6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot directly be compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to paroxetine in the following randomized, placebo-controlled trials for the treatment of moderate to severe VMS associated with menopause [see Clinical Studies ( 14 )]: (1) one 8-week Phase 2 trial, (2) one 12-week Phase 3 trial and (3) one 24-week Phase 3 trial.
In these trials, a total of 635 postmenopausal females received paroxetine 7.5 mg administered orally once daily and 641 postmenopausal females received placebo. In these trials, 68% were White, 30% were Black or African American (30%), and 2% were other races, with a mean age of 55 years (range 40 to 73 years). Postmenopausal females with a history of suicidal ideation or suicidal behavior were excluded from these trials.
Serious Adverse Reactions: In the pooled Phase 2 and Phase 3 trials, three paroxetine-treated patients reported a serious adverse reaction of suicidal ideation and one paroxetine-treated patient reported a serious adverse reaction of suicide attempt. There were no serious adverse reactions of suicidal ideation or suicide attempt reported among the placebo-treated patients. Adverse Reactions Leading to Study Discontinuation : A total of 4.7% of females taking paroxetine capsules discontinued from the clinical trials due to an adverse reaction, compared to 3.7% of females on placebo; the most frequent adverse reactions leading to discontinuation among paroxetine-treated females were: abdominal pain (0.3%), attention disturbances (0.3%), headache (0.3%), and suicidal ideation (0.3%).
Common Adverse Reactions : Overall, based on investigators’ determinations about what events were likely to be drug-related, about 20% of postmenopausal females treated with paroxetine capsules reported at least 1 adverse reaction in the three controlled trials. The most common adverse reactions (≥ 2% and at a higher incidence in paroxetine capsules-treated females compared to placebo-treated females) reported in these trials were headache, fatigue/malaise/lethargy, and nausea/vomiting.
Of these commonly reported adverse reactions, nausea occurred primarily within the first 4 weeks of paroxetine treatment and fatigue occurred primarily within the first week of paroxetine treatment, and decreased in frequency with continued therapy. The adverse reactions that occurred in ≥ 2% of paroxetine-treated patients and at a higher incidence in paroxetine-treated females compared to placebo-treated females are shown in Table 1 for the pooled Phase 2 and Phase 3 trials.
Table 1: Incidence of Common Adverse Reactions in the Phase 2 and Phase 3 Trials of Postmenopausal Females with Moderate to Severe VMS 1 Incidence n (%) Paroxetine Capsules (n = 635) Placebo (n = 641) Headache 40 (6.3) 31 (4.8) Fatigue, malaise, lethargy 31 (4.9) 18 (2.8) Nausea, vomiting 27 (4.3) 15 (2.3) 1 ≥ 2% Paroxetine-treated patients and at a higher incidence in paroxetine-treated females compared to placebo-treated females.
Adverse Reactions After Discontinuing Paroxetine Certain symptoms were seen more frequently in postmenopausal females at the time of discontinuation of paroxetine compared to discontinuation of placebo and have also been reported upon discontinuation of other paroxetine products, particularly after abrupt discontinuation. Adverse reactions reported after discontinuation of paroxetine included increased dreaming/nightmares, muscle cramps/spasms/twitching, headache, nervousness/anxiety, fatigue/tiredness, restless feeling in legs, and trouble sleeping/insomnia.
While these adverse reactions were generally self-limiting, there have been reports of serious discontinuation symptoms with other paroxetine products.
6.2Postmarketing Experience
The following adverse reactions have been identified during post-approval use of this and other paroxetine products. Because some of 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. Blood and Lymphatic System Disorders : Idiopathic thrombocytopenic purpura, Events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, agranulocytosis).
Cardiac Disorders : Atrial fibrillation, Pulmonary edema, Ventricular fibrillation, Ventricular tachycardia (including torsades de pointes). Gastrointestinal Disorders : Pancreatitis, Pancreatitis hemorrhagic, Vomiting. General Disorders and Administration Site Conditions : Death, Drug withdrawal syndrome, Malaise. Hepatobiliary Disorders : Drug-induced liver injury, Hepatic failure, Jaundice. Immune System Disorders : Anaphylaxis, Angioedema, Toxic epidermal necrolysis.
Investigations : Elevated liver tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction). Metabolism and Nutrition Disorders : Diabetes mellitus inadequate control, Type 2 diabetes mellitus. Nervous System Disorders : Neuroleptic malignant syndrome, Paresthesia, Somnolence, Tremor, Anosmia, Hyposmia. Psychiatric Disorders : Aggression, Agitation, Anxiety, Confusional state, Depression, Disorientation, Homicidal ideation, Insomnia, Restlessness.
Respiratory, Thoracic and Mediastinal Disorders : Pulmonary hypertension. Skin and Subcutaneous Tissue Disorders : Hyperhidrosis, Stevens-Johnson syndrome, Drug reaction with eosinophilia and systemic symptoms (DRESS).
