Nalmefeneside effects

The following serious adverse reactions are discussed elsewhere in the labeling: Recurrent Respiratory and Central Nervous System Depression Precipitation of Severe Opioid Withdrawal Most common adverse reactions (incidence at least 2%) are nasal discomfort, headache, nausea, dizziness, hot flush, vomiting, anxiety, fatigue, nasal congestion, throat irritation, rhinalgia, decreased appetite, dysgeusia, erythema, and hyperhidrosis. To report SUSPECTED ADVERSE REACTIONS, contact Indivior Inc. at 1-877-782-6966 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 the rates in clinical trials of another drug and may not reflect the rates observed in practice. The safety of OPVEE nasal spray is supported by safety and pharmacokinetic studies of OPVEE nasal spray in healthy subjects in a normal state and under steady state opioid agonism. The following adverse reactions were observed. In a pharmacokinetic study of 66 healthy adult volunteers exposed to one spray of OPVEE nasal spray in one nostril the most common adverse reactions were: nasal discomfort and dizziness. In a second pharmacokinetic study of 24 healthy adult volunteers exposed to one spray of OPVEE nasal spray in one nostril, two sprays of OPVEE nasal spray in one nostril or one spray of OPVEE nasal spray in each nostril, the most common adverse reactions were: rhinalgia, nasal congestion, nasal discomfort and nausea. In a pharmacodynamic study of 61 healthy adult volunteers exposed to one spray of OPVEE nasal spray in one nostril, the most common adverse reactions were: headache, nausea, hot flush and dizziness.

Table 1: Relative Frequencies of Treatment-Related Common Adverse Events That Occurred in Greater Than 1% of Healthy Adult Volunteers Nalmefene 2.7 mg Nalmefene 5.4 mg System Organ Class Preferred Term Total 2.7 mg N=150 n (%) PD Study N=61 n (%) PK Studies N=89 n (%) PK Study (1 spray in each nostril) N=23 n (%) PK Study (2 sprays in one nostril) N=24 n (%) PK Studies OPNT003-PK-001 + OPNT003-PK-002 and PD Study OPNT003-OOD-001 Respiratory, thoracic and mediastinal disorders Nasal discomfort 43 (28.7%) 5 (8.2%) 38 (42.7%) 3 (13.0%) 3 (12.5%) Nasal congestion 6 (4.0%) 2 (3.3%) 4 (4.5%) 1 (4.3%) 4 (16.7%) Throat irritation 6 (4.0%) 3 (4.9%) 3 (3.4%) 0 0 Rhinalgia 4 (2.7%) 1 (1.6%) 3 (3.4%) 2 (8.7%) 6 (25.0%) Dyspnea 2 (1.3%) 2 (3.3%) 0 0 0 Oropharyngeal pain 2 (1.3%) 2 (3.3%) 0 1 (4.3%) 1 (4.2%) Nervous system disorders Headache 40 (26.7%) 34 (55.7%) 6 (6.7%) 1 (4.3%) 0 Dizziness 14 (9.3%) 9 (14.8%) 5 (5.6%) 0 1 (4.2%) Dysgeusia 3 (2.0%) 2 (3.3%) 1 (1.1%) 0 0 Paresthesia 2 (1.3%) 2 (3.3%) 0 1 (4.3%) 1 (4.2%) Presyncope 0 0 0 1 (4.3%) 0 Gastrointestinal disorders Nausea 25 (16.7%) 22 (36.1%) 3 (3.4%) 5 (21.7%) 1 (4.2%) Vomiting 9 (6.0%) 7 (11.5%) 2 (2.2%) 1 (4.3%) 0 Abdominal pain 2 (1.3%) 1 (1.6%) 1 (1.1%) 0 0 Dry mouth 1 (0.7%) 1 (1.6%) 0 1 (4.3%) 0 Constipation 0 0 0 0 1 (4.2%) Vascular disorders Hot flush 12 (8.0%) 12 (19.7%) 0 0 0 Psychiatric disorders Anxiety 7 (4.7%) 7 (11.5%) 0 0 0 Agitation 2 (1.3%) 2 (3.3%) 0 0 0 Claustrophobia 2 (1.3%) 2 (3.3%) 0 0 0 Insomnia 1 (0.7%) 0 1 (1.1%) 1 (4.3%) 0 General disorders and administration site conditions Fatigue 6 (4.0%) 3 (4.9%) 3 (3.4%) 0 0 Chills 2 (1.3%) 2 (3.3%) 0 0 0 Chest discomfort 0 0 0 1 (4.3%) 0 Skin and subcutaneous tissue disorders Erythema 3 (2.0%) 0 3 (3.4%) 1 (4.3%) 1 (4.2%) Hyperhidrosis 3 (2.0%) 3 (6.6%) 0 0 1 (4.2%) Urticaria 0 0 0 0 1 (4.2%) Metabolism and nutrition disorders Decreased appetite 3 (2.0%) 2 (3.3%) 1 (1.1%) 0 0 Infections and infestations Rhinitis 1 (0.7%) 0 1 (1.1%) 1 (4.3%) 0 Eye disorders Dry eye 0 0 0 1 (4.3%) 0 Cardiac disorders Tachycardia 0 0 0 1 (4.3%) 0 Adverse reaction information was obtained following administration of nalmefene injection to 152 normal volunteers and in controlled clinical trials to 1127 patients for the treatment of opioid overdose or for postoperative opioid reversal. Table 2. Relative Frequencies of Common Adverse Reactions with an Incidence Greater than 1% (all patients, all clinical settings) Adverse Reaction Nalmefene Placebo N=1127 N=77 Nausea 18% 6% Vomiting 9% 4% Tachycardia 5% - Hypertension 5% - Postoperative Pain 4% N/A Fever 3% - Dizziness 3% 1% Headache 1% 4% Chills 1% - Hypotension 1% - Vasodilatation 1% - Incidence less than 1% Cardiovascular: Bradycardia, arrhythmia Digestive: Diarrhea, dry mouth Nervous System: Somnolence, depression, agitation, nervousness, tremor, confusion, withdrawal syndrome, myoclonus Respiratory: Pharyngitis Skin: Pruritus Urogenital: Urinary retention The incidence of adverse events was highest in patients who received more than the recommended dose of nalmefene injection.

6.2 Postmarketing

Experience The following adverse reactions have been identified during post-approval use of nalmefene. 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. Abrupt reversal of opioid depression using nalmefene in both postoperative and emergency department settings has resulted in nausea, vomiting, sweating, tremulousness, seizures, and cardiovascular instability including tachycardia, hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. These events have primarily occurred in patients who had pre-existing cardiovascular disorders or received other drugs that may have similar adverse cardiovascular effects. In persons who were physically dependent on opioids, abrupt reversal of opioid effects has precipitated an acute withdrawal syndrome. Signs and symptoms have included: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shiver or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, tachycardia. In some patients, there may be aggressive behavior upon abrupt reversal of an opioid overdose. In the neonate, opioid withdrawal symptoms also included convulsions, excessive crying, and hyperactive reflexes.