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.

COBENFY was evaluated for safety in a total of 1,594 subjects exposed to one or more doses, including 1,135 adult patients with schizophrenia and 389 healthy subjects. A total of 347 COBENFY-treated patients had at least 6 months of exposure and 150 patients had at least 1 year of exposure (defined as ≥ 50 weeks) from open-label studies.

The adverse reaction findings are based on two pooled 5-week, placebo-controlled, flexible-dose studies in 504 adult patients with schizophrenia in which COBENFY or placebo was started at an initial dose of 50 mg/20 mg twice daily for the first 2 days followed by 100 mg/20 mg twice daily for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated to 125 mg/30 mg twice daily unless the patient could not tolerate it. All patients had the option to return to 100 mg/20 mg twice daily for the remainder of the treatment period [see Clinical Studies (14)]. 

In the 5-week placebo-controlled studies, 6% of patients treated with COBENFY and 4% of placebo-treated patients discontinued participation due to adverse reactions. Adverse reactions that led to study discontinuation in ≥1% of patients treated with COBENFY include nausea (2%) and vomiting (1%).

The most common adverse reactions (≥5% and at least twice placebo) were nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease.

Adverse reactions reported with COBENFY at an incidence of at least 2% in patients exposed to COBENFY and greater than the rate of placebo are shown in Table 1.

Increases in Heart Rate  
In a dedicated 8-week clinical study, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted in 133 patients with schizophrenia. A total of 95 patients had acceptable ABPM recordings at both baseline and Week 8. In that group, there was a mean change in 24-hour heart rate of 9.8 beats per minute (bpm) (95% CI 7.5, 12.2) from baseline to Week 8.

In the two placebo-controlled schizophrenia studies, COBENFY was associated with increases in heart rate compared to placebo, with peak elevation occurring on Day 8 of study treatment (13.5 bpm in the COBENFY group and 4.0 bpm in the placebo group), partially attenuating with continued dosing (11.4 bpm in the COBENFY group and 5.5 bpm in the placebo group at Week 5). 

Liver Enzyme Elevations   
In the 5-week, placebo-controlled schizophrenia studies, the proportions of patients with ALT or AST elevations of ≥3 times the upper limits of the normal reference range were 2.8% (6/214) for COBENFY-treated patients compared to 0.4% (1/224) of placebo-treated patients. Twenty-five (1.6%) of the total 1,594 subjects exposed to COBENFY had elevated liver enzymes. The majority of liver enzyme elevations occurred within the first month of treatment and resolved with continued COBENFY use, suggestive of liver adaptation; some cases required treatment interruption, and one was associated with an increase in bilirubin.

Urinary Retention  
In the 5-week, placebo-controlled studies, urinary retention (urinary hesitation, dysuria, and urinary retention) was reported in 0.8% of COBENFY-treated patients and 0.4% on placebo. In the long-term, open-label studies, urinary retention was reported in 3.5% of COBENFY-treated patients. Urinary retention was more common in males, geriatric patients, and those with certain risk factors [see Warnings and Precautions (5.1)]. Urinary retention occurred at all doses but was predominately observed at the maximum COBENFY dose. In the long-term, open-label studies, urinary tract infections were reported in 2.3% of COBENFY-treated patients and were more commonly reported in females than males. Of the total 1,594 subjects exposed to COBENFY (including healthy volunteers and patients with schizophrenia or other conditions), four subjects required a Foley catheter, including one with elevated serum creatinine and one with urinary tract infections. Four subjects with urinary retention required reduction of COBENFY dose, four discontinued COBENFY, and four received medications for the treatment of benign prostatic hyperplasia (BPH).