Consumer medicine information

Cerdelga

Eliglustat

BRAND INFORMATION

Brand name

Cerdelga

Active ingredient

Eliglustat

Schedule

What is in this leaflet

This leaflet answers some common questions about Cerdelga. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Cerdelga against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Cerdelga is used for

Cerdelga contains the active substance eliglustat. It belongs to a group of medicines that decrease the production of a substance called glucosylceramide in the body.

Cerdelga is used for the long term treatment of adult patients with Gaucher disease type 1.

Gaucher disease type 1 is a rare, inherited condition in which a substance called glucosylceramide builds up in the cells of your spleen, liver and bones.

The build-up can prevent these organs from working properly.

Cerdelga decreases the production of glucosylceramide, preventing its build-up. In turn this helps your affected organs to work better.

Some people's bodies break down this medicine faster than others. As a result the amount of this medicine in the blood can differ between patients which could affect how you will respond. Cerdelga is meant to be used in patients whose body breaks down this medicine at normal speed (known as intermediate metaboliser and extensive metaboliser) or slow speed (known as poor metaboliser). Your doctor will determine if Cerdelga is suitable for you before you start taking it, using a simple laboratory test.

Gaucher disease type 1 is a lifelong condition and you must continue to take Cerdelga as prescribed by your doctor to gain the maximum benefit from your medicine.

Ask your doctor if you have any questions about why it has been prescribed for you.

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

There is not enough information to recommend the use of this medicine for children under the age of 18 years.

Before you take it

When you must not take it

Do not take Cerdelga if you:

are allergic to eliglustat or any of the other ingredients listed at the end of this leaflet.
Some symptoms of an allergic reaction include skin rash, hives, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.
are being treated with any medicines other than Cerdelga until after you have consulted with your doctor. Certain medicines can interfere with your body's ability to breakdown Cerdelga and this can result in higher levels of Cerdelga than needed in your body (see the section 'Taking other medicines' for an expanded list of medicines).
are having any problems with your liver or kidney function until after you have consulted with your doctor. Certain problems with liver or kidney function can result in higher levels of Cerdelga than needed in your body.

Do not give Cerdelga to a child under the age of 18 years. Safety and effectiveness in children have not been established.

Do not take it after the expiry date (exp) printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor or pharmacist if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor immediately if you:

are currently treated or about to start treatment with any of the medicines listed in section 'Taking other medicines'
have liver or kidney problems
have had a heart attack or heart failure
have a slow heart rate
have an irregular, or abnormal heart beat, including a heart condition called long QT syndrome
have any other heart problems
are taking an antiarrhythmic medicine (for irregular heart beats) like quinidine, amiodarone, sotalol.

If you are unsure about whether you should take Cerdelga with your current medicines, check with your doctor or pharmacist.

Tell your doctor if you are or intend to become pregnant. Your doctor will discuss with you the risks and benefits involved.

Tell your doctor if you are breastfeeding or planning to breastfeed. It is unknown if Cerdelga enters breast milk. Breast-feeding is not recommended during treatment with this medicine.

If you have not told your doctor about any of the above, tell him/her before you take Cerdelga.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Medicines that must not be taken in combination with each other and Cerdelga:
Cerdelga must not be used with certain type of medicines. These medicines can interfere with your body's ability to break down Cerdelga and this can result in higher levels of Cerdelga in your blood. These medicines are known as strong or moderate CYP2D6 inhibitors and strong or moderate CYP3A inhibitors. There are many medicines in these categories and depending on how your body breaks down Cerdelga the effects may differ from person to person. Please speak to your doctor about these medicines before you start taking Cerdelga. Your doctor will determine which medicines you can use based on how fast your body breaks down Cerdelga.

Some medicines may increase the level of Cerdelga in the blood:

paroxetine, fluoxetine, fluvoxamine, duloxetine, fluvoxamine, moclobemide - antidepressants used to treat depression
quinidine, dronedarone, verapamil - antiarrhythmics used to treat irregular heartbeat
bupropion- used in smoking cessation
cyclosporine – used in transplant patients
clarithromycin, erythromycin, ciprofloxacin - antibiotics used to treat infections
terbinafine, itraconazole, fluconazole, posaconazole, voriconazole - antifungals used to treat fungal infections
mirabegron - used to treat overactive bladders
cinacalcet - calcimimetic used in some dialysis patients and specific cancers
atazanavir, darunavir, fosamprenavir, elvitegravir, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir – antiretrovirals used to treat HIV
cobicistat - used to improve the effects of antiretrovirals (used to treat HIV)
aprepitant - antiemetic used to reduce vomiting
diltiazem - antihypertensive used to increase blood flow and decrease heart rate
boceprevir, telaprevir - antiviral used to treat Hepatitis C
imatinib - anticancer used to treat cancer
amlodipine, ranolazine - used to treat angina pectoris
cilostazol - used to treat cramp-like pain in your legs when you walk caused by insufficient blood supply in your legs
isoniazid - an antibiotic used to treat tuberculosis
cimetidine, ranitidine - antacids used to treat indigestion
goldenseal (also known as Hydrastis canadensis) - a herbal preparation obtained without a prescription, used as a digestive aid.

Some medicines may decrease the level of Cerdelga in the blood:

rifampicin, rifabutin - antibiotics used to treat infections
carbamazepine, phenobarbital, phenytoin - anti-epileptics used to treat epilepsy and seizures
St. John's wort (also known as Hypericum perforatum) - a herbal preparation obtained without a prescription, used to treat depression and other conditions.

Cerdelga may increase the level of the following types of medicines in the blood:

dabigatran - anticoagulant used to thin the blood
phenytoin - anti-epileptic used to treat epilepsy and seizures
nortryptyline, amitriptyline, imipramine, desipramine - antidepressants used to treat depression
flecainide and propafenone - antiarrhythmics used to treat irregular heartbeat
phenothiazines - antipsychotics used to treat schizophrenia and psychosis
digoxin - used to treat heart failure and atrial fibrillation
colchicine - used to treat gout
metoprolol - used to lower blood pressure and/or reduce heart rate
dextromethorphan - cough medicine
atomoxetine - used to treat attention deficit hyperactivity disorder (ADHD)
pravastatin - used to lower cholesterol and prevent heart disease

These medicines will be affected by Cerdelga or may affect how Cerdelga works. You may need different amounts of your medicines, or take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Cerdelga.

How to take it

Follow all directions given to you by your doctor or pharmacist carefully and always take this medicine exactly as your doctor or pharmacist has told you.

How much to take

If you are an intermediate metaboliser or extensive metaboliser:
Swallow one 84 mg capsule whole twice per day. Take one capsule in the morning and one capsule at night.

If you are a poor metaboliser:
Swallow one 84 mg capsule whole once per day. Take the capsule at the same time every day.

Your doctor may have prescribed a different dose. If you have liver problems and/or you are taking other medicines, you should consult with your doctor.

Make sure you tell your doctor about any other medicines that you are taking.

Ask your doctor or pharmacist if you are unsure of the correct dose for you.

How to take it

It may be taken with or without food.

Swallow the capsules whole with a full glass of water.

Do not open, crush, dissolve, or chew capsule before swallowing. If you cannot swallow the capsule whole, tell your doctor.

Avoid grapefruit or grapefruit products since grapefruit may increase the level of Cerdelga in your blood.

When to take it

Take Cerdelga at about the same time each morning and night.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

Continue taking your medicine for as long as your doctor or pharmacist tells you.

The medicine helps control your condition, but it does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

If there is still a long time to go before your next dose, take it as soon as you remember, and then go back to taking it as you would normally.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Cerdelga. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include: dizziness marked by loss of balance, slow heart rate, nausea, vomiting and light-headedness.

While you are taking it

Things you must do

Tell all the doctors, dentists and pharmacists who are treating you that you are taking Cerdelga. Remember to provide your Cerdelga Patient Card to any health care professional when seeking treatment.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Cerdelga.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking Cerdelga. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor or pharmacist immediately.

Things you must not do

Do not take more than the recommended dose unless your doctor tells you to.

Avoid grapefruit or grapefruit products since grapefruit may increase the level of Cerdelga in your blood.

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not use this medicine to treat any other complaints unless your doctor tells you to.

Do not stop taking Cerdelga, or lower the dosage, without checking with your doctor.

Do not start taking any new medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop without consulting your doctor or pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how Cerdelga affects you.

Side effects

All medicines have some unwanted side effects. Sometimes they are serious, but most of the time they are not. Your doctor or pharmacist has weighed the risks of using this medicine against the benefits they expect it will have for you.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Cerdelga.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

indigestion
stomach ache
feeling sick (nausea)
diarrhoea
constipation
heartburn
bloating
feeling of hard or irregular heart beat
headache
dizziness
joint pain
tiredness (fatigue)

These are the more common side effects of Cerdelga.

In clinical studies, a small number of patients fainted. All of these patients had risk factors for fainting. Please tell your doctor immediately if you are feeling faint or you have fainted.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some people.

After taking it

Storage

Keep your capsules in the pack until it is time to take them. If you take the capsules out of the pack they may not keep well.

Keep the medicine in a cool dry place where the temperature stays below 25°C.

Do not store it or any other medicine in the bathroom or near a sink. Do not leave it in the car on hot days or on window sills.

Keep it where children cannot reach it.

Disposal

If your doctor or pharmacist tells you to stop taking Cerdelga or the expiry date has passed, ask your pharmacist what to do with any capsules that are left over.

Return any unused medicine to your pharmacist.

Product description

What it looks like

Cerdelga capsules have a pearl blue-green opaque cap and a pearl white opaque body with "GZ02" printed in black on the capsule.

Each carton contains 56 hard capsules in 4 blister wallets of 14 capsules each.

Ingredients

Active ingredient:
Each capsule contains 84 mg of the active ingredient, eliglustat (as tartrate).

Inactive ingredients:
Lactose monohydrate, microcrystalline cellulose, hypromellose, glycerol dibehenate.

The ingredients of the capsule shell are: gelatin, candurin silver fine (E555 and E171), iron oxide yellow (E172) and indigo carmine (E132).

The ingredients of the printing ink are: shellac glaze, iron oxide black (E172), propylene glycol and ammonium hydroxide.

Supplier

Cerdelga® is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113

® = Registered Trademark

This leaflet was prepared in May 2019

AUST R 218172

cer-ccdsv8-cmiv3-31may19

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Cerdelga

Active ingredient

Eliglustat

Schedule

1 Name of Medicine

Cerdelga (eliglustat).

2 Qualitative and Quantitative Composition

Each Cerdelga capsule contains 84 mg eliglustat (equivalent to 100 mg eliglustat tartrate).
For the full list of excipients, see Section 6.1 List of Excipients.
Eliglustat is a synthetic small molecule and is a white to off-white powder. Eliglustat tartrate is highly soluble in water. It has a pKa of 8.79 and log P of 2.84.

3 Pharmaceutical Form

Cerdelga is formulated as a hard capsule for oral administration.
Cerdelga is available as pearl blue-green opaque cap and pearl white opaque body capsules with "GZ02" printed in black on the capsule. The size of the capsule is 'size 2' (dimensions 18.0 x 6.4 mm).

4 Clinical Particulars

4.1 Therapeutic Indications

Cerdelga is indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1).

4.2 Dose and Method of Administration

Therapy with Cerdelga should be initiated and supervised by a physician knowledgeable in the management of Gaucher disease.
Before initiation of treatment with eliglustat, patients should be genotyped for CYP2D6 to determine the CYP2D6 metaboliser status.
Eliglustat can be taken with or without food. Avoid consumption of grapefruit or grapefruit juice with eliglustat because grapefruit is a strong CYP3A inhibitor.
The capsules should be swallowed whole, preferably with water, and should not be crushed, dissolved, or opened.
If a dose is missed, the prescribed dose should be taken at the next scheduled time; the next dose should not be doubled.

CYP2D6 intermediate metabolisers (IMs) and extensive metabolisers (EMs).

The recommended dose of Cerdelga in CYP2D6 IMs and EMs is 84 mg twice daily taken orally.

Important dosing information.

Co-administration of eliglustat with other CYP2D6 or CYP3A inhibitors affects its systemic exposure (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) and the following doses are recommended (see Table 1).

CYP2D6 poor metabolisers (PMs).

The recommended dose in CYP2D6 PMs is 84 mg once daily taken orally.
Dosing of Cerdelga 84 mg once daily has not been studied in CYP2D6 PMs. Based on physiologically based pharmacokinetic (PBPK) modelling, the systemic exposures in PMs with 84 mg once daily dosing are predicted to be within the range of those observed in non-PM patients. Appropriate adverse event monitoring is recommended.
Co-administration of eliglustat in CYP2D6 PMs concomitantly with strong CYP3A inhibitors is contraindicated (see Section 4.3 Contraindications).

CYP2D6 ultra-rapid metabolisers (URMs) and indeterminate metabolisers.

Patients who are CYP2D6 ultra-rapid metabolisers (URMs) may not achieve adequate concentrations of Cerdelga to achieve a therapeutic effect.
A specific dosage cannot be recommended for those patients whose CYP2D6 genotype cannot be determined (indeterminate metabolisers).
Therefore, eliglustat should not be used in patients who are CYP2D6 ultra-rapid (URM), or indeterminate metabolisers.

Prior treatment with enzyme replacement therapy.

In clinical trials enzyme replacement treatment was allowed up to the day before the first dose of eliglustat.
For patients with stable disease who switch from enzyme replacement therapy to eliglustat, monitoring for disease progression (e.g. after 6 months with regular monitoring thereafter) should be performed for all disease domains to evaluate disease stability. Reinstitution of enzyme replacement therapy or an alternative treatment modality should be considered in individual patients who have a sub-optimal response.

Special populations.

Hepatic impairment.

Cerdelga is contraindicated in CYP2D6 IMs or PMs with any degree of hepatic impairment and in CYP2D6 EMs with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.
In CYP2D6 EMs with mild hepatic impairment (Child-Pugh Class A), no dose adjustment is required and the recommended dose is 84 mg eliglustat twice daily (see Section 5.2 Pharmacokinetic Properties). See Table 2.

Renal impairment.

In CYP2D6 EMs with end stage renal disease, Cerdelga is not recommended.
In CYP2D6 IMs or PMs with mild, moderate or severe renal impairment or end stage renal disease, Cerdelga is not recommended.
In CYP2D6 EMs with mild, moderate or severe renal impairment, no dosage adjustment is required and the recommended dose is 84 mg eliglustat twice daily.
See Section 5.2 Pharmacokinetic Properties, Special populations.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Cerdelga is contraindicated in patients who are:
CYP2D6 intermediate metabolisers (IMs) or extensive metabolisers (EMs) taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor;
CYP2D6 poor metabolisers (PMs) who are taking a strong CYP3A inhibitor.
Use of Cerdelga under these conditions results in substantially elevated eliglustat plasma concentrations. For a list of strong and moderate CYP2D6 and CYP3A inhibitors, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
Limited or no data are available in CYP2D6 IMs or PMs with any degree of hepatic impairment; use of Cerdelga in these patients is contraindicated since metabolism is the predominant route of elimination.
Due to significantly increased eliglustat plasma concentrations, Cerdelga is contraindicated in CYP2D6 EMs with moderate or severe hepatic impairment and in CYP2D6 EMs with mild hepatic impairment taking a strong or moderate CYP2D6 inhibitor.

4.4 Special Warnings and Precautions for Use

Before initiation of treatment with Cerdelga, patients should be genotyped for CYP2D6 to determine the CYP2D6 metaboliser status. Cerdelga 84 mg should not be used in patients who are ultra-rapid metabolisers (URMs), or indeterminate metabolisers.

Drug-drug interactions.

Cerdelga is contraindicated in patients who are:
CYP2D6 intermediate metabolisers (IMs) or extensive metabolisers (EMs) taking a strong (e.g. paroxetine, fluoxetine, quinidine) or moderate (e.g. duloxetine, terbinafine) CYP2D6 inhibitor concomitantly with a strong (e.g. clarithromycin, itraconazole) or moderate (e.g. erythromycin, fluconazole) CYP3A inhibitor;
CYP2D6 poor metabolisers (PMs) taking a strong CYP3A inhibitor.
Under these conditions both major metabolic pathways for eliglustat metabolism are impaired, with predicted substantially elevated eliglustat plasma concentrations. Although no significant QTc increases were seen in a thorough QT/QTc study in healthy volunteers (see Section 5.1 Pharmacodynamic Properties, Electrocardiographic evaluation), based on PK/PD modelling, eliglustat plasma concentrations 11-fold above those expected at the indicated dose are predicted to cause mild increases in the PR, QRS, and QTc intervals of 20.4, 7.1, and 14.2 msec, respectively. For more information see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
For use of Cerdelga with one strong or moderate inhibitor of CYP2D6 or CYP3A, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
Use of Cerdelga with strong CYP3A inducers substantially decreases the exposure to eliglustat, which may reduce the therapeutic effectiveness of Cerdelga; therefore co-administration is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Patients with pre-existing cardiac conditions.

Use of Cerdelga in patients with pre-existing cardiac conditions has not been studied during clinical trials. Because eliglustat is predicted to cause mild increases in ECG intervals at substantially elevated plasma concentrations, use of eliglustat should be avoided in patients with cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia and structural heart disease associated with arrhythmia), long QT syndrome, and in combination with class IA (e.g. quinidine) and class III (e.g. amiodarone, sotalol) antiarrhythmic medications.

Lactose.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use in hepatic impairment.

Concomitant use of Cerdelga with CYP2D6 or CYP3A inhibitors in CYP2D6 EMs with mild hepatic impairment can result in further elevation of eliglustat plasma concentrations, with the magnitude of the effect depending on the enzyme inhibited and the potency of the inhibitor. In CYP2D6 EMs with mild hepatic impairment taking a weak CYP2D6 inhibitor or a strong, moderate or weak CYP3A inhibitor, a dose of 84 mg eliglustat once daily should be considered (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special populations.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special populations.

Use in the elderly.

A limited number of patients aged 65 and over were enrolled in clinical trials. No significant differences were found in the efficacy and safety profiles of older patients and younger patients.

Paediatric use.

The safety and efficacy of eliglustat in children under the age of 18 years has not been established. No data are available.

Effects on laboratory tests.

There is no data available on the effects of Cerdelga on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Eliglustat is metabolised primarily by CYP2D6 and to a lesser extent by CYP3A4. Eliglustat is also a substrate of the P-glycoprotein (P-gp) efflux transporter. Eliglustat is an inhibitor of P-gp and CYP2D6 in vitro.
The list of substances in this section is not an inclusive list and the prescriber is advised to consult the PI of all other prescribed medicines for potential drug-drug interactions with eliglustat.

Agents that may increase eliglustat exposure.

Cerdelga is contraindicated in patients who are:
CYP2D6 intermediate metabolisers (IMs) or extensive metabolisers (EMs) taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor (see Table 3);
CYP2D6 poor metabolisers (PMs) taking a strong CYP3A inhibitor.
Under these conditions both major metabolic pathways for eliglustat metabolism are impaired, with predicted substantially elevated eliglustat plasma concentrations (predicted increase of up to 17-fold for C_max and 25-fold for AUC_0-12).

CYP2D6 inhibitors.

In intermediate (IMs) and extensive metabolisers (EMs).

After repeated 84 mg twice daily doses of eliglustat in non-PMs, concomitant administration with repeated 30 mg once daily doses of paroxetine, a strong inhibitor of CYP2D6, resulted in a 7- and 9-fold increase in eliglustat C_max and AUC_0-12, respectively.
A dose of eliglustat 84 mg once daily should be considered when a strong CYP2D6 inhibitor (e.g. paroxetine, fluoxetine, quinidine, bupropion) is used concomitantly in IMs and EMs.
At 84 mg twice daily dosing with eliglustat in non-PMs, it is predicted that concomitant use of moderate CYP2D6 inhibitors (e.g. duloxetine, terbinafine) would increase eliglustat exposure approximately 4-fold. Use caution with moderate CYP2D6 inhibitors in IMs and EMs.

In extensive metabolisers (EMs) with hepatic impairment.

See Table 4.

CYP3A inhibitors.

In intermediate (IMs) and extensive metabolisers (EMs).

After repeated 84 mg twice daily doses of eliglustat in non-PMs, concomitant administration with repeated doses of ketoconazole, a strong inhibitor of CYP3A and P-gp, resulted in 4-fold increases in eliglustat C_max and AUC_0-12; similar effects would be expected for other strong inhibitors of CYP3A (e.g. clarithromycin, itraconazole). Caution should be used with strong CYP3A inhibitors in IMs and EMs.
At 84 mg twice daily dosing with eliglustat in non-PMs, it is predicted that moderate CYP3A inhibitors (e.g. erythromycin, fluconazole) would increase eliglustat exposure approximately 3-fold. Use caution with moderate CYP3A inhibitors in IMs and EMs.

In extensive metabolisers (EMs) with hepatic impairment.

See Table 5.

In poor metabolisers (PMs).

At 84 mg once daily dosing with eliglustat in PMs, it is predicted that concomitant use of strong CYP3A inhibitors (e.g. ketoconazole, clarithromycin, itraconazole) would increase the C_max and AUC_0-24 of eliglustat 4- and 6-fold. The use of strong CYP3A inhibitors is contraindicated in PMs.
At 84 mg once daily dosing with eliglustat in PMs, it is predicted that concomitant use of moderate CYP3A inhibitors (e.g. erythromycin, fluconazole) would increase the C_max and AUC_0-24 of eliglustat 2- and 3-fold, respectively. Use of moderate CYP3A inhibitors with eliglustat is not recommended in PMs.
Caution should be used with weak CYP3A inhibitors (e.g. amlodipine, cilostazol, fluvoxamine, goldenseal, isoniazid, ranitidine, ranolazine) in PMs.
CYP2D6 inhibitors used simultaneously with CYP3A inhibitors.

In intermediate (IMs) and extensive metabolisers (EMs).

At 84 mg twice daily dosing with eliglustat in non-PMs, it is predicted that the concomitant use of strong or moderate CYP2D6 inhibitors and strong or moderate CYP3A inhibitors would increase C_max and AUC_0-12 up to 17- and 25-fold, respectively. The use of a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor is contraindicated in IMs and EMs.
Grapefruit products contain one or more components that inhibit CYP3A and can increase plasma concentrations of eliglustat. Excessive consumption of grapefruit or its juice should be avoided.

Agents that may decrease eliglustat exposure.

See Table 6.

Strong CYP3A inducers.

After repeated 127 mg twice daily doses of eliglustat in non-PMs, concomitant administration of repeated 600 mg daily doses of rifampicin (a strong inducer of CYP3A as well as the efflux transporter P-gp) resulted in an approximately 85% decrease in eliglustat exposure. After repeated 84 mg twice daily doses of eliglustat in PMs, concomitant administration of repeated 600 mg once daily doses of rifampicin resulted in an approximately 95% decrease in eliglustat exposure. Use of strong CYP3A inducer (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, rifabutin and St John's wort) with Cerdelga is not recommended in IMs, EMs and PMs.

Agents whose exposure may be increased by eliglustat.

Eliglustat is an inhibitor of P-gp and CYP2D6 in vitro. See Table 7.

P-gp substrates.

Concomitant administration with digoxin, a P-gp substrate, resulted in a 1.7 and 1.5-fold increase in digoxin C_max and AUC_last, respectively. Lower doses of P-gp substrate drugs (e.g. digoxin, colchicine, dabigatran etexilate, phenytoin, pravastatin) may be required.

CYP2D6 substrates.

Concomitant administration with metoprolol, a CYP2D6 substrate, resulted in a 1.5 and 2.1-fold increase in metoprolol C_max and AUC, respectively. Lower doses of CYP2D6 substrate drugs may be required. These include certain antidepressants (tricyclic antidepressants, e.g. nortriptyline, amitriptyline, imipramine, desipramine), phenothiazines, dextromethorphan, atomoxetine and class 1C antiarrhythmics (e.g. propafenone, flecainide).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility studies in rats revealed no evidence of impaired fertility due to eliglustat treatment.
In a reproductive toxicity study with mature male rats reversible inhibition of spermatogenesis together with effects on sperm motility and morphology were observed at a systemically toxic dose (200 mg/kg/day: equivalent to approx. 20 times the clinical exposure, based on AUC) as well as increased germ cell necrosis and seminal vesicle inflammation at 100 mg/kg/day (equivalent to 10 times the clinical exposure, based on AUC).
(Category B3)
There are no or limited amount of data from the use of eliglustat in pregnant women. Eliglustat showed no embryofoetal toxicity in rats or rabbits at oral doses corresponding to approximately 4 times the clinical exposure (based on AUC). However, higher maternotoxic doses in rats (> 16-fold clinical exposure based on AUC) showed an increased incidence of delayed ossification and skeletal malformations in an embryofoetal development study and increased postimplantation loss, reduced pup numbers, and lower pup body weight in a rat pre/ postnatal study. Because animal reproduction studies are not always predictive of human response, eliglustat should only be used during pregnancy if the benefit clearly outweighs the risk.
It is unknown whether eliglustat or its metabolites are excreted in human milk. However, in rats, there was decreased body weight gain in dams and offspring following daily administration of eliglustat through weaning. Therefore, a risk to the newborns/ infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/ abstain from eliglustat therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

Cerdelga has no or negligible influence on the ability to drive and use machines. Patients should take care when driving or operating machinery until they know how this medicine could affect them.

4.8 Adverse Effects (Undesirable Effects)

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 www.tga.gov.au/reporting-problems (Australia).

Summary of the safety profile.

The majority of adverse drug reactions seen in clinical trials are mild and transient. The most commonly reported adverse reaction with Cerdelga is dyspepsia, in approximately 6% of the patients. About 2% of patients receiving Cerdelga in clinical trials permanently discontinued treatment due to any adverse reaction.
The most frequently reported serious adverse reaction in clinical studies was syncope (0.8%). All events were associated with predisposing risk factors and appeared to be vasovagal in nature. None of these events led to discontinuation from the study.
For information on using Cerdelga in special patient populations see Section 4.4 Special Warnings and Precautions for Use.

Tabulated list of adverse reactions.

The overall adverse reaction profile of eliglustat is based on 1400 patient-years of treatment exposure and pooled results from the primary analysis periods and extension periods of two pivotal Phase 3 studies (ENGAGE and ENCORE) and one 8-year Phase 2 study (study 304), and one supporting Phase 3b study (EDGE). In these four studies, a total of 393 patients between the ages of 16-75 years received eliglustat for a median treatment duration of 3.5 years (up to 9.3 years) and between the ages of 16-69 years.
The most common adverse drug reactions are presented in Table 8 using the following categories of frequency: common (≥ 1/100 to < 1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Post marketing.

The following additional adverse reaction has been reported during post-approval use of Cerdelga. The adverse reaction is derived from spontaneous reports and therefore, the frequency is "not known" (cannot be estimated from the available data).

Respiratory, thoracic and mediastinal disorders.

Cough.

4.9 Overdose

The highest eliglustat plasma concentration experienced to date occurred in a Phase 1 single dose dose escalation study in healthy subjects, in a subject taking a dose equivalent to approximately 21 times the recommended dose for GD1 patients. At the time of the highest plasma concentration (59-fold higher than normal therapeutic conditions), the subject experienced dizziness marked by disequilibrium, hypotension, bradycardia, nausea, and vomiting.
In the event of acute overdose, the patient should be carefully observed and given symptomatic and supportive treatment.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract and metabolism products, ATC code: A16AX10.

Mechanism of action.

Gaucher disease is caused by a deficiency of the lysosomal enzyme, acid β-glucosidase, which results in the accumulation of its major natural substrate, glucosylceramide (GL-1), especially in the liver, spleen, and bone marrow. Eliglustat is a potent and specific inhibitor of glucosylceramide synthase, and acts as a substrate reduction therapy for Gaucher disease type 1 (GD1). The goal of this approach is to reduce the rate of synthesis of glucosylceramide to match its impaired rate of catabolism in patients with GD1, thereby preventing glucosylceramide accumulation and alleviating clinical manifestations.
In clinical trials in treatment naïve GD1 patients, plasma GL-1 levels were elevated in the majority of these patients and decreased with eliglustat treatment. Additionally, in a clinical trial in GD1 patients stabilised on enzyme replacement therapy (ERT) (i.e. having already achieved therapeutic goals on ERT prior to initiating eliglustat treatment), plasma GL-1 levels were normal in most patients and decreased with eliglustat treatment.
Cardiac effects. Eliglustat was found to inhibit the hERG tail current (K⁺ channel), hNav1.5 (Na⁺ channel), and hCav1.2 (Ca²⁺ channel) in vitro at 8, 117 and 240 times the clinical exposure (based on C_max), respectively. Overall, the nonclinical safety pharmacology and repeat dose toxicity data suggest that there will be no ECG effects of eliglustat in humans at plasma levels up to 7-fold clinical C_max.

Electrocardiographic evaluation.

No clinically significant QTc prolonging effect of eliglustat was observed for single doses up to 675 mg.
Prolongation of QT interval was evaluated in a randomised, placebo controlled and active controlled (moxifloxacin 400 mg) single dose crossover study in 47 healthy subjects. In this trial, the upper bound of one sided 95% confidence interval for the largest placebo adjusted, baseline corrected QTcF was below 10 msec. The largest time matched mean differences (LTMMDs) versus placebo for QTcF interval were 0.7 msec (one sided 95% CI upper bound of 3.5 msec at hour 10) and 6.5 msec (one sided 95% CI upper bound of 9.3 msec at hour 7) for the single therapeutic (200 mg) and supratherapeutic (800 mg) doses, respectively.
While there was no apparent effect on heart rate, concentration related increases were observed for the placebo corrected change from baseline in the PR, QRS, and QTc intervals.

Clinical trials.

Clinical efficacy and safety. The efficacy and safety of Cerdelga was evaluated in two randomised, controlled pivotal studies (ENGAGE and ENCORE) and one open label, long-term study (study 304), in 226 patients with GD1.

Pivotal study of Cerdelga in treatment-naïve GD1 patients - ENGAGE.

ENGAGE was a randomised, double-blind, placebo-controlled, multicentre clinical study evaluating the efficacy and safety of Cerdelga in 40 treatment-naïve GD1 patients 16 years of age or older (median age 30.4 years) with pre-existing splenomegaly and haematological abnormalities. Patients were required to have received no treatment with substrate reduction therapy within 6 months or enzyme replacement therapy within 9 months prior to randomisation; all but 5 patients in the study had no prior therapy. Patients were stratified according to baseline spleen volume (≤ 20 or > 20 multiples of normal [MN]) and randomised in a 1:1 ratio to receive eliglustat or placebo for the duration of the 9-month blinded primary analysis period. Patients randomised to eliglustat treatment received a starting dose of 42 mg twice daily, with a dose increase to 84 mg twice daily possible at week 4 based on the plasma trough concentration at week 2 (patients with a plasma trough concentration of < 5 nanogram/mL at week 2 received a dose increase at week 4).
The primary endpoint was the percentage change in spleen volume (in MN) from baseline to 9 months as compared to placebo. Secondary endpoints were absolute change in haemoglobin level, percentage change in liver volume (in MN), and percentage change in platelet count from baseline to 9 months compared to placebo.
At baseline, mean spleen volumes were 12.5 and 13.9 MN in the placebo and Cerdelga groups, respectively, and mean liver volumes were 1.4 MN for both groups. Mean haemoglobin levels were 128 and 121 g/L, and platelet counts were 78.5 and 75.1 x 10⁹/L, respectively.
During the 9-month primary analysis period, Cerdelga demonstrated statistically significant improvements in all primary and secondary endpoints compared to placebo, as shown in Table 9.

During an open-label long term treatment period with Cerdelga (extension phase), all patients with complete data who continued to receive Cerdelga showed further improvements throughout the extension phase. Results (change from baseline) after 18 months, 30 months, and 4.5 years of exposure to Cerdelga on the following endpoints were: mean increase in haemoglobin level (1.1 g/dL) [n=39], 1.4 g/dL [n=35], and 1.4 g/dL [n=12]), mean increase in platelet count [mm³] (58.5% [n=39], 74.6% [n=35], and 86.8% [n=12]), mean reduction in spleen volume [MN] (46.5% [n=38], 54.2% [n=32], and 65.6% [n=13]) and mean reduction of liver volume [MN] (13.7% [n=38], 18.5% [n=32], and 23.4 [n=13]).

Long-term clinical outcomes in treatment-naïve patients - study 304.

Study 304 was a single-arm, open-label, multicentre study of Cerdelga in 26 treatment-naïve adult patients with GD1. Patients were required to have received no treatment with miglustat, enzyme replacement therapy, or corticosteroids for GD1 within 12 months, or bisphosphonates within 3 months prior to enrolment. Twenty-six patients were enrolled, of which 77% (p < 0.0001) met the primary endpoint at 12 months, defined as a response in at least 2 of 3 parameters (haemoglobin, platelets, and spleen) that were abnormal at study entry: an increase of ≥ 5 g/L in haemoglobin; an increase of ≥ 15% in platelets; and/or a reduction of ≥ 15% in total spleen volume (based on MRI or spiral CT). Long-term data on visceral and haematological endpoints for up to 19 patients who had an efficacy endpoint assessment at Year 4 and up to 16 patients who had an efficacy endpoint assessment at year 8 are shown in Table 10.

Pivotal study in patients switching from enzyme replacement therapy to Cerdelga - ENCORE.

ENCORE was a randomised, open label, active controlled, noninferiority, multicentre clinical study evaluating the safety and efficacy of Cerdelga compared with Cerezyme in 159 GD1 patients (median age 37.4 years) previously treated with enzyme replacement therapy (≥ 3 years of enzyme replacement therapy, dosed at 30-130 U/kg/month in at least 6 of the prior 9 months) who met prespecified therapeutic goals at baseline. Patients were randomised 2:1 to receive Cerdelga or Cerezyme for the duration of the 12 month primary analysis period. Enzyme replacement treatment was allowed up to the day before the first dose of Cerdelga. Seventy five percent of patients randomised to Cerdelga were previously treated with imiglucerase; 21% with velaglucerase alfa and 4% were unreported. Patients randomised to Cerdelga treatment received a starting dose of 42 mg twice daily, with dose increases to 84 mg twice daily and 127 mg twice daily possible at weeks 4 and 8 based on plasma trough concentrations of Cerdelga at weeks 2 and 6 respectively (patients with a plasma trough concentration of < 5 nanogram/mL at weeks 2 and/or 6 received a dose increase at weeks 4 and/or 8, respectively).
At baseline, mean spleen volumes were 2.6 and 3.2 MN in the Cerezyme and Cerdelga groups, respectively, and liver volumes were 0.9 MN in both groups. Mean haemoglobin levels were 138 and 136 g/L, and platelet counts were 192 and 207 x 10⁹/L, respectively.
The primary composite endpoint required stability in all four component domains (haemoglobin level, platelet count, liver volume, and spleen volume) based on changes between baseline and 12 months. Stability was defined by the following prespecified thresholds of change: haemoglobin level < 15 g/L decrease, platelet count < 25% decrease, liver volume < 20% increase, and spleen volume < 25% increase. The percentages of patients meeting the criteria for stability in the individual components of the composite endpoint were assessed as secondary efficacy endpoints.
Cerdelga met the criteria to be declared noninferior to Cerezyme in maintaining patient stability. After 12 months of treatment, the percentage of patients meeting the primary composite endpoint was 84.8% for the Cerdelga group compared to 93.6% for the Cerezyme group. The lower bound of the 95% CI of the 8.8% difference, -17.6%, was within the prespecified noninferiority margin of -25%. At month 12, the percentages of Cerdelga and Cerezyme patients, respectively, who met stability criteria for the individual components of the composite endpoint were: haemoglobin level, 94.9% and 100%; platelet count, 92.9% and 100%; spleen volume, 95.8% and 100%; and liver volume, 96.0% and 93.6%. Of the patients who did not meet stability criteria for the individual components, 12 of 15 Cerdelga patients and 3 of 3 Cerezyme patients remained within therapeutic goals for GD1.
Mean changes from baseline in the haematological and visceral parameters through 12 months of treatment are shown in Table 11. There were no clinically meaningful differences between groups for any of the four parameters.

During an open-label long term treatment period with Cerdelga (extension phase) the percentage of patients with complete data meeting the composite stability endpoint was maintained at 84.6% (n=136) after 2 years, 84.4% (n=109) after 3 years and 91.1% (n=45) after 4 years. The majority of extension period discontinuations were due to transition to commercial product from year 3 onwards. Individual disease parameters of spleen volume, liver volume, haemoglobin levels and platelet count remained stable through 4 years.
Clinical experience in CYP2D6 poor metabolisers (PMs) and ultra-rapid metabolisers (URMs). There is limited experience with Cerdelga treatment of patients who are PMs or URMs. In the primary analysis periods of the three clinical studies, a total of 5 PMs and 5 URMs were treated with Cerdelga. All PMs received 42 mg eliglustat twice daily, and four of these (80%) had an adequate clinical response. The majority of URMs (80%) received a dose escalation to 127 mg eliglustat twice daily, all of which had adequate clinical responses. The one URM who received 84 mg twice daily did not have an adequate response.
The predicted exposures with 84 mg eliglustat once daily in patients who are PMs are expected to be similar to exposures observed with 84 mg eliglustat twice daily in CYP2D6 intermediate metabolisers (IMs). Patients who are URMs may not achieve adequate concentrations to achieve a therapeutic effect. No dosing recommendation for URMs can be given.
Effects on skeletal pathology. In the single-arm, open-label study in treatment-naïve patients (study 304), improvements in bone marrow infiltration of the femur (as assessed by MRI) were observed in the majority of patients after 8 years (n=15) of treatment with Cerdelga. The mean total lumbar spine bone mineral density (BMD) increased by 9.9% g/cm² (p = 0.0176) after 4 years of treatment, and by 12.6% (SD 16.56) after 8 years. Baseline mean (SD) BMD lumbar spine T-score was in the osteopenic range -1.63 (1.07) and reached the normal range after 4 years of treatment -0.88 (1.26) (p = 0.0139). After 8 years of treatment, the mean (SD) lumbar spine T-score increased to -0.59 (1.294). Baseline mean (SD) lumbar spine Z-score was -1.21 (0.948) and after 4 years of treatment was -0.48 (1.073) (p = 0.0039). After 8 years of treatment, the mean (SD) lumbar spine Z-score was -0.29 (1.088). Femur BMD was in the normal range at baseline and showed little change.
After 9 months of treatment with Cerdelga in the placebo-controlled pivotal study ENGAGE in treatment-naïve patients, bone marrow infiltration by Gaucher cells, as determined by the Total Bone Marrow Burden (BMB) Score (assessed by MRI in lumbar spine and femur), decreased by a mean of 1.1 points in Cerdelga-treated patients (n = 19); 5 Cerdelga-treated patients (26%) achieved a reduction of at least 2 points in the BMB score after 9 months compared to none in the placebo treated patients (n=20). After 18 months and 30 months of treatment, BMB score had decreased by a mean of 2.2 (n=18) and 2.7 (n=15) points, respectively, for the patients originally randomized to Cerdelga, compared to a mean decrease of 1 point (n=20) and 0.8 (n=16) in those originally randomized to placebo. Baseline mean (SD) BMD lumbar spine T-score was -1.07 (0.82) in the Cerdelga group (n = 17) and -1.12 (1.19) in the placebo group (n = 18). After 9 months of treatment, mean lumbar spine T-score was -1.03 (0.83) in the Cerdelga group and -1.22 (1.15) in the placebo group. After 18 months of treatment with Cerdelga in an open-label extension phase, the mean (SD) lumbar spine BMD T-score increased from -1.14 (1.0118) at baseline (n=34) to -0.918 (1.1601) (n=33) in the normal range. After 30 months and 4.5 years of treatment, the T-score further increased to -0.722 (1.1250) (n=27) and -0.533 (0.8031) (n=9), respectively. Mean Z-scores increased in all patients in a similar pattern.
In the pivotal study ENCORE in patients previously treated with enzyme replacement therapy, at baseline, mean lumbar spine and femur BMD were in the normal range and mean BMB Scores were in the moderately affected range for both Cerdelga and Cerezyme groups. After 12 months of treatment, the mean changes in BMD and BMB scores were similar for both arms and were not significantly different from baseline. Lumbar spine and femur BMD T- and Z-scores were maintained within the normal range in patients treated with Cerdelga for up to 4 years.

5.2 Pharmacokinetic Properties

At a given dose of eliglustat, the systemic exposure (C_max and AUC) depends on the CYP2D6 phenotype. In CYP2D6 extensive metabolisers (EMs) and intermediate metabolisers (IMs), the eliglustat pharmacokinetics is time-dependent and the systemic exposure increases in a more than dose proportional manner. Following repeated dosing of eliglustat 84 mg twice daily, steady state was reached by 4 days, with an accumulation ratio of 3-fold or less.

Absorption.

Median time to reach maximum plasma concentrations occurs between 1.5 to 3 hours after dosing with 84 mg twice daily. The oral bioavailability is low (< 5%) due to significant first pass metabolism. Eliglustat is a substrate of the efflux transporter P-gp. Administration of eliglustat with a high fat meal resulted in a 15% decrease in C_max but no change in AUC. Food does not have a clinically relevant effect on eliglustat pharmacokinetics.

Distribution.

Eliglustat is moderately bound to human plasma proteins (76 to 83%) without significant red blood cell partitioning. The estimated volume of distribution is 816 L in CYP2D6 intermediate and extensive metabolisers (IMs and EMs), suggesting wide distribution to tissues.

Metabolism.

Eliglustat is extensively metabolised with high clearance, mainly by CYP2D6 and to a lesser extent CYP3A4. Primary metabolic pathways of eliglustat involve sequential oxidation of the octanoyl moiety followed by oxidation of the 2,3-dihydro-1,4-benzodioxane moiety, or a combination of the two pathways, resulting in multiple oxidative metabolites.

Excretion.

Metabolism was the predominant route of elimination, as indicated by the < 1% total radioactivity of unchanged free base in urine and faeces. After oral administration, the majority of the administered dose is excreted in urine (41.8%) and faeces (51.4%), mainly as metabolites.
Total body clearance of eliglustat was estimated to be 86 L/h. Mean renal clearance of the unchanged free base was 5.27 L/h.
After repeated oral doses of 84 mg eliglustat twice daily, eliglustat elimination half-life is approximately 4-7 hours in non-PMs and 9 hours in PMs.