Tramadol

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 • Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosages or duration, and persist over the course of therapy, [see Warnings and Precautions (5.1)], reserve opioid analgesics, including tramadol hydrochloride extended-release tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated or would be otherwise inadequate to provide sufficient management of pain. • Tramadol hydrochloride extended-release tablets are not indicated as an as-needed (prn) analgesic. Tramadol hydrochloride extended-release tablets are an opioid agonist 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. (1) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosages or duration and persist over the course of therapy, reserve opioids analgesics, including tramadol hydrochloride extended-release tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. (1) Tramadol hydrochloride extended-release tablets are not indicated as an as-needed (prn) analgesic. (1)

12.1 Mechanism of Action Tramadol hydrochloride extended-release tablets contain tramadol, an opioid agonist and an inhibitor of reuptake of norepinephrine and serotonin. Although the mode of action of tramadol is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Opioid activity of tramadol is due to both low affinity binding of the parent compound and higher affinity binding of the O-desmethyl 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 opioid 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 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.

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 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. Do not use tramadol hydrochloride extended-release tablets concomitantly with other tramadol products [see Warnings and Precautions (5.3), (5.15)]. Do not administer tramadol hydrochloride extended-release tablets at a dose exceeding 300 mg per day. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)] . Because the risk of overdose increases as opioid doses increase, 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. Initiate the dosing regimen for each patient individually, taking i

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 dis

5 WARNINGS AND PRECAUTIONS Opioid Induced Hyperalgesia (OIH) and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (5.8) Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected. (5.9) Increased Risk of Seizures : Present within recommended dosage range. Risk is increased with higher than recommended doses and concomitant use of SSRIs, SNRIs, anorectics, tricyclic antidepressants and other tricyclic compounds, other opioids, MAOIs, neuroleptics, other drugs that reduce seizure threshold, in patients with epilepsy or at risk for seizures. (5.10, 7) Risk of Suicide : Do not use tramadol hydrochloride extended-release tablets in suicidal or addiction-prone patients. Use with caution in those taking tranquilizers, antidepressants or abuse alcohol. (5.11) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate closely, particularly during initiation and titration. (5.12) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.13) Severe Hypotension : Regularly evaluate during dosage initiation and titration. Avoid use of tramadol hydrochloride extended-release tablets in patients with circulatory shock. (5.14) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of tramadol hydrochloride extended-release tablets in patients with impaired consciousness or coma. (5.15) 5.1 Addiction, Abuse, and Misuse Tramadol hydrochloride extended-release tablet contains tramadol, a Schedule IV controlled substance. As an opioid, tramadol hydrochloride extended-release tablet exposes users to the risks of addiction, abuse, and misuse. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed tramadol hydrochloride extended-release tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2)]. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing tramadol hydrochloride extended-release tablets, and reassess all patients receiving tramadol hydrochloride extended-release tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as tramadol hydrochloride extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of tramadol hydrochloride extended-release tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. Abuse or misuse of tramadol hydrochloride extended-release tablets by cutting, breaking, chewing, crushing, snorting, or injecting the dissolved product will result in t

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)

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 hydrochloride extended-release tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. Tramadol hydrochloride extended-release tablets will continue to release tramadol and add to the tramadol load for 24 to 48 hours or longer following ingestion, necessitating prolonged monitoring. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product’s prescribing informa