Tramadol hydrochloride tablet, extended release

Description

Tramadol Hydrochloride Extended-Release Tablets are a centrally acting analgesic composed of a dual-matrix delivery system with both immediate-release and extended-release characteristics. The chemical name for tramadol hydrochloride is () cis-2-[(dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:


C 16H 25NO 2HCl


The molecular weight of tramadol hydrochloride is 299.8. Tramadol hydrochloride is a white crystalline powder that is freely soluble in water and ethanol. Tramadol Hydrochloride Extended-Release Tablets are for oral administration and contain 100 mg, 200 mg or 300 mg of tramadol hydrochloride. The tablets are white to off-white in color. The inactive ingredients in the tablet are colloidal silicon dioxide, pregelatinized modified starch, hydrogenated vegetable oil, magnesium stearate, polyvinyl acetate, povidone, sodium lauryl sulfate and xanthan gum.

Clinical pharmacology

Mechanism of action

Tramadol Hydrochloride Extended-Release Tablets are a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, at least two complementary mechanisms that demonstrate three different types of activity appear applicable: binding of parent and M1 metabolite to -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 mu-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in mu-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.

Apart from analgesia, tramadol hydrochloride administration may produce various 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.

Pharmacokinetics

The analgesic activity of tramadol hydrochloride is due to both parent drug and the M1 metabolite (see CLINICAL PHARMACOLOGY, Mechanism of Action).

Tramadol Hydrochloride Extended-Release Tablets are formulated as a racemate and both tramadol and M1 are detected in the circulation.

The pharmacokinetics of tramadol and M1 are dose-proportional over a 100 to 300 mg dose range in healthy subjects.

Contraindications

Tramadol Hydrochloride Extended-Release Tabletsshould 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 patients with significant respiratory depression in unmonitored settings or the absence of resuscitative equipment. Tramadol Hydrochloride Extended-Release Tablets are also contraindicated in patients with acute or severe bronchial asthma or hypercapnia in unmonitored settings or the absence of resuscitative equipment.

Warnings

Precautions

Information for patients

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 and 2-adrenergic blockers. Caution is advised when Tramadol Hydrochloride Extended-Release 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. Johns Wort. If concomitant treatment of Tramadol Hydrochloride Extended-Release 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 Extended-Release Tabletsare coadministered with a triptan. If concomitant treatment of Tramadol Hydrochloride Extended-Release Tabletswith a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).

Carcinogenesis, mutagenesis, 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/m 2or 0.5 times the maximum daily human dosage of 185 mg/m 2) 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 a rat carcinogenicity study (dosing orally up to 30 mg/kg to 180 mg/m 2equal to the maximum daily human dosage of tramadol).

Tramadol was not mutagenic in the following assays: Ames Salmonellamicrosomal 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. Positive mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Relevance of the finding in humans is unknown.

No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (300 mg/m 2) in male rats and 75 mg/kg (450 mg/m 2) in female rats. These dosages are 1.6 and 2.4 times the maximum daily human dosage of 185 mg/m 2, respectively.

Pregnancy

Adverse reactions

Tramadol Hydrochloride Extended-Release Tabletswere administered to a total of 2707 subjects (2406 patients and 301 healthy volunteers) during clinical studies, including four randomized double-blind studies (treatment 12 weeks) and two open-label long-term studies (treatment up to 12 months) in patients with moderate to severe pain due to osteoarthritis of the knee. A total of 844 patients were exposed to Tramadol Hydrochloride Extended-Release Tabletsfor 12 weeks, 493 patients for 6 months and 243 patients for 12 months. Treatment emergent adverse events increased with dose from 100 mg to 300 mg in the three twelve-week, randomized, double-blind, placebo-controlled studies (Table 2).

Table 2.Percentage of Patients with Incidence of Adverse Events 2% from Three 12-week Placebo-Controlled Studies (MDT3-002, MDT3-003 and MDT3-005).
*Due to the difference in study design of MDT3-005, only the results of the double-blind phase of the study are presented and the dose specific results include maintenance period data only.
ADVERSE EVENTS (MEDRA Preferred Terms) Tramadol Hydrochloride
Extended-Release Tablets
Placebo
100 mg 200 mg 300 mg Total*
N=216
N=311
N=530
N=1095
N=668
Nausea 28 (13%) 42 (14%) 76 (14%) 179 (16%) 37 (6%)
Constipation 21 (10%) 36 (12%) 52 (10%) 140 (13%) 26 (4%)
Dizziness 16 (7%) 28 (9%) 52 (10%) 106 (10%) 18 (3%)
Somnolence 11 (5%) 22 (7%) 23 (4%) 77 (7%) 12 (2%)
Vomiting 7 (3%) 16 (5%) 31 (6%) 58 (5%) 4 (1%)
Pruritus 9 (4%) 15 (5%) 18 (3%) 51 (5%) 7 (1%)
Headache 10 (5%) 9 (3%) 15 (3%) 41 (4%) 21 (3%)
Sweating increased 1 (0%) 9 (3%) 14 (3%) 35 (3%) 5 (1%)
Dry mouth 7 (3%) 13 (4%) 6 (1%) 32 (3%) 8 (1%)
Fatigue 6 (3%) 7 (2%) 9 (2%) 26 (2%) 6 (1%)
Anorexia 4 (2%) 4 (1%) 10 (2%) 25 (2%) 2 (0%)
Vertigo 2 (1%) 3 (1%) 6 (1%) 21 (2%) 3 (0%)
Insomnia 2 (1%) 6 (2%) 9 (2%) 18 (2%) 8 (1%)

The majority of patients who experienced the most common adverse events (5%) reported mild to moderate symptoms. Less than 3% of adverse events were rated as severe. Overall, onset of these adverse events usually occurred within the first two weeks of treatment.

Overdosage

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.

Death due to overdose has been reported with abuse and misuse of tramadol, by ingesting, inhaling, or injecting the crushed tablets. The risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol and 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

Tramadol Hydrochloride Extended-Release Tabletsshould be taken once a day. The tablets should be swallowed whole with liquid and not split, chewed, dissolved or crushed. Tramadol Hydrochloride Extended-Release Tablets produce a continuous release of active ingredient over 24 hours: a repeat dosage within 24 hours is not recommended.

Patients Not Currently on Tramadol Immediate-Release Products:

Treatment with Tramadol Hydrochloride Extended-Release Tabletsshould be initiated at a dose of 100 mg/day. Daily doses should be titrated by 100 mg/day increments every 2 to 3 days (i.e., start 200 mg/day on day 3 or 4 of therapy) to achieve a balance between adequate pain control and tolerability for the individual patient. For patients requiring the 300 mg daily dose, titration should take at least 4 days (i.e. 300 mg/day on day 5). The usual daily dose is 200 or 300 mg. The daily dose and titration should be individualized for each patient. Therapy should be continued with the lowest effective dose. Tramadol Hydrochloride Extended-Release Tabletsshould not be administered at a dose exceeding 300 mg per day.

Clinical experience suggests that signs and symptoms of withdrawal may be reduced by tapering medication when discontinuing tramadol therapy.

Patients Currently on Tramadol Immediate-Release Products:

For patients maintained on tramadol immediate release (IR) products, the 24-hour tramadol IR dose should be calculated and the patient should be initiated on a total daily dose of Tramadol Hydrochloride Extended-Release Tabletsrounded 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 Extended-Release Tablets, some patients maintained on tramadol IR products may not be able to convert to Tramadol Hydrochloride Extended-Release Tablets. Tramadol Hydrochloride Extended-Release Tabletsshould not be administered at a dose exceeding 300 mg per day.Do not use Tramadol Hydrochloride Extended-Release Tabletswith other tramadol products (see WARNINGS).

How supplied

Tramadol Hydrochloride Extended-Release Tablets are supplied in a number of packages and dose strengths:


100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.

Bottle of 30 tablets NDC 42858-901-03


200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other side.

Bottle of 30 tablets NDC 42858-902-03


300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other side.

Bottle of 30 tablets NDC 42858-903-03


Ingredients and appearance - Product information

Tramadol hydrochloride tablet, extended release- Tramadol hydrochloride

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 42858-901
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Tramadol hydrochloride ( UNII: 9N7R477WCK)( Tramadol - UNII: 39J1LGJ30J ) 100 mgin 1

Inactive Ingredients

Ingredient Name Code
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Starch, corn ( UNII: O8232NY3SJ)
Magnesium stearate ( UNII: 70097M6I30)
Povidone ( UNII: FZ989GH94E)
Sodium lauryl sulfate ( UNII: 368GB5141J)
Xanthan gum ( UNII: TTV12P4NEE)

Product Characteristics

Color WHITE Imprint Code PP;100
Shape ROUND Size 10 mm
Score 1

Packaging

# Item Code Package Description Marketing Start Date
1 NDC: 42858-901-03 30 in 1 BOTTLE 2011/12/30

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA authorized generic NDA021745 USA 2011/12/30

Tramadol hydrochloride tablet, extended release- Tramadol hydrochloride

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 42858-902
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Tramadol hydrochloride ( UNII: 9N7R477WCK)( Tramadol - UNII: 39J1LGJ30J ) 200 mgin 1

Inactive Ingredients

Ingredient Name Code
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Starch, corn ( UNII: O8232NY3SJ)
Magnesium stearate ( UNII: 70097M6I30)
Povidone ( UNII: FZ989GH94E)
Sodium lauryl sulfate ( UNII: 368GB5141J)
Xanthan gum ( UNII: TTV12P4NEE)

Product Characteristics

Color WHITE Imprint Code PP;200
Shape ROUND Size 10 mm
Score 1

Packaging

# Item Code Package Description Marketing Start Date
1 NDC: 42858-902-03 30 in 1 BOTTLE 2011/12/30

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA authorized generic NDA021745 USA 2011/12/30

Tramadol hydrochloride tablet, extended release- Tramadol hydrochloride

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 42858-903
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Tramadol hydrochloride ( UNII: 9N7R477WCK)( Tramadol - UNII: 39J1LGJ30J ) 300 mgin 1

Inactive Ingredients

Ingredient Name Code
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Starch, corn ( UNII: O8232NY3SJ)
Magnesium stearate ( UNII: 70097M6I30)
Povidone ( UNII: FZ989GH94E)
Sodium lauryl sulfate ( UNII: 368GB5141J)
Xanthan gum ( UNII: TTV12P4NEE)

Product Characteristics

Color WHITE Imprint Code PP;300
Shape ROUND Size 13 mm
Score 1

Packaging

# Item Code Package Description Marketing Start Date
1 NDC: 42858-903-03 30 in 1 BOTTLE 2011/12/30

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA authorized generic NDA021745 USA 2011/12/30

Labeler - Rhodes Pharmaceuticals L.P.( 831928986)

Establishment

Name ID/FEI Business Operations
Rhodes Pharmaceuticals L.P. 831928986 MANUFACTURE( 42858-901, 42858-902, 42858-903)

Package label.principal display panel



100 mgBottles of 30 tablets

Rx Only NDC 42858-901-03

200 mgBottles of 30 tablets

Rx Only NDC 42858-902-03





300 mgBottles of 30 tablets

Rx Only NDC 42858-903-03