CARDAMYST Nasal spray Ref.[116097] Active ingredients: Etripamil

Cardiac Electrophysiology

Etripamil prolonged the baseline PR interval by 8% to 10% approximately 5 minutes following an intranasal dose of 70 mg. This PR interval prolongation begins to decline shortly after the etripamil maximum concentration (C_max) and falls below the 8 to 10% threshold between 25 and 50 minutes. Etripamil mean maximum change from baseline PR interval was approximately 13% following a single 70 mg dose and 20% following two 70 mg doses in the NODE-103 trial. At a dose of 1 to 2 times the maximum recommended therapeutic dose, etripamil does not prolong the QTc interval.

Hemodynamics

In patients with induced supraventricular tachycardia in an electrophysiology laboratory, a single intranasal etripamil administration was associated with a maximal systolic blood pressure reduction of approximately 21 mm Hg with 140 mg (2 x maximum approved dose), 17 mm Hg with 105 mg (1.5 x maximum approved dose), and 3 mm Hg with 70 mg dose. No reduction in blood pressure was observed with etripamil 35 mg dose

After one 70 mg dose of etripamil, mean (%CV) area under the concentration-time curve (AUC) is approximately 5461 (51.6%) ng*min/mL and the C_max is approximately 99 (64.6%) ng/mL. After a second 70 mg dose of etripamil administered 10 minutes after the first dose, mean (%CV) AUC is approximately 7721 (50.3%) ng*min/mL and the C_max is approximately 132 (59.1%) ng/mL.

Absorption

Etripamil median (range) time to C_max (T_max) is 7 minutes (3 to 20 minutes) following a single intranasal administration of 70 mg. Median T_max is 13 minutes (3 to 35 minutes) following a second intranasal administration of 70 mg. Distribution Etripamil mean apparent volume of distribution ranges from approximately 2200 to 3500 L. Etripamil plasma protein binding is approximately 50%.

Elimination

Average etripamil concentration fell by approximately 60% of its peak value (C_max) at 25 minutes and 80% of the C_max by 60 minutes after dosing. Subsequently, concentrations decrease at a slower rate, and this decline is associated with a half-life of approximately 2.5 hours.

Metabolism

Etripamil metabolic pathways include hydrolysis, demethylation, N-dealkylation, and secondary oxidation, glucuronidation, and taurine conjugation. Etripamil is primarily metabolized by blood esterases and hepatic metabolism, primarily via CYP3A4, and CYP3A5. Etripamil contains a methyl ester which renders it metabolically sensitive to bloodborne esterases.

Excretion

After a single dose of radiolabeled intranasal etripamil 70 mg to healthy subjects, approximately 29% of the dose was recovered in urine (<0.05% unchanged), 26% was recovered in feces (<0.05% unchanged), and the remainder was recovered on nose and face tissues. Approximately 71% of the total administered dose was recovered in 7-10 days.

Specific Populations

No clinically significant differences in the pharmacokinetics of etripamil were observed based on age (19 to 56 years old), body weight (49 to 91 kg), height (157 to 194 cm), sex, or race (Caucasian, Asian, or African American). The effect of renal impairment (eGFR <90 mL/min) or hepatic impairment (Child Pugh A, B, or C) on etripamil pharmacokinetics is unknown. It is unknown whether etripamil is dialyzable.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Negative chronotropic and inotropic agents: CARDAMYST was safely administered to patients taking beta blockers or calcium channel blockers. In RAPID, 107 (42%) patients were on beta blockers and 81 (32%) patients were on calcium channel blockers.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Etripamil is a CYP3A4 and CYP3A5 substrate. Etripamil inhibits CYP2D6, CYP3A4, and CYP2C9 but does not inhibit CYP2B6 or CYP2C8. Etripamil does not induce CYP1A2, CYP2B6, or CYP3A4.

Transporter Systems: Etripamil is a substrate of P-gp and OATP1B1, but not BCRP, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, and MATE2-K. Etripamil inhibits P-gp and MATE1, but not BCRP, BSEP, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2.

Carcinogenesis

Long term carcinogenicity studies in rodents have not been conducted with etripamil.

Mutagenesis

Etripamil was not genotoxic in a bacterial reverse mutation assay, an in vitro chromosome aberration assay in human peripheral lymphocytes, and an in vivo micronucleus study in rats (IV administration).

Impairment of Fertility

In a male and female fertility study, rats were dosed once daily via intravenous administration at etripamil doses of 0.05 to 0.374 mg/kg/day. Male rats were dosed for 28 days prior to mating, and female rats were dosed for 14 days prior to mating and continuing up to day 7 of pregnancy. There was no effect on fertility of male and female rats at doses up to 0.374 mg/kg/day, approximately 3× the C_max and 0.4× the AUC at the MRHD.

The RAPID study (NCT #03464019) was a randomized, double-blind, placebo-controlled, multicenter, event-driven, phase 3 study designed to evaluate the efficacy and safety of CARDAMYST in patients with a history of symptomatic PSVT. Six hundred ninety-two (692) patients were randomized 1:1 to CARDAMYST 70 mg or placebo. Patients with an episode of perceived PSVT were to self-administer the study drug intranasally in a medically unsupervised setting and self-administer a second dose of the study drug if symptoms persisted at 10 minutes after the first dose. Continuously obtained electrocardiographic data during the episode of PSVT were blindly adjudicated. The primary endpoint was time-to-conversion of confirmed PSVT to sinus rhythm for at least 30 seconds within 30 minutes of the first dose.

Of the 692 randomized patients, 255 patients perceived an episode of PSVT and self-administered the study drug; 184 (72%) episodes were confirmed by blinded adjudication to be PSVT. Patients had a median age of 54 years (range 19 to 78 years) and were 71% female, 93% Caucasian, 3% Black and 4% other. Sixty-three percent (63%) of patients with confirmed PSVT episode were taking concomitant beta blocker or calcium channel blocker.

In the study's primary analysis, patients with confirmed episodes of PSVT, Kaplan-Meier Estimates of those who converted to sinus rhythm within 30 minutes were 64% and 31% for CARDAMYST and placebo, respectively, with a hazard ratio of 2.6 [95% CI: (1.7, 4.2)], p-value <0.001. Median time-to-conversion was 17.2 minutes (95% CI: 13.4, 26.5) with CARDAMYST versus 53.5 minutes (95% CI: 38.7, 87.3) with placebo. Kaplan-Meier estimates of conversion remained in favor of CARDAMYST at 300 minutes; hazard ratio 1.7 [95% CI: (1.2, 2.4)].

Kaplan-Meier plot of estimated probabilities of achieving sinus rhythm following treatment with CARDAMYST are shown in Figure 1.

Figure 1. RAPID Primary Efficacy Outcome Kaplan Meier Curve: Conversion to Sinus Rhythm in the Patient Population with Confirmed PSVT¹:

¹ 71/255 (28%) patients who self-administered CARDAMYST for a perceived episode of PSVT did not have confirmed PSVT and are excluded.

Seventy-one (71) of 255 (28%) patients who self-administered CARDAMYST for a perceived episode of PSVT did not have PSVT confirmed due to missing ECG data (4%), resolution of PSVT prior to dosing (5%), or other rhythm diagnoses (19%). In an analysis assuming all 71 of these patients did not convert, the Kaplan-Meier estimates for conversion to sinus rhythm within 30 minutes were 50% and 23% for the CARDAMYST and placebo groups, respectively, with a hazard ratio of 2.6 [95% CI: (1.6, 4.1)].

In RAPID, the results for the primary efficacy endpoint were generally consistent across major subgroups including geographic region, sex, age group, concomitant medications, and duration from onset of symptoms to first dose (Figure 2).

Figure 2. Conversion to Sinus Rhythm at 30 Minutes Hazard Ratios by Baseline Characteristics - RAPID Study: