Tramadol
FDA Drug Information • Also known as: TRAMADOL HYDROCHLORIDE
- Brand Names
- TRAMADOL HYDROCHLORIDE
- Route
- ORAL
- Product Type
- HUMAN PRESCRIPTION DRUG
⚠ Boxed Warning (Black Box)
WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF TRAMADOL HYDROCHLORIDE EXTENDED-RELEASE TABLETS Addiction, Abuse, and Misuse Because the use of tramadol hydrochloride extended-release tablets exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of tramadol hydrochloride extended-release tablets , especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of tramadol hydrochloride extended-release tablets are essential [see Warnings and Precautions (5.2)]. Instruct patients to swallow tramadol hydrochloride extended-release tablets whole to avoid exposure to a potentially fatal dose of tramadol [see Warnings and Precautions (5.2)]. Accidental Ingestion Accidental ingestion of even one dose of tramadol hydrochloride extended-release tablets , especially by children, can result in a fatal overdose of tramadol [see Warnings and Precautions (5.2)] . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of tramadol hydrochloride extended-release tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3), Drug Interactions (7)] . Neonatal Opioid Withdrawal Syndrome (NOWS) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4)] . Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.5)] . Ultra-Rapid Metabolism Of Tramadol And Other Risk Factors For Life-Threatening Respiratory Depression In Children Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy, and in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism [ see Warnings and Precautions (5.6) ]. Tramadol hydrochloride extended-release tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [ see Contraindications (4) ] . Avoid the use of tramadol hydrochloride extended-release tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol. [see Warnings and Precautions (5.6)] Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride extended-release tablets requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 [see Warnings and Precautions (5.7), Drug Interactions (7)] . WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF TRAMADOL HYDROCHLORIDE EXTENDED-RELEASE TABLETS See full prescribing information for complete boxed warning . Tramadol hydrochloride extended-release tablets expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and reassess regularly for these behaviors and conditions. (5.1) Serious, life-threatening, or fatal respiratory depression may occur, especially upon initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration are essential. Instruct patients to swallow tramadol hydrochloride extended-release tablets whole to avoid exposure to a potentially fatal dose of tramadol. (5.2) Accidental ingestion of tramadol hydrochloride extended-release tablets, especially by children, can result in a fatal overdose of tramadol. (5.2) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.3, 7) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be lifethreatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (5.4)
Description
11 DESCRIPTION Tramadol hydrochloride is an opioid agonist in an extended-release tablet formulation for oral use. The chemical name is (±) cis -2-[(dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is: The molecular weight of tramadol hydrochloride is 299.84. 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, USP 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 maize 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. Meets USP dissolution test 4. tramadol-structure
What Is Tramadol Used For?
1 INDICATIONS AND USAGE Tramadol hydrochloride extended-release tablets are indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids. Limitations of Use
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Tramadol hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (2.1) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of tramadol hydrochloride extended-release tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (2.1, 5) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (2.1, 5.1) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with tramadol hydrochloride extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1, 5.2) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with tramadol hydrochloride extended-release tablets, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. (2.2, 5.1, 5.2, 5.3) Tramadol hydrochloride extended-release tablets should be taken once daily, at approximately the same time every day. (2.3) For patients currently on tramadol IR, calculate total 24-hr IR dose, and initiate tramadol hydrochloride extended-release tablets at a dose rounded down to next lower 100 mg increment; then adjust dose according to need and tolerance. See full prescribing information for instructions on conversion, titration, and maintenance of therapy. (2.3, 2.4) For patients converting from other opioid analgesics, discontinue all opioid analgesics other than as needed for breakthrough pain and initiate tramadol hydrochloride extended-release tablets at a dose of 100 mg once daily, then titrate up by 100 mg increments every 5 days according to need and tolerance. (2.3, 2.4) Do not exceed a daily dose of 300 mg tramadol. Do not use with other tramadol products. (2.4) Periodically reassess patients receiving tramadol hydrochloride extended-release tablets to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. (2.4) Do not rapidly reduce or abruptly discontinue tramadol hydrochloride extended-release tablets in a physically-dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.5, 5.18) 2.1 Important Dosage and Administration Instructions...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following serious or otherwise important adverse reactions are described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions (5.6)] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.3)] Opioid-Induced Hyperalgesia and Allodynia [See Warnings and Precautions (5.8)] Serotonin Syndrome [see Warnings and Precautions (5.9)] Seizures [see Warnings and Precautions (5.10)] Suicide [see Warnings and Precautions (5.11)] Adrenal Insufficiency [see Warnings and Precautions (5.13)] Severe Hypotension [see Warnings and Precautions (5.14)] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.16)] Hypersensitivity Reactions [see Warnings and Precautions (5.17)] Withdrawal [see Warnings and Precautions (5.18)] Most common adverse reactions (≥10% and ≥2 x placebo rate): Dizziness, constipation, nausea, headache, somnolence, flushing, pruritus, vomiting, insomnia, dry mouth. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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 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 reactions 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 Table 1). The most common adverse reactions from Table 1 occurring in ≥10% and ≥2 x placebo rate of the patients treated with tramadol hydrochloride extended-release tablets are dizziness (not vertigo), nausea, constipation, headache, somnolence, flushing, pruritus, vomiting, insomnia, and dry mouth. Table 1: Incidence (%) of patients with adverse reaction rates ≥ 5% from two 12-week placebo-controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1811). MedDRA Preferred Term Tramadol Hydrochloride Extended-Release Tablets Placebo 100 mg (N=403) n (%) 200 mg (N=400) n (%) 300 mg (N=400) n (%) 400 mg (N=202) n (%) (N=406) n (%) Dizziness (not vertigo) 64 (16) 81 (20) 90 (23) 57 (28) 28 (7) Nausea 61 (15) 90 (23) 102 (26) 53 (26) 32 (8) Constipation 49 (12) 68 (17) 85 (21) 60 (30) 17 (4) Headache 49 (12) 62 (16) 46 (12) 32 (16) 43 (11) Somnolence 33 (8) 45 (11) 29 (7) 41 (20) 7 (2) Flushing 31 (8) 40 (10) 35 (9) 32 (16) 18 (4) Pruritus 25 (6) 34 (9) 30 (8) 24 (12) 4 (1) Vomiting 20 (5) 29 (7) 34 (9) 19 (9) 11 ( 3) Insomnia 26 (7) 32 (8) 36 (9) 22 (11) 13 (3) Dry Mouth 20 (5) 29 (7) 39 (10) 18 (9) 6 (2) Diarrhea 15 (4) 27 (7) 37 (9) 10 (5) 17 (4) Asthenia 14 (4) 24 (6) 26 (7) 13 (6) 7 (2) Postural hypotension 7 (2) 17 (4) 8 (2) 11 (5) 9 (2) Sweating increased 6 (2) 8 (2) 15 (4) 13 (6) 1 (0) Anorexia 3 (1) 7 (2) 21 (5) 12 (6) 1 (0) Adverse reactions With Incidence Rates of 1.0% to <5.0% During Clinical Trials The following adverse reactions were reported from all the chronic pain studies (N=3108). The lists below include adverse reactions not otherwise noted in Table 1. Eye disorders: vision blurred Gastrointestinal...
Drug Interactions
7 DRUG INTERACTIONS Table 2 includes clinically significant drug interactions with tramadol hydrochloride extended-release tablets. Table 2: Clinically Significant Drug Interactions with Tramadol Hydrochloride Extended-Release Tablets Inhibitors of CYP2D6 Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology ( 12.3 )] . Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, evaluate patients at frequent intervals for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Evaluate patients at frequent intervals for adverse events including respiratory depression and sedation. Examples Quinidine, fluoxetine, paroxetine and bupropion Inhibitors of CYP3A4 Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Intervention: If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Inform...
Contraindications
4 CONTRAINDICATIONS Tramadol hydrochloride extended-release tablets are contraindicated for: all children younger than 12 years of age [see Warnings and Precautions (5.4)] post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.4)] . Tramadol hydrochloride extended-release tablets are also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.3)] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.12)] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.15)] Hypersensitivity to tramadol (e.g., anaphylaxis) [see Warnings and Precautions (5.17), Adverse Reactions (6.2)] Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days [see Drug Interactions (7)] . Children younger than 12 years of age (4) Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. (4) Significant respiratory depression (4) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment (4) Known or suspected gastrointestinal obstruction, including paralytic ileus (4) Hypersensitivity to tramadol (4) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days (4)
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)] . Available data with tramadol hydrochloride extended-release tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD). Tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms and signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4)] . Neonatal seizures, neonatal...
Overdosage
10 OVERDOSAGE Clinical Presentation Acute overdosage with tramadol hydrochloride extended-release tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, QT prolongation, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology ( 12.2 )] . Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. For clinically significant respiratory or circulatory depression secondary to tramadol overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. While an opioid overdose reversal agent will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with reversal agent administration. In animals, convulsions following the administration of toxic doses of tramadol hydrochloride extended-release tablets 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. Because the duration of opioid reversal is expected to be less than the duration of action of tramadol in tramadol...
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Tramadol hydrochloride extended-release tablets, USP 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. Bottles of 30's with Child Resistant Cap ……………... NDC 47335-859-83 Bottles of 100's with Child Resistant Cap ……………. NDC 47335-859-88 Bottles of 100's with Non Child Resistant Cap ……… NDC 47335-859-08 Bottles of 1000's with Non Child Resistant Cap …….. NDC 47335-859-18 200 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. Bottles of 30's with Child Resistant Cap ……………... NDC 47335-860-83 Bottles of 100's with Child Resistant Cap ……………. NDC 47335-860-88 Bottles of 100's with Non Child Resistant Cap ……… NDC 47335-860-08 Bottles of 1000's with Non Child Resistant Cap …….. NDC 47335-860-18 300 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. Bottles of 30's with Child Resistant Cap ……………... NDC 47335-861-83 Bottles of 100's with Child Resistant Cap ……………. NDC 47335-861-88 Bottles of 100's with Non Child Resistant Cap ……… NDC 47335-861-08 Bottles of 1000's with Non Child Resistant Cap …….. NDC 47335-861-18 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. Store tramadol hydrochloride extended-release tablets securely and dispose of properly [see Patient Counseling Information (17) ].
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.