours Note: Some clinicians suggest a daily dose of 15-20 mg/kg for all patients with normal renal function. This dose is at least as efficacious with similar, if not less, toxicity than conventional dosing.
Hospital-acquired pneumonia (HAP): 20 mg/kg/day with antipseudomonal beta-lactam or carbapenem (American Thoracic Society/ATS guidelines)
Meningitis(Pseudomonas aeruginosa): 5 mg/kg every 8 hours (administered with another bacteriocidal drug)
Mycobacterium fortuitum, M. chelonae, or M. abscessus: 10-15 mg/kg daily for at least 2 weeks with high dose cefoxitin
DOSING: PEDIATRIC — Usual dosage range: Infants and Children: I.M., I.V.: 5-7.5 mg/kg/dose every 8 hours
(For additional information see "Amikacin: Pediatric drug information")
Note: Individualization is critical because of the low therapeutic index
Use of ideal body weight (IBW) for determining the mg/kg/dose appears to be more accurate than dosing on the basis of total body weight (TBW) In morbid obesity, dosage requirement may best be estimated using a dosing weight of IBW + 0.4 (TBW - IBW) Initial and periodic peak and trough plasma drug levels should be determined, particularly in critically-ill patients with serious infections or in disease states known to significantly alter aminoglycoside pharmacokinetics (eg, cystic fibrosis, burns, or major surgery)
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — Individualization is critical because of the low therapeutic index. Some patients may require larger or more frequent doses if serum levels document the need (ie, cystic fibrosis or febrile granulocytopenic patients). Clcr 60 mL/minute: Administer every 8 hours Clcr 40-60 mL/minute: Administer every 12 hours Clcr 20-40 mL/minute: Administer every 24 hours Clcr <20 mL/minute: Loading dose, then monitor levels
Dialyzable (50% to 100%)
Administer dose postdialysis or administer 2/3 normal dose as a supplemental dose postdialysis and follow levels.
Peritoneal dialysis effects: Dose as for Clcr <20 mL/minute: Follow levels.
Continuous arteriovenous or venovenous hemodiafiltration effects: Dose as for Clcr 10-40 mL/minute: Follow levels.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Injection, solution, as sulfate: 50 mg/mL (2 mL, 4 mL); 62.5 mg/mL (8 mL) [DSC]; 250 mg/mL (2 mL, 4 mL) Amikin®: 50 mg/mL (2 mL); 250 mg/mL (2 mL, 4 mL) [contains metabisulfite]
DOSAGE FORMS: CONCISE Injection, solution: 50 mg/mL (2 mL, 4 mL); 250 mg/mL (2 mL, 4 mL) Amikin®: 50 mg/mL (2 mL); 250 mg/mL (2 mL, 4 mL)
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — Administer around-the-clock to promote less variation in peak and trough serum levels. Do not mix with other drugs, administer separately.
I.M.: Administer I.M. injection in large muscle mass.
I.V.: Infuse over 30-60 minutes.
Some penicillins (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate in vitro. This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in vivo, particularly in the setting of profound renal impairment. However, definitive clinical evidence is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.
COMPATIBILITY — Stable in dextran 75 6% in NS, D5LR, D51/4NS, D51/3NS, D51/2NS, D5NS, D10NS, D5W, D10W, D20W, mannitol 20%, 1/4NS, 1/2NS, NS; variable stability (consult detailed reference) in peritoneal dialysis solutions.
Y-site administration: Compatible: Acyclovir, alatrofloxacin, amifostine, amiodarone, amsacrine, aztreonam, cefpirome, cisatracurium, cyclophosphamide, dexamethasone sodium phosphate, diltiazem, docetaxel, enalaprilat, esmolol, etoposide, filgrastim, fluconazole, fludarabine, foscarnet, furosemide, gatifloxacin, gemcitabine, granisetron, idarubicin, IL-2, labetalol, levofloxacin, linezolid, lorazepam, magnesium sulfate, melphalan, midazolam, morphine, ondansetron, paclitaxel, perphenazine, remifentanil, sargramostim, teniposide, thiotepa, vinorelbine, warfarin, zidovudine. Incompatible: Allopurinol, amphotericin B cholesteryl sulfate complex, hetastarch, propofol.
Compatibility in syringe: Compatible: Clindamycin, doxapram. Incompatible: Heparin.
Compatibility when admixed: Compatible: Amobarbital, ascorbic acid injection, bleomycin, calcium chloride, calcium gluconate, cefepime, cefoxitin, chloramphenicol, chlorpheniramine, cimetidine, ciprofloxacin, clindamycin, colistimethate, dimenhydrinate, diphenhydramine, epinephrine, ergonovine, fluconazole, furosemide, hyaluronidase, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, lincomycin, metaraminol, metronidazole, metronidazole with sodium bicarbonate, norepinephrine, pentobarbital, phenobarbital, phytonadione, polymyxin B sulfate, prochlorperazine edisylate, promethazine, ranitidine, sodium bicarbonate, succinylcholine, vancomycin, verapamil. Incompatible: Amphotericin B, ampicillin, cefazolin, chlorothiazide, heparin, phenytoin, thiopental, vitamin B complex with C. Variable (consult detailed reference): Aminophylline, dexamethasone sodium phosphate, oxacillin, penicillin G potassium, potassium chloride.
USE — Treatment of serious infections (bone infections, respiratory tract infections, endocarditis, and septicemia) due to organisms resistant to gentamicin and tobramycin, including Pseudomonas, Proteus, Serratia, and other gram-negative bacilli; documented infection of mycobacterial organisms susceptible to amikacin
ADVERSE REACTIONS SIGNIFICANT 1% to 10%: Central nervous system: Neurotoxicity Otic: Ototoxicity (auditory), ototoxicity (vestibular) Renal: Nephrotoxicity
<1% (Limited to important or life-threatening): Allergic reaction, dyspnea, eosinophilia
CONTRAINDICATIONS — Hypersensitivity to amikacin sulfate or any component of the formulation; cross-sensitivity may exist with other aminoglycosides
WARNINGS / PRECAUTIONS Box Warnings: Nephrotoxicity: See "Concerns related to adverse effects" below. Neuromuscular blockade and respiratory paralysis: See "Concerns related to adverse effects" below. Neurotoxicity: See "Concerns related to adverse effects" below.
Concerns related to adverse effects: Nephrotoxicity: [U.S. Boxed Warning]: May cause nephrotoxicity; usual risk factors include pre-existing renal impairment, concomitant nephrotoxic medications, advanced age and dehydration. Discontinue treatment if signs of nephrotoxicity occur; renal damage is usually reversible. Neuromuscular blockade and respiratory paralysis: [U.S. Boxed Warning]: May cause neuromuscular blockade and respiratory paralysis; especially when given soon after anesthesia or muscle relaxants. Neurotoxicity: [U.S. Boxed Warning]: May cause neurotoxicity; usual risk factors include pre-existing renal impairment, concomitant neuro-/nephrotoxic medications, advanced age and dehydration. Ototoxicity is proportional to the amount of drug given and the duration of treatment. Tinnitus or vertigo may be indications of vestibular injury and impending bilateral irreversible damage. Discontinue treatment if signs of ototoxicity occur. Superinfection: Prolonged use may result in superinfection, including pseudomembranous colitis.
Disease-related concerns: Hearing impairment: Use with caution in patients with pre-existing vertigo, tinnitus, or hearing loss. Hypocalcemia: Use with caution in patients with hypocalcemia. Neuromuscular disorders: Use with caution in patients with neuromuscular disorders, including myasthenia gravis. Renal impairment: Use with caution in patients with pre-existing renal insufficiency; dosage modification required.
Dosage form specific issues: Sulfite: Solution contains sodium metabisulfate; use caution in patients with sulfite allergy.
DRUG INTERACTIONS Decreased effect of aminoglycoside: High concentrations of penicillins and/or cephalosporins (in vitro data)
Increased toxicity of aminoglycoside: Indomethacin I.V., amphotericin, loop diuretics, vancomycin, enflurane, methoxyflurane; increased effect of neuromuscular-blocking agents and polypeptide antibiotics with administration of aminoglycosides
PREGNANCY RISK FACTOR — D (show table)
LACTATION — Enters breast milk/compatible
BREAST-FEEDING CONSIDERATIONS — Amikacin is excreted into breast milk in trace amounts; however, it is not absorbed when taken orally. This limited oral absorption may minimize exposure to the nursing infant. Nondose-related effects could include modification of bowel flora.
Although breast-feeding is not recommended by the manufacturer, based on available data, amikacin is generally considered compatible (low risk to infant) while breast-feeding [human data].
DIETARY CONSIDERATIONS — Sodium content of 1 g: 29.9 mg (1.3 mEq)
MONITORING PARAMETERS — Urinalysis, BUN, serum creatinine, appropriately timed peak and trough concentrations, vital signs, temperature, weight, I & O, hearing parameters
Some penicillin derivatives may accelerate the degradation of aminoglycosidesin vitro. This may be clinically-significant for certain penicillin (ticarcillin, piperacillin, carbenicillin) and aminoglycoside (gentamicin, tobramycin) combination therapy in patients with significant renal impairment. Close monitoring of aminoglycoside levels is warranted.
REFERENCE RANGE Sample size: 0.5-2 mL blood (red top tube) or 0.1-1 mL serum (separated)
Therapeutic levels: Peak: Life-threatening infections: 25-40 mcg/mL Serious infections: 20-25 mcg/mL Urinary tract infections: 15-20 mcg/mL Trough: Serious infections: <8 mcg/mL Life-threatening infections: <8 mcg/mL The American Thoracic Society (ATS) recommends trough levels of <4-5 mcg/mL for patients with hospital-acquired pneumonia.
Toxic concentration: Peak: >40 mcg/mL; Trough: >10 mcg/mL
Timing of serum samples: Draw peak 30 minutes after completion of 30-minute infusion or at 1 hour following initiation of infusion or I.M. injection; draw trough within 30 minutes prior to next dose
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Symptoms include ototoxicity, nephrotoxicity, and neuromuscular toxicity. Treatment of choice, following a single acute overdose, appears to be the maintenance of good urine output of at least 3 mL/kg/hour. Dialysis is of questionable value in the enhancement of aminoglycoside elimination. If required, hemodialysis is preferred over peritoneal dialysis in patients with normal renal function.
CANADIAN BRAND NAMES — Amikacin Sulfate Injection, USP; Amikin®
INTERNATIONAL BRAND NAMES — Akacin (TH); Akicin (TH); Akim (EC); Alostil (ID); Amicacina (ES); Amicasil (IT); Amicin (IN); Amikacin Sulfate Injection, USP (CA); Amikacina (CL); Amikafur (MX); Amikan (IT); Amikayect (MX); Amikin (AU, BF, BG, BJ, BR, CA, CH, CI, CO, CZ, EC, EE, ET, GB, GH, GM, GN, HK, HU, ID, IE, KE, KR, LR, MA, ML, MR, MU, MW, MX, MY, NE, NG, PE, PH, PK, PL, SC, SD, SG, SL, SN, TH, TW, TZ, UG, ZA, ZM, ZW); Amiklin (FR); Amikozit (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Amiktam (KR); Amukin (BE, NL); Biklin (AR, AT, DE, DK, FI, PH, SE, VE); Biodacyna (PL); Biokacin (PY); Briclin (UY); Briklin (GR); Chemacin (IT); Cidacid (PH); Cinmik (PH); Gamikal (MX); Glukamin (EC); Kacinth-A (ZA); Kamin (PH); Kanbine (ES); Kormakin (PH); Lanomycin (GR); Likacin (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Lukadin (IT); Miacin (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Nica (PH); Novamin (BR); Orlobin (GR); Pierami (TW); Riklinak (AR); Savox (TW); Selaxa (GR); Selemycin (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, MY, OM, QA, SA, SY, YE); Sikacin (TW); Tybikin (TH); Yectamid (MX)
MECHANISM OF ACTION — Inhibits protein synthesis in susceptible bacteria by binding to 30S ribosomal subunits
PHARMACODYNAMICS / KINETICS Absorption: I.M.: Rapid Oral: Poorly absorbed
Distribution: Primarily into extracellular fluid (highly hydrophilic); penetrates blood-brain barrier when meninges inflamed Relative diffusion of antimicrobial agents from blood into CSF: Good only with inflammation (exceeds usual MICs) CSF:blood level ratio: Normal meninges: 10% to 20%; Inflamed meninges: 15% to 24%
Protein-binding: 0% to 11%
Half-life elimination (renal function and age dependent): Infants: Low birth weight (1-3 days): 7-9 hours; Full-term >7 days: 4-5 hours Children: 1.6-2.5 hours Adults: Normal renal function: 1.4-2.3 hours; Anuria/end-stage renal disease: 28-86 hours
Time to peak, serum: I.M.: 45-120 minutes
Excretion: Urine (94% to 98%)
PATIENT INFORMATION — Report loss of hearing, ringing or roaring in the ears, or feeling of fullness in head.
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