Cardamyst

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.

4 CONTRAINDICATIONS CARDAMYST is contraindicated in patients with: Hypersensitivity to CARDAMYST or any of its components. Heart failure – New York Heart Association (NYHA) Class II to IV. Wolff-Parkinson-White (WPW), Lown-Ganong-Levine (LGL) syndromes, or manifest pre-excitation (delta wave) on a 12-lead electrocardiogram (ECG). Sick sinus syndrome without a permanent pacemaker. Second degree atrioventricular (AV) Mobitz 2 block or higher degree of AV block. Hypersensitivity to CARDAMYST or any of its components ( 4 ). Heart failure - New York Heart Association (NYHA) Class II to IV ( 4 ). Wolff-Parkinson-White (WPW), Lown-Ganong-Levine (LGL) syndromes, or manifest pre-excitation (delta wave) on a 12-lead ECG ( 4 ). Sick sinus syndrome (except in patients with a permanent pacemaker) ( 4 ) Second degree atrioventricular (AV) Mobitz 2 block or higher degree of AV block ( 4 )

5 WARNINGS AND PRECAUTIONS Syncope: May cause dizziness and/or syncope, especially in patients with a history of syncope. Administer in a sitting position ( 5.1 ). 5.1 Syncope Related to Hemodynamic Effects Because of effects on blood pressure, heart rate, and cardiac conduction, CARDAMYST may cause dizziness and/or syncope, especially in patients with a history of syncope and high-grade AV block or sinus node dysfunction, or those with a history of syncope during an episode of PSVT. In clinical trials, a small percentage of patients (0.4%) experienced clinically significant hypotension during test dosing prior to randomization, which precluded further participation in the study. Patients with a history of hypotensive episodes or those at increased risk for hemodynamic instability should be monitored appropriately when initiating CARDAMYST. If syncope occurs, patients should be placed in the recumbent position and treated supportively. Patients should be cautioned about these possible adverse effects and advised to administer CARDAMYST in a sitting position, and in a location where the risk of fall is minimal.

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

8.1 Pregnancy Risk Summary There are no available data on the use of CARDAMYST during pregnancy to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Reproductive studies conducted with intravenous administration of etripamil in pregnant rats and rabbits during organogenesis did not show any evidence of fetal harm or malformations in rats at exposures up to approximately 3x the maximum concentration (C max ) and 0.4x the AUC at the maximum recommended human dose (MRHD) and in rabbits at exposures approximately equivalent to the C max and 10x the AUC at the MRHD, at which maternal toxicities were observed (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data In pregnant rats, intravenous administration of etripamil throughout the period of organogenesis did not result in any adverse effects on embryofetal development at doses up to 0.375 mg/kg/day, approximately 3x the C max and 0.4x the AUC at the MRHD. In pregnant rabbits, intravenous administration of etripamil throughout the period of organogenesis did not result in embryofetal abnormalities at doses up to 0.1 mg/kg/day, approximately equivalent to the C max and 10x the AUC at the MRHD. Abortion in one animal was noted at the high dose of 0.1 mg/kg/day, a dose that caused maternal toxicity. In the pre- and post-natal toxicity study in rats, intravenous administration of etripamil from gestation day 7 through the lactation period (post-partum day 20), did not show any adverse effects on pre- and postnatal development at doses up to 0.374 mg/kg/day, approximately 3x the C max and 0.4x the AUC at the MRHD. Post-implantation loss was noted at 0.374 mg/kg/day, a dose that also caused significant maternal toxicity, including mortality, transient adverse clinical signs, and body weight reduction.