Prescription Drug Name:

Tramadol Hydrochloride Tablets, USP CIV, Rx only, Full Prescribing Information

ID:

7f30ad02-f1b9-4976-85b8-3a4d0a61241b

Code:

34391-3

DESCRIPTION


id: a314ce34-8142-41b5-ae3e-9d7f04d916da
displayName: Description Section
FDA Article Code: 34089-3

Tramadol hydrochloride tablets are a centrally acting analgesic. The chemical name for tramadol hydrochloride is (±)cis-2-[(dimethylamino)methyl]-1-(3­-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:

The molecular weight of tramadol hydrochloride is 299.8. Tramadol hydrochloride USP is a white, crystalline powder. It 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 tablets, USP contain 50 mg of tramadol hydrochloride USP and are white in color. Inactive ingredients in the tablet are carnauba wax, corn starch, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate, povidone, sodium starch glycolate, and titanium dioxide.

CLINICAL STUDIES


id: 6c09b9c4-33cf-40de-9071-29270356eed0
displayName: Clinical Studies Section
FDA Article Code: 34092-7

Tramadol hydrochloride has been given in single oral doses of 50, 75 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars).

In single-dose models of pain following oral surgery, pain relief was demonstrated in some patients at doses of 50 mg and 75 mg. A dose of 100 mg tramadol hydrochloride tended to provide analgesia superior to codeine sulfate 60 mg, but it was not as effective as the combination of aspirin 650 mg with codeine phosphate 60 mg.

Tramadol hydrochloride has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol hydrochloride. Patients with a variety of chronic painful conditions were studied in double-blind trials of one to three months duration. Average daily doses of approximately 250 mg of tramadol hydrochloride in divided doses were generally comparable to five doses of acetaminophen 300 mg with codeine phosphate 30 mg (TYLENOL® with Codeine #3) daily, five doses of aspirin 325 mg with codeine phosphate 30 mg daily, or two to three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (TYLOX
®
) daily.

Titration Trials
 
In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily tramadol hydrochloride dose of 200 mg (50 mg four times per day), attained in 50 mg increments every 3 days, was found to result in fewer discontinuations due to dizziness or vertigo than titration over only 4 days or no titration.

Figure 2:

INDICATIONS AND USAGE


id: 4c740bdc-351b-4dc6-9981-435a7ab9a007
displayName: Indications & Usage Section
FDA Article Code: 34067-9

Tramadol hydrochloride tablets, USP are indicated for the management of moderate to moderately severe pain in adults.

CONTRAINDICATIONS


id: 0a0de6e4-0140-47f6-8a80-c748d24555fb
displayName: Contraindications Section
FDA Article Code: 34070-3

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

PRECAUTIONS


id: b894688d-3008-4eca-beeb-4bb58d9c7c4e
displayName: Precautions Section
FDA Article Code: 42232-9

Acute Abdominal Conditions

The administration of tramadol hydrochloride may complicate the clinical assessment of patients with acute abdominal conditions.

Use in Renal and Hepatic Disease
 
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, dosing reduction is recommended (see
DOSAGE AND ADMINISTRATION
). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended (see
DOSAGE AND ADMINISTRATION
).

With the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop.

ADVERSE REACTIONS


id: 9c349412-8753-42c6-9967-ec8872cdebd3
displayName: Adverse Reactions Section
FDA Article Code: 34084-4

Tramadol hydrochloride was administered to 550 patients during the double-blind or open-label extension periods in U.S. studies of chronic nonmalignant pain. Of these patients, 375 were 65 years old or older. Table 2 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. Although the reactions listed in the table are felt to be probably related to tramadol hydrochloride administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication. The overall incidence rates of adverse experiences in these trials were similar for tramadol hydrochloride and the active control groups, TYLENOL® with Codeine #3 (acetaminophen 300 mg with codeine phosphate 30 mg), and aspirin 325 mg with codeine phosphate 30 mg, however, the rates of withdrawals due to adverse events appeared to be higher in the tramadol hydrochloride groups.

Table 2: Cumulative Incidence of Adverse Reactions for Tramadol Hydrochloride in Chronic Trials of Nonmalignant Pain (N=427)
Up to 7 Days Up to 30 Days Up to 90 Days
1 “CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations
   Dizziness/Vertigo 26% 31% 33%
   Nausea 24% 34% 40%
   Constipation 24% 38% 46%
   Headache 18% 26% 32%
   Somnolence 16% 23% 25%
   Vomiting 9% 13% 17%
   Pruritus 8% 10% 11%
   “CNS Stimulation”1

 7% 11% 14%
   Asthenia 6% 11% 12%
   Sweating 6% 7% 9%
   Dyspepsia 5% 9% 13%
   Dry Mouth 5% 9% 10%
   Diarrhea 5% 6% 10%
Incidence 1
% to less than 5% possibly causally related

The following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with tramadol hydrochloride exists.

Body as a Whole: Malaise.

Cardiovascular: Vasodilation.

Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder.

Gastrointestinal: Abdominal pain, Anorexia, Flatulence.

Musculoskeletal: Hypertonia.

Skin: Rash.

Special Senses: Visual disturbance.

Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention.

Incidence less than 1
%, possibly causally related

The following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials and/or reported in postmarketing experience.

Body as a Whole: Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma).

Cardiovascular: Orthostatic hypotension, Syncope, Tachycardia.

Central Nervous System: Abnormal gait, Amnesia, Cognitive dysfunction, Depression, Difficulty in concentration, Hallucinations, Paresthesia, Seizure (see
WARNINGS
), Tremor.

Respiratory: Dyspnea.

Skin: Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles.

Special Senses: Dysgeusia.

Urogenital: Dysuria, Menstrual disorder.

Other adverse experiences, causal relationship unknown

A variety of other adverse events were reported infrequently in patients taking tramadol hydrochloride during clinical trials and/or reported in postmarketing experience. A causal relationship between tramadol hydrochloride and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.

Cardiovascular: Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism.

Central Nervous System: Migraine, Speech disorders.

Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.

Laboratory Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria.

Sensory: Cataracts, Deafness, Tinnitus.

OVERDOSAGE


id: d5e26676-6d56-4542-b67b-5458a15b07d5
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, 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 re­establishment 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 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


id: 0eeed1a8-910f-4c7c-83a3-d1336594329c
displayName: Dosage & Administration Section
FDA Article Code: 34068-7

Adults (17 years of age and over)

For patients with moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect, the tolerability of tramadol hydrochloride tablets can be improved by initiating therapy with a titration regimen: The total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg q.i.d.). After titration, tramadol hydrochloride tablets 50 mg to 100 mg can be administered as needed for pain relief every 4 to 6 hours not to exceed
400 mg/day.

For the subset of patients for whom rapid onset of analgesic effect is required and for whom the benefits outweigh the risk of discontinuation due to adverse events associated with higher initial doses, tramadol hydrochloride tablets 50 mg to 100 mg can be administered as needed for pain relief every four to six hours, not to exceed 400 mg per day.

Individualization of Dose
 
Good pain management practice dictates that the dose be individualized according to patient need using the lowest beneficial dose. Studies with tramadol in adults have shown that starting at the lowest possible dose and titrating upward will result in fewer discontinuations and increased tolerability. In all patients with creatinine clearance less than 30 mL/min, it is recommended that the dosing interval of tramadol hydrochloride tablets be increased to 12 hours, with a maximum daily dose of 200 mg. Since only 7% of an administered dose is removed by hemodialysis, dialysis patients can receive their regular dose on the day of dialysis. 
The recommended dose for adult patients with cirrhosis is 50 mg every 12 hours. 
In general, dose selection for an elderly patient over 65 years old should be cautious, 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. For elderly patients over 75 years old, total dose should not exceed 300 mg/day.

HOW SUPPLIED


id: 61749cff-203f-4bc0-9a2a-b1b7cf726461
displayName: How Supplied Section
FDA Article Code: 34069-5

Tramadol Hydrochloride Tablets USP, 50 mg are white to off-white, capsule shaped, coated tablet, debossed ‘T’ on one side and ‘03’ on the other side.                Bottles of 100                  NDC 57237-238-01
               Bottles of 500                  NDC 57237-238-05
               Bottles of 1,000                NDC 57237-238-99

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight container. Tylenol® is a registered trademark of McNeil Cons. Tylox® is a registered trademark of Ortho McNeil Pharm. Distributed by:
Citron Pharma LLC
Suite -1101
2 Tower Center Blvd
East Brunswick NJ 08816

Code No.: DRUGS/AP/22/2009

Made in India

Issued: 01/2016

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL – 50 mg (100 Tablets Bottle)


id: b12c1a85-2d60-4a8f-9b55-ec50ed401bf8
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4

100 Tablets                 NDC 57237-238-01

traMADOL Hydrochloride Tablets, USP

50 mg

Rx only

Citron Pharma