Reporting Adverse Events
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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 4 months following discontinuation
  • Assess left ventricular ejection fraction (LVEF) by echocardiogram. Initiation or up-titration of CAMZYOS in patients with LVEF <55% is not recommended.
  • Consider contraindications and drug interactions prior to and throughout treatment
  • Perform CYP2C19 genotyping in order to determine appropriate CAMZYOS dose. If treatment initiation occurs prior to determination of CYP2C19 phenotype, follow the dosing instructions for poor metabolizers until CYP2C19 phenotype is determined.

During treatment

  • The recommended starting dose of CAMZYOS is 2.5 mg orally once daily for CYP2C19 poor metabolizer phenotype patients, and 5 mg orally once daily for CYP2C19 intermediate, normal, rapid and ultra-rapid metabolizer phenotype patients. 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 , 8 and 12 and every 12 weeks thereafter. Additional echocardiograms may be required if there is a dose change or treatment interruption, as described in Figures 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 clinic visit; restart treatment after 4 weeks if LVEF ≥ 50%. See Figure 5. For patients with CYP2C19 poor metabolizer phenotype, initiate treatment at 2.5 mg once daily, only if LVEF ≥55%. At Week 4 visit if Valsalva LVOT gradient is < 20 mmHg, the treatement should be withheld and patient should return at week 8. If LVOT gradient with Valsalva maneuver is ≥ 20 mmHg, maintain 2.5mg once daily. At Week 8 visit if Valsalva LVOT gradient is ≥ 20 mmHg, the dose of 2.5 mg once daily is maintained or restarted. If LVOT gradient with Valsalva maneuver is < 20 mmHg, the treatement should be 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 once daily. A 4-week follow-up visit will be required to recheck clinical status, Valsalva LVOT gradient and LVEF in 4 weeks and maintain the current dose for the next 8 weeks unless LVEF < 50%, and then the instructions provided in Figure 4: Treatment Maintenance should be followed. 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 clinic visit; restart treatment after 4 weeks if LVEF ≥ 50%. See Figure 5.

Figure 3: Treatment initiation in CYP2C19 intermediate, normal, rapid and ultra-rapid metabolizer phenotype

*Interrupt treatment if LVEF < 50% at any clinic visit; restart treatment after 4 weeks if LVEF ≥ 50%. See Figure 5. For patients with CYP2C19 intermediate, normal, rapid and ultra-rapid metabolizer phenotypes, 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 once daily or 5 mg once daily should be maintained. If LVOT gradient with Valsalva maneuver is < 20 mmHg, the daily dose should be decreased from 5 mg to 2.5 mg; patients who are already on the 2.5 mg dose once daily 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, Valsalva LVOT gradient and LVEF to determine if the patient should maintain 2.5 mg dose for 8 weeks, and then the instructions provided in Figure 4: Treatment Maintenance should be followed. 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 is < 50% at any clinical visit; restart treatment after 4 weeks if LVEF ≥ 50% (see figure 5).

Figure 4: Treatment Maintenance

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, Valsalva LVOT gradient and LVEF at week 4 after dose increase and maintain the current dose for the next 8 weeks unless LVEF <50%. Further up-titration is allowed after 3 months of treatment on the same dose level if LVEF > 55%. Recheck at week 4. The maximum daily dose is 15mg for CYP2C19 intermediate, normal, rapid and ultra-rapid metabolizer phenotype. For For CYP2C19 poor metaboliser phenotype, if LVEF ≥ 55% and LVOT gradient with Valsalva maneuver ≥ 30 mmHg at week 12 visit and subseequent visits, the maximum dose is 5 mg. If titrating from 2.5 mg to 5 mg; follow up 4 and 8 weeks later. 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.

Figure 5: Treatment Interruption at any clinical visit 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, Valsalva LVOT gradient and LVEF in 4 weeks and maintain the current 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% twice on 2.5 mg daily.

Concomitant therapy

Follow Table 1 for concomitant treatment with inhibitors and inducers of CYP2C19 or CYP3A4.

Table 1: Dose modification with concomitant medicinal products

Concomitant medicinal product

CYP2C19 poor metabolizer 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 CAMZYOS 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 CAMZYOS, their dose should be reduced to 2.5 mg.

No dose adjustment.

Inducers

Discontinuing or decreasing the dose of strong CYP2C19 inducer and strong CYP3A4 inducer

The dose should be reduced from 5 mg to 2.5 mg or pause treatment if on 2.5 mg.

The dose should be reduced by one dose level when on doses 5 mg or higher when discontinuing or decreasing the dose of strong inducers while on CAMZYOS.

No dose adjustment when on 2.5 mg.

Discontinuing or decreasing the dose of moderate or weak CYP3A4 inducer

Decrease CAMZYOS dose to 2.5 mg or pause treatment if on 2.5 mg.

No dose adjustment.

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