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adverse reactions
ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see WARNINGS ] Life-Threatening Respiratory Depression [see WARNINGS ] Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children [see WARNINGS ] Neonatal Opioid Withdrawal Syndrome [see WARNINGS ] Interactions with Benzodiazepines or Other CNS Depressants [see WARNINGS ] Serotonin Syndrome [see WARNINGS ] Seizures [see WARNINGS ] Suicide [see WARNINGS ] Adrenal Insufficiency [see WARNINGS ] Severe Hypotension [see WARNINGS ] Gastrointestinal Adverse Reacti ons [see WARNINGS ] Hypersensitivity Reactions [see WARNINGS ] Withdrawal [see WARNINGS ] 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 2707 subjects (2406 patients and 301 healthy volunteers) during clinical studies, including four randomized double-blind studies (treatment ≥ 12 weeks) and two open-label long-term studies (treatment up to 12 months) in patients with moderate to severe pain due to osteoarthritis of the knee. A total of 844 patients were exposed to Tramadol Hydrochloride Extended-Release Tablets for 12 weeks, 493 patients for 6 months and 243 patients for 12 months. Treatment emergent adverse events increased with dose from 100 mg to 300 mg in the three twelve-week, randomized, double-blind, placebo-controlled studies ( Table 2). Table 2. Percentage of Patients with Incidence of Adverse Events ≥ 2% from Three 12-week Placebo- Controlled Studies (MDT3-002, MDT3-003 and MDT3-005). Tramadol Hydrochloride Extended-Release Tablets Placebo ADVERSE EVENTS (MEDRA Preferred Terms) 100 mg 200 mg 300 mg Total* N=216 N=311 N=530 N=1095 N=668 Nausea 28 (13%) 42 (14%) 76 (14%) 179 (16%) 37 (6%) Constipation 21 (10%) 36 (12%) 52 (10%) 140 (13%) 26 (4%) Dizziness 16 (7%) 28 (9%) 52 (10%) 106 (10%) 18 (3%) Somnolence 11 (5%) 22 (7%) 23 (4%) 77 (7%) 12 (2%) Vomiting 7 (3%) 16 (5%) 31 (6%) 58 (5%) 4 (1%) Pruritus 9 (4%) 15 (5%) 18 (3%) 51 (5%) 7 (1%) Headache 10 (5%) 9 (3%) 15 (3%) 41 (4%) 21 (3%) Sweating increased 1 (0%) 9 (3%) 14 (3%) 35 (3%) 5 (1%) Dry mouth 7 (3%) 13 (4%) 6 (1%) 32 (3%) 8 (1%) Fatigue 6 (3%) 7 (2%) 9 (2%) 26 (2%) 6 (1%) Anorexia 4 (2%) 4 (1%) 10 (2%) 25 (2%) 2 (0%) Vertigo 2 (1%) 3 (1%) 6 (1%) 21 (2%) 3 (0%) Insomnia 2 (1%) 6 (2%) 9 (2%) 18 (2%) 8 (1%) *Due to the difference in study design of MDT3-005, only the results of the double-blind phase of the study are presented and the dose specific results include maintenance period data only. The majority of patients who experienced the most common adverse events (≥5%) reported mild to moderate symptoms. Less than 3% of adverse events were rated as severe. Overall, onset of these adverse events usually occurred within the first two weeks of treatment. Adverse reactions with an incidence of 1.0% to <5.0% Ear and labyrinth disorders: vertigo Gastrointestinal disorders: abdominal pain, diarrhea, dry mouth, dyspepsia, upper abdominal pain General disorders: fatigue, weakness Investigations: weight decreased Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: arthralgia Nervous system disorders: headache, tremor Psychiatric disorders: anxiety, insomnia Skin and subcutaneous tissue disorders: pruritus, sweating increased Vascular disorders: hot flushes Adverse reactions with an incidence of <1.0% Blood and lymphatic system disorders: anemia, thrombocytopenia Cardiac disorders: bradycardia Eye disorders: blurred vision, visual disturbance Gastrointestinal disorders: abdominal discomfort, abdominal distension, abdominal tenderness, change in bowel habit, constipation aggravated, diverticulitis, diverticulum, dyspepsia aggravated, dysphagia, fecal impaction, gastric irritation, gastritis, gastrointestinal hemorrhage, gastrointestinal irritation, gastro-esophageal reflux disease, lower abdominal pain, pancreatitis aggravated, rectal hemorrhage, rectal prolapse, retching General disorders: asthenia, malaise Hepatobiliary disorders: biliary tract disorder, cholelithiasis Immune system disorders: hypersensitivity Investigations: alanine aminotransferase decreased, alanine aminotransferase increased, aspartate aminotransferase decreased, aspartate aminotransferase increased, blood amylase increased, blood creatinine increased, blood in stool, blood potassium abnormal, blood pressure increased gamma glutamyltransferase increased Metabolism and nutrition disorders: appetite decreased, dehydration Nervous system disorders: ataxia, disturbance in attention, dysarthria, gait abnormal, headache aggravated, mental impairment, sedation, seizure, sleep apnea syndrome, syncope, tremor Psychiatric disorders: abnormal behavior, agitation, anxiety, confusion, depression, emotional disturbance, euphoric mood, indifference, irritability, libido decreased, nervousness, sleep disorder Renal and urinary disorders: difficulty in micturition, urinary hesitation, urinary retention Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders: dyspnea Skin and subcutaneous tissue disorders: allergic dermatitis, cold sweat, dermatitis, night sweats, pallor, generalized pruritus, urticaria Vascular disorders: flushing, hypertension, hypotension, orthostatic hypotension 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 tramadol hydrochloride 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 chronic use of opioids [see CLINICAL PHARMACOLOGY ] .
adverse reactions
DRUG ABUSE AND DEPENDENCE Controlled Substance Tramadol Hydrochloride Extended-Release Tablets contain tramadol, a Schedule IV controlled substance. Abuse Tramadol Hydrochloride Extended-Release Tablets contain tramadol, a substance with a high potential for abuse similar to other opioids. Tramadol Hydrochloride Extended-Release Tablets can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS ]. All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful, or potentially harmful, consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating health care providers. “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. Tramadol Hydrochloride Extended-Release Tablets, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Tramadol Hydrochloride Extended-Release Tablets Tramadol Hydrochloride Extended-Release Tablets are for oral use only. The abuse of Tramadol Hydrochloride Extended-Release Tablets poses a risk of overdose and death. The risk is increased with concurrent use of Tramadol Hydrochloride Extended-Release Tablets with alcohol and other central nervous system depressants. With intravenous abuse the inactive ingredients in Tramadol Hydrochloride Extended-Release Tablets can result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Do not abruptly discontinue Tramadol Hydrochloride Extended-Release Tablets in a patient physically dependent on opioids. Rapid tapering of Tramadol Hydrochloride Extended-Release Tablets in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing Tramadol Hydrochloride Extended-Release Tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Tramadol Hydrochloride Extended-Release Tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [ see DOSAGE AND ADMINISTRATION , WARNINGS ] . Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see PRECAUTIONS; Pregnancy ].