Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 09 February 2017

Indication(s)

INDICATIONS & USAGE Tramadol hydrochloride and acetaminophen tablets, 37.5 mg/325 mg, are indicated for the short-term (5 days or less) management of acute pain.

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Advisory information

contraindications

CONTRAINDICATIONS Tramadol hydrochloride and acetaminophen tablets should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, acetaminophen, any other component of this product or opioids.

Tramadol hydrochloride and acetaminophen tablets are contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs.

Tramadol hydrochloride and acetaminophen tablets may worsen central nervous system and respiratory depression in these patients.

Special warnings and precautions
PRECAUTIONS General The recommended dose of tramadol hydrochloride and acetaminophen tablets should not be exceeded. Do not coadminister tramadol hydrochloride and acetaminophen tablets with other tramadol or acetaminophen-containing products. (SeeWARNINGS: Use With Other Acetaminophen-containing ProductsandRisk of Overdosage.)
Adverse reactions

ADVERSE REACTIONS Table 2 reports the incidence rate of treatment-emergent adverse events over five days of tramadol hydrochloride and acetaminophen tablet use in clinical trials (subjects took an average of at least 6 tablets per day).

Table 2: Incidence of Treatment-Emergent Adverse Events (2 %) * Number of males = 62Body System Preferred TermTramadol Hydrochloride and Acetaminophen Tablets (N=142) %Gastrointestinal System DisorderConstipation6Diarrhea3Nausea3Dry Mouth2Psychiatric DisordersSomnolence6Anorexia3Insomnia2Central & Peripheral Nervous SystemDizziness3Skin and AppendagesSweating Increased4Pruritus2Reproductive Disorders, Male * Prostatic Disorder2 Incidence At Least 1 %, Causal Relationship At Least Possible Or Greater The following lists adverse reactions that occurred with an incidence of at least 1 % in single-dose or repeated-dose clinical trials of tramadol hydrochloride and acetaminophen tablets.

Body as a Whole:Asthenia, fatigue, hot flushes.

Central and Peripheral

Nervous System:Dizziness, headache, tremor.

Gastrointestinal System:Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting.

Psychiatric Disorders:Anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence.

Skin and Appendages:Pruritus, rash, increased sweating.

Selected Adverse Events Occurring At Less Than 1 % The following lists clinically relevant adverse reactions that occurred with an incidence of less than 1 % in tramadol hydrochloride and acetaminophen tablet clinical trials.

Body as a Whole:Chest pain, rigors, syncope, withdrawal syndrome.

Cardiovascular Disorders: Hypertension, aggravated hypertension, hypotension.

Central and Peripheral Nervous System:Ataxia, convulsions, hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paresthesias, stupor, vertigo.

Gastrointestinal System:Dysphagia, melena, tongue edema.

Hearing and Vestibular Disorders:Tinnitus.

Heart

Rate and Rhythm Disorders:Arrhythmia, palpitation, tachycardia.

Liver and Biliary System:Hepatic function abnormal.

Metabolic and Nutritional Disorders:Weight decrease.

Psychiatric Disorders:Amnesia, depersonalization, depression, drug abuse, emotional lability, hallucination, impotence, paroniria, abnormal thinking.

Red Blood Cell Disorders:Anemia.

Respiratory System:Dyspnea.

Urinary System:Albuminuria, micturition disorder, oliguria, urinary retention.

Vision Disorders:Abnormal vision.

Other Clinically Significant Adverse Experiences Previously Reported With Tramadol Hydrochloride Other events which have been reported with the use of tramadol products and for which a causal association has not been determined include: vasodilation, orthostatic hypotension, myocardial ischemia, pulmonary edema, allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson Syndrome/TENS), cognitive dysfunction, difficulty concentrating, depression, suicidal tendency, hepatitis liver failure and gastrointestinal bleeding.

Reported laboratory abnormalities included elevated creatinine and liver function tests.

Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAOIs.

Other Clinically Significant Adverse Experiences Previously Reported With Acetaminophen Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to acetaminophen are rare and generally controlled by discontinuation of the drug and, when necessary, symptomatic treatment.

Usage information

Dosing and administration

DOSAGE & ADMINISTRATION For the short-term (5 days or less) management of acute pain, the recommended dose of tramadol hydrochloride and acetaminophen tablets, 37.5 mg/325 mg, is two tablets every 4 to 6 hours as needed for pain relief up to a maximum of eight tablets per day.

Individualization of Dose In patients with creatinine clearances of less than 30 mL/min, it is recommended that the dosing interval of tramadol hydrochloride and acetaminophen tablets, 37.5 mg/325 mg, be increased not to exceed two tablets every 12 hours.

Dose selection for an elderly patient should be cautious, in view of the potential for greater sensitivity to adverse events.

Use in special populations

USE IN SPECIFIC POPULATIONS Renal The pharmacokinetics of tramadol hydrochloride and acetaminophen tablets in patients with renal impairment have not been studied.

Based on studies using tramadol alone, excretion of tramadol and metabolite M1 is reduced in patients with creatinine clearance of less than 30 mL/min, adjustment of dosing regimen in this patient population is recommended.

(SeeDOSAGE AND ADMINISTRATION.)

The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7 % of the administered dose based on studies using tramadol alone.

Hepatic The pharmacokinetics and tolerability of tramadol hydrochloride and acetaminophen tablets in patients with impaired hepatic function has not been studied.

Since tramadol and acetaminophen are both extensively metabolized by the liver, the use of tramadol hydrochloride and acetaminophen tablets in patients with hepatic impairment is not recommended (seePRECAUTIONSandDOSAGE AND ADMINISTRATION).

Geriatric A population pharmacokinetic analysis of data obtained from a clinical trial in patients with chronic pain treated with tramadol hydrochloride and acetaminophen tablets which included 55 patients between 65 and 75 years of age and 19 patients over 75 years of age, showed no significant changes in pharmacokinetics of tramadol and acetaminophen in elderly patients with normal renal and hepatic function (seePRECAUTIONS: Geriatric Use).

Gender Tramadol clearance was 20 % higher in female subjects compared to males on four phase I studies of tramadol hydrochloride and acetaminophen tablets in 50 male and 34 female healthy subjects.

The clinical significance of this difference is unknown.

Pediatric Pharmacokinetics of tramadol hydrochloride and acetaminophen tablets have not been studied in pediatric patients below 16 years of age.

Pregnancy and lactation

NURSING MOTHERS Tramadol hydrochloride and acetaminophen tablets are not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.

Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 mcg of tramadol (0.1 % of the maternal dose) and 27 mcg of M1.

Interactions

DRUG INTERACTIONS In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when tramadol is administered concomitantly at therapeutic doses.

Tramadol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single-dose data.

Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.

Use With Carbamazepine Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol.

Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride and acetaminophen tablets and carbamazepine is not recommended.

Use With Quinidine Use With Inhibitors of CYP2D6 In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.

Use With Cimetidine Concomitant administration of tramadol hydrochloride and acetaminophen tablets and cimetidine has not been studied.

Concomitant administration of tramadol and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics.

Therefore, no alteration of the tramadol hydrochloride and acetaminophen tablets dosage regimen is recommended.

Use With MAO Inhibitors Interactions with MAO Inhibitors, due to interference with detoxification mechanisms, have been reported for some centrally acting drugs (seeWARNINGS: Use With MAO Inhibitors).

Use With Digoxin Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.

Use With Warfarin Like Compounds Post-marketing surveillance of both tramadol and acetaminophen individual products have revealed rare alterations of warfarin effect, including elevation of prothrombin times.

While such changes have been generally of limited clinical significance for the individual products, periodic evaluation of prothrombin time should be performed when tramadol hydrochloride and acetaminophen tablets and warfarin-like compounds are administered concurrently.

More information

Category Value
Authorisation number ANDA077858
Orphan designation No
Product NDC 49349-791
Date Last Revised 17-10-2011
Type HUMAN PRESCRIPTION DRUG
RXCUI 836395
Storage and handling STORAGE AND HANDLING Store at 20to 25(68to 77[See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as described in the USP using a child-resistant closure.
Marketing authorisation holder REMEDYREPACK INC.