Consumer medicine information

Camzyos

Mavacamten

BRAND INFORMATION

Brand name

Camzyos

Active ingredient

Mavacamten

Schedule

SUMMARY CMI

Camzyos^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using Camzyos?

Camzyos contains the active ingredient mavacamten. Camzyos is used to treat adults with symptomatic obstructive hypertrophic cardiomyopathy. This is a type of heart disease with a thickened muscle in the heart which makes it harder for blood to leave the heart. For more information, see Section 1. Why am I using Camzyos? in the full CMI.

2. What should I know before I use Camzyos?

Do not use if you have ever had an allergic reaction to Camzyos or any of the ingredients listed at the end of the CMI. Some medicines should NOT be used with Camzyos. The risk of heart failure is increased when Camzyos is taken with certain other medicines. Tell your doctor about the medicines you take, including prescription, non-prescription and herbal medicines, before and during treatment with Camzyos. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use Camzyos? in the full CMI.

3. What if I am taking other medicines?

Some medicines can increase the levels of Camzyos in your body and make it more likely for you to get new side effects that are possibly severe. Some medicines can decrease the levels of Camzyos in your body which can reduce its beneficial effects.

It is important to check the list of medicines in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Camzyos?

Your doctor will tell you how much Camzyos to take. Camzyos should be taken once a day, by mouth (orally), and it does not matter if you take it with or without food. More instructions can be found in Section 4. How do I use Camzyos? in the full CMI.

5. What should I know while using Camzyos?

Things you should do	Remind any doctor (including surgeon), dentist or pharmacist you visit that you are using Camzyos. If you undergo major heart surgery this could increase your risk of developing heart dysfunction. Tell your doctor straight away if you get any of these symptoms during treatment: - new or worsening shortness of breath, chest pain, fatigue, palpitations (a sensation or awareness of your heart beating), or leg swelling. These could be signs and symptoms of heart dysfunction or heart failure (a condition where the heart cannot pump with enough force), which can be life-threatening. - if you develop a serious infection or arrhythmia (irregular heart beat) as this could increase your risk of developing heart dysfunction.
Things you should not do	Do not stop taking Camzyos unless your doctor tells you to. If you wish to stop taking Camzyos, notify your doctor and discuss the best way to discontinue. Do not take Camzyos during pregnancy and for at least 4 months before getting pregnant. Camzyos may cause harm to your unborn baby. Do not stop or change the dose of a medicine or start a new medicine without telling your doctor. Do not drink grapefruit juice while on treatment with Camzyos
Driving or using machines	If you feel dizzy while taking this medicine, do not drive a vehicle, cycle or use any tools or machines.

For more information, see Section 5. What should I know while using Camzyos? in the full CMI.

6. Are there any side effects?

Camzyos can cause serious side effects, including: Heart failure with reduced ejection fraction. The most common side effect of Camzyos in clinical trials was dizziness. You may need medical attention if you get some of the side effects.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

WARNING: Before you take Camzyos, your doctor and pharmacist will make sure you understand how to take Camzyos safely, which will include returning for echocardiograms when advised by your doctor. Taking Camzyos with certain medicines or grapefruit juice may cause heart failure. Do not stop or change the dose of a medicine or start a new medicine without telling your doctor. Some medicines should not be used with Camzyos.

FULL CMI

Camzyos^® (kam zye' ose)

Active ingredient(s): Mavacamten

Consumer Medicine Information (CMI)

This leaflet provides important information about using Camzyos. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Camzyos.

Where to find information in this leaflet:

1. Why am I using Camzyos?
2. What should I know before I use Camzyos?
3. What if I am taking other medicines?
4. How do I use Camzyos?
5. What should I know while using Camzyos?
6. Are there any side effects?
7. Product details

1. Why am I using Camzyos?

Camzyos contains the active ingredient mavacamten.

Camzyos is used to treat adults with symptomatic obstructive hypertrophic cardiomyopathy (obstructive HCM).

Hypertrophic cardiomyopathy (HCM) is a condition where the walls of the heart chamber (left ventricle) contract harder and become thicker than normal. This can be caused by abnormal genes in the heart muscle or it may be due to unknown causes. As the walls thicken they can reduce (obstruct) the flow of blood out of the heart and can also make the heart stiff. This obstruction makes it more difficult for blood to flow into and out of the heart and get pumped to the body with each heartbeat. When this happens, the disease is called obstructive hypertrophic cardiomyopathy (obstructive HCM). Symptoms of obstructive HCM are: chest pain and shortness of breath (especially with physical exercise); fatigue, abnormal heart rhythms, dizziness, feeling that you are about to faint, fainting (syncope) and swelling in the ankle, feet, legs, abdomen and veins in the neck.

Camzyos works by reducing excess contraction of the heart and reducing the obstruction to blood flow to the body. As a result, it may improve your symptoms and your ability to exercise.

2. What should I know before I use Camzyos?

Warnings

Do not use Camzyos if:

you are allergic to mavacamten, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.

Do not take Camzyos with the following medicines:

fluconazole, voriconazole, ketoconazole, posaconazole, voriconazole, itraconazole (medicines used to treat fungal infections)
fluoxetine, fluvoxamine (medicines used to treat depression)
clarithromycin, rifampicin (medicines used to treat bacterial infections)
phenytoin, carbamazepine (medicines used to treat seizures or epilepsy)
ritonavir, cobicistat, efavirenz (anti-viral medicines for hepatitis C or HIV)
apalutamide, dabrafenib, enzalutamide, lorlatinib (medicines used to treat types of cancer)
St. John's Wort (a herbal medicine for depression)

Check with your doctor if you have any other medical conditions.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Pregnancy

Do not take Camzyos during pregnancy and for at least 4 months before getting pregnant. Camzyos may cause harm to your unborn baby. If you are a woman who could become pregnant, your doctor will inform you about this risk and will check if you are pregnant before starting treatment.

Contraception

You must use effective contraception during treatment with Camzyos and for at least 4 months after you stop treatment. Talk to your doctor about contraception methods that may be right for you while you are taking this medicine. Your doctor will check if you are pregnant before treatment, and may consider it throughout treatment with Camzyos.

If you do become pregnant while taking Camzyos, tell your doctor straight away.

Breast-feeding

It is not known if Camzyos passes through breastmilk. Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines including prescription, non-prescription or herbal medicines.

This is because some other medicines can affect the way Camzyos works. Some medicines can increase the levels of Camzyos in your body and make it more likely for you to get new side effects that are possibly severe. Some medicines reduce the levels of Camzyos in your body and may reduce its beneficial effects.

In particular, do not take with the following medicines with Camzyos:

fluconazole, voriconazole, ketoconazole, posaconazole, voriconazole, itraconazole (medicines used to treat fungal infections)
fluoxetine, fluvoxamine (medicines used to treat depression)
clarithromycin, rifampicin (medicines used to treat bacterial infections)
phenytoin, carbamazepine (medicines used to treat seizures or epilepsy)
ritonavir, cobicistat, efavirenz (anti-viral medicines for hepatitis C or HIV)
apalutamide, dabrafenib, enzalutamide, lorlatinib (medicines used to treat types of cancer)
St. John's Wort (a herbal medicine for depression)

Tell your doctor or pharmacist if you are taking or have recently taken or changed the dose of any of the following medicines:

medicines used to reduce the amount of acid in your stomach (e.g., omeprazole and esomeprazole)
medicines used to treat bacterial infections (e.g., erythromycin)
medicines used to treat types of cancer (e.g., crizotinib, vemurafenib )
medicines that affect your heart (such as beta blockers and calcium channel blockers e.g. verapamil and diltiazem)
medicines to treat nausea and vomiting from chemotherapy (e.g., aprepitant)
immunosuppressants such as a medicine called cyclosporine
medicines that improve wakefulness (e.g., armodafinil, modafinil)
medicines that make your heart more resistant to abnormal activity (such as sodium channel blockers e.g. disopyramide)

Tell your doctor if you are using goldenseal (a herbal medicine) as it may affect the level of Camzyos in your body.

Your doctor needs to closely monitor you, and may need to change your dose of Camzyos, or consider alternative treatments if you are taking any of these medicines, or have changed the dose.

If you are not sure whether you are taking any of the medicines mentioned above, ask your doctor or pharmacist.

Before stopping or changing the dose of a medicine or starting a new medicine, tell your doctor or pharmacist.

4. How do I use Camzyos?

How much to take / use

The recommended starting dose is 5 mg taken by mouth once daily.

Your doctor will monitor how well your heart is working while you are taking Camzyos using echocardiograms and may change your dose (increase, lower, or temporarily stop) based on the results.

Your doctor may change your dose, temporarily stop, or permanently stop your treatment with Camzyos if you have certain side effects.

Your doctor will tell you how much Camzyos to take.

The first echocardiogram will be done 4 weeks after the start of treatment, follow-up visits at week 8 and 12 will assess your response to Camzyos using echocardiograms. Routine echocardiograms will be done every 12 weeks. If your doctor changes your dose of Camzyos at any point, an echocardiogram will be done 4 weeks afterwards to make sure you are receiving a beneficial dose.

Your doctor will prescribe you a single daily dose of either 2.5 mg, 5 mg, 10 mg or 15 mg. The maximum single dose is 15 mg once daily.

Always take Camzyos as prescribed by your doctor.

Taking this medicine

Swallow the capsule whole with a glass of water at about the same time each day.
Do not chew, dissolve or open the capsules.
You can take the medicine with food or between meals.

If you forget to use Camzyos

Camzyos should be used regularly at the same time each day. If you miss your dose at the usual time, take your dose as soon as you remember on the same day and take your next dose at the usual time the next day.

Do not take a double dose to make up for the dose you missed.

If you use too much Camzyos

If you think that you have used too much Camzyos, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

If you stop taking Camzyos

Do not stop taking Camzyos unless your doctor tells you to. If you wish to stop taking Camzyos, notify your doctor and discuss the best way to discontinue. Camzyos may remain in the body for at least 4 months after you stop treatment.

You may experience side effects from the drug after you stop treatment.

5. What should I know while using Camzyos?

Things you should do

Keep all of your doctor's appointments so that your progress can be checked.
Tell any other doctors (including surgeons), dentists and pharmacists who are treating you that you are being treated with Camzyos. If you undergo major heart surgery this could increase your risk of developing heart dysfunction. Tell your doctor immediately if you become pregnant or plan to become pregnant while being treated with Camzyos.
Use an effective method of contraception during treatment and for 4 months after stopping treatment.

Things you should not do

Do not stop using this medicine unless your doctor tells you to.
Do not stop or change the dose of a medicine or start a new medicine without telling your doctor.
Do not drink grapefruit juice while on treatment with Camzyos as it may cause heart failure

Routine Tests

Your heart will be assessed by an echocardiogram (a type of test that takes images of your heart to see how well it is working) before your first dose and regularly during treatment with Camzyos. This is because your doctor needs to check how well your heart is working. It is very important to keep echocardiogram appointments to monitor the effect of Camzyos on your heart. Your treatment dose may need to be adjusted to achieve maximum benefit, whilst minimising side effects.

Call your doctor straight away:

if you get any of these symptoms during your treatment with Camzyos: new or worsening shortness of breath, chest pain, fatigue, palpitations (a sensation or awareness of your heart beating), or leg swelling. These could be signs and symptoms of heart dysfunction or heart failure, a condition where the heart cannot pump with enough force, which can be life-threatening.
if you develop a serious infection or arrhythmia (irregular heart beat) as this could increase your risk of developing heart dysfunction.

Your doctor may need to additionally assess your heart function, interrupt the treatment or change your dose depending on how you feel.

Remind any doctor (including surgeon), dentist or pharmacist you visit that you are using Camzyos.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Camzyos affects you.

Camzyos may cause dizziness in some people. If you feel dizzy while taking this medicine, do not drive a vehicle, cycle or use any tools or machines.

Looking after your medicine

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions. It is recommended to store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effects	What to do
new or worsening shortness of breath, chest pain, fatigue, palpitations (a sensation or awareness of your heart beating), or leg swelling. These could be signs and symptoms of heart dysfunction or heart failure, which can be life-threatening.	Tell your doctor, pharmacist immediately if you get any of these symptoms during treatment with Camzyos.

Other side effects

Very Common side effects	What to do
Dizziness	Speak to your doctor if you have any of these side effects and they worry you.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Camzyos contains

Active ingredient
(main ingredient)

Mavacamten

Other ingredients
(inactive ingredients)

Capsule content:

Silicon dioxide
Mannitol
Hypromellose
Croscarmellose Sodium
Magnesium Stearate

Capsule shell:

Gelatin
Titanium Dioxide
Black Iron Oxide
Red Iron Oxide
Yellow Iron Oxide

Do not take this medicine if you are allergic to any of these ingredients.

What Camzyos looks like

The Camzyos 2.5 mg, size 2 hard capsule has light purple opaque cap and white opaque body imprinted in black ink with "2.5 mg" on the cap and "Mava" on the body. (AUST R 386129)

The Camzyos 5 mg, size 2 hard capsule has yellow opaque cap and white opaque body imprinted in black ink with "5 mg" on the cap and "Mava" on the body. (AUST R 386128)

The Camzyos 10 mg, size 2 hard capsule has pink opaque cap and white opaque body imprinted in black ink with "10 mg" on the cap and "Mava" on the body. (AUST R 386127)

The Camzyos 15 mg, size 2 hard capsule has grey opaque cap and white opaque body imprinted in black ink with "15 mg" on the cap and "Mava" on the body. (AUST R 373115)

The hard capsules are packaged in aluminium foil blisters containing 14 hard capsules.

Each pack contains 28 hard capsules.

Who distributes Camzyos

Bristol-Myers Squibb Australia Pty Ltd
4 Nexus Court, Mulgrave,
Victoria 3170, Australia.
Toll free number: 1800 067 567
Email: [email protected]

CAMZYOS^® is a registered trademark of MyoKardia Inc, a Bristol-Myers Squibb Company

This leaflet was prepared in July 2023.

Published by MIMS November 2023

BRAND INFORMATION

Brand name

Camzyos

Active ingredient

Mavacamten

Schedule

1 Name of Medicine

Mavacamten.

2 Qualitative and Quantitative Composition

Each 2.5 mg hard capsule contains 2.5 mg mavacamten.
Each 5 mg hard capsule contains 5 mg mavacamten.
Each 10 mg hard capsule contains 10 mg mavacamten.
Each 15 mg hard capsule contains 15 mg mavacamten.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Hard capsule (capsule).

Camzyos 2.5 mg capsules.

Light purple opaque cap imprinted with "2.5 mg" in black, and white opaque body imprinted with "Mava" in black, both in radial direction. Capsule size: 2.

Camzyos 5 mg capsules.

Yellow opaque cap imprinted with "5 mg" in black, and white opaque body imprinted with "Mava" in black, both in radial direction. Capsule size: 2.

Camzyos 10 mg capsules.

Pink opaque cap imprinted with "10 mg" in black, and white opaque body imprinted with "Mava" in black, both in radial direction. Capsule size: 2.

Camzyos 15 mg capsules.

Gray opaque cap imprinted with "15 mg" in black, and white opaque body imprinted with "Mava" in black, both in radial direction. Capsule size: 2.

4 Clinical Particulars

4.1 Therapeutic Indications

Camzyos is indicated for the treatment of adults with symptomatic NYHA class II-III obstructive hypertrophic cardiomyopathy.

4.2 Dose and Method of Administration

Treatment with mavacamten should be initiated and supervised by a specialist cardiologist, or consultant physician with experience in the management of obstructive hypertrophic cardiomyopathy (HCM).

Monitoring on treatment.

It is important to regularly monitor the patient's symptoms of obstructive HCM, left ventricular outflow tract (LVOT) gradient with Valsalva manoeuvre and left ventricular ejection fraction (LVEF) using echocardiogram assessments.
Once an individualized maintenance dose is achieved, patients should be assessed every 12 weeks.
If at any visit the patient's LVEF is < 50%, the treatment should be interrupted for 4 weeks and until LVEF returns to ≥ 50%.
Assessment of LVEF is recommended if clinical status changes or in patients with a serious intercurrent illness such as infection or arrhythmia (including atrial fibrillation or other uncontrolled tachyarrhythmia) (see Section 4.4 Special Warnings and Precautions for Use).

Testing prior to initiation with Camzyos.

Prior to initiating treatment with Camzyos, assess LVEF by echocardiography (see Section 4.4 Special Warnings and Precautions for Use). Treatment should not be initiated in patients with LVEF < 55%.

Recommended dosage.

The recommended starting dose of Camzyos is 5 mg orally once daily. The capsule should be swallowed whole with water and can be taken with or without food.

Initiation of treatment.

The patient should be assessed for early clinical response 4 and 8 weeks after treatment initiation.

Week 4 visit.

If LVOT gradient with Valsalva maneuver is < 20 mmHg, the dose should be decreased to 2.5 mg once daily. If LVOT gradient with Valsalva maneuver is ≥ 20 mmHg and LVEF remains ≥ 50%, maintain 5 mg once daily.

Week 8 visit.

If LVOT gradient with Valsalva maneuver is ≥ 20 mmHg and LVEF remains ≥ 50%, 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 lowest 2.5 mg dose should have their treatment paused until week 12.
All patients should return at week 12 for re-assessment. See Figure 1.

Treatment maintenance.

Week 12 visit.

Patients should be assessed at Week 12 after initiating treatment with Camzyos, including echocardiogram assessment of LVOT gradient with Valsalva manoeuvre and LVEF with echocardiogram for safety. If symptoms of obstructive HCM persist and LVOT gradient with Valsalva manoeuvre is ≥ 30 mmHg, a step-wise dose increase may be considered in patients with an LVEF ≥ 55%.
Patients who have not had their treatment paused, and who have a LVEF ≥ 55% and a LVOT gradient with Valsalva maneuver ≥ 30 mmHg may have their dose increased by one level (e.g. 2.5 to 5 mg; 5 to 10 mg). A 4-week follow-up visit is required for any dose increase. If the patients 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.
Patients that withheld 2.5 mg treatment at week 8 should be reassessed and if LVEF ≥ 50% can restart their treatment on 2.5 mg, regardless of LVOT gradient. A 4-week follow-up assessment visit will be required to determine if the patient should maintain 2.5 mg dose for 8 weeks. See Figure 2.

Treatment interruption if LVEF < 50%.

If at any clinical visit LVEF is < 50%, treatment should be interrupted. Restart treatment after 4 weeks at one lower dose level (e.g. 5 to 2.5 mg; 10 to 5 mg; 15 to 10 mg) if LVEF ≥ 50%. Patients on 2.5 mg who temporarily interrupt treatment due to LVEF < 50% on two consecutive occasions should discontinue treatment. Patients on 2.5 mg, whose LVEF is ≥ 50% and resumed treatment for four weeks after a temporary interruption due to LVEF < 50%, should discontinue treatment permanently if their LVEF is found to < 50%. at the next scheduled visit. See Figure 3.

Subsequent 12-weekly assessment visits.

The patient's individualized daily dose of Camzyos will be either 2.5, 5, 10 or 15 mg. The maximum dose is 15 mg once daily.
If during future 12-weekly assessment visits the patient's obstructive HCM symptoms have not improved and the LVOT gradient is ≥ 30 mmHg, a further dose increase by one level may be considered in patients with an LVEF ≥ 55% up to a maximum daily dose of 15 mg.
Dose increases should not occur more frequently than every 12 weeks. Following any dose increase, LVOT gradient with Valsalva maneuver and LVEF should be assessed after 4 weeks, and the patient should return 8 weeks later (then resume 12-weekly visits).
Dose increases are not recommended if the patient is experiencing an intercurrent illness such as infections or arrhythmia (including atrial fibrillation or other uncontrolled tachyarrhythmia) which may impair systolic function.

Dose modification with concomitant medicinal products.

It is recommended that patients who initiate or modify treatment with weak CYP2C19 inhibitors or moderate CYP3A4 inhibitors, consider additional monitoring of LVEF and adjust dose based on clinical assessment.

Missed or delayed doses.

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. Two doses should not be taken on the same day.

Renal impairment.

No dosage adjustment is needed in patients with mild (eGFR 60 to < 90 mL/min/1.73 m²) to moderate (eGFR 30 - < 60 mL/min/1.73 m²) renal impairment. Caution should be used in patients with severe (eGFR < 30 mL/min/1.73 m²) renal impairment, as Camzyos has not been studied in this population (see Section 5.2 Pharmacokinetic Properties, Special populations).

Hepatic impairment.

No dosage adjustment is required for patients with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment. Caution should be used in patients with severe (Child-Pugh class C) hepatic impairment, as Camzyos has not been studied in this population (see Section 5.2 Pharmacokinetic Properties, Special populations).

Paediatric and adolescent.

The safety and efficacy of Camzyos in paediatric patients aged less than 18 years of age have not been established. No data are available.

Elderly.

No dosage adjustment is required in patients 65 years and older (see Section 5.2 Pharmacokinetic Properties, Special populations).

4.3 Contraindications

Hypersensitivity to mavacamten or to any of the excipients (see Section 6.1).
Concomitant use with:
moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions);
moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Heart failure with reduced ejection fraction.

Camzyos reduces LVEF and may cause heart failure with reduced ejection fraction (HFrEF) defined as symptomatic LVEF < 50%. Patients with a serious intercurrent illness such as serious infections or arrhythmia (including atrial fibrillation or other uncontrolled tachyarrhythmia) or those undergoing major cardiac surgery may be at greater risk of systolic dysfunction and progress to heart failure (see Section 4.8 Adverse Effects (Undesirable Effects)). New or worsening dyspnoea, chest pain, fatigue, palpitations, leg oedema or elevations in N-terminal-pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of a reduced LVEF and should prompt an evaluation of cardiac function. LVEF should be measured prior to initiating treatment and closely monitored thereafter. Treatment with Camzyos should not be initiated in patients with LVEF < 55%. Treatment interruption may be necessary to ensure that LVEF remains ≥ 50% (see Section 4.2 Dose and Method of Administration).

Risk of heart failure or loss of response to mavacamten due to drug-drug interactions.

Camzyos is primarily metabolised by cytochrome P450 (CYP) 2C19 and CYP 3A4 enzymes. Concomitant administration of Camzyos with CYP2C19 or CYP3A4 inhibitors or inducers may lead to increased risk of HFrEF or a loss of therapeutic response (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions):
Prior to and during Camzyos treatment, the potential for drug interactions, including over-the-counter medications (such as omeprazole or esomeprazole), should be considered. Advise patients to inform their healthcare provider of all concomitant products prior to and during Camzyos treatment.

Concomitant use of negative inotropes.

Due to limited data, the safety of concomitant use of Camzyos with disopyramide, or use of Camzyos in patients taking beta blockers in combination with verapamil or diltiazem has not been established. Therefore, caution should be used when taking these concomitant medications and patients should be closely monitored (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Embryo-fetal toxicity.

Based on animal studies, mavacamten may cause embryo-fetal harm when administered to a pregnant woman. Women of childbearing potential and women becoming pregnant while receiving the treatment should be informed of the potential risk to the fetus. Women of childbearing potential have to use highly effective contraception during treatment with Camzyos and for at least 4 months after discontinuing treatment (see Section 4.6 Fertility, Pregnancy and Lactation).

Use in hepatic impairment.

Caution should be used in patients with severe (Child-Pugh class C) hepatic impairment, as Camzyos has not been studied in this population (see Section 5.2 Pharmacokinetic Properties, Special populations).

Use in renal impairment.

Caution should be used in patients with severe (eGFR < 30 mL/min/1.73 m²) renal impairment, as Camzyos has not been studied in this population (see Section 5.2 Pharmacokinetic Properties, Special populations).

Use in the elderly.

Safety, effectiveness, and pharmacokinetics were consistent between elderly patients (≥ 65 years) and younger patients (18 to < 65 years) (see Section 5.2 Pharmacokinetic Properties, Special populations).

Paediatric use.

No data available.

Effects on laboratory tests.

The effects of Camzyos on laboratory tests were not considered clinically significant.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of other drugs on Camzyos.

Camzyos is primarily metabolised by CYP2C19 and to a lesser extent by CYP3A4. Strong CYP3A4 inhibitors/ inducers or any CYP2C19 inhibitors/ inducers may thus affect the clearance of Camzyos and increase/decrease Camzyos plasma concentration (see Section 4.4 Special Warnings and Precautions for Use).

CYP 2C19 and CYP 3A4 inhibitors.

Coadministration of mavacamten with a weak CYP2C19 inhibitor (omeprazole) resulted in a 48% increase in mavacamten AUC_inf with no effect on C_max. Coadministration of mavacamten with a strong CYP3A4 inhibitor (itraconazole) resulted in an increase in mavacamten plasma concentration of up to 59% and 40% in AUC_0-24 and C_max, respectively.
Coadministration of mavacamten with a moderate CYP3A4 inhibitor (verapamil) resulted in an increase in mavacamten plasma concentration of 16% and 52% in AUC_inf and C_max, respectively.
Concomitant use with a moderate to strong CYP2C19 inhibitor or a strong CYP3A4 inhibitor is contraindicated (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
If initiating or adjusting the dose of a concomitant weak CYP2C19 inhibitor or moderate CYP3A4 inhibitor, increased clinical assessments and dose adjustment should be considered (see Section 4.2 Dose and Method of Administration).

CYP 2C19 and CYP 3A4 inducers.

Coadministration of mavacamten with a strong CYP2C19 and CYP3A4 inducer following a 7-day lead-in induction period, is predicted by PBPK modelling to result in a decrease in mavacamten of up to 60% and 7% in AUC_0-t and C_max, respectively in CYP2C19 normal metabolisers (NM). In CYP2C19 poor metabolisers (PM) a decrease of up to 69% and 4% in AUC_0-t and C_max was predicted. Mavacamten clearance is expected to increase for both NM and PM by 2.5-fold and 3.2-fold, respectively, under induction conditions.
Concomitant use with a moderate or strong CYP2C19 inducer or a moderate or strong CYP3A4 inducer is contraindicated (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Coadministration of mavacamten with a weak CYP2C19 or a weak CYP3A4 inducer may result in a decrease in mavacamten plasma concentration. If discontinuing concomitant treatment with a weak CYP2C19 or CYP3A4 inducer, monitor LVEF 4 weeks after inducer discontinuation, subsequently resume the monitoring and titration schedule (see Section 4.2 Dose and Method of Administration, Figure 1, Figure 2).

Effect of Camzyos on CYP3A4 substrates.

Coadministration of a 16-day course of mavacamten resulted in a decrease in midazolam plasma concentration. This change was not considered clinically significant. Coadministration of a 17-day course of mavacamten did not decrease the exposure to ethinyl oestradiol and norethindrone, which are the components of typical oral contraceptives and substrates for CYP3A4.

Effect of mavacamten on other CYP substrates.

Based on pre-clinical data, mavacamten is not an inhibitor of CYP 1A2, 2B6, 2C8, 2D6, 2C9, 2C19, or 3A4 at clinically relevant concentrations.
In vitro, mavacamten is an inducer of CYP 2B6, and 3A4, 2C8, 2C19 and 2C9.

Effect of mavacamten on transporters.

In vitro data indicate that mavacamten is not an inhibitor of major efflux transporters (P-gp, BCRP, BSEP, MATE1, or MATE2-K) or major uptake transporters (organic anion transporting polypeptides [OATPs], organic cation transporters [OCTs], or organic anion transporters [OATs]) at therapeutic concentrations.

Other interactions.

Drugs that reduce cardiac contractility.

In the EXPLORER-HCM study, 119 of 123 patients who received Camzyos received concomitant treatment with either beta blockers, verapamil, or diltiazem (see Section 5.1 Pharmacodynamic Properties, Clinical trials). In the VALOR-HCM study, 53 of the 56 patients who received Camzyos during the randomised controlled period received concomitant therapy with the following medications (alone or in combination with other treatment): beta blocker, verapamil or diltiazem, and/or disopyramide. In the overall study, including patients who were treated with Camzyos after the double-blind period, 36 of 112 patients (32%) received Camzyos with combination background HCM therapy; 22 of 112 patients (20%) received disopyramide as monotherapy or in combination with other treatments and no evidence of systolic dysfunction was observed. There is limited information available on the potential for a pharmacodynamic (PD) interaction between Camzyos and other drugs that also reduce cardiac contractility. If treatment with a new negative inotrope is initiated, or if the dose of a negative inotrope is increased, in a patient receiving Camzyos, close medical supervision with echocardiographic monitoring of LVEF should be provided until stable doses and clinical response have been achieved (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In reproductive toxicity studies, there was no evidence of effects of mavacamten on mating and fertility in male or female rats or on the viability and fertility of offspring of dams at any dose tested. Plasma exposures (AUC) of mavacamten at the highest doses tested are less than in humans at the maximum recorded human dose (MRHD).
(Category D)
There are no adequate data on the developmental risk associated with the use of Camzyos in pregnant females. Based on animal data, Camzyos may cause fetal harm when administered to a pregnant female.
Camzyos should not be administered to patients who are pregnant. Females of reproductive potential who undergo treatment with Camzyos should be informed of the potential hazard to the foetus and should be advised to avoid becoming pregnant prior to or during treatment and for at least 4 months after discontinuation.
If the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the foetus.

Pregnancy testing.

Confirm a negative pregnancy test in women of reproductive potential prior to initiation of treatment.

Contraception.

Advise females of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment with Camzyos and for at least 4 months after discontinuing treatment.

Animal data.

When mavacamten was administered orally to pregnant rats during the period of organogenesis, decreased mean fetal body weight, and increases in post implantation loss and fetal malformations (visceral and skeletal) were observed in the high dose group (1.5 mg/kg/day). Visceral malformations (heart malformation in foetuses, including one total situs inversus) and increased incidences of skeletal malformations (mainly fused sternebrae) were observed. Plasma exposure (AUC) at the no effect dose for embryo-fetal development in rats and rabbits are less than those in humans at the MRHD.
When mavacamten was administered orally to pregnant rabbits during the period of organogenesis, fetal malformations (external, visceral and skeletal) were increased at doses of 1.2 mg/kg/day and higher. Visceral findings consisted of malformations of the great vessels (pulmonary trunk atresia, dilatation of pulmonary trunk) and malformations of the heart, kidney, ureter and testis at 2.0 mg/kg/day. Skeletal malformations consisted of higher incidences of fused sternebrae at 2.0 mg/kg/day. External findings consisted of cleft palate at doses of 1.2 mg/kg/day and higher. Plasma exposure (AUC) at the no effect dose for embryo-fetal development in rabbits is less than those in humans at the MRHD.
It is unknown whether mavacamten or its metabolites are excreted in human milk. Because of the unknown adverse effects of mavacamten in breastfed newborns/infants, a decision must be made whether to discontinue breastfeeding during treatment and for 4 months after the last dose or to discontinue treatment, taking into account the benefit of breastfeeding for the child and the benefit of treatment for the woman.
In a pre- and post-natal development study, mavacamten was administered orally to pregnant rats from gestation day 6 to lactation/post-partum day 20. No adverse effects were observed in the dams or offspring exposed daily from before birth (in utero) through lactation. The maternal exposure was inferred from the embryo-fetal developmental toxicity study dosed at the same level, and the exposure was less than the MRHD.

4.7 Effects on Ability to Drive and Use Machines

Camzyos may have minor influence on the ability to drive and use machines. Dizziness may occur following administration of mavacamten. Patients should be advised not to drive or use machines if they experience dizziness.

4.8 Adverse Effects (Undesirable Effects)

Clinical experience.

The safety of Camzyos was evaluated in EXPLORER-HCM, a Phase 3, double-blind, randomized, placebo controlled, trial. Of the 251 obstructive HCM adult patients in this trial, 123 patients were treated with a daily dose of either 2.5 mg, 5 mg, 10 mg or 15 mg of Camzyos and 128 were treated with placebo. Camzyos-treated patients received a median duration of exposure of 30.4 weeks (range: 1.6 to 40.3 weeks).
There were no adverse reactions leading to discontinuation. Two patients out of 123 (1.6%) in the Camzyos group and no patients (0%) in the placebo group discontinued trial drug. In the Camzyos group, the adverse events leading to discontinuation were syncope (0.8%) and atrial fibrillation (0.8%) in one patient each.
Adverse events reported by ≥ 5% of subjects in any treatment group are provided in Table 1.

The adverse drug reactions (ADRs) according to system organ class in MedDRA are listed in Table 2. Within each system organ class, the ADRs are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each ADR is defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

The safety of Camzyos in patients was further evaluated in VALOR-HCM, a phase 3, double-blind, randomized, placebo-controlled trial. Of the 112 adults with symptomatic obstructive HCM, 56 patients were treated with Camzyos 2.5-15 mg daily and 55 were treated with placebo. Camzyos treated patients had a median duration of exposure of 17 weeks (range: 3-19 weeks) during the double-blind period (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
There were no adverse drug reactions leading to discontinuation in patients receiving Camzyos. During the placebo-controlled period of the study, adverse reaction occurring in > 5% of patients and more commonly on Camzyos than on placebo was dizziness (13% vs. 6%).
Adverse events reported by ≥ 5% of subjects in any treatment group during placebo-controlled period of VALOR-HCM trial are provided in Table 3.

Effects on systolic function.

In the EXPLORER-HCM trial, 7 (6%) patients in the Camzyos group and 2 (2%) patients in the placebo group experienced reversible reductions in LVEF < 50% (median 48%: range 35-49%) while on treatment. None of the 7 patients receiving mavacamten had systolic dysfunction leading to heart failure. In 3 of the 7 Camzyos patients and in 1 of the 2 placebo patients, these reductions were observed without other clinical manifestations (e.g. symptoms). In all 7 patients treated with Camzyos, LVEF recovered following interruption of Camzyos and they completed the study (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

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. There was one serious adverse reaction of vasovagal reaction, hypotension, and asystole lasting 38 seconds reported at that dose. In healthy subjects, doses of up to 25 mg have been administered for up to 25 days. Three out of 8 participants treated at the 25 mg dose level experienced 20% or greater reductions in LVEF. Systolic dysfunction is the most likely result of overdosage of Camzyos.

Management of overdose.

If warranted, treatment of overdose with Camzyos consists of discontinuation of Camzyos treatment as well as medically supportive measures to maintain hemodynamic status (e.g. initiation of inotropic support with adrenergic agents), including close monitoring of vital signs and LVEF and management of the clinical status of the patient.
In an open-label randomised pharmacokinetic (PK) study in healthy subjects fasted overnight, administration of activated charcoal 2 hours (approximately T_max) after ingestion of a 15 mg dose of mavacamten reduced AUC and half-life of mavacamten, with a geometric mean ratio of 0.658 and 0.648, respectively. Administration of activated charcoal 6 hours after the mavacamten dose had minimal effect on mavacamten exposure and elimination. Thus, early administration (prior to or as soon after T_max as possible) of activated charcoal may be considered in the management of mavacamten overdose or accidental ingestion. Under fed conditions, activated charcoal may still be effective beyond 2-hour post mavacamten dose because of the delayed T_max by food (see Section 5.2 Pharmacokinetic Properties).
In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Mavacamten is a selective, allosteric, and reversible cardiac myosin inhibitor. Mavacamten modulates the number of myosin heads that can enter power-generating states, thus reducing, (or in HCM normalizing), the probability of force-producing systolic and residual diastolic crossbridge formation. Mavacamten also shifts the overall myosin population towards an energy sparing, but recruitable, super-relaxed state. Excess cross-bridge formation and dysregulation of the super-relaxed state of myosin are mechanistic hallmarks of HCM, which can result in hypercontractility, impaired relaxation, excess energy consumption, and myocardial wall stress. In HCM patients, myosin inhibition with mavacamten normalizes contractility, reduces dynamic LVOT obstruction, and improves cardiac filling pressures and biomarkers of cardiac stress, improving symptoms and exercise capacity.

LVEF.

A reduction in ejection fraction is expected with mavacamten treatment. In the EXPLORER-HCM trial, mean (SD) resting LVEF was 74% (6) at baseline in both treatment groups. Consistent with the mechanism of action of Camzyos, reductions in mean (SD) absolute change from baseline in LVEF was -4% (8) in the Camzyos group and 0% (7) in the placebo group over the 30-week treatment period. At Week 38, following an 8-week interruption of trial drug, mean LVEF was similar to baseline for both treatment groups.

LVOT obstruction.

In the EXPLORER-HCM trial, patients achieved significant reductions in mean resting and provoked (Valsalva) LVOT gradient by Week 4 which were sustained throughout the 30-week trial. At Week 30, the mean (SD) change from baseline in resting and Valsalva LVOT gradients were 39 (29) mmHg and -49 (34) mmHg, respectively, for the Camzyos group and -6 (28) mmHg and -12 (31) mmHg, respectively, for the placebo group. The clinically significant reductions in LVOT gradient were mediated by the mechanism of action of mavacamten, which resulted in small decreases in LVEF, attenuating the hypercontractility typical of obstructive HCM while maintaining LVEF within the normal range. The reductions in LVOT gradient while maintaining stable heart rate and systemic blood pressure demonstrate improvement in forward blood flow. At Week 38, following 8 weeks of trial drug washout, mean LVEF and LVOT gradients were similar to baseline for both treatment groups.

Cardiac structure.

In the EXPLORER-HCM trial, echocardiographic measurements of cardiac structure showed a mean (SD) reduction from baseline at Week 30 in left ventricular mass index (LVMI) in the mavacamten group of -7.4 (17.8) g/m² versus an increase in LVMI in the placebo group of 9.0 (15.3) g/m². There was also a mean (SD) reduction from baseline in left atrial volume index (LAVI) in the mavacamten group -7.5 (7.8) mL/m² versus no change in the placebo group with -0.1 (8.7) mL/m².

Cardiac electrophysiology.

In HCM, the QT interval may be intrinsically prolonged due to the underlying disease, in association with ventricular pacing, or in association with drugs with potential for QT prolongation commonly used in HCM population. An exposure-response analysis across all clinical studies in HCM patients has shown a concentration-dependent shortening of the QTcF interval. The mean placebo corrected change from baseline in obstructive HCM patients was -8.7 ms (upper and lower limit of the 90% CI -6.7 ms and -10.8 ms, respectively) at the median steady-state C_max of 452 nanogram/mL. Patients with longer baseline QTcF intervals tended to display the greatest shortening. In the EXPLORER-HCM trial, there was no evidence of an increase in clinical events suggestive of ventricular arrhythmias (e.g. sudden deaths, syncope, or seizures) in the mavacamten group compared to placebo. There is limited experience on co-administration of mavacamten with QT prolonging drugs or in patients with potassium channel variants resulting in a long QT interval. In the VALOR-HCM trial, addition of mavacamten did not appear to worsen the prolongation of QTcF that can be present with disopyramide treatment.
Consistent with nonclinical findings in normal hearts, in one clinical trial in healthy subjects sustained exposure to mavacamten at supratherapeutic levels leading to marked depression of systolic function was associated with QTc prolongation (< 20 ms). No acute QTc changes have been observed at comparable (or higher) exposures after single doses.
Preclinical studies to investigate the observed QTc prolongation in healthy hearts in animals demonstrated no proarrhythmic and/or torsadogenic potential either in vivo, in vitro, and/or in silico, and confirmed that the QTc prolongation observed in healthy hearts is not the result of an off-target direct effect of mavacamten on late-repolarization currents like hERG ion channel activity and/or trafficking. The findings in healthy hearts are attributed to an adaptive response to the cardiac mechanical/functional changes (marked mechanical LV depression) occurring in response to myosin inhibition in hearts with normal physiology and LV contractility.

Cardiac biomarkers.

In the EXPLORER-HCM trial, reductions in a biomarker of cardiac wall stress, N-terminal pro-B-type natriuretic peptide (NT-proBNP) were observed by Week 4, and sustained through the end of treatment. The Week 30 ratio to baseline geometric mean was 0.20 for mavacamten and 1.02 for placebo (proportion of geometric mean ratio between the two arms 0.20, [95% CI: 0.17, 0.24]); therefore, the reduction in NT-proBNP after mavacamten treatment was 80% greater than for placebo.

Clinical trials.

Clinical efficacy and safety.

EXPLORER-HCM trial.

The efficacy of Camzyos was evaluated in a double-blind, randomised, placebo-controlled, parallel-arm, multicentre, international, Phase 3 study (EXPLORER-HCM) enrolling 251 adult patients with symptomatic NYHA class II and III obstructive HCM, LVEF ≥ 55%, and LVOT peak gradient ≥ 50 mmHg at rest or with provocation. The majority of patients received background HCM treatment for a total of 96% in Camzyos arm (beta blockers 76%, calcium channel blockers 20%) and of 87% in the placebo arm (beta blockers 74%, calcium channel blockers 13%).
Patients were randomised in a 1:1 ratio to receive either a starting dose of 5 mg of Camzyos (123 patients) or matching placebo (128 patients) once daily for 30 weeks. The dose was periodically adjusted based on plasma concentrations of Camzyos and pharmacodynamic response (decrease in LVOT gradient with Valsalva manoeuvre and maintenance of LVEF ≥ 50%) to optimise patients' response. Within the dose range of 2.5 mg to 15 mg, a total of 81% (100/123) of patients were receiving either the 5 mg or 10 mg dose at the end of the treatment period, with 49% (60/123) receiving the 5 mg dose. During the study, 3 of 7 patients on Camzyos had LVEF < 50% prior to the Week 30 visit and temporarily interrupted their dose; 2 patients resumed treatment at the same dose and 1 patient had the dose reduced from 10 mg to 5 mg.
Treatment assignment was stratified by baseline disease severity NYHA functional class (II or III), current treatment with beta blockers (yes or no), type of ergometer (treadmill or exercise bicycle) used for assessment of peak oxygen consumption (pVO₂). Patients on background dual treatment with beta blocker and calcium channel blocker treatment or disopyramide or ranolazine were excluded. Patients with known infiltrative or storage disorder causing cardiac hypertrophy that mimicked obstructive HCM, such as Fabry disease, amyloidosis, or Noonan syndrome with LV hypertrophy, were also excluded.
The baseline demographic and disease characteristics are shown in Table 4.

The primary endpoint was comprised of a composite of change at Week 30 in exercise capacity measured by pVO₂ and symptoms measured by NYHA functional classification, defined as an improvement of pVO₂ by ≥ 1.5 mL/kg/min and an improvement in NYHA class by at least 1 or an improvement of pVO₂ by ≥ 3.0 mL/kg/min and no worsening in NYHA class.
A greater proportion of patients met the primary endpoint at Week 30 in the Camzyos arm compared to the placebo arm (36.6% versus 17.2%, respectively, p = 0.0005) (see Table 5).

A range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes. Results of the primary analysis consistently favoured Camzyos across all subgroups analysed (see Figure 4).

The benefit of mavacamten on the primary endpoint was smaller in patients on background beta blocker therapy versus those who were not. Beta blocker therapy blunts heart rate, which attenuates improvements in pVO₂. Analyses of other secondary endpoints (symptoms, LVOT gradient) as well as other non-heart rate-dependent cardiopulmonary exercise testing measurements (VE/VCO₂ slope) suggest that patients may benefit from mavacamten treatment regardless of beta blocker use.
The treatment effects of Camzyos on LVOT obstruction, functional capacity, and health status were assessed by change from baseline through Week 30 in post-exercise LVOT peak gradient, change in pVO₂, proportion of patients with improvement in NYHA class, Kansas city cardiomyopathy questionnaire-23 (KCCQ-23) Clinical summary score (CSS), and Hypertrophic cardiomyopathy symptom questionnaire (HCMSQ) Shortness of breath (SoB) domain score. At Week 30, patients receiving Camzyos had greater improvement compared to placebo arm across all secondary endpoints (see Table 6).

The KCCQ-23 CSS favoured Camzyos compared to placebo at Week 30. The mean improvement from baseline on the KCCQ-23 CSS was greater in the Camzyos arm compared to placebo at Week 30 (p < 0.0001), with effects observed as early as 6 weeks (see Figure 5).

A greater proportion of patients taking Camzyos compared to placebo achieved a clinically meaningful improvement of ≥ 10 points between baseline and Week 30 in health status (symptoms and physical limitations) (see Figure 6).

The HCMSQ SoB domain favoured Camzyos compared to placebo at Week 30. The mean improvement from baseline on the HCMSQ SoB domain was greater in the Camzyos arm compared to placebo at Week 30 (p < 0.0001), with effects observed as early as 4 weeks (see Figure 7).

A greater proportion of patients taking Camzyos compared to placebo achieved a clinically meaningful improvement of ≤ -2.5 points between baseline and Week 30 in the HCMSQ SoB domain (see Figure 8).

VALOR-HCM trial.

The efficacy of Camzyos was evaluated in a double-blind, randomized, 16 week placebo-controlled, multicentre, international Phase 3 study (VALOR-HCM) enrolling 112 adult patients with symptomatic obstructive HCM who were eligible for septal reduction therapy (SRT). Patients with severely symptomatic drug-refractory obstructive HCM (including 33% on any combination of beta-blocker, calcium channel blocker and/or disopyramide; 20% on disopyramide alone or in combination with other treatment), and NYHA class II with exertional syncope or near syncope (N=8 [7.1%]), class III (N=103 [92.0%]) or class IV (N=1 [0.9%]), were included in the study. Patients were required to have LVOT peak gradient ≥ 50 mmHg at rest or with provocation, and LVEF ≥ 60%. Patients must have been referred or under active consideration within the past 12 months for SRT and actively considering scheduling the procedure.
Patients were randomized 1:1 to receive either a starting dose of 5 mg of Camzyos (56 patients) or placebo (56 patients) once daily for 16 weeks. Dose adjustment was based on clinical echocardiogram parameters.
Camzyos was shown to be superior to placebo in reducing the proportion of patients who met the primary endpoint (the composite of patient decision to proceed with SRT prior to or at Week 16 or met SRT eligibility (LVOT gradient of ≥ 50 mmHg and NYHA class III-IV, or class II with exertional syncope or near syncope)) at Week 16 (18% vs. 77%, respectively, p < 0.0001; (see Table 7)).

The treatment effects of Camzyos on LVOT obstruction, functional capacity, health status, and cardiac biomarkers were assessed by change from baseline through Week 16 in post-exercise LVOT gradient, proportion of patients with improvement in NYHA class, KCCQ-23 CSS, NT-proBNP, and cardiac troponin I. In the VALOR-HCM study, hierarchical testing of secondary efficacy endpoints showed significant improvement in the Camzyos group compared to the placebo group (see Table 8).

The KCCQ-23 CSS favored Camzyos compared to placebo at Week 16. The mean improvement from baseline on the KCCQ-23 CSS was greater in the Camzyos group compared to the placebo at Week 16 (p < 0.0001), with effects observed as early as 4 weeks (see Figure 9).

The proportion of patients with improved KCCQ-23 CSS from baseline to Week 16 was higher at various levels of improvement for the Camzyos treated group compared to the placebo group (see Figure 10 KCCQ-23 Clinical Summary Score: Cumulative Distribution of Change from Baseline to Week 16).

5.2 Pharmacokinetic Properties

Mavacamten has a variable terminal t½ that depends on CYP 2C19 metabolic status (6 to 9 days in normal metabolisers and 23 days in poor metabolisers). Exposure to mavacamten increased approximately dose proportionally between 2 mg and 48 mg.

Absorption.

Mavacamten is readily absorbed (T_max of 1 to 2 hours) after oral administration with an estimated oral bioavailability of approximately 85% within the clinical dose range. The increase in mavacamten exposure is generally dose proportional after once daily doses of mavacamten (2 mg to 48 mg).

Effect of food.

A high fat, high calorie meal delayed absorption resulting in a T_max of 4 hours in the fed state compared to 1 hour in the fasted state. Administration with food resulted in a 13% decrease in AUC_0-inf, however this decrease is not considered clinically significant. Camzyos may be administered with or without food.

Distribution.

Specific studies to assess distribution of mavacamten have not been conducted in humans, however data are consistent with a high volume of distribution. Plasma protein binding of mavacamten is 97-98% in clinical studies. The blood-to-plasma concentration ratio is 0.79.
Based upon measurements of mavacamten in semen of 10 male subjects who received either an 18.5 mg (n=4) or 25 mg (n=6) dose for up to 28 days, the mean (SD) mavacamten semen-to-plasma ratio was 0.039 (0.0047) and 0.044 (0.016), respectively.

Metabolism.

Mavacamten is extensively metabolised, primarily through CYP 2C19 (74%), CYP 3A4 (18%), and CYP 2C9 (7.6%). Three metabolites have been detected in human plasma. The exposure of the most abundant metabolite MYK-1078 in human plasma was less than 4% of the exposure of mavacamten, and the other two metabolites had exposures less than 3% of the exposure of mavacamten indicating these would have minimal to no impact on the overall activity of mavacamten.

Elimination.

Mavacamten is cleared from plasma primarily by metabolism through cytochrome P450 enzymes. Terminal half-life is 6 to 9 days in CYP 2C19 NM. Drug accumulation occurs with an accumulation ratio about 2-fold for C_max and about 7-fold for AUC.
At steady-state, the peak-to-trough plasma concentration ratio with once daily dosing is approximately 1.5. Intersubject pharmacokinetic (PK) variability is moderate, with a coefficient of variation for exposure in of approximately 30 to 50% for C_max and AUC.

CYP 2C19 poor metabolisers.

After a single dose of 15 mg mavacamten, C_max and AUC_inf increased by 47% and 241%, respectively, in CYP 2C19 poor metabolisers (PM) compared to NM. Mean half-life is prolonged in CYP 2C19 PM compared to NM (23 days vs 6 to 9 days, respectively). The incidence of CYP 2C19 PM ranges from approximately 2% in Caucasian to 18% in Asian populations.

Excretion.

Following a single 25 mg dose of ¹⁴C labeled mavacamten, 7% and 85% of the total radioactivity was recovered in the faeces and urine, respectively. Unchanged drug accounted for approximately 1% and 3% of the administered dose in the faeces and urine, respectively.

Special populations.

No clinically significant differences in the pharmacokinetics of mavacamten were observed using population PK modelling based on age, sex, race or ethnicity.