DailyMed Label: Tramadol Hydrochloride and Acetaminophen

DailyMed Label: TRAMADOL HYDROCHLORIDE

2009

DailyMed Prescription

TRAMADOL HYDROCHLORIDE

tramadol hydrochloride

Rebel Distributors Corp.

NDC: 21695-699

NDC: 21695-699

NDC: 21695-700

NDC: 21695-700

Tramadol hydrochloride is a centrally acting synthetic analgesic in an extended-release formulation. The chemical name is (±) cis-2-[(dimethylamino)methyl]­-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is: The molecular weight of tramadol hydrochloride is 299.8. It is a white, bitter, crystalline and odorless powder that is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7. Tramadol hydrochloride Extended-Release (ER) tablets contain 100 mg or 200 mg of tramadol hydrochloride in an extended-release formulation. The tablets are white to off-white in color and contain the inactive ingredients colloidal silicone dioxide, dibutyl sebacate, ethylcellulose, magnesium stearate, polyvinyl alcohol, povidone K-90, and an imprinting agent, Opacode S-1-17823 black, which contains the following ingredients: shellac, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol, and ammonium hydroxide. structure

Tramadol hydrochloride ER tablets are indicated for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time.

Tramadol hydrochloride ER tablets should not be used in patients with: creatinine clearance less than 30 mL/min, severe hepatic impairment (Child-Pugh Class C) (See PRECAUTIONS - Use in Renal and Hepatic Disease. ) Tramadol hydrochloride ER tablets must be swallowed whole and must not be chewed, crushed, or split (see WARNINGS - Misuse, Abuse and Diversion of Opioids and DRUG ABUSE AND ADDICTION ). For patients not currently treated with tramadol immediate-release (IR) products, tramadol hydrochloride ER tablets should be initiated at a dose of 100 mg once daily and titrated up as necessary by 100 mg increments every five days for relief of pain and depending upon tolerability. Tramadol hydrochloride ER tablets should not be administered at a dose exceeding 300 mg per day. For patients maintained on tramadol IR products, calculate the 24 hour tramadol IR dose and initiate a total daily dose of tramadol hydrochloride ER tablets rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with tramadol hydrochloride ER tablets, some patients maintained on tramadol IR products may not be able to convert tramadol hydrochloride ER tablets. Tramadol hydrochloride ER tablets should not be administered at a dose exceeding 300 mg per day. The concomitant use of tramadol hydrochloride ER tablets with other tramadol products is not recommended (see WARNINGS ). Good pain management practice dictates that the dose be individualized according to patient need using the lowest beneficial dose. Start at the lowest possible dose and titrate upward as tolerated to achieve an adequate effect. Clinical studies of tramadol hydrochloride ER tablets have not demonstrated a clinical benefit at a total daily dose exceeding 300 mg. In general, dosing of an elderly patient (over 65 years of age) should be initiated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. Tramadol hydrochloride ER tablets should be administered with even greater caution in patients over 75 years, due to the greater frequency of adverse events seen in this population.

Tramadol hydrochloride ER tablets should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids. Tramadol hydrochloride ER 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 ER tablets may worsen central nervous system and respiratory depression in these patients

The administration of tramadol hydrochloride ER tablets may complicate the clinical assessment of patients with acute abdominal conditions. Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. Tramadol hydrochloride ER tablets have not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths and once daily dosing of tramadol hydrochloride ER tablets does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, tramadol hydrochloride ER tablets should not be used in patients with severe renal impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. The pharmacokinetics of tramadol hydrochloride ER tablets has not been studied in patients with severe hepatic impairment. The limited availability of dose strengths and once daily dosing of tramadol hydrochloride ER tablets does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, tramadol hydrochloride ER tablets should not be used in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ). Patients should be informed that tramadol hydrochloride ER tablets are for oral use only and should be swallowed whole. The tablets should not be chewed, crushed, or split. Patients should be informed that tramadol hydrochloride ER tablets may cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SRIs, NRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol. Patients should be informed that tramadol hydrochloride ER tablets may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Patients should be informed that tramadol hydrochloride ER tablets should not be taken with alcohol containing beverages. Patients should be informed that tramadol hydrochloride ER tablets should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics. Female patients should be instructed to inform the prescriber if they are pregnant, think they might become pregnant, or are trying to become pregnant (see PRECAUTIONS - Labor and Delivery ). Patients should be educated regarding the single-dose and 24 hour dosing regimen, as exceeding these recommendations can result in respiratory depression, seizures or death. Tramadol hydrochloride is an opioid with no approved use in the management of addictive disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission, is for the management of pain requiring opioid analgesia. 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 and α2-adrenergic blockers. Caution is advised when tramadol hydrochloride ER 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 ER 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 ER tablet is coadministered with a triptan. If concomitant treatment of tramadol hydrochloride ER 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 ). Patients taking carbamazepine , a CYP3A4 inducer, 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 ER tablets and carbamazepine is not recommended. Coadministration of quinidine with tramadol hydrochloride ER tablets resulted in a 50 to 60% increase in tramadol exposure and a 50 to 60% decrease in M1 exposure (see CLINICAL PHARMACOLOGY - Drug Interactions ). The clinical consequences of these findings are unknown. Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times. 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 ER tablets may affect the metabolism of tramadol leading to altered tramadol exposure. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when administered concomitantly at therapeutic doses. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals. No carcinogenic effect of tramadol was observed in p53(+/–)-heterozygous mice at oral doses up to 150 mg/kg/day (approximately 2-fold maximum daily human dose [MDHD] of 400 mg/day for a 60 kg adult based on body surface conversion) for 26 weeks and in rats at oral doses up to 75 mg/kg/day for males and 100 mg/kg/day for females (approximately 2-fold MDHD) for two years. However, the excessive decrease in body weight gain observed in the rat study might have reduced their sensitivity to any potential carcinogenic effect of the drug. Tramadol was not mutagenic in the following assays: a bacterial reverse mutation assay using Salmonella and E. coli , a mouse lymphoma assay (in the absence of metabolic activation), and a bone marrow micronucleus test in mice. Mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay. 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/day in male and female rats (approximately equivalent to MDHD). Tramadol was not teratogenic at oral dose levels up to 50 mg/kg/day (approximately equivalent to MDHD) in rats and 100 mg/kg (approximately 5-fold MDHD) in rabbits during organogenesis. However, embryo-fetal lethality, reductions in fetal weight and skeletal ossification, and increased supernumerary ribs were observed at a maternal toxic dose of 140 mg/kg in mice (approximately 2-fold MDHD), 80 mg/kg in rats (2-fold MDHD) or 300 mg/kg in rabbits (approximately 15-fold MDHD). Tramadol caused a reduction in neonatal body weight and survival at an oral dose of 80 mg/kg (approximately 2-fold MDHD) when rats were treated during late gestation throughout lactation period. There are no adequate and well-controlled studies in pregnant women. Tramadol hydrochloride ER 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 during post-marketing reports with tramadol HCl immediate-release products. Tramadol hydrochloride ER 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 ADDICTION ). 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 treated with tramadol HCl during labor. The effect of tramadol hydrochloride ER tablets, if any, on the later growth, development, and functional maturation of the child is unknown. Tramadol hydrochloride ER 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 sixteen hours post-dose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1. The safety and efficacy of tramadol hydrochloride ER tablets in patients under 18 years of age have not been established. The use of tramadol hydrochloride ER tablets in the pediatric population is not recommended. Nine-hundred-one elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride ER tablets in clinical trials. Of those subjects, 156 were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: constipation, fatigue, weakness, postural hypotension and dyspepsia. For this reason, tramadol hydrochloride ER tablets should be used with great caution in patients older than 75 years of age (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).

Tramadol hydrochloride ER tablets were administered to a total of 3108 patients during studies conducted in the U.S. These included four double-blind studies in patients with osteoarthritis and/or chronic low back pain and one open-label study in patients with chronic non-malignant pain. A total of 901 patients were 65 years or older. The frequency of adverse events generally increased with doses from 100 mg to 400 mg in the two pooled, twelve-week, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain (see

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 and α2-adrenergic blockers. Caution is advised when tramadol hydrochloride ER 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 ER 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 ER tablet is coadministered with a triptan. If concomitant treatment of tramadol hydrochloride ER 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 ). Patients taking carbamazepine , a CYP3A4 inducer, 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 ER tablets and carbamazepine is not recommended. Coadministration of quinidine with tramadol hydrochloride ER tablets resulted in a 50 to 60% increase in tramadol exposure and a 50 to 60% decrease in M1 exposure (see CLINICAL PHARMACOLOGY - Drug Interactions ). The clinical consequences of these findings are unknown. Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times. 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 ER tablets may affect the metabolism of tramadol leading to altered tramadol exposure. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when administered concomitantly at therapeutic doses. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.

Tramadol hydrochloride extended-release tablets are supplied in the following package and dose strength forms: 100 mg, round, white to off-white tablets, imprinted with “Par821” on one side of the tablet in black ink Bottle of 30 tablets – NDC 21695-699-30 200 mg, round, white to off-white tablets, imprinted with “Par822” on one side of the tablet in black ink Bottle of 30 tablets – NDC 21695-700-30 Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Manufactured by: Par Pharmaceutical Companies, Inc. Spring Valley, NY 10977 Rebel Distributors, Corp Thousand Oaks, CA 91320 Issued: 06/09

Tramadol hydrochloride 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 to µ-opioid receptors 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 to µ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-opioid binding. 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. 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. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in the tramadol hydrochloride ER tablets clinical studies. 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. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed. The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. Tramadol hydrochloride ER tablet is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of tramadol hydrochloride ER tablets are approximately dose-proportional over a 100 to 400 mg dose range in healthy subjects. The observed tramadol AUC values for the 400 mg dose were 26% higher than predicted based on the AUC values for the 200 mg dose. The clinical significance of this finding has not been studied and is not known. In healthy subjects, the bioavailability of a tramadol hydrochloride ER 200 mg tablet relative to a 50 mg every six hours dosing regimen of the immediate-release dosage form (tramadol hydrochloride) was approximately 85 to 90%. Consistent with the extended-release nature of the formulation, there is a lag time in drug absorption following tramadol hydrochloride ER tablets administration. The mean peak plasma concentrations of tramadol and M1 after administration of tramadol hydrochloride ER tablets to healthy volunteers are attained at about 12 hours and 15 hours, respectively, after dosing (see Table 1 and Figure 2). Following administration of the tramadol hydrochloride ER tablet, steady-state plasma concentrations of both tramadol and M1 are achieved within four days with once daily dosing. The mean (%CV) pharmacokinetic parameter values for tramadol hydrochloride ER tablet 200 mg administered once daily and tramadol hydrochloride immediate-release 50 mg administered every six hours are provided in Table 1 . Table 1. Mean (%CV) Steady-State Pharmacokinetic Parameter Values (n=32) AUC 0-24 : Area Under the Curve in a 24 hour dosing interval; C max : Peak Concentration in a 24 hour dosing interval; C min : Trough Concentration in a 24 hour dosing interval; T max : Time to Peak Concentration   Tramadol M1 Metabolite   Pharmacokinetic Parameter Tramadol HCl ER 200 mg Tablet Once Daily Tramadol HCl 50 mg Tablet Every 6 Hours Tramadol HCl ER 200 mg Tablet Once Daily Tramadol HCl 50 mg Tablet Every 6 Hours AUC 0-24 (ng.h/mL) 5975 (34) 6613 (27) 1890 (25) 2095 (26) C max (ng/mL) 335 (35) 383 (21) 95 (24) 104 (24) C min (ng/mL) 187 (37) 228 (32) 69 (30) 82 (27) T max (h) 12 (27) 1.5 (42) 15 (27) 1.9 (57) % Fluctuation 61 (57) 59 (35) 34 (72) 26 (47) Figure 2: Mean Steady-State Tramadol (a) and M1 (b) Plasma Concentrations on Day 8 Post Dose after Administration of 200 mg Tramadol Hydrochloride ER Tablet Once Daily and 50 mg Tramadol Hydrochloride Tablets Every 6 Hours. After a single dose administration of 200 mg tramadol hydrochloride ER tablet with a high fat meal, the C max and AUC 0-∞ of tramadol decreased 28% and 16%, respectively, compared to fasting conditions. Mean T max was increased by 3 hour (from 14 hour under fasting conditions to 17 hour under fed conditions). While tramadol hydrochloride ER tablet may be taken without regard to food, it is recommended that it be taken in a consistent manner. The volume of distribution of tramadol was 2.6 and 2.9 liters/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. Tramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N – (mediated by CYP3A4 and CYP2B6) and O – (mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyl tramadol, denoted M1) 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 ). Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 after administration of tramadol hydrochloride ER tablets are approximately 7.9 and 8.8 hours, respectively. Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The pharmacokinetics of tramadol were studied in patients with mild or moderate renal impairment after receiving multiple doses of tramadol hydrochloride ER tablets 100 mg. There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50 to 80 mL/min) or moderate (CLcr: 30 to 50 mL/min) renal impairment in comparison to patients with normal renal function. However, exposure of M1 increased 20 to 40% with increased severity of the renal impairment (from normal to mild and moderate). Tramadol hydrochloride ER tablets have not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths of tramadol hydrochloride ER tablets does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, tramadol hydrochloride ER tablets should not be used in patients with severe renal impairment (see PRECAUTIONS - Use in Renal and Hepatic Disease and 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. Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of tramadol hydrochloride ER tablets 100 mg. The exposure of (+)- and (-)-tramadol was similar in mild and moderate hepatic impairment patients in comparison to patients with normal hepatic function. However, exposure of (+)- and (-)-­M1 decreased ~50% with increased severity of the hepatic impairment (from normal to mild and moderate). The pharmacokinetics of tramadol after the administration of tramadol hydrochloride ER tablets has not been studied in patients with severe hepatic impairment. After the administration of tramadol immediate-release tablets to patients with advanced cirrhosis of the liver, tramadol area under the plasma concentration time curve was larger and the tramadol and M1 half-lives were longer than subjects with normal hepatic function. The limited availability of dose strengths of tramadol hydrochloride ER tablets does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, tramadol hydrochloride ER tablets should not be used in patients with severe hepatic impairment (see PRECAUTIONS - Use in Renal and Hepatic Disease and DOSAGE AND ADMINISTRATION ). The effect of age on the absorption of tramadol from tramadol hydrochloride ER tablets in patients over the age of 65 years has not been studied and is unknown (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ). Based on pooled multiple-dose pharmacokinetics studies for tramadol hydrochloride ER tablets in 166 healthy subjects (111 males and 55 females), the dose-normalized AUC values for tramadol were somewhat higher in females than in males. There was a considerable degree of overlap in values between male and female groups. Dosage adjustment based on gender is not recommended. The formation of the active metabolite, M1, is mediated by CYP2D6. Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. Based on a population PK analysis of Phase I studies with immediate-release tablets in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers," while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 (fluoxetine, norfluoxetine, amitriptyline, and quinidine) inhibit the metabolism of tramadol to various degrees, suggesting that concomitant administration of these compounds could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Tramadol is also metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John’s Wort, with tramadol hydrochloride ER tablets may affect the metabolism of tramadol leading to altered tramadol exposure (see PRECAUTIONS - Drug Interactions ). Tramadol is metabolized to M1 by CYP2D6. A study was conducted to examine the effect of quinidine, a selective inhibitor of CYP2D6, on the pharmacokinetics of tramadol by administering 200 mg quinidine two hours before the administration of tramadol hydrochloride ER tablets 100 mg. The results demonstrated that the exposure of tramadol increased 50 to 60% and the exposure of M1 decreased 50 to 60% (see PRECAUTIONS - Drug Interactions). In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride ER tablets and carbamazepine is not recommended (see PRECAUTIONS - Drug Interactions ). Concomitant administration of tramadol immediate-release tablets with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the tramadol hydrochloride ER tablets dosage regimen with cimetidine is recommended. figure2a figure2b

Tramadol hydrochloride ER tablets were studied in patients with chronic, moderate to moderately severe pain due to osteoarthritis and/or low back pain in four 12 week, randomized, double-blind, placebo-controlled trials. To qualify for inclusion into these studies, patients were required to have moderate to moderately severe pain as defined by a pain intensity score of ≥40 mm, off previous medications, on a 0 to 100 mm visual analog scale (VAS). Adequate evidence of efficacy was demonstrated in the following two studies: In one 12 week randomized, double-blind, placebo-controlled study, patients with moderate to moderately severe pain due to osteoarthritis of the knee and/or hip were administered doses from 100 mg to 400 mg daily. Treatment was initiated at 100 mg QD for four days then increased by 100 mg per day increments every five days to the randomized fixed dose. Between 51% and 59% of patients in the tramadol hydrochloride ER tablets treatment groups completed the study and 56% of patients in the placebo group completed the study. Discontinuations due to adverse events were more common in tramadol hydrochloride ER tablets 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with tramadol hydrochloride ER tablets 100 mg and 20% of patients treated with placebo. Pain, as assessed by the WOMAC Pain subscale, was measured at 1, 2, 3, 6, 9, and 12 weeks and change from baseline assessed. A responder analysis based on the percent change in WOMAC Pain subscale demonstrated a statistically significant improvement in pain for the 100 mg and 200 mg treatment groups compared to placebo (see Figure 3). Figure 3 In one 12 week randomized, double-blind, placebo-controlled flexible-dosing trial of tramadol hydrochloride ER tablets in patients with osteoarthritis of the knee, patients titrated to an average daily tramadol hydrochloride ER tablets dose of approximately 270 mg/day. Forty-nine percent of patients randomized to tramadol hydrochloride ER tablets completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the tramadol hydrochloride ER tablets treatment group were due to adverse events, accounting for 27% of the early discontinuations in contrast to 7% of the discontinuations from the placebo group. Thirty-four percent of the placebo-treated patients discontinued the study due to lack of efficacy compared to 15% of tramadol hydrochloride ER tablets-treated patients. The tramadol hydrochloride ER tablets group demonstrated a statistically significant decrease in the mean VAS score, and a statistically significant difference in the responder rate, based on the percent change from baseline in the VAS score, measured at 1, 2, 4, 8, and 12 weeks, between patients receiving tramadol hydrochloride ER tablets and placebo (see Figure 4). Figure 4 figure3 figure4

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