12/22. Mavacamten (CAMZYOS)- (Apr 2022)- To treat classes of Obstructive Hypertrophic Cardiomyopathy
Drug Name:12/22. Mavacamten (CAMZYOS)- (Apr 2022)- To treat classes of Obstructive Hypertrophic Cardiomyopathy
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS-(summary)
• Weak CYP2C19 inhibitors and moderate CYP3A4 inhibitors: May increase
risk of heart failure. If initiating an inhibitor, CAMZYOS dose reduction
and additional monitoring are required.
• Negative inotropes: Close medical supervision and LVEF monitoring is
recommended if a negative inotrope is initiated, or the dose of a negative
inotrope is increased. Avoid certain combinations of negative inotropes.
Indication:
BRIEF SUMMARY
MAVACAMTEN-(April 2022)
Indn- To treat Helicobacterial Pylori Infection
Comp- Capsules: 2.5 mg, 5 mg, 10 mg, and 15 mg CAMZYOS is a cardiac myosin inhibitor indicated for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms.
ADR- Adverse reactions occurring in >5% of patients and more commonly used were dizziness (27%) and syncope (6%).
CI- Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors . Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers
WARNINGS-
Heart Failure: Consider interruption of CAMZYOS in patients with intercurrent illness.
Drug Interactions Leading to Heart Failure or Loss of Effectiveness:
Advise patients of the potential for drug interactions including with overthe-
counter medications.
Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential to use effective contraception until 4 months after the last dose. Use a contraceptive not affected by CYP450 enzyme induction or add nonhormonal contraception.
Pat inform
Heart Failure- nform patients that cardiac function monitoring must be performed using echocardiography to monitor for heart failure .
Advise patients to report any signs or symptoms of heart failure immediately to their healthcare provider.
Drug Interactions-
Advise patients to inform their healthcare providers of all concomitant products, including over-the-counter medications (such as omeprazole, esomeprazole, or cimetidine) and supplements, prior to and during treatment.
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U.S. FDA APPROVED DRUGS SURING 2022
Serial No 12
Name of the Drug- CANZYOS
Active Ingredient - Vonoprazan, Amoxicilin and Clarithromycin
Pharmacological Classification- To treat Helicobacterial Pylori Infection Date of Approval- 5/3/22
HIGHLIGHTS OF PRESCRIBING INFORMATION-
These highlights do not include all the information needed to use
CAMZYOS safely and effectively. See full prescribing information for
CAMZYOS.
CAMZYOSTM (mavacamten) capsules for oral use
Initial U.S. Approval: 2022
WARNING: RISK OF HEART FAILURE
See full prescribing information for complete boxed warning.
• CAMZYOS can cause heart failure due to systolic dysfunction.
• Echocardiogram assessments of left ventricular ejection fraction
(LVEF) required before and during CAMZYOS use.
• Initiation in patients with LVEF <55% not recommended.
Interrupt if LVEF <50% or if worsening clinical status.
• Certain CYP450 inhibitors and inducers are contraindicated in
patients taking CAMZYOS because of an increased risk of heart
failure.
• CAMZYOS is available only through a restricted program called
the CAMZYOS REMS Program.
INDICATIONS AND USAGE-
CAMZYOS is a cardiac myosin inhibitor indicated for the treatment of adults
with symptomatic New York Heart Association (NYHA) class II-III
obstructive hypertrophic cardiomyopathy (HCM) to improve functional
capacity and symptoms.
Adverse Reaction:
ADVERSE REACTIONS-
Adverse reactions occurring in >5% of patients and more commonly on
CAMZYOS than on placebo were dizziness (27%) and syncope (6%).
Contra-Indications:
CONTRAINDICATIONS-
• Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors
• Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4
inducers
WARNINGS AND PRECAUTIONS-
• Heart Failure: Consider interruption of CAMZYOS in patients with
intercurrent illness.
• Drug Interactions Leading to Heart Failure or Loss of Effectiveness:
Advise patients of the potential for drug interactions including with overthe-
counter medications.
• Embryo-Fetal Toxicity: May cause fetal harm. Advise females of
reproductive potential to use effective contraception until 4 months after
the last dose. Use a contraceptive not affected by CYP450 enzyme
induction or add nonhormonal contraception.
Dosages/ Overdosage Etc:
DOSAGE AND ADMINISTRATION_
Dosage must be individualized based on clinical status and echocardiographic
assessment of patient response. Refer to the Full Prescribing Information for
instructions
DOSAGE FORMS AND STRENGTHS-
Capsules: 2.5 mg, 5 mg, 10 mg, and 15 mg
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).
Heart Failure
Inform patients that cardiac function monitoring must be performed using echocardiography to monitor for heart failure .
Advise patients to report any signs or symptoms of heart failure immediately to their healthcare provider.
Drug Interactions
Advise patients to inform their healthcare providers of all concomitant products, including over-the-counter medications (such as omeprazole, esomeprazole, or cimetidine) and supplements, prior to and during CAMZYOS treatment.
CAMZYOS REMS Program
CAMZYOS is available only through a restricted program called the CAMZYOS REMS
Program . Inform the patient of the following notable requirements:
• Patients must enroll in the program and comply with ongoing monitoring requirements
CAMZYOS is only prescribed by certified healthcare providers and only dispensed from
certified pharmacies participating in the program. Provide patients with the telephone number and website for information on how to obtain the product.
Embryo-Fetal Toxicity
Advise pregnant females and females of reproductive potential of the potential risk to a fetus.
Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy .
Advise females of reproductive potential to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. Advise patients using CHCs to use an alternative contraceptive method or add nonhormonal contraception because CAMZYOS may decrease the efficacy of CHCs.
Use in Specific Populations-
Advise females who are exposed to CAMZYOS during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage these patients to report their pregnancies to Bristol-Myers Squibb at 1-800-721-5072 or www.bms.com.
Instructions for Taking CAMZYOS
CAMZYOS capsules should be swallowed whole. Advise patients that if they miss a dose of CAMZYOS, to take the dose as soon as possible that day and the next scheduled dose should be taken at the usual time the following day. The patient should not take two doses in the same day.
Distributed by:
MyoKardia, Inc., a wholly-owned subsidiary of Bristol Myers Squibb
Brisbane, CA 94005
CAMZYOS is a trademark of MyoKardia, Inc., a wholly-owned subsidiary of Bristol
Myers Squibb.
©2022 MyoKardia, Inc.
Reference ID: 4975922
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
Mavacamten is an allosteric and reversible inhibitor selective for cardiac myosin.
2. Pharmacodynamics
Left Ventricular Ejection Fraction and Left Ventricular Outflow Tract Obstruction
In the EXPLORER-HCM trial, patients achieved reductions in mean resting and provoked (Valsalva) LVOT gradient by Week 4 which were sustained throughout the 30-week trial.
Cardiac Electrophysiology
In healthy volunteers receiving multiple doses of CAMZYOS, a concentration-dependent
increase in the QTc interval was observed at doses up to 25 mg once daily. No acute QTc changes have been observed at similar exposures during single-dose studies. The mechanism of the QT prolongation effect is not known.
3. Pharmacokinetics
Mavacamten exposure increases generally dose proportionally after multiple once-daily doses of 1 mg to 15 mg. At the same dose level of CAMZYOS, 170% higher exposures of mavacamten are observed in patients with HCM compared to healthy subjects.
Absorption
Mavacamten has an estimated oral bioavailability of at least 85% and time to maximum
concentration (Tmax) of 1 hour.
Effect of Food
No clinically significant differences in mavacamten pharmacokinetics were observed following its administration with a high fat meal. The Tmax was increased by 4 hours.
Distribution
Plasma protein binding of mavacamten is between 97 and 98%.
Elimination
Mavacamten has a variable terminal t1/2 that depends on CYP2C19 metabolic status.
Mavacamten terminal half-life is 6-9 days in CYP2C19 normal metabolizers (NMs), which is prolonged in CYP2C19 poor metabolizers (PMs) to 23 days.
Drug accumulation occurs with an accumulation ratio of about 2-fold for Cmax and about 7-fold for AUC in CYP2C19 NMs.
The accumulation depends on the metabolism status for CYP2C19 with the largest accumulation observed in CYP2C19 PMs. At steady-state, the peak-to-trough plasma concentration ratio with once daily dosing is approximately 1.5.
Metabolism
Mavacamten is extensively metabolized, primarily through CYP2C19 (74%), CYP3A4 (18%),and CYP2C9 (8%).
Excretion
Following a single 25 mg dose of radiolabeled mavacamten, 7% of the dose was recovered in feces (1% unchanged) and 85% in urine (3% unchanged).
Specific Populations
No clinically significant differences in the pharmacokinetics of mavacamten were observed based on age (range: 18-82 years), sex, race, ethnicity, or mild (eGFR: 60 to 89 mL/min/1.73 m2) to moderate (eGFR: 30 to 59 mL/min/1.73 m2) renal impairment.
The effects of severe (eGFR: 15 to 30 mL/min/1.73 m2) renal impairment and kidney failure (eGFR: <15 mL/min/1.73 m2; including patients on dialysis) are unknown.
Hepatic Impairment-
Mavacamten exposures (AUC) increased up to 220% in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. The effect of severe (Child-Pugh C) hepatic impairment is unknown.
Drug Interactions-
Clinical Studies and Model-Informed Approaches
Weak CYP2C19 Inhibitors: Concomitant use of mavacamten (15 mg) with omeprazole (20 mg) once daily increased mavacamten AUCinf by 48% with no effect on Cmax in healthy CYP2C19
Moderate CYP3A4 Inhibitors: Concomitant use of mavacamten (25 mg) with verapamil
sustained release (240 mg) increased mavacamten AUCinf by 15% and Cmax by 52% in intermediate metabolizers (IMs; e.g., *1/*2, *1/*3, *2/*17, *3/*17) and NMs of CYP2C19.
Concomitant use of mavacamten with diltiazem in CYP2C19 PMs is predicted to increase mavacamten AUC0-24h and Cmax up to 55% and 42%, respectively.
Strong CYP3A4 Inhibitors: Concomitant use of mavacamten (15 mg) with ketoconazole 400 mg once daily is predicted to increase mavacamten AUC0-24 and Cmax up to 130% and 90%, respectively.
Strong CYP2C19 and CYP3A4 Inducers: Concomitant use of mavacamten (a single 15 mg dose) with a strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted to decrease mavacamten AUC0-inf and Cmax by 87% and 22%, respectively, in CYP2C19 NMs, and by 69% and 4%, respectively, in CYP2C19 PMs.
CYP3A4 Substrates: Concomitant use of a 16-day course of mavacamten (25 mg on days 1 and 2, followed by 15 mg for 14 days) resulted in a 13% and 7% decrease in midazolam AUCinf and Cmax, respectively, in healthy CYP2C19 NMs.
Following coadministration of mavacamten once daily in HCM patients, midazolam AUCinf and Cmax are predicted to decrease by 21 to 64% and 13 to 48%, respectively, depending on the dose of mavacamten and CYP2C19 phenotype.
CYP2C8 Substrates: Concomitant use of mavacamten once daily in HCM patients is predicted to decrease AUC and Cmax of repaglinide, a CYP2C8 and CYP3A substrate, by 12 to 39%, depending on the dose of mavacamten and CYP2C19 phenotype.
CYP2C9 Substrates: Concomitant use of mavacamten once daily in HCM patients is predicted to decrease AUC and Cmax of tolbutamide, a CYP2C9 substrate, by 33 to 65%, depending on the dose of mavacamten and CYP2C19 phenotype.
CYP2C19 Substrates: Concomitant use of mavacamten once daily in HCM patients is predicted to decrease AUC and Cmax of omeprazole, a CYP2C19 substrate, by 48 to 67%, depending on the dose of mavacamten and CYP2C19 phenotype.
In Vitro Studies
CYP Enzymes: Mavacamten does not inhibit CYP1A2, CYP2B6, or CYP2C8. At clinically relevant concentrations, mavacamten is not an inhibitor of CYP2D6, CYP2C9, CYP2C19, or CYP3A4. Mavacamten is a CYP2B6 inducer.
Transporter Systems: Mavacamten does not inhibit P-gp, BCRP, BSEP, MATE1, MATE2-K,organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs), or organic anion transporters (OATs).
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Risk Summary
Based on animal data, CAMZYOS may cause fetal harm when administered to a pregnant female. There are no human data on the use of CAMZYOS during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes
The underlying maternal condition during pregnancy poses a risk to the mother and fetus (see Clinical Considerations). Advise pregnant females about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy.
The estimated 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% to 4% and 15% to 20%, respectively.
There is a pregnancy safety study for CAMZYOS. If CAMZYOS is administered during
pregnancy, or if a patient becomes pregnant while receiving CAMZYOS or within 4 months after the last dose of CAMZYOS, healthcare providers should report CAMZYOS exposure by contacting Bristol-Myers Squibb at 1-800-721-5072 or www.bms.com.
Clinical Considerations
Disease-Associated Maternal and Embryo-Fetal Risk
Obstructive HCM in pregnancy has been associated with increased risk for preterm birth.
2. Lactation
Risk Summary
The presence of mavacamten in human or animal milk, the drug’s effects on the breastfed infant, and the effects on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CAMZYOS and any potential adverse effects on the breastfed child from CAMZYOS or from the underlying maternal condition.
3.. Females and Males of Reproductive Potential
Based on animal data, CAMZYOS may cause fetal harm when administered to a pregnant female'.
Pregnancy Testing
Confirm absence of pregnancy in females of reproductive potential prior to initiation of
CAMZYOS.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. Use of CAMZYOS may reduce the
effectiveness of CHCs. Advise patients using CHCs to use an alternative contraceptive method or add nonhormonal contraception.
4. Pediatric Use
The safety and effectiveness of CAMZYOS have not been established in pediatric patients.
5. Geriatric Use
Clinical trials included 263 patients dosed with CAMZYOS, 95 of whom were 65 years of age or older (36.1%), and 17 of whom (6.5%) were age 75 years or older. Safety, effectiveness, and pharmacokinetics were similar between patients =65 years and younger patients.
6. Hepatic Impairment
No dosage adjustment is required in patients with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment. Mavacamten exposure (AUC) increased up to 220% in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function.
However, no additional dose adjustment is required in patients with mild to moderate hepatic impairment with the recommended dose titration algorithm and monitoring plan. The effect of severe (Child-Pugh C) hepatic impairment is unknown .
OVERDOSAGE
Human experience of overdose with CAMZYOS is limited. CAMZYOS has been given as a single dose of up to 144 mg in patients with HCM.
One subject administered a single dose of 144 mg experienced serious adverse events including vasovagal reaction, hypotension, and asystole, but the subject recovered. In healthy subjects, doses of up to 25 mg have been administered for up to 25 days, with 3 of 8 participants treated at the 25-mg dose level experiencing 20% or greater reductions in LVEF. An infant death was reported after accidental ingestion of three 15-mg capsules.
Systolic dysfunction is the most likely result of overdosage of CAMZYOS.
Treatment of overdose with CAMZYOS consists of discontinuation of CAMZYOS treatment as well as medically supportive measures to maintain hemodynamic stability, including close monitoring of vital signs and LVEF and management of the clinical status of the patient. Overdose in humans can be life-threatening and result in asystole refractory to any medical intervention.
