Acetaminophen and tramadol: Drug information

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(For additional information see "Acetaminophen and tramadol: Patient drug information")
U.S. BRAND NAMES — Ultracet™
PHARMACOLOGIC CATEGORY Analgesic, MiscellaneousAnalgesic, Nonopioid
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
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.
DRUG INTERACTIONS Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)
Tramadol: Substrate of CYP2D6 (major), 3A4 (minor)
Amphetamines: May increase the risk of seizures with tramadol.
Anesthetic agents: May increase risk of CNS and respiratory depression; use together with caution and in reduced dosage.
Barbiturates: Barbiturates may increase the hepatotoxic effects of acetaminophen; in addition, acetaminophen levels may be lowered.
Carbamazepine: Carbamazepine decreases half-life of tramadol by 33% to 50%; also have increased risk of seizures; in addition, carbamazepine may increase the hepatotoxic effects and lower serum levels of acetaminophen; concomitant use is not recommended.
CYP2D6 inhibitors: May decrease the effects of tramadol. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.
Digoxin: Rare reports of digoxin toxicity with concomitant tramadol use.
Hydantoin anticonvulsants: Phenytoin may increase the hepatotoxic effects of acetaminophen; in addition, acetaminophen levels may be lowered.
MAO inhibitors: May increase the risk of seizures. Use extreme caution.
Naloxone: May increase the risk of seizures (if administered in tramadol overdose).
Neuroleptic agents: May increase the risk of tramadol-associated seizures and may have additive CNS depressant effects.
Narcotics: May increase risk of CNS and respiratory depression; use together with caution and in reduced dosage.
Opioids: May increase the risk of seizures, and may have additive CNS depressant effects. Use together with caution and in reduced dosage.
Phenothiazines: May increase risk of CNS and respiratory depression; use together with caution and in reduced dosage.
Rifampin: Rifampin may increase the clearance of acetaminophen.
Quinidine: May increase the tramadol serum concentrations by inhibiting CYP metabolism.
SSRIs: May increase the risk of seizures with tramadol by inhibiting CYP metabolism (citalopram, fluoxetine, paroxetine, sertraline).
Sulfinpyrazone: Sulfinpyrazone may increase the hepatotoxic effects of acetaminophen; in addition, acetaminophen levels may be lowered.
Tricyclic antidepressants: May increase the risk of seizures.
Warfarin: Acetaminophen and tramadol may lead to an elevation of prothrombin times; monitor.
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): $27.67
Tablets (Ultracet) 37.5-325 mg (30): $35.51
MONITORING PARAMETERS — Pain relief, respiratory rate, blood pressure, and pulse; signs of tolerance or abuse
CANADIAN BRAND NAMES — Tramacet
INTERNATIONAL BRAND NAMES — Dolcet (PH); Ixprim (FR); Tramacet (CA, CR, DO, GB, GT, HN, IE, MX, NI, PA, SV); Ultracet (HK, KR, TH); Zaldiar (FR, MX)
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.