Tramadolside effects

The following serious or otherwise important adverse reactions are described in greater detail, in other sections: Addiction, Abuse, and Misuse Life-Threatening Respiratory Depression Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children Neonatal Opioid Withdrawal Syndrome Interactions with Benzodiazepines and Other CNS Depressants Opioid-Induced Hyperalgesia and Allodynia Serotonin Syndrome Seizures Suicide Adrenal Insufficiency Severe Hypotension Gastrointestinal Adverse Reactions Hypersensitivity Reactions Withdrawal Most common adverse reactions (≥10% and ≥2 x placebo rate): Dizziness, constipation, nausea, headache, somnolence, flushing, pruritus, vomiting, insomnia, dry mouth. 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 81 90 57 28 Nausea 61 90 102 53 32 Constipation 49 68 85 60 17 Headache 49 62 46 32 43 Somnolence 33 45 29 41 7 Flushing 31 40 35 32 18 Pruritus 25 34 30 24 4 Vomiting 20 29 34 19 11 Insomnia 26 32 36 22 13 Dry Mouth 20 29 39 18 6 Diarrhea 15 27 37 10 17 Asthenia 14 24 26 13 7 Postural hypotension 7 17 8 11 9 Sweating increased 6 8 15 13 1 Anorexia 3 7 21 12 1 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 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 Reactions With Incidence Rates of 0.5% to <1.0% and Serious Adverse Reactions Reported in at Least 2 patients During Clinical Trials 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, urticaria Vascular disorders: hypertension aggravated, hypertension, peripheral ischemia

6.2 Postmarketing

Experience The following adverse reactions have been identified during post approval use of tramadol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in tramadol hydrochloride extended-release tablets. Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time. Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use. Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in overdose setting. Metabolism and nutrition disorders Hyponatremia: cases of severe hyponatremia and/or SIADH have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy. Hypoglycemia: Cases of hypoglycemia have been reported in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients. Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids, and may occur more frequently in patients taking higher doses of opioid, and/or in patients taking opioids longer term. Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months:

approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and

approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ], respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5- to 11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.