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

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.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Risk of syncope [see Warnings and Precautions (5.1)]

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 Reactions¹ 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.

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.

Risk Summary

There are no data on the presence of etripamil in human milk or animal milk. However, the structurally related compound, verapamil, is known to be present in human milk. There are no data on the effects of etripamil on the breastfed infant or on milk production. Because the presence of etripamil in breastmilk has not been characterized, and there is a potential for adverse reactions in the breastfed infant including hypotension and bradycardia, lactating women should interrupt breastfeeding and pump and discard milk for 12 hours (approximately 5 terminal half-lives) after treatment with CARDAMYST.

The safety and effectiveness of CARDAMYST have not been established in the pediatric population.

Etripamil is structurally similar to another drug in the same pharmacologic class that has been associated with a high risk of potentially non-reversible electromechanical dissociation or cardiovascular collapse in pediatric patients less than 1 year of age, including neonates.

Of the total number of patients in clinical trials of CARDAMYST, 41% (681/1662) were 60 years of age and over, and 14% (238/1662) were 70 years of age and over. No meaningful differences in safety or effectiveness were observed between these patients and younger groups.