IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNING
WARNING: ARRHYTHMIA RISK WITH CONCOMITANT USE OF QTc INTERVAL PROLONGING DRUGS
ETCAMAH in combination with ribociclib, a QTc interval prolonging drug and a strong CYP3A inhibitor, or in combination with other QTc interval prolonging drugs, can increase the risk of Torsades de Pointes (TdP), other ventricular arrhythmias, and sudden death.
Avoid concomitant use of ETCAMAH with products (other than ribociclib) known to prolong the QTc interval and/or have a known risk of TdP. If concomitant use with other products cannot be avoided, monitor the QTc interval more frequently.
Obtain electrocardiogram (ECG) prior to initiation and monitor heart rate (HR) and QTc interval during treatment. Assess and correct electrolyte abnormalities prior to initiation and during treatment. Withhold ETCAMAH until resolution of QTc interval prolongation and resume or permanently discontinue ETCAMAH based on severity.
WARNINGS AND PRECAUTIONS
QTc Interval Prolongation: ETCAMAH in combination with a CDK4/6 inhibitor (CDK4/6i) is associated with QTc interval prolongation. When ETCAMAH is used in combination with ribociclib, a CDK4/6i, there is potential for increased risk of TdP, other ventricular arrhythmias, and sudden death. One Grade 4 case of TdP was observed in a dose-finding trial when ETCAMAH was used with ribociclib. In SERENA-6, QTc interval prolongation occurred in 2.6% of patients treated with ETCAMAH in combination with a CDK4/6i. QTc interval prolongation led to dose interruption in 0.6% of patients. No patients in SERENA-6 discontinued ETCAMAH due to QTc interval prolongation. ETCAMAH also causes bradycardia, which increases the risk of QTc interval prolongation.
Perform an ECG prior to initiating ETCAMAH, then every week for the first 2 weeks of treatment, and periodically during treatment as clinically indicated. Obtain serum electrolytes at baseline and during treatment as clinically indicated, and correct electrolyte abnormalities. Avoid concomitant use of ETCAMAH in combination with a CDK4/6i with products that cause QTc interval prolongation, are strong CYP3A inhibitors, and/or are drugs known to lower HR.
For QTc >500 msec or QTc >480 msec and prolongation from baseline >60 msec, withhold ETCAMAH. If other contributing causes are identified, then treat or correct the contributing causes. Resume ETCAMAH when QTc returns to <480 msec. Reassess ECGs weekly for the first 2 weeks of treatment, and periodically during treatment as clinically indicated. Permanently discontinue ETCAMAH if QTc interval prolongation is either >500 msec or >60 msec change from baseline AND associated with any: TdP, polymorphic ventricular tachycardia, syncope, or signs/symptoms of serious arrhythmia.
Bradycardia: ETCAMAH causes a decrease in HR. Bradycardia increases the risk for life-threatening arrhythmias and sudden death when concomitant QTc interval prolongation is present, such as when ETCAMAH is used in combination with ribociclib, both a QTc interval prolonging product and a strong CYP3A inhibitor. In SERENA-6, bradycardia occurred in 8% of patients. The mean HR decrease from baseline was approximately 13 beats per minute (bpm) with the maximum decrease observed on day 15. Median time to onset was 17 days (range 13 to 283) after starting ETCAMAH. No patients discontinued ETCAMAH due to bradycardia. Dose interruption occurred in 3.9% of patients. The safety of ETCAMAH has not been established in patients with a baseline resting HR <55 bpm as these patients were excluded from SERENA-6. Monitor HR more frequently during the first 30 days of treatment in patients with bradycardia (HR <60 bpm) at baseline and those on concomitant medications known to lower HR (eg, beta-blockers).
For symptomatic (Grade 2 or above) bradycardia, withhold ETCAMAH until symptoms resolve. Obtain ECG to evaluate etiology. If a contributing concomitant medication is identified, modify the dosage or discontinue this medication, as appropriate, until bradycardia symptoms resolve, then resume ETCAMAH. Consider reassessing the HR after restart. Permanently discontinue for persistent symptomatic bradycardia.
Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ETCAMAH can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ETCAMAH and for 4 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ETCAMAH and for 1 week after the last dose.
ADVERSE REACTIONS
The most common (≥20%) adverse reactions, including laboratory abnormalities, with ETCAMAH in combination with a CDK4/6i were decreased neutrophils (68%), decreased leukocytes (66%), decreased hemoglobin (47%), decreased lymphocytes (39%), decreased platelets (36%), visual disturbances (34%), and fatigue (23%).
Permanent discontinuation due to adverse reactions occurred in 1.3% of patients. Adverse reactions that resulted in permanent discontinuation of ETCAMAH included gastroesophageal reflux disease, cholestasis and hepatic cytolysis (0.6% each). Dosage interruption of ETCAMAH due to adverse reactions occurred in 22% of patients.
Visual disturbances: For visual disturbances limiting instrumental ADLs (activities of daily living) (Grade 2) or above, withhold ETCAMAH until symptoms resolve to Grade 1 or below. Refer to an eye professional for an ophthalmic examination and treatment and reassess at the next visit.
For other Grade 3 or higher adverse reactions: Withhold ETCAMAH until resolution to Grade 2 or below, then resume. Permanently discontinue for recurrence of Grade 3 or higher adverse reactions.
DRUG INTERACTIONS
- Strong CYP3A Inhibitors: Monitor for increased adverse reactions to ETCAMAH and modify the dosage as recommended
- Strong and Moderate CYP3A Inducers: Avoid the use of strong CYP3A inducers. Use caution with the co-administration of a moderate CYP3A inducer
- Avoid concomitant use of moderate CYP3A inducers for patients who are receiving ETCAMAH in combination with abemaciclib or palbociclib. If concomitant use cannot be avoided, increase the ETCAMAH dosage from 75 mg once daily to 150 mg once daily. After the moderate CYP3A inducer has been discontinued for at least 14 days, resume the ETCAMAH dosage used prior to initiation of the moderate CYP3A inducer
- For patients who are receiving ETCAMAH in combination with ribociclib concomitantly with a moderate CYP3A inducer, no ETCAMAH dosage modification is recommended
- CYP2C9 and/or CYP2C19 Substrates: Avoid concomitant use of ETCAMAH with CYP2C9 or CYP2C19 substrates during treatment with ETCAMAH and at least 2 weeks after the last dose of ETCAMAH, unless otherwise recommended in the Prescribing Information of the CYP2C9 or CYP2C19 substrate
- Certain CYP3A Substrates: Refer to the Prescribing Information for CYP3A substrates where minimal increases in the concentration may lead to serious adverse reactions
- Drugs that Prolong the QTc Interval: ETCAMAH is indicated in combination with a CDK4/6i and there is increased risk of QTc interval prolongation with ribociclib, a strong CYP3A inhibitor that can prolong the QTc interval. Refer to the ribociclib Prescribing Information for dosage modifications. Avoid concomitant use of ETCAMAH with products (other than ribociclib) known to prolong the QTc interval and/or have a known risk of TdP. If concomitant use with other products cannot be avoided, monitor the QTc interval more frequently. ETCAMAH in combination with a CDK4/6i is associated with QTc interval prolongation
- Drugs that Cause Bradycardia: Avoid concomitant use of ETCAMAH with other products known to cause bradycardia. Monitor for signs and symptoms of bradycardia if concomitant use cannot be avoided. ETCAMAH causes decreases in HR that are dose and baseline HR dependent
Refer to the Prescribing Information for the co-administered CDK4/6i for dosage modification guidelines related to adverse reactions, organ impairment, and drug-drug interactions.
SPECIAL POPULATIONS
Pregnancy: Based on findings in animals and mechanism of action, ETCAMAH can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
Lactation: Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ETCAMAH and for 1 week after the last dose.
Females and Males of Reproductive Potential: ETCAMAH can cause fetal harm when administered to pregnant women. Verify pregnancy status of female patients of reproductive potential prior to initiating ETCAMAH. Advise female patients of reproductive potential to use effective non-hormonal contraception during treatment with ETCAMAH and for 4 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ETCAMAH and for 1 week after the last dose. Refer to the Prescribing Information of the CDK4/6i palbociclib, if used in combination with ETCAMAH, for contraception information and use for the longest recommended post-treatment duration. ETCAMAH may impair fertility in female and male patients.
Pediatric Use: Safety and effectiveness have not been established in pediatric patients.
Hepatic Impairment: In patients with severe (Child-Pugh C) hepatic impairment, when ETCAMAH is combined with ribociclib, reduce the dosing frequency to every other day.
No dosage modifications are required in other patients with hepatic impairment of any level, or when ETCAMAH is combined with abemaciclib or palbociclib, although patients with moderate or severe hepatic impairment (Child-Pugh B or C) should be monitored for increased adverse reactions and dosage modified as recommended.
For US healthcare professionals
