Acetaminophen and tramadol

Acetaminophen and tramadol: Drug information
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(For additional information see “Acetaminophen and tramadol: Patient drug information”)

Special Alerts
Acetaminophen: Change in Maximum Content of Prescription Products and Labeling Changes January 2011
The Food and Drug Administration (FDA) is asking manufacturers to limit the strength of acetaminophen in prescription products to 325 mg per dosage unit. Drug manufacturers will have until January 14, 2014 to comply with the FDA’s request. The dosing instructions of prescription acetaminophen products will not change. For example, the instructions of 1-2 tablets every 4-6 hours for a combination product of acetaminophen 500 mg with an opioid can still be used for a combination product of acetaminophen 325 mg with an opioid.

The FDA is also notifying healthcare professionals of labeling changes for all prescription products that contain acetaminophen. A Boxed Warning will be required on all prescription acetaminophen products to describe the potential risk of severe liver injury. Additionally, the FDA has asked manufacturers to add a Warning regarding the potential for allergic reactions, including anaphylaxis.

Healthcare professionals should advise patients:

– not to exceed 4 g/day of acetaminophen

– not to take multiple acetaminophen-containing products (including over-the-counter products)

– not to consume alcohol while taking acetaminophen-containing products

– that severe liver injury and cases of hypersensitivity reactions (including anaphylaxis) have occurred with the use of acetaminophen

– to report taking more acetaminophen than directed

– to report any adverse events that may have occurred with the use of acetaminophen

Further information may be found at: file://www.fda.gov/Drugs/DrugSafety/ucm239821.htm

ALERT: U.S. Boxed Warning The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Brand Names: U.S. Ultracet®
Brand Names: Canada Apo-Tramadol/Acet®; Tramacet
Pharmacologic Category Analgesic, Miscellaneous; Analgesic, Opioid
Dosing: Adult 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: Geriatric 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: U.S. 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

Generic Equivalent Available: U.S. Yes
Administration May be administered with or without food.
Use Short-term (≤5 days) management of acute pain
Medication Safety Issues
Sound-alike/look-alike issues:
Ultracet® may be confused with Ultane®, Ultram®

Other safety concerns:
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.

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
Note: Based on Canadian product labeling: Tramadol is contraindicated during or within 14 days following MAO inhibitor therapy

Warnings/Precautions
Boxed warnings:

• Hepatotoxicity: See “Concerns related to adverse effects” below.

Concerns related to adverse effects:

• Anaphylactoid reactions: Rare but serious anaphylactoid reactions (including fatalities) often following initial dosing have been reported. Pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome also have been reported with use. Previous anaphylactoid reactions to opioids may increase risks for similar reactions to tramadol.

• 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: [U.S. Boxed Warning]: Acetaminophen may cause severe hepatotoxicity, potentially requiring liver transplant or resulting in death; hepatotoxicity is usually associated with excessive acetaminophen intake (>4 g/day). Risk is increased with alcohol use, pre-existing liver disease, and intake of more than one source of acetaminophen-containing medications. Chronic daily dosing in adults has also 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), other opioids, tricyclic antidepressants or other cyclic compounds (including cyclobenzaprine, promethazine), neuroleptics, MAO inhibitors, drugs which may lower seizure threshold, or drugs which impair metabolism of tramadol (ie, CYP2D6 and 3A4 inhibitors). 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.

• Suicide risk: Avoid use in patients who are suicidal; use with caution in patients taking tranquilizers and/or antidepressants, or those with an emotional disturbance including depression.

Concurrent drug therapy issues:

• CNS depressants: Use with caution and reduce dosage when administering to patients receiving other CNS depressants; may cause CNS depression and/or respiratory depression.

• Serotonin syndrome: Avoid use, if possible, with serotonergic agents such as TCAs, MAO inhibitors (use with extreme caution; contraindicated in Canadian product labeling), triptans, venlafaxine, trazodone, lithium, sibutramine, meperidine, dextromethorphan, St John’s wort, SNRIs, and SSRIs; use caution with drugs which impair metabolism of tramadol (ie, CYP2D6 and 3A4 inhibitors); concomitant use may increase the risk of serotonin syndrome.

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.

Other warnings/precautions:

• Abuse/misuse/diversion: Healthcare provider should be alert to problems of abuse, misuse, and diversion.

• Dosage limit: Limit acetaminophen dose from all sources (prescription and OTC) 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
(For additional information: Launch Lexi-Interact™ Drug Interactions Program )
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification

Ammonium Chloride: May increase the excretion of Analgesics (Opioid). Risk C: Monitor therapy

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). 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

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). 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. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). 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

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Cyproterone: May decrease the serum concentration of CYP2E1 Substrates. Risk C: Monitor therapy

Dasatinib: Acetaminophen may enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Imatinib: Acetaminophen may enhance the hepatotoxic effect of Imatinib. 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. TraMADol may enhance the serotonergic effect of MAO Inhibitors. Management: Consider alternatives to combined treatment with tramadol and monoamine oxidase inhibitors due to an increased risk of serotonin syndrome and seizures. Avoid transdermal selegiline. Risk D: Consider therapy modification

Metyrapone: May increase the serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Risk C: Monitor therapy

Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of Analgesics (Opioid). Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk D: Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

Probenecid: May increase the serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Risk D: Consider therapy modification

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

Selective Serotonin Reuptake Inhibitors: Analgesics (Opioid) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk C: Monitor therapy

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

SORAfenib: Acetaminophen may enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Risk C: Monitor therapy

Thiazide Diuretics: Analgesics (Opioid) may enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

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

Vitamin K Antagonists (eg, warfarin): TraMADol may enhance the anticoagulant effect of Vitamin K Antagonists. 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.
Pricing: U.S. (www.drugstore.com)
Tablets (Tramadol-Acetaminophen)

37.5-325 mg (30): $27.99

Tablets (Ultracet)

37.5-325 mg (30): $63.99

Monitoring Parameters Pain relief, respiratory rate, blood pressure, and pulse; signs of tolerance, abuse, or suicidal ideation
International Brand Names Acetram-Semi (KP); Analgan Tram (EC); Beartra (KP); Calmex (PY); Cetamadole (KP); Cetodol (PH); Cetra (PH); Dolantag (EC); Dolcet (PH); Doltramcet (KP); Duodyne (KP); Fastfen (CO); Ixprim (FR); Metagesic (EC); Neutracet (KP); Rapicet (KP); Traldiar (GT, HN, PA, SV); Tralex (CO); Tramacet (BB, BM, BS, BZ, CO, DO, GB, GY, IE, JM, MX, NL, PR, SR, TT); Tramiphen (KP); Ultracet (BR, CL, HK, ID, KP, MY, SG, TH, TW, VE); Ultramac Semi (KP); Zafin (EC); Zaldiar (AT, BE, CH, CN, CO, CR, CZ, DE, DO, EE, ES, FR, GT, HN, ID, IL, MX, NI, PA, PE, PL, RU, 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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