Tramadol Capsules

Tramadol Hydrochloride Extended-Release is available in 150 mg capsules.

150 mg Capsules: White capsule imprinted with gold ink “G 322” on cap and “150” between lines on the body

The following serious or otherwise important adverse reactions are described in greater detail, in other sections:

- Seizure risk [see WARNINGS AND PRECAUTIONS (5.1)]

- Suicide risk [see WARNINGS AND PRECAUTIONS (5.2)]

- Serotonin syndrome [see WARNINGS AND PRECAUTIONS (5.3)]

- Anaphylactoid and allergic reactions [see WARNINGS AND PRECAUTIONS (5.4)]

- Respiratory depression [see WARNINGS AND PRECAUTIONS (5.5)]

- Withdrawal symptoms [see WARNINGS AND PRECAUTIONS (5.10)]

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Tramadol Hydrochloride Extended-Release capsules were administered to a total of 1987 patients in clinical trials. These included four double-blind and one long-term, open-label study in patients with osteoarthritis of the hip and knee. A total of 812 patients were 65 years or older. Adverse reactions with doses from 100 mg to 300 mg in the four pooled, randomized, double-blind, placebo- controlled studies in patients with chronic non-malignant pain are presented in the following table (see Table1).

The following adverse reactions were reported from all chronic pain studies

(N=1917). The lists below include adverse reactions not otherwise noted in Table 1.

Adverse reactions with incidence rates of 1.0% to <5.0%

Cardiac disorders: hypertension

Gastrointestinal disorders: dyspepsia, flatulence

General disorders: abdominal pain, accidental injury, chills, fever, flu syndrome, neck pain, pelvic pain

Investigations: hyperglycemia, urine abnormality

Metabolism and nutrition disorders: peripheral edema, weight loss Musculoskeletal, connective tissue and bone disorders: myalgia Nervous system disorders: paresthesia, tremor, withdrawal syndrome

Psychiatric disorders: agitation, anxiety, apathy, confusion, depersonalization, depression, euphoria, nervousness

Respiratory, thoracic and mediastinal disorders: bronchitis, pharyngitis, rhinitis, sinusitis

Skin and subcutaneous tissue disorders: rash

Urogenital disorders: prostatic disorder, urinary tract infection

Vascular disorders: vasodilatation

Adverse reactions with incidence rates of 0.5% to <1.0% at any dose and serious adverse reactions reported in at least two patients.

Cardiac disorders: EKG abnormal, hypotension, tachycardia

Gastrointestinal disorders: gastroenteritis General disorders: neck rigidity, viral infection Hematologic/Lymphatic disorders: anemia, ecchymoses

Metabolism and nutrition disorders: blood urea nitrogen increased, GGT increased, gout, SGPT increased

Musculoskeletal disorders: arthritis, arthrosis, joint disorder, leg cramps

Nervous system disorders: emotional lability, hyperkinesia, hypertonia, thinking abnormal, twitching, vertigo

Respiratory disorders: pneumonia

Skin and subcutaneous tissue disorders: hair disorder, skin disorder, urticaria

Special Senses: eye disorder, lacrimation disorder

Urogenital disorders: cystitis, dysuria, sexual function abnormality, urinary retention

12.1 Mechanism of Action

Tramadol Hydrochloride Extended-Release contains tramadol, 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.

12.2 Pharmacodynamics

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 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.

12.3 Pharmacokinetics

The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. Tramadol Hydrochloride Extended-Release is administered as a racemate and both tramadol and M1 are detected in the circulation. The Cmax and AUC of Tramadol Hydrochloride Extended-Release capsules have been observed to be dose-proportional over an oral dose range of 100 to 300 mg in healthy subjects.

Absorption:

After a single dose administration of Tramadol Hydrochloride Extended-Release, Tmax occurs around 10-12 hours.

The mean Cmax and AUC of Tramadol Hydrochloride Extended-Release capsules after a 300 mg single dose was 308 ng/mL and 6777 ng*hr/mL, respectively under fasting conditions. Tramadol Hydrochloride Extended-Release is bioequivalent to a reference extended-release tramadol product following a single 300 mg dose under fasting conditions.

At steady-state, Tramadol Hydrochloride Extended-Release at 200 mg has been observed to be bioequivalent to a reference extended-release tramadol product at 200 mg under fasting conditions (Table 2). Following administration of Tramadol Hydrochloride Extended-Release 200 mg capsules, steady-state plasma concentrations of both tramadol and M1 are achieved within four days of once daily dosing.

AUC0-24: Area under the Curve in a 24-hour dosing interval

Cmax: Peak Concentration in a 24-hour dosing interval Cmin: Trough Concentration in a 24-hour dosing interval Tmax: Time to Peak Concentration

Food Effects:

The rate and extent of absorption of Tramadol Hydrochloride Extended-Release capsules (300 mg) are similar following oral administration with or without food. Therefore, Tramadol Hydrochloride Extended-Release capsules can be administered without regard to meals.

Distribution:

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 tramadol dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 µg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.

Metabolism:

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 and polymorphism, which may affect the therapeutic response [see DRUG INTERACTIONS (7)].

Elimination:

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 plasma elimination half-lives of racemic tramadol and racemic M1 after administration of Tramadol Hydrochloride Extended-Release capsules are approximately 10 and 11 hours, respectively.

Special Populations:

Renal Impairment

Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The pharmacokinetics of tramadol was studied in patients with mild or moderate renal impairment after receiving multiple doses of an extended-release tramadol product at 100 mg. There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50-80 mL/min) or moderate (CLcr: 30-50 mL/min) renal impairment in comparison to patients with normal renal function (CLcr > 80 mL/min). However, exposure of M1 increased 20-40% with increased severity of the renal impairment (from normal to mild and moderate). The pharmacokinetics of tramadol has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths of Tramadol Hydrochloride Extended-Release does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, Tramadol Hydrochloride Extended-Release should not be used in patients with severe renal impairment [see DOSAGE AND ADMINISTRATION (2.5), and USE IN SPECIFIC POPULATIONS (8.6)]. The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.

Hepatic Impairment

Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of an extended-release tramadol product at 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 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 Extended-Release does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, Tramadol Hydrochloride Extended-Release should not be used in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION (2.6) and USE IN SPECIFIC POPULATIONS (8.7)].

Gender

Based on pooled multiple-dose pharmacokinetics studies for an extended-release tramadol product 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.

Age

The effect of age on pharmacokinetics of Tramadol Hydrochloride Extended-Release has not been studied. Healthy elderly subjects aged 65 to 75 years administered an immediate-release formulation of tramadol, have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, mean maximum plasma concentrations are elevated (208 vs. 162 ng/mL) and the mean elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years [see DOSAGE AND ADMINISTRATION (2.4)].

Drug Interactions:

Poor / Extensive Metabolizers, CYP2D6

The formation of the active metabolite, M1, is mediated by CYP2D6, a polymorphic enzyme. Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450 metabolizing enzyme system. These individuals are “poor metabolizers” of debrisoquine, dextromethorphan and tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies with IR tablets in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers," while M1 concentrations were 40% lower.

CYP2D6 Inhibitors

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.

Quinidine

Tramadol is metabolized to active metabolite M1 by CYP2D6. Coadministration of quinidine, a selective inhibitor of CYP2D6, with tramadol ER resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure. The clinical consequences of these findings are unknown.

To evaluate the effect of tramadol, a CYP2D6 substrate on quinidine, an in vitro drug interaction study in human liver microsomes was conducted. The results from this study indicate that tramadol has no effect on quinidine metabolism. [See DRUG INTERACTIONS (7.2, 7.6)].

CYP3A4 Inhibitors and Inducers

Since tramadol is also metabolized by CYP3A4, administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or CYP3A4 inducers, such as rifampin and St. John’s Wort, with Tramadol Hydrochloride Extended-Release may affect the metabolism of tramadol leading to altered tramadol exposure [see WARNINGS AND PRECAUTIONS (5.1) and DRUG INTERACTIONS (7.2)].

Cimetidine

Concomitant administration of tramadol immediate-release tablets with cimetidine, a weak CYP3A4 inhibitor, does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the Tramadol Hydrochloride Extended-Release dosage regimen with cimetidine is recommended.

Carbamazepine

Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Concomitant administration of Tramadol Hydrochloride Extended-Release and carbamazepine is not recommended.

Tramadol Hydrochloride Extended-Release is bioequivalent under fasting conditions to another extended-release tramadol product [see CLINICAL PHARMACOLOGY (12.3)] which did demonstrate efficacy in two of four clinical trials of patients with chronic pain. 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 – 100 mm visual analog scale (VAS).

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 with the extended- release tramadol product was initiated at 100 mg once daily 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 active 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 the extended-release tramadol product 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with the extended-release tramadol product 100 mg and 10% 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 2).

Figure 2 Tamadol ER Tablets Study 023 WOMAC Pain Responder Analysis Patients Achieving Various Levels of Response Threshold

In one 12-week randomized, double-blind, placebo-controlled flexible-dosing trial of the extended-release tramadol product in patients with osteoarthritis of the knee, patients titrated to an average daily dose of approximately 270 mg/day. Forty-nine percent of patients randomized to the active treatment group completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the active 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-seven percent of the placebo-treated patients discontinued the study due to lack of efficacy compared to 15% of active-treated patients. The active treatment group demonstrated a statistically significant decrease in the mean Visual Analog Scale (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 the extended-release tramadol product and placebo (see Figure 3).

Figure 3 Tamadol ER Tablets Study 015 Arthritis Pain Intensity VAS Responder Analysis Patients Achieving Various Levels of Response Threshold

Four randomized, placebo-controlled clinical trials of Tramadol Hydrochloride Extended-Release were conducted, none of which demonstrated efficacy but which differed in design from the preceding clinical studies described. Two trials were 12-week randomized placebo-controlled trials of Tramadol Hydrochloride Extended-Release 100 mg/day, 200 mg/day, and 300 mg/day versus placebo in patients with moderate to moderately severe osteoarthritis pain of the hip and knee. The other two 12 week trials were similar in design, but only studied Tramadol Hydrochloride Extended-Release 300 mg/day. In this fixed-dose design, subjects were required to titrate to a fixed dose, even if their pain responded to a lower titration dose.

NDC 69420-3002-1
Tramadol
Hydrochloride
Extended-Release Capsules
150 mg per capsule