1 INDICATIONS AND USAGE Tramadol hydrochloride tablets are indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration ( 5.1 ), reserve tramadol hydrochloride tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products): • Have not been tolerated, or are not expected to be tolerated, (1) • Have not provided adequate analgesia, or are not expected to provide adequate analgesia (1) Tramadol hydrochloride tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

Tramadol hydrochloride tablets are an opioid agonist indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate (1) .

Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses , reserve tramadol hydrochloride tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]: • Have not been tolerated or are not expected to be tolerated.

• Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

• Have not provided adequate analgesia, or are not expected to provide adequate analgesia (1) Tramadol hydrochloride tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

6 ADVERSE REACTIONS The following serious adverse reactions are described, or 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)] • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)] • Ultra-Rapid Metabolism and Other Risk Factors for Life-threatening Respiratory Depression in Children [see Warnings and Precautions (5.6)] • 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)] The most common incidence of treatment-emergent adverse events (≥15.0%) in patients from clinical trials were dizziness/vertigo, nausea, constipation, headache, somnolence, vomiting and pruritus (6) .

To report SUSPECTED ADVERSE REACTIONS, ACI Healthcare USA, Inc.

at 1-888-802-1213 or www.acihealthcareusa.com or FDA at 1-800-FDA-1088 orwww.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 tablets were administered to 550 patients during the double-blind or open-label extension periods in U.S.

studies of chronic nonmalignant pain.

Of these patients, 375 were 65 years old or older.

Table 1 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days).

The most frequently reported events were in the central nervous system and gastrointestinal system.

Although the reactions listed in the table are felt to be probably related to tramadol hydrochloride tablets administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication.

The overall incidence rates of adverse experiences in these trials were similar for tramadol hydrochloride tablets and the active control groups, TYLENOL with Codeine #3 (acetaminophen 300 mg with codeine phosphate 30 mg), and aspirin 325 mg with codeine phosphate 30 mg, however, the rates of withdrawals due to adverse events appeared to be higher in the tramadol hydrochloride tablets groups.

Table 1: Cumulative Incidence of Adverse Reactions for Tramadol Hydrochloride Tablets in Chronic Trials of Nonmalignant Pain (N=427) Up to 7 Days Up to 30 Days Up to 90 Days Dizziness/Vertigo 26% 31% 33% Nausea 24% 34% 40% Constipation 24% 38% 46% Headache 18% 26% 32% Somnolence 16% 23% 25% Vomiting 9% 13% 17% Pruritus 8% 10% 11% “CNS Stimulation” 1 7% 11% 14% Asthenia 6% 11% 12% Sweating 6% 7% 9% Dyspepsia 5% 9% 13% Dry Mouth 5% 9% 10% Diarrhea 5% 6% 10% 1 “CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations Incidence 1% to Less than 5% Possibly Causally Related The following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with tramadol hydrochloride tablets exist.

Body as a Whole : Malaise.

Cardiovascular : Vasodilation.

Central Nervous System : Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder.

Gastrointestinal : Abdominal pain, Anorexia, Flatulence.

Musculoskeletal : Hypertonia.

Skin : Rash.

Special Senses : Visual disturbance.

Urogenital : Menopausal symptoms, Urinary frequency, Urinary retention.

Incidence Less than 1%, Possibly Causally Related The following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials of tramadol and/or reported in postmarketing experience with tramadol-containing products.

Body as a Whole : Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma).

Cardiovascular : Orthostatic hypotension, Syncope, Tachycardia.

Central Nervous System : Abnormal gait, Amnesia, Cognitive dysfunction, Depression, Difficulty in concentration, Hallucinations, Paresthesia, Seizure, Tremor.

Respiratory : Dyspnea.

Skin : Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles.

Special Senses : Dysgeusia.

Urogenital : Dysuria, Menstrual disorder.

Other Adverse Experiences, Causal Relationship Unknown A variety of other adverse events were reported infrequently in patients taking tramadol hydrochloride tablets during clinical trials and/or reported in postmarketing experience.

A causal relationship between tramadol hydrochloride tablets and these events has not been determined.

However, the most significant events are listed below as alerting information to the physician.

Cardiovascular : Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism.

Central Nervous System : Migraine.

Gastrointestinal : Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.

Laboratory Abnormalities : Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria.

Sensory : Cataracts, Deafness, Tinnitus.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tramadol hydrochloride tablets.

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.

Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)].

Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.8)] 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 the overdose setting.

Eye disorders – mydriasis 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 [see Warnings and Precautions ( 5.19 )] .

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 [see Warnings and Precautions ( 5.20 )] .

Nervous system disorders – movement disorder, speech disorder Psychiatric disorders – delirium