Cerdelga

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• headache with chest pain;
• a light-headed feeling, like you might pass out; or
• pounding heartbeats or fluttering in your chest.

Common side effects may include:

• diarrhea, nausea, stomach pain;
• headache;
• back pain; or
• pain in your arms or legs.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Cerdelga falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Avoid taking an herbal supplement containing St. John's wort at the same time you are taking eliglustat.

Grapefruit and grapefruit juice may interact with eliglustat and lead to unwanted side effects. Avoid the use of grapefruit products while taking eliglustat.

Administration

Oral Administration

Administer orally without regard to meals.1 Swallow capsules whole, preferably with water; do not crush, dissolve, or open.1

Avoid consumption of grapefruit or grapefruit juice.1

If a dose of eliglustat is missed, take missed dose at next scheduled time; do not double dose.1

Dosage

Available as eliglustat tartrate; dosage expressed in terms of eliglustat.1

Adults

Dosage based on CYP2D6 metabolizer status.1

Extensive or intermediate CYP2D6 metabolizers: 84 mg twice daily.1

Poor CYP2D6 metabolizers: 84 mg once daily; monitor for adverse effects.1

Indeterminate metabolizers: Manufacturer states a specific dosage cannot be recommended.1

In patients currently receiving imiglucerase, velaglucerase alfa, or taliglucerase alfa, may administer eliglustat 24 hours after last dose of enzyme replacement therapy.1

Concomitant use with drugs that inhibit CYP2D6 or CYP3A may require dosage adjustments depending on the patient's CYP2D6 metabolizer status.1 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Extensive or intermediate CYP2D6 metabolizers receiving a potent or moderate CYP2D6 inhibitor: Reduce dosage to 84 mg once daily.1

Extensive CYP2D6 metabolizers receiving a potent or moderate CYP3A inhibitor: Reduce dosage to 84 mg once daily.1

Special Populations

Renal Impairment

No dosage adjustment is required for patients with mild renal impairment.1 Not evaluated in patients with moderate to severe renal impairment or end-stage renal disease.1

Metabolized principally by CYP2D6 and, to a lesser extent, by CYP3A.1 Inhibitor of CYP2D6 and a weak inhibitor of CYP3A in vitro.1

Substrate and inhibitor of P-glycoprotein (P-gp).1

Does not appear to be a substrate for organic anion-transporting polypeptide (OATP).1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP2D6 and CYP3A inhibitors: May substantially increase eliglustat exposure and cause prolongation of PR, QTc and/or QRS intervals, possibly resulting in cardiac arrhythmias.1 Avoid concomitant use or approach with caution.1 9 (See Contraindications under Cautions.) Dosage adjustments may be required depending on the patient's CYP2D6 metabolizer status.1 9 (See Concomitant Use with CYP2D6 and CYP3A Inhibitors under Dosage and Administration.)

Potent CYP3A inhibitors: Contraindicated in patients who are intermediate or poor CYP2D6 metabolizers; reduce dosage to 84 mg once daily in extensive CYP2D6 metabolizers.1

Moderate CYP3A inhibitors: Not recommended in patients who are intermediate or poor CYP2D6 metabolizers; reduce dosage to 84 mg once daily in extensive CYP2D6 metabolizers.1

Weak CYP3A inhibitors: Not recommended in patients who are poor CYP2D6 metabolizers.1

Potent CYP2D6 inhibitors: Reduce dosage to 84 mg once daily in extensive or intermediate CYP2D6 metabolizers.1

Moderate CYP2D6 inhibitors: Reduce dosage to 84 mg once daily in extensive or intermediate CYP2D6 metabolizers.1

Potent/moderate CYP2D6 inhibitor concomitantly with a potent/moderate CYP3A inhibitor: Contraindicated in extensive and intermediate CYP2D6 metabolizers.1

Potent CYP3A inducers: May substantially decrease eliglustat exposure; therefore, not recommended in extensive, intermediate, or poor CYP2D6 metabolizers.1

CYP2D6 substrates: May increase concentrations of the CYP2D6 substrate.1 Manufacturer recommends therapeutic drug monitoring or dosage reduction (and subsequent titration to clinical effect) of the substrate drug as indicated.1

Drugs Affecting or Affected by P-glycoprotein

P-gp substrates: May increase concentrations of the P-gp substrate.1 Therapeutic drug monitoring or dosage reduction (and subsequent titration to clinical effect) of the substrate drug is recommended as indicated.1

P-gp inhibitors: Effect on eliglustat exposure not evaluated clinically.1

Drugs Affecting Gastric pH

No clinically important effect on eliglustat exposure.1

Specific Drugs and Foods

• If you have an allergy to Cerdelga (eliglustat) or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have heart problems, like heart block, heart failure, long QT syndrome, or slow heartbeat.
• If you have had a recent heart attack.
• If you have any of these health problems: Kidney disease or liver disease.
• If you are taking any drugs used for a heartbeat that is not normal.
• If you take any drugs (prescription or OTC, natural products, vitamins) that must not be taken with Cerdelga, like certain drugs that are used for seizures, fungal infections, or rifampin. There are many drugs that must not be taken with this medicine.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with Cerdelga.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions to Cerdelga (occurring in ≥10% of the 126 GD1 patients treated with Cerdelga across Trials 1 and 2) were fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain.

The adverse reaction profile of Cerdelga is based on two controlled studies, Trials 1 and 2. Table 1 presents the profile from the 9-month double-blind, randomized, placebo-controlled trial of 40 treatment-naïve patients (Trial 1). Patients were between the ages of 16 and 63 on the date of the first dose of study drug, and included 20 males and 20 females.

Table 2 presents the profile from the 12-month open-label, randomized, imiglucerase-controlled trial of 159 treated patients switching from enzyme replacement therapy (ERT) (Trial 2). Patients were between the ages of 18 and 69 on the date of the first dose of Cerdelga, and included 87 females and 72 males.

In an uncontrolled study, with up to 4 years of treatment, in 26 patients, the types and incidences of adverse reactions were similar to Trials 1 and 2.

Potential for Other Drugs to Affect Cerdelga

Eliglustat is a CYP2D6 and CYP3A substrate.

CYP2D6 and CYP3A Inhibitors

Drugs that inhibit CYP2D6 and CYP3A pathways may significantly increase the exposure to eliglustat and result in prolongation of the PR, QTc, and/or QRS cardiac interval which could result in cardiac arrhythmias:

• Some inhibitors of CYP2D6 and CYP3A are contraindicated with Cerdelga depending on the patient's CYP2D6 metabolizer status [see Contraindications (4)].
• Co-administration of Cerdelga with other CYP2D6 and CYP3A inhibitors may require dosage adjustment depending on the patient's CYP2D6 metabolizer status to reduce the risk of potential significant adverse reactions (see Table 3 and Table 4).

CYP3A Inducers

Co-administration of Cerdelga with strong CYP3A inducers significantly decreases eliglustat exposure. Use of Cerdelga with strong CYP3A inducers (e.g., rifampin, carbamazepine, phenobarbital, phenytoin, and St. John's Wort) is not recommended in EMs, IMs, and PMs.

Potential for Cerdelga to Affect Other Drugs

Eliglustat is an inhibitor of P-gp and CYP2D6. Co-administration of Cerdelga with drugs that are substrates for P-gp or CYP2D6 may result in increased concentrations of the concomitant drug as shown in Table 5.

The efficacy of Cerdelga was evaluated in three clinical trials in patients with Gaucher disease type 1.

Cerdelga in Treatment-Naïve GD1 Patients – Trial 1

Trial 1 was a randomized, double-blind, placebo-controlled, multicenter 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 hematological abnormalities. Patients were required to have received no treatment with substrate reduction therapy within 6 months or ERT within 9 months prior to randomization; 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 randomized in a 1:1 ratio to receive Cerdelga or placebo for the duration of the 9-month blinded primary analysis period. The Cerdelga treatment group was comprised of IM (5%), EM (90%) and URM (5%) patients. Patients randomized to Cerdelga 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. The majority of patients (17 [85%]) received a dose escalation to 84 mg twice daily at Week 4, and 3 (15%) continued to receive 42 mg twice daily for the duration of the 9-month blinded primary analysis period.

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 hemoglobin 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 hemoglobin levels were 12.8 and 12.1 g/dL, 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 6.

In an uncontrolled study of treatment naïve GD1 patients, improvements in spleen and liver volume, hemoglobin level, and platelet count continued through the 4 year treatment period.

Patients Switching from Enzyme Replacement Therapy to Cerdelga – Trial 2

Trial 2 was a randomized, open-label, active-controlled, non-inferiority, multicenter clinical study evaluating the efficacy and safety of Cerdelga compared with imiglucerase in 159 treated 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 pre-specified therapeutic goals at baseline. Pre-specified baseline therapeutic goals included: no bone crisis and free of symptomatic bone disease within the last year; mean hemoglobin level of ≥ 11 g/dL in females and ≥ 12 g/dL in males; mean platelet count ≥ 100,000/mm3; spleen volume < 10 times normal and liver volume < 1.5 times normal.

Patients were randomized 2:1 to receive Cerdelga or imiglucerase for the duration of the 12-month primary analysis period. Seventy-five percent of patients randomized to Cerdelga were previously treated with imiglucerase; 21% with velaglucerase alfa and 4% were unreported. Patients randomized 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. The percentage of patients receiving the 3 possible Cerdelga doses was: 42 mg twice daily (20%), 84 mg twice daily (32%) and 127 mg twice daily (48%). The Cerdelga treatment group was comprised of PM (4%), IM (10%), EM (80%) and URM (4%) patients.

At baseline, mean spleen volumes were 2.6 and 3.2 MN in the imiglucerase and Cerdelga groups, respectively, and liver volumes were 0.9 MN in both groups. Mean hemoglobin levels were 13.8 and 13.6 g/dL, and platelet counts were 192 and 207 x 109/L, respectively.

The primary composite endpoint required stability in all four component domains (hemoglobin level, platelet count, liver volume, and spleen volume) based on changes between baseline and 12 months. Stability was defined by the following pre-specified thresholds of change: hemoglobin level <1.5 g/dL 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 non-inferior to imiglucerase 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 imiglucerase group. The lower bound of the 95% CI of the 8.8% difference, -17.6%, was within the pre-specified non-inferiority margin of -25%. At Month 12, the percentages of Cerdelga and imiglucerase patients respectively, who met stability criteria for the individual components of the composite endpoint were: hemoglobin 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 imiglucerase patients remained within therapeutic goals for GD1.

Mean changes from baseline in the hematological and visceral parameters through 12 months of treatment are shown in Table 7. There were no clinically meaningful differences between groups for any of the four parameters.

NDC 58468-0220-1

Cerdelga™
(eliglustat) capsules

84 mg*

*Each capsule contains 84 mg of eliglustat which is
equivalent to 100 mg of eliglustat tartrate

Dispense the enclosed Medication Guide to each patient

Four cartons of 14 capsules each

Rx Only

Sometimes it is not safe to use certain medications at the same time. Some drugs can raise or lower your blood levels of eliglustat, which may cause side effects or make Cerdelga less effective. Eliglustat can also affect blood levels of certain other drugs, making them less effective or increasing side effects.

Your doctor may need to change your treatment plan if you use any of the following drugs:

• antifungal medicine;

• tuberculosis medicine;

• seizure medicine;

• heart or blood pressure medications;

• an antidepressant; or

• medicine to treat a mental illness.

You should not use Cerdelga if you are allergic to eliglustat, or if you have severe liver disease.

To make sure this medicine is safe for you, tell your doctor if you have:

• long QT syndrome or other heart rhythm disorder;

• heart disease or prior heart attack;

• liver disease; or

• kidney disease.

FDA pregnancy category C. It is not known whether Cerdelga will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether eliglustat passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Do not give this medication to anyone under 18 years old without medical advice.

Take Cerdelga exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Your doctor will perform a genotype blood test to make sure Cerdelga is the right treatment for you.

If you switched to Cerdelga from another enzyme replacement medicine, wait at least 24 hours after your last dose of the other medicine before you start taking Cerdelga.

Cerdelga is usually taken 1 or 2 times per day, based on the results of your genotype test. Follow your doctor's dosing instructions very carefully.

Take this medicine with a full glass of water.

You may take Cerdelga with or without food. Take the medicine at the same time each day.

Do not crush, open, or dissolve the capsule. Swallow it whole.

Your heart function may need to be checked using an electrocardiograph or ECG (sometimes called an EKG).

Use Cerdelga regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Store at room temperature away from moisture and heat.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Applies to eliglustat: oral capsule

Along with its needed effects, eliglustat (the active ingredient contained in Cerdelga) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking eliglustat:

• Fast, irregular, pounding, or racing heartbeat or pulse

• Dizziness
• fainting

Get emergency help immediately if any of the following symptoms of overdose occur while taking eliglustat:

• Blurred vision
• chest pain or discomfort
• confusion
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• nausea
• shortness of breath
• sweating
• unusual tiredness or weakness
• vomiting

Some side effects of eliglustat may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• back pain
• belching
• bloated
• cough
• diarrhea
• difficulty with moving
• excess air or gas in the stomach or intestines
• full feeling
• headache
• heartburn
• indigestion
• lack or loss of strength
• muscle pain or stiffness
• pain in the arms or legs
• pain in the joints
• passing gas
• sore throat
• stomach discomfort, upset, or pain
• upper abdominal or stomach pain

• Difficulty having a bowel movement (stool)
• rash

In rats, doses about 6 times the recommended human dose increased the number of late resorptions, dead fetuses and post implantation loss, reduced fetal body weight, and caused fetal cerebral variations (dilated cerebral ventricles), fetal skeletal variations (poor bone ossification) and fetal malformations (abnormal number of ribs or lumbar vertebra). However, no fetal harm was observed with oral administration of eliglustat to pregnant rabbits at dose levels 10 times the recommended human dose. There are no controlled data in human pregnancy US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus. US FDA pregnancy category: C