Cariprazine 6 mg · Hard-gelatin capsules

The mechanism of action of cariprazine is unknown. However, the efficacy of cariprazine could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Cariprazine forms two major metabolites, desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR), that have in vitro receptor binding profiles similar to the parent drug.

VRAYLAR activity is thought to be mediated by cariprazine and its two major active metabolites, desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR), which are pharmacologically equipotent to cariprazine.

After multiple dose administration of VRAYLAR, mean cariprazine and DCAR concentrations reached steady state at around Week 1 to Week 2 and mean DDCAR concentrations appeared to be approaching steady state at around Week 4 to Week 8 in a 12-week study (Figure 1). The half-lives based on time to reach steady state, estimated from the mean concentration-time curves, are 2 to 4 days for cariprazine, about 1 to 2 days for DCAR, and approximately 1 to 3 weeks for DDCAR. The time to reach steady state for the major active metabolite DDCAR was variable across patients, with some patients not achieving steady state at the end of the 12 week treatment [ s ee Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.6 ) ]. Mean concentrations of DCAR and DDCAR are approximately 30% and 400%, respectively, of cariprazine concentrations by the end of 12-week treatment.

After discontinuation of VRAYLAR, cariprazine, DCAR, and DDCAR plasma concentrations declined in a multi-exponential manner. Mean plasma concentrations of DDCAR decreased by about 50% 1 week after the last dose, and mean cariprazine and DCAR concentration dropped by about 50% in about 1 day. There was an approximately 90% decline in plasma exposure within 1 week for cariprazine and DCAR, and at about 4 weeks for DDCAR. Following a single dose of 1 mg of cariprazine administration, DDCAR remained detectable 8 weeks post-dose.

After multiple dosing of VRAYLAR, plasma exposure of cariprazine, DCAR, and DDCAR increases approximately proportionally over the therapeutic dose range.

12-weeks of Treatment with Cariprazine 6 mg/day a — a Trough concentrations shown during treatment with cariprazine 6 mg/day.

SE: standard error; TOTAL CAR: sum concentration of cariprazine, DCAR and DDCAR; CAR: cariprazine

Absorption — After single dose administration of VRAYLAR, the peak plasma cariprazine concentration occurred in approximately 3-6 hours.

Administration of a single dose of 1.5 mg VRAYLAR capsule with a high-fat meal did not significantly affect the Cmax and AUC of cariprazine or DCAR.

Distribution — Cariprazine and its major active metabolites are highly bound (91 to 97%) to plasma proteins.

Metabolism — Cariprazine is extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 to DCAR and DDCAR. DCAR is further metabolized into DDCAR by CYP3A4 and CYP2D6. DDCAR is then metabolized by CYP3A4 to a hydroxylated metabolite.

Excretion — Following administration of 12.5 mg/day cariprazine to patients with schizophrenia for 27 days, about 21% of the daily dose was found in urine, with approximately 1.2% of the daily dose excreted in urine as unchanged cariprazine.

Patients with Hepatic Impairment — Compared to healthy subjects, exposure (Cmax and AUC) in patients with either mild or moderate hepatic impairment (Child-Pugh score between 5 and 9) was approximately 25% higher for cariprazine and 20% to 30% lower for the major metabolites (DCAR and DDCAR) following daily doses of 0.5 mg cariprazine for 14 days [ see Use in Specific Populations ( 8.6 )].

Patients with Renal Impairment — Cariprazine and its major active metabolites are minimally excreted in urine. Pharmacokinetic analyses indicated no significant relationship between plasma clearance and creatinine clearance [see Use in Specific Populations ( 8.7 )].

CYP2D6 Poor Metabolizers — CYP2D6 poor metabolizer status does not have clinically relevant effect on pharmacokinetics of cariprazine, DCAR, or DDCAR.

Age , Sex, Race — Age, sex, or race does not have clinically relevant effect on pharmacokinetics of cariprazine, DCAR, or DDCAR in adult population.