Tapentadolside effects

The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse Life-Threatening Respiratory Depression Interaction with Benzodiazepine or Other CNS Depressants Neonatal Opioid Withdrawal Syndrome Opioid-Induced Hyperalgesia and Allodynia Serotonin Syndrome Adrenal Insufficiency Severe Hypotension Gastrointestinal Adverse Reactions Seizures Withdrawal The most common (≥10%) adverse reactions were nausea, constipation, dizziness, headache, and somnolence. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical

Trial 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 clinical practice. Commonly-Observed Adverse Reactions in Clinical Studies with tapentadol extended-release tablets in Patients with Chronic Pain due to Low Back Pain or Osteoarthritis The safety data described in Table 1 below are based on three pooled, randomized, double-blind, placebo-controlled, parallel group, 15-week studies of tapentadol extended-release tablets (dosed 100 to 250 mg BID after a 50 mg BID starting dose) in patients with chronic pain due to low back pain (LBP) and osteoarthritis (OA). These trials included 980 tapentadol extended-release tablet-treated patients and 993 placebo-treated patients. The mean age was 57 years old; 63% were female and 37% were male; 83% were White, 10% were Black, and 5% were Hispanic. The most common adverse reactions (reported by ≥10% in any tapentadol extended-release tablet dose group) were: nausea, constipation, dizziness, headache, and somnolence. The most common reasons for discontinuation due to adverse reactions in eight Phase 2/3 pooled studies reported by ≥1% in any tapentadol extended-release tablet dose group for tapentadol extended-release tablet- and placebo-treated patients were nausea (4% vs. 1%), dizziness (3% vs. <1%), vomiting (3% vs. <1%), somnolence (2% vs. <1%), constipation (1% vs. <1%), headache (1% vs. <1%), and fatigue (1% vs. <1%), respectively. Table 1. Adverse Drug Reactions Reported by ≥ 1% of tapentadol extended-release tablet-Treated Patients and Greater than Placebo-Treated Patients in Pooled Parallel-Group Trials MedDRA preferred terms. The trials included forced titration during the first week of dosing. Tapentadol extended-release tablets 50 to 250 mg BID Tapentadol extended-release tablet dosed between 100 and 250 mg BID after a starting dose of 50 mg BID (n=980) Placebo (n=993) Nausea 21% 7% Constipation 17% 7% Dizziness 17% 6% Headache 15% 13% Somnolence 12% 4% Fatigue 9% 4% Vomiting 8% 3% Dry mouth 7% 2% Hyperhidrosis 5% <1% Pruritus 5% 2% Insomnia 4% 2% Dyspepsia 3% 2% Lethargy 2% <1% Asthenia 2% <1% Anxiety 2% 1% Decreased appetite 2% <1% Vertigo 2% <1% Hot flush 2% <1% Disturbance in attention 1% <1% Tremor 1% <1% Chills 1% 0% Abnormal dreams 1% <1% Depression 1% <1% Vision blurred 1% <1% Erectile dysfunction 1% <1% Commonly-Observed Adverse Reactions in Clinical Studies with tapentadol extended-release tablets in Patients with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The types of adverse reactions seen in the studies of patients with painful diabetic peripheral neuropathy (DPN) were similar to what was seen in the low back pain and osteoarthritis trials. The safety data described in Table 2 below are based on two pooled, randomized withdrawal, double-blind, placebo-controlled, 12-week studies of tapentadol extended-release tablets (dosed 100 to 250 mg BID) in patients with neuropathic pain associated with diabetic peripheral neuropathy. These trials included 1040 tapentadol extended-release tablet-treated patients and 343 placebo-treated patients. The mean age was 60 years old; 40% were female and 60% were male; 76% were White, 12% were Black, and 12% were "Other". The most commonly reported ADRs (incidence ≥10% in tapentadol extended-release tablet-treated subjects) were: nausea, constipation, vomiting, dizziness, somnolence, and headache. Table 2 lists the common adverse reactions reported in 1% or more of tapentadol extended-release tablet-treated patients and greater than placebo-treated patients with neuropathic pain associated with diabetic peripheral neuropathy in the two pooled studies. Table 2. Adverse Drug Reactions Reported by ≥ 1% of tapentadol extended-release tablet-Treated Patients and Greater than Placebo-Treated Patients in Pooled Trials (Studies DPN-1 and DPN-2) MedDRA preferred terms. Tapentadol extended-release tablets 50 to 250 mg BID Tapentadol extended-release tablets dosed between 100 and 250 mg BID after a starting dose of 50 mg BID. It includes ADR reported in the open-label titration period for all subjects and in the double-blind maintenance period for the subjects who were randomized to tapentadol extended-release tablet. (n=1040) Placebo It includes ADR reported in the double-blind maintenance period for the subjects who were randomized to placebo after receiving tapentadol extended-release tablets during the open-label titration period. (n=343) Nausea 27% 8% Dizziness 18% 2% Somnolence 14% <1% Constipation 13% <1% Vomiting 12% 3% Headache 10% 5% Fatigue 9% <1% Pruritus 8% 0% Dry mouth 7% <1% Diarrhea 7% 5% Decreased appetite 6% <1% Anxiety 5% 4% Insomnia 4% 3% Hyperhidrosis 3% 2% Hot flush 3% 2% Tremor Tremor was observed in 3.4% of tapentadol extended-release tablet-treated subjects vs. 3.2% in placebo group, chills in 1.3% vs.1.2% in placebo, and feeling cold- in 1.3% vs.1.2% in placebo. 3% 3% Abnormal dreams 2% 0% Lethargy 2% 0% Asthenia 2% <1% Irritability 2% 1% Dyspnea 1% 0% Nervousness 1% 0% Sedation 1% 0% Vision blurred 1% 0% Pruritus generalized 1% 0% Vertigo 1% <1% Abdominal discomfort 1% <1% Hypotension 1% <1% Dyspepsia 1% <1% Hypoesthesia 1% <1% Depression 1% <1% Rash 1% <1% Chills 1% 1% Feeling cold 1% 1% Drug withdrawal syndrome 1% <1% Other Adverse Reactions Observed During the Premarketing Evaluation of tapentadol extended-release tablets The following additional adverse drug reactions occurred in less than 1% of tapentadol extended-release tablet-treated patients in ten Phase 2/3 clinical studies: Nervous system disorders: paresthesia, balance disorder, syncope, memory impairment, mental impairment, depressed level of consciousness, dysarthria, presyncope, coordination abnormal Gastrointestinal disorders: impaired gastric emptying General disorders and administration site conditions: feeling abnormal, feeling drunk Psychiatric disorders: perception disturbances, disorientation, confusional state, agitation, euphoric mood, drug dependence, thinking abnormal, nightmare Skin and subcutaneous tissue disorders: urticaria Metabolism and nutrition disorders: weight decreased Cardiac disorders: heart rate increased, palpitations, heart rate decreased, left bundle branch block Vascular disorder: blood pressure decreased Respiratory, thoracic and mediastinal disorders: respiratory depression Renal and urinary disorders: urinary hesitation, pollakiuria Reproductive system and breast disorders: sexual dysfunction Eye disorders: visual disturbance Immune system disorders: drug hypersensitivity

6.2 Postmarketing

Experience The following adverse reactions have been identified during post approval use of tapentadol. 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.

Psychiatric disorders: hallucination, suicidal ideation, panic attack 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 tapentadol extended-release tablet.

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.

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).