Tramadol Hydrochloride

Product Type: HUMAN PRESCRIPTION DRUG

Route: ORAL

Dosage Form:

NDC: 68180-383

Application: ANDA200503

Effective: 20231211

INDICATIONS AND USAGE 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.

DOSAGE AND ADMINISTRATION 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 tablet 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 ). Adults (18 years of age and over) Patients Not Currently on Tramadol Immediate-Release Products For patients not currently treated with tramadol immediate-release (IR) products, Tramadol hydrochloride extended-release tablet should be initiated at a dose of 100 mg once daily and titrated up as necessary by 100-mg increments every five days to relief of pain and depending upon tolerability. Tramadol hydrochloride extended-release tablets should not be administered at a dose exceeding 300 mg per day. Patients Currently on Tramadol Immediate-Release Products For patients maintained on tramadol IR products, calculate the 24-hour tramadol IR dose and initiate a total daily dose of tramadol hydrochloride extended-release tablet rounded 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 tablet. Tramadol hydrochloride extended-release tablet should not be administered at a dose exceeding 300 mg per day. The concomitant use of tramadol hydrochloride extended-release tablet with other tramadol products is not recommended (see WARNINGS) . Individualization of Dose Good pain management practice dictates that the dose be individualized according to patient need using the lowest beneficial dose. Start at the lowest possible dose and titrate upward as tolerated to achieve an adequate effect. Clinical studies of tramadol hydrochloride extended-release tablet have not demonstrated a clinical benefit at a total daily dose exceeding 300 mg. In general, dosing of an elderly patient (over 65 years of age) should be initiated cautiously, 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. Tramadol hydrochloride extended-release tablet should be administered with even greater caution in patients over 75 years, due to the greater frequency of adverse events seen in this population.

CONTRAINDICATIONS Tramadol hydrochloride extended-release tablet 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 tablet is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, and narcotics, centrally acting analgesics, opioids or psychotropic drugs. Tramadol hydrochloride extended-release tablet may worsen central nervous system and respiratory depression in these patients.

WARNINGS Seizure Risk Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking: Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics), Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or Other opioids. Administration of tramadol may enhance the seizure risk in patients taking: MAO inhibitors ( see also WARNINGS - Use with MAO Inhibitors ), Neuroleptics, or Other drugs that reduce the seizure threshold. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol overdose, naloxone administration may increase the risk of seizure. Suicide Risk Do not prescribe tramadol hydrochloride extended-release tablets for patients who are suicidal or addiction-prone. Prescribe tramadol hydrochloride extended-release tablets with caution for patients taking tranquilizers or antidepressant drugs and patients who use alcohol in excess. Tell your patients not to exceed the recommended dose and to limit their intake of alcohol. Serotonin Syndrome Risk The development of a potentially life-threatening serotonin syndrome may occur with use of tramadol products, including tramadol hydrochloride extended-release tablets, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, with drugs which impair metabolism of serotonin (including MAOIs) and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose. (See CLINICAL PHARMACOLOGY—Pharmacokinetics ). Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Tramadol products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a major cause of drug-related deaths. Fatalities within the first hour of overdosage are not uncommon. Tramadol should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations. Many of the tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. Patients taking tramadol should be warned not to exceed the dose recommended by their physician Anaphylactoid Reactions Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive tramadol hydrochloride extended-release tablets (see CONTRAINDICATIONS ). Respiratory Depression Administer tramadol hydrochloride extended-release tablets cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered. When large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see WARNINGS Seizure Risk and OVERDOSAGE ). Interaction With Central Nervous System (CNS) Depressants Tramadol hydrochloride extended-release tablets should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Tramadol hydrochloride extended-release tablets increases the risk of CNS and respiratory depression in these patients. Increased Intracranial Pressure or Head Trauma Tramadol hydrochloride extended-release tablets should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving tramadol hydrochloride extended-release tablets. (see WARNINGS - Respiratory Depression. ) Use in Ambulatory Patients Tramadol hydrochloride extended-release tablets may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly. Use With MAO Inhibitors and Serotonin Re-uptake Inhibitors Use Tramadol hydrochloride extended-release tablets with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of Tramadol hydrochloride extended-release tablets with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome. Withdrawal Withdrawal symptoms may occur if tramadol hydrochloride extended-release tablet is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience suggests that withdrawal symptoms may be reduced by tapering tramadol hydrochloride extended-release tablets. Misuse, Abuse and Diversion of Opioids Tramadol is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Tramadol can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing tramadol hydrochloride extended-release tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Tramadol hydrochloride extended-release tablets could be abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND ADDICTION ). Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Interactions with Alcohol and Drugs of Abuse Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

ADVERSE REACTIONS Tramadol hydrochloride extended-release tablet was 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 generally 7 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). Table 2: Incidence (%) of patients with adverse event 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 Tranadol hydrochloride extended - release tablets Placebo 100 mg 200 mg 300 mg 400 mg ( N = 406 ) ( N = 403 ) ( N = 400 ) ( N = 400 ) ( N = 202 ) n (%) n (%) n (%) n (%) n (%) Dizziness (not vertigo) 64 (15.9) 81 (20.3) 90 (22.5) 57 (28.2) 28 ( 6.9) Nausea 61 (15.1) 90 (22.5) 102 (25.5) 53 (26.2) 32 ( 7.9) Constipation 49 (12.2) 68 (17) 85 (21.3) 60 (29.7) 17 ( 4.2) Headache 49 (12.2) 62 (15.5) 46 (11.5) 32 (15.8) 43 (10.6) Somnolence 33 ( 8.2) 45 (11.3) 29 ( 7.3) 41 (20.3) 7 ( 1.7) Flushing 31 ( 7.7) 40 (10) 35 ( 8.8) 32 (15.8) 18 ( 4.4) Pruritus 25 ( 6.2) 34 ( 8.5) 30 ( 7.5) 24 (11.9) 4 ( 1) Vomiting 20 ( 5) 29 ( 7.3) 34 ( 8.5) 19 ( 9.4) 11 ( 2.7) Insomnia 26 ( 6.5) 32 ( 8) 36 ( 9) 22 (10.9) 13 ( 3.2) Dry Mouth 20 (5) 29 (7.3) 39 (9.8) 18 (8.9) 6 (1.5) Diarrhea 15 (3.7) 27 (6.8) 37 (8.5) 10 (5) 17 (4.2) Asthenia 14 ( 3.5) 24 ( 6) 26 ( 6.5) 13 ( 6.4) 7 ( 1.7) Postural hypotension 7 ( 1.7) 17 ( 4.3) 8 ( 2) 11 ( 5.4) 9 ( 2.2) Sweating increased 6 ( 1.5) 8 ( 2) 15 ( 3.8) 13 ( 6.4) 1 ( 0.2) Anorexia 3 (0.7) 7 (1.8) 21(5.3) 12 (5.9) 1( 0.2) The following adverse events were reported from all the chronic pain studies (N=3108). The lists below include adverse events not otherwise noted in Table 2. Adverse events with incidence rates of 1% to <5% Eye disorders Vision blurred Gastrointestinal disorders Abdominal pain upper, dyspepsia, abdominal pain, sore throat General disorders Weakness, pain, feeling hot, influenza like illness, fall, rigors, lethargy, pyrexia, chest pain Infections and infestations Nasopharyngitis, upper respiratory tract infection, sinusitis, influenza, gastroenteritis viral, urinary tract infection, bronchitis Investigations Blood creatine phosphokinase increased, weight decreased Metabolism and nutrition disorders Appetite decreased Musculoskeletal, connective tissue and bone disorders Arthralgia, back pain, pain in limb, neck pain Nervous system disorders tremor, paresthesia, hypoesthesia Psychiatric disorders Nervousness, anxiety, depression, restlessness Respiratory, thoracic and mediastinal disorders Sneezing, cough rhinorrhea, nasal congestion, dyspnea, sinus congestion Skin and subcutaneous tissue disorders Sweating increased, dermatitis Vascular disorders Hot flushes, vasodilatation Adverse events with incidence rates of 0.5% to <1% and serious adverse events reported in at least 2 patients. Cardiac disorders Palpitations, myocardial infarction Ear and labyrinth disorders Tinnitus, vertigo Gastrointestinal disorders Flatulence, toothache, constipation aggravated, appendicitis, pancreatitis General disorders Feeling jittery, edema lower limb, shivering, joint swelling, malaise, drug withdrawal syndrome, peripheral swelling Hepato-biliary disorders Cholelithiasis, cholecystitis Infections and infestations Cellulitis, ear infection, gastroenteritis, pneumonia, viral infection Injury and poisoning Joint sprain, muscle injury Investigations Alanine aminotransferase increased, blood pressure increased, aspartate aminotransferase increased, heart rate increased, blood glucose increased, liver function tests abnormal Musculoskeletal, connective tissue and bone disorders Muscle cramps, muscle spasms, joint stiffness, muscle twitching, myalgia, osteoarthritis aggravated Nervous system disorders Migraine, sedation, syncope, disturbance in attention, dizziness aggravated Psychiatric disorders Euphoric mood, irritability, libido decreased, sleep disorder, agitation, disorientation, abnormal dreams Renal and urinary disorders Difficulty in micturition, urinary frequency, hematuria, dysuria, urinary retention Respiratory, thoracic and mediastinal disorders Yawning Skin and subcutaneous tissue disorders Contusion, piloerection, clamminess, night sweats, urticarial Vascular disorders Hypertension aggravated, hypertension, peripheral ischemia