Treatment and dosing

Before starting treatment

Confirm a negative pregnancy test and advise patients of reproductive potential to use effective contraception during treatment with CAMZYOS and for 6 months following discontinuation
Assess left ventricular ejection fraction (LVEF) by echocardiogram. Do not initiate CAMZYOS in patients with LVEF <55%
Consider contraindications and drug interactions prior to and throughout treatment
Patients should be genotyped for CYP2C19 phenotype in order to determine appropriate CAMZYOS dose

During treatment

The recommended starting dose of CAMZYOS is 2.5 mg orally once daily for patients with CYP2C19 poor metaboliser phenotype and 5 mg orally once daily for patients with CYP2C19 intermediate, normal, rapid and ultra-rapid phonotype. Patients should follow dosing instructions for poor metabolisers until CYP2C19 phenotype is determined. CAMZYOS may be taken without regard to food. If a dose is missed, it should be taken as soon as possible, and the next scheduled dose should be taken at the usual time the following day. The exact timing of dosing during the day is not essential, but two doses should not be taken on the same day. Swallow capsules whole. Do not break, open or chew the capsule
Assess patient response to treatment, including LVOT gradient with Valsalva maneuver and LVEF, at Weeks 4 and 8 after treatment initiation. Once an individualised maintenance dose is achieved, patients should be assessed every 12 weeks. Additional echocardiograms may be required if there is a dose change or treatment interruption, as described in Figures 3, 4 and 5. Adjust the dose based on Figures 2–5
Patients may develop heart failure while taking CAMZYOS. Regular LVEF and LVOT gradient with Valsalva maneuver assessments are required for careful dose titration to achieve an appropriate target LVOT gradient with Valsalva maneuver while maintaining LVEF ≥ 50% and avoiding heart failure symptoms (see Figures 2, 3 and 4)
Dose increases should not occur more frequently than every 12 weeks. Do not up-titrate CAMZYOS in patients with LVEF <55% or those experiencing an intercurrent illness such as infections or arrhythmia (including atrial fibrillation or other uncontrolled tachyarrhythmias) that may impair systolic function. Interrupt treatment if LVEF is <50% at any visit; restart treatment after 4 weeks if LVEF is ≥ 50% (see Figure 5)

Figure 2: Treatment initiation in CYP2C19 poor metabolizer phenotype *Interrupt treatment if LVEF <50% at any clinical visit; restart treatment after 4 weeks if LVEF ≥50%. (see Figure 5.) LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract Treatment should be initiated at 2.5 mg once daily, only in patients with LVEF ≥55%. At Week 4 visit if Valsalva LVOT gradient is < 20 mmHg, the dose should be paused. If LVOT gradient with Valsalva maneuver is ≥ 20 mmHg, maintain 2.5 mg once daily. At Week 8 visit if Valsalva LVOT gradient is ≥ 20 mmHg, the dose of 2.5 mg once daily can be restarted again or maintained. If LVOT gradient with Valsalva maneuver is < 20 mmHg, the dose should be paused. At Week 12, patients withheld 2.5 mg treatment at week 8 should be reassessed and if LVEF ≥ 50% can restart their treatment on 2.5 mg. A 4-week follow-up visit will be required to recheck clinical status and echocardiogram to determine if the patient should maintain 2.5 mg dose for 8 weeks, consistent with Figure 4: Treatment Maintenance, unless LVEF <50%. Patients who have not had their treatment withheld at week 8 should follow the instructions provided in Figure 4: Treatment Maintenance.

*Interrupt treatment if LVEF <50% at any clinical visit; restart treatment after 4 weeks if LVEF ≥ 50%. (see Figure 5.)
LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract

Figure 3: Treatment initiation in CYP2C19 intermediate, normal, rapid and ultra-rapid metabolizer phenotypes *Interrupt treatment if LVEF < 50% at any clinic visit; restart treatment after 4 weeks if LVEF ≥ 50%. See Figure 4. Treatment should be initiated at 5 mg once daily, only in patients with LVEF ≥55%. At Week 4 visit if Valsalva LVOT gradient is < 20 mmHg, the dose should be down-titrated to 2.5 mg once daily. If LVOT gradient with Valsalva maneuver is ≥ 20 mmHg, maintain 5 mg once daily. At Week 8 visit if Valsalva LVOT gradient is ≥ 20 mmHg, the dose of 2.5 mg or 5 mg once daily should be maintained. If LVOT gradient with Valsalva maneuver is < 20 mmHg, the dose should be decreased from 5 mg to 2.5 mg; patients who are already on the 2.5 mg dose should have their treatment withheld and return at week 12. At Week 12, patients withheld 2.5 mg treatment at week 8 should be reassessed and if LVEF ≥ 50% can restart their treatment on 2.5 mg. A 4-week follow-up visit will be required to recheck clinical status and echocardiogram to determine if the patient should maintain 2.5 mg dose for 8 weeks, consistent with Figure 4: Treatment Maintenance, unless LVEF <50%. Patients who have not had their treatment withheld at week 8 should follow the instructions provided in Figure 4: Treatment Maintenance.

Figure 4: Maintenance phase At week 12 visit and subsequent 12-weekly visits, patients may have their dose up-titrated to next higher daily (mg) dose level (e.g., 2.5 to 5 mg; 5 to 10 mg; 10 to 15 mg) if LVEF ≥ 55% and LVOT gradient with Valsalva maneuver ≥ 30 mmHg. Recheck clinical status and echocardiogram in 4 weeks and maintain the same dose for the next 8 weeks unless LVEF <50%. Further up-titration is allowed after 12 weeks of treatment on the same dose level. If the patient’s LVEF is between 50% to 55%, regardless of Valsalva LVOT gradient or LVEF > 55% and Valsalva LVOT gradient < 30 mmHg the patient should maintain their current dose and be followed-up 12 weeks later. If LVEF <50% at any point in treatment, interrupt treatment and follow the instructions in Figure 5: Treatment Interruption.

LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract

Figure 5: Treatment interruption at any clinic if LVEF <50% If at any clinical visit LVEF is <50%, treatment should be interrupted. Recheck echocardiogram parameters every 4 weeks until LVEF ≥ 50%. Restart treatment at one lower daily (mg) dose level (e.g., 5 to 2.5 mg; 10 to 5 mg; 15 to 10 mg; if interrupted at 2.5 mg, restart at 2.5 mg) if LVEF ≥ 50%. Recheck clinical status and echocardiogram in 4 weeks and maintain the same dose for the next 8 weeks unless LVEF<50%. Then follow the instructions in Figure 4: Treatment Maintenance. Permanently discontinue treatment for patients if LVEF < 50% on two consecutive occasions while on 2.5 mg daily.

LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract

Dose modification with concomitant medicinal products

For concomitant treatment with inhibitors of CYP2C19 or CYP3A4, follow the steps shown in Table 1.

Table 1: Dose modification with concomitant medicinal products (refer to the Approved SmPC Sections 4.3 and 4.5 for further details)

Concomitant medicine/product	CYP2C19 poor metaboliser phenotype*	CYP2C19 intermediate, normal, rapid and ultra rapid phenotype
Inhibitors
Combined use of a strong CYP2C19 inhibitor and a strong CYP3A4 inhibitor	Contra-indicated.	Contra-indicated.
Strong CYP2C19 inhibitor	No dose adjustment. If CYP2C19 phenotype has not yet been determined: No adjustment of the starting dose of 2.5 mg is needed. The dose should be reduced from 5 mg to 2.5 mg or pause treatment if on 2.5 mg.	Initiate mavacamten at a dose of 2.5 mg. The dose should be reduced from 15 mg to 5 mg and from 10 mg and 5 mg to 2.5 mg or pause treatment if on 2.5 mg.
Strong CYP3A4 inhibitor	Contra-indicated.	No dose adjustment.
Moderate CYP2C19 inhibitor	No dose adjustment. If CYP2C19 phenotype has not yet been determined: No adjustment of the starting dose of 2.5 mg is needed. The dose should be reduced from 5 mg to 2.5 mg or pause treatment if on 2.5 mg.	No adjustment of the starting dose of 5 mg is needed. The dose should be reduced by one dose level or pause treatment if on 2.5 mg.
Moderate or weak CYP3A4 inhibitor	No adjustment of the starting dose of 2.5 mg is needed. If patients are receiving a 5 mg dose of mavacamten, their dose should be reduced to 2.5 mg.	No dose adjustment.

* includes patients for whom the CYP2C19 phenotype has not yet been determined