TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN- tramadol hydrochloride and acetaminophen tablet
REMEDYREPACK INC.
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DESCRIPTION
Tramadol hydrochloride and acetaminophen tablets combine two analgesics, tramadol 37.5 mg and acetaminophen 325 mg.
The chemical name for tramadol hydrochloride is (cyclohexanol hydrochloride. Its structural formula is:
The molecular weight of tramadol hydrochloride is 299.84. Tramadol hydrochloride is a white, bitter, crystalline and odorless powder.
The chemical name for acetaminophen is N-acetyl-p-aminophenol. Its structural formula is
The molecular weight of acetaminophen is 151.16. Acetaminophen is an analgesic and antipyretic agent which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste.
Tramadol hydrochloride and acetaminophen tablets contain 37.5 mg tramadol hydrochloride and 325 mg acetaminophen and are beige in color. Inactive ingredients in the tablet are carnauba wax, crospovidone, microcrystalline cellulose, Opadrybeige, pregelatinized starch, povidone, sodium starch glycolate and stearic acid. Opadry Beige contains: iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.
CLINICAL PHARMACOLOGY
The following information is based on studies of tramadol alone or acetaminophen alone, except where otherwise noted:
Pharmacodynamics
Tramadol is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite toreceptors and weak inhibition of reuptake of norepinephrine and serotonin.
Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 toreceptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent inbinding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see
CLINICAL PHARMACOLOGY, Pharmacokinetics
).
Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol.
Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids.
Acetaminophen is a non-opiate, non-salicylate analgesic.
Pharmacokinetics
Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of plasma tramadol and acetaminophen following oral administration of one tramadol hydrochloride and acetaminophen tablet are shown in Table 1. Tramadol has a slower absorption and longer half-life when compared to acetaminophen.
Table 1: Summary of Mean (Pharmacokinetic Parameters of the (+)- and (-) Enantiomers of Tramadol and M1 and Acetaminophen Following A Single Oral Dose Of One Tramadol Hydrochloride and Acetaminophen Combination Tablet (37.5 mg/325 mg) in Volunteers.Parameter a(+)-Tramadol(-)-Tramadol(+)-M1(-)-M1acetaminophenCmax (ng/mL)64.3(9.3)55.5(8.1)10.9(5.7)12.8(4.2)4.2(0.8)tmax (h)1.8(0.6)1.8(0.7)2.1(0.7)2.2(0.7)0.9(0.7)CL/F (mL/min)588(226)736(244)----365(84)t(h)5.1(1.4)4.7(1.2)7.8(3.0)6.2(1.6)2.5(0.6)a For acetaminophen, Cmax was measured as mcg/mL.
A single dose pharmacokinetic study of tramadol hydrochloride and acetaminophen tablets in volunteers showed no drug interactions between tramadol and acetaminophen. Upon multiple oral dosing to steady state, however, the bioavailability of tramadol and metabolite M1 was lower for the combination tablets compared to tramadol administered alone. The decrease in AUC was 14% for (+)-tramadol, 10.4% for (-)-tramadol, 11.9% for (+)-M1 and 24.2% for (-)-M1. The cause of this reduced bioavailability is not clear. Following single- or multiple-dose administration of tramadol hydrochloride and acetaminophen tablets, no significant change in acetaminophen pharmacokinetics was observed when compared to acetaminophen given alone.
Absorption
The absolute bioavailability of tramadol from tramadol hydrochloride and acetaminophen tablets has not been determined. Tramadol hydrochloride has a mean absolute bioavailability of approximately 75% following administration of a single 100 mg oral dose of tramadol hydrochloride tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of two tramadol hydrochloride and acetaminophen tablets occurs at approximately two and three hours, respectively, post-dose.
Peak plasma concentrations of acetaminophen occur within one hour and are not affected by co-administration with tramadol. Oral absorption of acetaminophen following administration of tramadol hydrochloride and acetaminophen tablets occurs primarily in the small intestine.
Food Effects
When tramadol hydrochloride and acetaminophen tablets were administered with food, the time to peak plasma concentration was delayed for approximately 35 minutes for tramadol and almost one hour for acetaminophen. However, peak plasma concentrations, and the extents of absorption, of tramadol and acetaminophen were not affected. The clinical significance of this difference is unknown.
Distribution
The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 mcg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
Acetaminophen appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relative small portion (~20%) of acetaminophen is bound to plasma protein.
Metabolism
Following oral administration, tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver. Metabolite M1 (O-desmethyltramadol) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see
PRECAUTIONS, Drug Interactions
).
Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals arepoor metabolizersof debrisoquine, dextromethorphan, tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies in healthy subjects, concentrations of tramadol were approximately 20% higher inpoor metabolizersversusextensive metabolizers, while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicates that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of SEROTONIN re-uptake INHIBITORS and MAO INHIBITORS may enhance the risk of adverse events, including seizure (see
WARNINGS
) and serotonin syndrome.
Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways:
b) conjugation with sulfate; and
c) oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways.
In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity. In premature infants, newborns, and young infants, the sulfate conjugate predominates.
Elimination
Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The plasma elimination half-lives of racemic tramadol and M1 are approximately 5 to 6 and 7 hours, respectively, after administration of tramadol hydrochloride and acetaminophen tablets. The apparent plasma elimination half-life of racemic tramadol increased to 7 to 9 hours upon multiple dosing of tramadol hydrochloride and acetaminophen tablets.
The half-life of acetaminophen is about 2 to 3 hours in adults. It is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Less than 9% of acetaminophen is excreted unchanged in the urine.
Special Populations
Renal
The pharmacokinetics of tramadol hydrochloride and acetaminophen 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. (see
DOSAGE 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 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 combined in patients with hepatic impairment is not recommended (see
PRECAUTIONS
and
DOSAGE 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 combined 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 (see
PRECAUTIONS, Geriatric Use
).
Gender
Tramadol clearance was 20% higher in female subjects compared to males on four phase I studies of tramadol hydrochloride and acetaminophen 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.
Clinical Studies
Single Dose Studies for Treatment of Acute Pain
In pivotal single-dose studies in acute pain, two tablets of tramadol hydrochloride and acetaminophen administered to patients with pain following oral surgical procedures provided greater relief than placebo or either of the individual components given at the same dose. The onset of pain relief after tramadol hydrochloride and acetaminophen was faster than tramadol alone. Onset of analgesia occurred in less than one hour. The duration of pain relief after tramadol hydrochloride and acetaminophen tablets was longer than acetaminophen alone. Analgesia was generally comparable to that of the comparator, ibuprofen.
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 is 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 may worsen central nervous system and respiratory depression in these patients.
PRECAUTIONS
General
The recommended dose of tramadol hydrochloride and acetaminophen tablets should not be exceeded.
Do not co-administer tramadol hydrochloride and acetaminophen tablets with other tramadol or acetaminophen-containing products (see
WARNINGS, Use With Other Acetaminophen-containing Products and Risk of Overdosage
Pediatric Use
The safety and effectiveness of tramadol hydrochloride and acetaminophen tabletshas not been studied in the pediatric population.
Geriatric Use
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function; of concomitant disease and multiple drug therapy.
Acute Abdominal Conditions
The administration of tramadol hydrochloride and acetaminophen tablets may complicate the clinical assessment of patients with acute abdominal conditions.
Use in Renal Disease
Tramadol hydrochloride and acetaminophen tablets has not been studied in patients with impaired renal function. Experience with tramadol suggests that impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, it is recommended that the dosing interval of tramadol hydrochloride and acetaminophen tablets be increased not to exceed 2 tablets every 12 hours.
Use in Hepatic Disease
Tramadol hydrochloride and acetaminophen tablets have not been studied in patients with impaired hepatic function. The use of tramadol hydrochloride and acetaminophen tablets in patients with hepatic impairment is not recommended (see
WARNINGS, Use With Alcohol
).
INFORMATION FOR PATIENTS
- Patients should be informed that tramadol hydrochloride and acetaminophen tabletsmay cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol.
- Tramadol hydrochloride and acetaminophen tablets may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
- Tramadol hydrochloride and acetaminophen tablets should not be taken with alcohol containing beverages.
- The patient should be instructed not to take tramadol hydrochloride and acetaminophen tablets in combination with other tramadol or acetaminophen-containing products, including over-the-counter preparations.
- Tramadol hydrochloride and acetaminophen tablets should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics.
- The patient should be instructed to inform the physician if they are pregnant, think they might become pregnant, or are trying to become pregnant (see PRECAUTIONS, Labor and Delivery).
- The patient should understand the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures, hepatic toxicity and death.
DRUG INTERACTIONS
CYP2D6 and CYP3A4 Inhibitors
Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors (see
CLINICAL PHARMACOLOGY, Pharmacokinetics
), such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome.
Serotonergic Drugs
There have been postmarketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs andblockers. Caution is advised when tramadol hydrochloride and acetaminophen tablets are coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John's Wort. If concomitant treatment of tramadol hydrochloride and acetaminophen tablets with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see
WARNINGS, Serotonin Syndrome
).
Triptans
Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when tramadol hydrochloride and acetaminophen tablets are coadministered with a triptan. If concomitant treatment of tramadol hydrochloride and acetaminophen tablets with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see
WARNINGS, Serotonin Syndrome
).
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
Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that isoenzyme; so that concomitant administration of quinidine and tramadol results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.
Potential for Other Drugs to Affect Tramadol
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. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John's Wort, with tramadol hydrochloride and acetaminophen tablets may affect the metabolism of tramadol leading to altered tramadol exposure.
Potential for Tramadol to Affect Other Drugs
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 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 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.
CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY
There are no animal or laboratory studies on the combination product (tramadol and acetaminophen) to evaluate carcinogenesis, mutagenesis, or impairment of fertility.
A slight but statistically significant increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.5 times the maximum daily human tramadol dosage of 185 mg/m2) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No such finding occurred in rat carcinogenicity study (dosing orally up to 30 mg/kg, 180 mg/m2 or 1 time the maximum daily human tramadol dosage).
Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.
No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (350 mg/m2) in male rats and 75 mg/kg (450 mg/m2) in female rats. These dosages are 1.6 and 2.4 times the maximum daily human tramadol dosage of 185 mg/m2.
PREGNANCY
Teratogenic Effects: Pregnancy Category C
No drug-related teratogenic effects were observed in the progeny of rats treated orally with tramadol and acetaminophen. The tramadol/acetaminophen combination product was shown to be embryotoxic and fetotoxic in rats at a maternally toxic dose, 50/434 mg/kg tramadol/acetaminophen (300/2604 mg/m2 or 1.6 times the maximum daily human tramadol/acetaminophen dosage of 185/1591 mg/m2), but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs.
Non-teratogenic Effects:
Tramadol alone was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300 mg/m2 or 1.6 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m2 or 2.6 times the maximum daily human tramadol dosage).
There are no adequate and well-controlled studies in pregnant women. Tramadol hydrochloride and acetaminophen tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported with tramadol hydrochloride during post-marketing.
LABOR & DELIVERY
Tramadol hydrochloride and acetaminophen tablets should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn (see
DRUG ABUSE AND DEPENDENCE
). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.
The effect of tramadol hydrochloride and acetaminophen tablets, if any, on the later growth, development, and functional maturation of the child is unknown.
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.
ADVERSE REACTIONS
Table 2 reports the incidence rate of treatment-emergent adverse events over five days of tramadol hydrochloride and acetaminophen tablets use in clinical trials (subjects took an average of at least 6 tablets per day).
Table 2: Incidence of Treatment-Emergent Adverse Events (Body System Preferred TermTramadol Hydrochloride and Acetaminophen Tablets (N=142) %Gastrointestinal System DisordersConstipation6Nausea3Diarrhea3Dry Mouth2Psychiatric DisordersSomnolence6Anorexia3Insomnia2Central & Peripheral Nervous SystemDizziness3Skin and AppendagesSweating Increased4Pruritus2Reproductive Disorders, Male *Prostatic Disorder2* Number of males = 62
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 tablets 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 DisordersArrhythmia, 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.
DRUG ABUSE AND DEPENDENCE
Abuse
Tramadol has mu-opioid agonist activity. Tramadol hydrochloride and acetaminophen tablets, a tramadol-containing product, can be abused and may be subject to criminal diversion.
Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. Drug addiction is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, use for non-medical purposes, continued use despite harm or risk of harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.
Drug-seekingbehavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeatedlossof prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s).Doctor shoppingto obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of tramadol hydrochloride and acetaminophen tablets can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances.
Concerns about abuse and addiction should not prevent the proper management of pain. However all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Proper assessment of the patient and periodic re-evaluation of therapy are appropriate measures that help to limit the potential abuse of this product.
Tramadol hydrochloride and acetaminophen tablets are intended for oral use only.
Dependence
Tolerance is the need for increasing doses of drugs to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist (see also
WARNINGS, Withdrawal
).
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Generally, tolerance and/or withdrawal are more likely to occur the longer a patient is on continuous therapy with tramadol hydrochloride and acetaminophen tablets.
OVERDOSAGE
Tramadol hydrochloride and acetaminophen tablets are a combination product. The clinical presentation of overdose may include the signs and symptoms of tramadol toxicity, acetaminophen toxicity or both. The initial symptoms of tramadol overdosage may include respiratory depression and or seizures. The initial symptoms seen within the first 24 hours following an acetaminophen overdose are: anorexia, nausea, vomiting, malaise, pallor and diaphoresis. An overdosage of tramadol hydrochloride and acetaminophen tablets may be a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended.
Tramadol
Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, seizures, bradycardia, hypotension, cardiac arrest, and death.
Deaths due to overdose have been reported with abuse and misuse of tramadol (see
WARNINGS, Misuse, Abuse, and Diversion
). Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids.
In the treatment of tramadol overdosage, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals convulsions following the administration of toxic doses of tramadol hydrochloride and acetaminophen tablets could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected
to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period..
Acetaminophen
Serious potential consequences of overdosage with acetaminophen are hepatic centrilobular necrosis, leading to hepatic failure and death. Renal tubular necrosis, hypoglycemia and coagulation defects also may occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post ingestion.
Standard recommendations should be followed for the treatment of acetaminophen overdose.
DOSAGE & ADMINISTRATION
For the short-term (five days or less) management of acute pain, the recommended dose of tramadol hydrochloride and acetaminophen tablets is 2 tablets every 4 to 6 hours as needed for pain relief up to a maximum of 8 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 be increased not to exceed 2 tablets every 12 hours. Dose selection for an elderly patient should be cautious, in view of the potential for greater sensitivity to adverse events.
HOW SUPPLIED
Tramadol hydrochloride and acetaminophen tablets are beige colored, film-coated, biconvex capsule shaped tablets withAN 617debossed on one side and plain on the other side and are available as follows:
Bottles of 30: NDC 65162-617-03
Bottles of 100: NDC 65162-617-10
Bottles of 500: NDC 65162-617-50
Bottles of 1000: NDC 65162-617-11
Blister packs: NDC 65162-617-60 (Packages of 100 unit doses, 10 cards of 10 tablets each)
| TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN
tramadol hydrochloride and acetaminophen tablet |
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| Labeler - REMEDYREPACK INC. (829572556) |