MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Ultracet® may be confused with Ultane®, Ultram®
Duplicate therapy issues: This product contains acetaminophen, which may be a component of other combination products. Do not exceed the maximum recommended daily dose of acetaminophen.
U.S. BRAND NAMES — Ultracet®
PHARMACOLOGIC CATEGORY
Analgesic, Miscellaneous
Analgesic, Opioid
DOSING: ADULTS — Acute pain: Oral: Two tablets every 4-6 hours as needed for pain relief (maximum: 8 tablets/day); treatment should not exceed 5 days
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — Clcr <30 mL/minute: Maximum of 2 tablets every 12 hours. Treatment should not exceed 5 days.
DOSING: HEPATIC IMPAIRMENT — Use is not recommended.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: Acetaminophen 325 mg and tramadol hydrochloride 37.5 mg
Ultracet®: Acetaminophen 325 mg and tramadol hydrochloride 37.5 mg
DOSAGE FORMS: CONCISE
Tablet: Acetaminophen 325 mg and tramadol 37.5 mg
Ultracet®: Acetaminophen 325 mg and tramadol 37.5 mg
GENERIC EQUIVALENT AVAILABLE — Yes
USE — Short-term (≤ 5 days) management of acute pain
ADVERSE REACTIONS SIGNIFICANT
1% to 10%:
Central nervous system: Somnolence (6%), dizziness (3%), insomnia (2%), anxiety, confusion, euphoria, fatigue, headache, nervousness, tremor
Dermatologic: Pruritus (2%), rash
Endocrine & metabolic: Hot flashes
Gastrointestinal: Constipation (6%), anorexia (3%), diarrhea (3%), nausea (3%), dry mouth (2%), abdominal pain, dyspepsia, flatulence, vomiting
Genitourinary: Prostatic disorder (2%)
Neuromuscular & skeletal: Weakness
Miscellaneous: Diaphoresis increased (4%)
<1% (Limited to important or life-threatening): Allergic reactions, amnesia, anaphylactoid reactions, anaphylaxis, arrhythmia, coma, depersonalization, drug abuse, dysphagia, dyspnea, emotional lability, hallucination, hepatitis, hypertonia, impotence, liver failure, migraine, muscle contractions (involuntary), oliguria, paresthesia, paroniria, pulmonary edema, rigors, seizure, serotonin syndrome, shivering, Stevens-Johnson syndrome, suicidal tendency, stupor, syncope, tinnitus, tongue edema, toxic epidermal necrolysis, urinary retention, urticaria, vertigo
A withdrawal syndrome may occur with abrupt discontinuation; includes anxiety, diarrhea, hallucinations (rare), nausea, pain, piloerection, rigors, sweating, and tremor. Uncommon discontinuation symptoms may include severe anxiety, panic attacks, or paresthesia.
CONTRAINDICATIONS — Hypersensitivity to acetaminophen, tramadol, opioids, or any component of the formulation; opioid-dependent patients; acute intoxication with ethanol, hypnotics, narcotics, centrally-acting analgesics, opioids, or psychotropic drugs; hepatic dysfunction
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Hepatotoxicity: May cause severe hepatic toxicity on acute overdose; in addition, chronic daily dosing in adults has resulted in liver damage in some patients. Seizures: Even when taken within the recommended dosage seizures may occur; risk is increased in patients receiving serotonin reuptake inhibitors (SSRIs or anorectics), tricyclic antidepressants, other cyclic compounds (including cyclobenzaprine, promethazine), neuroleptics, MAO inhibitors, or drugs which may lower seizure threshold. Patients with a history of seizures, or with a risk of seizures (head trauma, metabolic disorders, CNS infection, malignancy, or during alcohol/drug withdrawal) are also at increased risk.
Disease-related concerns: Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions. Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥ 3 alcoholic drinks/day may increase the risk of liver damage. G6PD deficiency: Use with caution in patients with known G6PD deficiency. Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur. Renal impairment: Use tramadol with caution and reduce dosage in patients with renal impairment. Respiratory disease: Patients with chronic respiratory disorders may be at greater risk of adverse events.
Concurrent drug therapy issues: CNS depressants: Use with caution and reduce dosage when administering to patients receiving other CNS depressants. MAO inhibitors: Should be used only with extreme caution in patients receiving MAO inhibitors.
Special populations: Debilitated patients: Use with caution in debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Elderly: Use with caution in the elderly; may be more sensitive to adverse effects. Decrease initial dose. Pediatrics: Safety and efficacy have not been established in children.
Other warnings/precautions: Dosage limit: Limit acetaminophen dose to <4 g/day. Withdrawal: Tolerance or drug dependence may result from extended use (withdrawal symptoms have been reported); abrupt discontinuation should be avoided. Tapering of dose at the time of discontinuation limits the risk of withdrawal symptoms.
METABOLISM / TRANSPORT EFFECTS
Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)
Tramadol: Substrate of CYP2D6 (major), 3A4 (major)
DRUG INTERACTIONS
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Anticonvulsants (Hydantoin): May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy
Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy
CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy
Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CYP2D6 Inhibitors (Moderate): May diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Imatinib: May increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification
Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy
MAO Inhibitors: TraMADol may enhance the neuroexcitatory and/or seizure-potentiating effect of MAO Inhibitors. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce dosage of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the neuroexcitatory and/or seizure-potentiating effect of TraMADol. TraMADol may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk D: Consider therapy modification
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination
Tricyclic Antidepressants: May enhance the neuroexcitatory and/or seizure-potentiating effect of TraMADol. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy
ETHANOL / NUTRITION / HERB INTERACTIONS
Ethanol: Avoid ethanol (increased liver toxicity with concomitant use).
Food: May delay time to peak plasma levels, however, the extent of absorption is not affected.
Herb/Nutraceutical:
Acetaminophen: Avoid St John's wort (may decrease acetaminophen levels).
Tramadol: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
PREGNANCY RISK FACTOR — C (show table)
PREGNANCY IMPLICATIONS — Tramadol has been shown to cross the placenta. Postmarketing reports following tramadol use during pregnancy include neonatal seizures, withdrawal syndrome, fetal death, and stillbirth. Not recommended for use during labor and delivery.
LACTATION — Tramadol: Enters breast milk/contraindicated
BREAST-FEEDING CONSIDERATIONS — Not recommended for postdelivery analgesia in nursing mothers.
DIETARY CONSIDERATIONS — May be taken with or without food. Avoid use of ethanol and ethanol-containing products.
PRICING — (data from drugstore.com)
Tablets (Tramadol-Acetaminophen)
37.5-325 mg (30): $27.99
Tablets (Ultracet)
37.5-325 mg (30): $54.32
MONITORING PARAMETERS — Pain relief, respiratory rate, blood pressure, and pulse; signs of tolerance or abuse
CANADIAN BRAND NAMES — Tramacet
INTERNATIONAL BRAND NAMES — Calmex (PY); Dolcet (PH); Ixprim (FR); Tramacet (BB, BM, BS, BZ, DO, GB, GY, IE, JM, MX, NL, SR, TT); Ultracet (BR, HK, ID, KP, MY, SG, TH, TW, VE); Zaldiar (BE, CH, CN, CO, CR, CZ, DE, DO, EE, ES, FR, GT, HN, ID, IL, MX, NI, NL, PA, PE, SV, VE); Zultracet (PK)
MECHANISM OF ACTION
Based on acetaminophen component: Inhibits the synthesis of prostaglandins in the central nervous system and peripherally blocks pain impulse generation; produces antipyresis from inhibition of hypothalamic heat-regulating center
Based on tramadol component: Binds to µ-opiate receptors in the CNS causing inhibition of ascending pain pathways, altering the perception of and response to pain; also inhibits the reuptake of norepinephrine and serotonin, which also modifies the ascending pain pathway
PHARMACODYNAMICS / KINETICS — See individual agents.
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