Etripamil

1 INDICATIONS AND USAGE CARDAMYST is indicated for the conversion of acute symptomatic episodes of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm in adults. CARDAMYST is a calcium channel blocker indicated for the conversion of acute symptomatic episodes of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm in adults ( 1 ).

2 DOSAGE AND ADMINISTRATION For intranasal use only ( 2.1 ). Initial dosage: A dose of 70 mg is administered as two nasal sprays, one spray into each nostril. Each nasal spray device delivers two sprays. The two sprays together contain a total of 70 mg etripamil ( 2.1 ). Repeat dosage (if needed): Should symptoms persist for 10 minutes after administration of CARDAMYST, take a second dose of 70 mg administered as two nasal sprays, one spray into each nostril. Do not exceed 140 mg in a 24-hour period ( 2.1 ). 2.1 Recommended Dosage Administer as soon as possible after PSVT symptom onset. Administer CARDAMYST by the nasal route only. Each CARDAMYST device delivers two sprays for a total of 70 mg. Recommended Dosage: Using one nasal spray device, administer one spray into each nostril for a total initial dose of 70 mg. If symptoms persist after 10 minutes, use the second nasal spray device to administer a second dose of one spray into each nostril (70 mg total). Patients and caregivers should call their healthcare provider or seek emergency medical help if symptoms do not improve within 20 minutes after a second dose. Do not exceed 140 mg in a 24-hour period. See Instructions for Use for proper nasal spray technique. If a full initial dose (i.e., 2 sprays, one in each nostril) is not administered due to device malfunction or misuse, the patient should wait at least 10 minutes before self-administering a second dose, if needed.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Risk of syncope [see Warnings and Precautions ( 5.1 )] Most common adverse reactions (incidence > 5%) are nasal discomfort, nasal congestion, rhinorrhea, throat irritation, and epistaxis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Milestone Pharmaceuticals USA, INC. at toll-free phone 1-877-207-4764 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 rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of CARDAMYST was evaluated using pooled data from double-blind, randomized, placebo-controlled trials including NODE-1, NODE-301 Part 1, RAPID, and RAPID Extension. A total of 321 patients were treated with CARDAMYST in randomized controlled studies. In the RAPID and RAPID Extension studies, in which patients had the option of self-administering a second dose of CARDAMYST for a perceived episode of PSVT, the majority of patients (65%) self-administered a second dose of CARDAMYST (2x70mg). In NODE-301 Part 1, RAPID, and RAPID Extension, to assess tolerability, a test dose(s) was given prior to randomization. A small percentage of patients failed the test dose due to hypotension (0.4%) [see Warnings and Precautions ( 5.1 )]. The majority of treatment-related adverse reactions reported in clinical studies with CARDAMYST have been related to local reactions to, at, or near the nasal administration site, including the nose, throat, and eyes. These local reactions included nasal discomfort, nasal congestion, throat irritation, oropharyngeal pain, lacrimation, rhinorrhea, bleeding from the nose, upper-airway cough syndrome, and sneezing. Table 1: Most frequent (≥5.0%) Adverse Reactions 1 Observed in Randomized Controlled Studies 1) Adverse reactions that occurred within 24 hours of study drug administration (TEAE24h) for perceived PSVT in the double-blind, placebo-controlled studies, NODE-1, NODE-301 Part 1, RAPID and RAPID Extension that had an overall incidence of 5% or greater and where the incidence is at least 1% greater than the placebo group. 2) 2x70 mg: first administration of etripamil 70 mg followed by a second dose of etripamil 70 mg 10 minutes later if symptoms persisted. Placebo N=223 % CARDAMYST 70 mg N=235 % CARDAMYST 2x70 mg 2 N=86 % Nasal Discomfort 6 28 23 Nasal Congestion 1 14 12 Rhinorrhea 2 12 10 Throat Irritation 1 7 6 Epistaxis 1 6 7

12.3 Pharmacokinetics 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.