Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 14 August 2018

Indication(s)

1 INDICATIONS AND USAGE CERDELGA is indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test [see Dosage and Administration (2.1)].

CERDELGA is a glucosylceramide synthase inhibitor indicated for the long-term treatment of adult patients with Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test.

(1) Limitations of Use: CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA to achieve a therapeutic effect (1) A specific dosage can not be recommended for CYP2D6 indeterminate metabolizers (1) Limitations of Use: Patients who are CYP2D6 ultra-rapid metabolizers (URMs) may not achieve adequate concentrations of CERDELGA to achieve a therapeutic effect [see Clinical Studies (14)].

A specific dosage can not be recommended for those patients whose CYP2D6 genotype can not be determined (indeterminate metabolizers) [see Clinical Studies (14)].

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Advisory information

contraindications

4 CONTRAINDICATIONS CERDELGA is contraindicated in the following patients due to the risk of significantly increased eliglustat plasma concentrations which may result in prolongation of the PR, QTc, and/or QRS cardiac intervals that could result in cardiac arrhythmias.

See Table 3 and Table 4 for examples of drugs in each of the categories described [see Drug Interactions (7.1)]: EMs or IMs taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor.

IMs or PMs taking a strong CYP3A inhibitor.

CYP2D6 EMs and IMs taking a strong or moderate CYP2D6 inhibitor with a strong or moderate CYP3A inhibitor (4, 5.1, 7.1, 12.2) CYP2D6 IMs and PMs taking a strong CYP3A inhibitor (4, 5.1, 7.1, 12.2)

Adverse reactions

6 ADVERSE REACTIONS The most common adverse reactions (?10 %) are: fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not 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-na?ve 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 1: Adverse Reactions Occurring in?10 % of Treatment-Na?ve GD1 Patients and More Frequently than Placebo (Trial 1) CERDELGA (N=20) Placebo (N=20) Adverse Reaction Patients n (%) Patients n (%) Arthralgia 9 (45) 2 (10) Headache 8 (40) 6 (30) Migraine 2 (10) 0 (0) Flatulence 2 (10) 1 (5) Nausea 2 (10) 1 (5) Oropharyngeal pain 2 (10) 1 (5) 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.

Table 2: Adverse Reactions Occurring in?

5 % of GD1 Patients Switching from Enzyme Replacement Therapy to

CERDELGA and More Frequently than

Imiglucerase (Trial 2)Trial 2 was not designed to support comparative claims for CERDELGA for the adverse reactions reported in this table.

CERDELGA (N=106) Imiglucerase (N=53) Adverse Reaction Patients n (%) Patients n (%) Fatigue 15 (14) 1 (2) Headache 14 (13) 1 (2) Nausea 13 (12) 0 (0) Diarrhea 13 (12) 2 (4) Back pain 13 (12) 3 (6) Pain in extremity 12 (11) 1 (2) Upper abdominal pain 11 (10) 0 (0) Dizziness 9 (8) 0 (0) Asthenia 9 (8) 0 (0) Cough 7 (7) 2 (4) Dyspepsia 7 (7) 1 (2) Gastroesophageal reflux disease 7 (7) 0 (0) Constipation 5 (5) 0 (0) Palpitations 5 (5) 0 (0) Rash 5 (5) 0 (0) 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.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION Select patients using an FDA-cleared test for determining CYP2D6 genotype (2.1) CYP2D6 EMs or IMs: 84 mg orally twice daily (2.2) CYP2D6 PMs: 84 mg orally once daily (2.2) Swallow capsules whole, do not crush, dissolve or open capsules (2.3) Avoid eating grapefruit or drinking grapefruit juice (2.3) 2.1 Patient Selection Select patients with Gaucher disease type 1 based on their CYP2D6 metabolizer status.

It is recommended patient genotypes be established using an FDA-cleared test for determining CYP2D6 genotype [see Indications and Usage (1)].

2.2 Recommended Adult Dosage The recommended dosage of CERDELGA is 84 mg twice daily in CYP2D6 EMs and I Ms. The recommended dosage in CYP2D6 PMs is 84 mg once daily; appropriate adverse event monitoring is recommended [see Adverse Reactions (6.1)].

The predicted exposures with 84 mg once daily in patients who are CYP2D6 PMs are expected to be similar to exposures observed with 84 mg twice daily in CYP2D6 IMs [see

Clinical Pharmacology (12.3)].

Some inhibitors of CYP2D6 and CYP3A are contraindicated with CERDELGA depending on the patient 's 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 potentially significant adverse reactions [see Table 3 and Table 4 in Drug Interactions (7.1)].

Reduce the dosage of CERDELGA to 84 mg once daily for: CYP2D6 EMs and IMs taking strong or moderate CYP2D6 inhibitors CYP2D6 EMs taking strong or moderate CYP3A inhibitors 2.3 Important Administration Instructions Swallow capsules whole, preferably with water, and do not crush, dissolve, or open the capsules.

CERDELGA can be taken with or without food.

Avoid the consumption of grapefruit or grapefruit juice with CERDELGA because grapefruit is a strong CYP3A inhibitor [see Drug Interactions (7.1)].

If a dose of CERDELGA is missed, take the prescribed dose at the next scheduled time; do not double the next dose.

For patients currently treated with imiglucerase, velaglucerase alfa, or taliglucerase alfa, CERDELGA may be administered 24 hours after the last dose of the previous enzyme replacement therapy (ERT).

Use in special populations

8 USE IN SPECIFIC POPULATIONS Pregnancy: Only administer if the potential benefit justifies the potential risk.

Based on animal data, may cause fetal harm (8.1) Nursing mothers: Discontinue drug or nursing based on importance of drug to mother (8.3) Renal impairment: Not recommended in moderate to severe impairment (8.6) Hepatic impairment: Not recommended (8.7) 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate or well-controlled studies with CERDELGA in pregnant women.

However, animal reproduction studies have been conducted for eliglustat.

In these animal studies, a spectrum of anomalies at doses 6 times the recommended human dose were observed in orally dosed rats.

No fetal harm was observed with oral administration of eliglustat to pregnant rabbits at dose levels 10 times the recommended human dose.

CERDELGA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Disease-associated maternal and embryo-fetal risk Women with Gaucher disease type 1 have an increased risk of spontaneous abortion, especially if disease symptoms are not treated and controlled pre-conception and during a pregnancy.

Pregnancy may exacerbate existing Gaucher disease type 1 symptoms or result in new disease manifestations.

Gaucher disease type 1 manifestations may lead to adverse pregnancy outcomes including, hepatosplenomegaly which can interfere with the normal growth of a pregnancy and thrombocytopenia which can lead to increased bleeding and possible hemorrhage.

Animal Data Reproduction studies have been performed in pregnant rats at oral doses up to 120 mg/kg/day (about 6 times the recommended human dose based on body surface area) and in pregnant rabbits at oral doses up to 100 mg/kg/day (about 10 times the recommended human dose based on body surface area).

In rats, at 120 mg/kg/day (about 6 times the recommended human dose based on body surface area), eliglustat 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 skeletal malformations (abnormal number of ribs or lumbar vertebra).

Eliglustat did not cause fetal harm in rabbits at oral doses up to 100 mg/kg/day (about 10 times the recommended human dose based on body surface area).

In a pre and postnatal development study in rats, eliglustat did not show any significant adverse effects on pre and postnatal development at doses up to 100 mg/kg/day (about 5 times the recommended human dose based on body surface area).

8.3 Nursing Mothers It is not known whether CERDELGA is present in human milk.

Because many drugs are present in human milk, and because of the potential for serious adverse reactions in nursing infants from CERDELGA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the lactating woman.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of CERDELGA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Clinical experience has not identified differences in responses between the elderly and younger patients.

8.6 Renal Impairment There is no dosage adjustment required for patients with mild renal impairment.

CERDELGA has not been studied in patients with moderate to severe renal impairment or end-stage renal disease (ESRD).

Use of CERDELGA in these patients is not recommended.

8.7 Hepatic Impairment CERDELGA has not been studied in patients with hepatic impairment.

Use of CERDELGA is not recommended in all stages of hepatic impairment or cirrhosis.

8.8 Poor Metabolizers Dosing of CERDELGA 84 mg once daily has not been studied in PMs, however the predicted systemic exposures in these patients are within the range of those observed in clinical studies.

Appropriate adverse event monitoring is recommended [see Adverse Reactions (6.1) and Clinical Studies (14)].

Pregnancy and lactation
8.3 Nursing Mothers It is not known whether CERDELGA is present in human milk. Because many drugs are present in human milk, and because of the potential for serious adverse reactions in nursing infants from CERDELGA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the lactating woman.

Interactions

7 DRUG INTERACTIONS Eliglustat is a CYP2D6 and CYP3A substrate.

Co-administration of CERDELGA with drugs that inhibit CYP2D6 and CYP3A 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.

Consider potential drug interactions prior to and during therapy (5.1, 7.1) CYP2D6 IMs and PMs taking moderate CYP3A inhibitors: not recommended (7.1) CYP2D6 PMs taking weak CYP3A inhibitors: not recommended (7.1) CYP2D6 EMs and IMs taking strong or moderate CYP2D6 inhibitors and CYP2D6 EMs taking strong or moderate CYP3A inhibitors: reduce the dosage to 84 mg once daily (2.2, 7.1) Eliglustat is an inhibitor of P-gp and CYP2D6.

Co-administration with drugs that are substrates for P-gp or CYP2D6 may result in increased concentrations of the other drug (7.2) See Full Prescribing Information for a list of clinically significant drug interactions (7.1, 7.2) 7.1

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).

Table 3: Established and Other Potentially Significant Drug Interactions: Alteration in CERDELGA Dosage May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction in EMs and IMs Recommended CERDELGA Dosage, by CYP2D6 Metabolizer Status CYP450 Inhibitors EM IM Strong or Moderate

CYP2D6 inhibitors concomitantly with Strong or Moderate CYP3A inhibitors Contraindicated Contraindicated Strong CYP2D6 inhibitors e.g., paroxetine 84 mg once daily 84 mg once daily Moderate CYP2D6 inhibitors e.g., terbinafine 84 mg once daily 84 mg once daily Strong CYP3A inhibitors e.g., ketoconazole 84 mg once daily Contraindicated Moderate CYP3A inhibitors e.g., fluconazole 84 mg once daily Not recommended Table 4: Established and Other Potentially Significant Drug Interactions: Alteration in CERDELGA Dosage May Be Recommended Based on Predicted Interaction in PMs CYP450 Inhibitors Recommended CERDELGA Dosage for PMs Strong CYP3A inhibitors e.g., ketoconazole Contraindicated Moderate CYP3A inhibitors e.g., fluconazole Not recommended Weak CYP3A inhibitors e.g., ranitidine Not recommended 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 P Ms. 7.2 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.

Table 5: Drug Interactions that Result in Increased Concentrations of the Concomitant Drug Drug Class or Drug Name Clinical Recommendations Digoxin (P-gp substrate) Measure serum digoxin concentrations before initiating CERDELGA. Reduce digoxin dose by 30 % and continue monitoring.

Other P-gp substrates (e.g., phenytoin, colchicine, dabigatran etexilate) Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the concomitant drug and titrate to clinical effect.

CYP2D6 substrates Metoprolol; tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine); phenothiazines (e.g., perphenazine, chloropromazine).

More information

Category Value
Authorisation number NDA205494
Agency product number DR40J4WA67
Orphan designation No
Product NDC 58468-0220
Date Last Revised 26-08-2014
Type HUMAN PRESCRIPTION DRUG
RXCUI 1547231
Storage and handling Store at 68 °F - 77 °F (20 °C - 25 °C) with excursions permitted between 59 °F and 86 °F (15 °C to 30 °C) [see USP Controlled Room Temperature].
Marketing authorisation holder Genzyme Corporation