Tramadol Hydrochloride Extended-Release Tablets

DESCRIPTION

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displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

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: Figure 1 The molecular weight of tramadol hydrochloride is 299.84. It is a white, crystalline powder that is freely soluble in water and methanol, very slightly soluble in acetone 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 tablets contain 100 mg, 200 mg or 300 mg of tramadol hydrochloride, USP in an extended-release formulation. The tablets are white in color and contain the inactive ingredients pregelatinized starch, hypromellose, mannitol, magnesium stearate, cellulose acetate and polyethylene glycol. Imprinting ink contains, shellac glaze, iron oxide black, N-butyl alcohol, ammonium hydroxide and propylene glycol.

CLINICAL STUDIES

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displayName: CLINICAL STUDIES SECTION
FDA Article Code: 34092-7

Tramadol hydrochloride was 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 mm 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 extended-release 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 the tramadol hydrochloride extended-release 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 extended-release 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). In one 12-week randomized, double-blind, placebo-controlled flexible-dosing trial of tramadol hydrochloride extended-release tablets in patients with osteoarthritis of the knee, patients titrated to an average daily tramadol hydrochloride extended-release tablets dose of approximately 270 mg/day. Forty-nine percent of patients randomized to tramadol hydrochloride extended-release tablets completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the tramadol hydrochloride extended-release 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 extended-release tablets-treated patients. The tramadol hydrochloride extended-release 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 extended-release tablets and placebo (see Figure 4).

INDICATIONS AND USAGE

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displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

Tramadol hydrochloride extended-release 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.

CONTRAINDICATIONS

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displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

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

WARNINGS

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displayName: WARNINGS SECTION
FDA Article Code: 34071-1

ADVERSE REACTIONS

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displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

Tramadol hydrochloride extended-release 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 generally7 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 Table 2).

OVERDOSAGE

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displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

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, bradycardia, hypotension, and death. Deaths due to overdose have been reported with abuse and misuse of tramadol, by ingesting, inhaling, or injecting the crushed tablets. 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 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.

DOSAGE AND ADMINISTRATION

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displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

Tramadol hydrochloride extended-release 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 extended-release 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 ).

HOW SUPPLIED

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displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Tramadol hydrochloride extended-release tablets are supplied in the following package and dose strength forms: 100 mg: White, round shape, biconvex, beveled edge, coated tablet with release portal on the center of the tablet on any one side, imprinted “531” with black ink on one side and plain on other side. 200 mg: White, round shape, biconvex, beveled edge, coated tablet with release portal on the center of the tablet on any one side, imprinted “533” with black ink on one side and plain on other side. 300 mg: White, round shape, biconvex, beveled edge, coated tablet with release portal on the center of the tablet on any one side, imprinted “537” with black ink on one side and plain on other side. 35356-790-30 Bottles of 30 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light resistant container. Warning: keep out of reach of children.

Image of Label

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displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4