Cerdelga Drug Information

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. Limitations of Use: CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA to achieve a therapeutic effect. A specific dosage cannot be recommended for CYP2D6 indeterminate metabolizers.

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.

Recommended Adult Dosage

The recommended dosage of CERDELGA in adults is based on the patient's CYP2D6 metabolizer status. Table 1: Recommended Dosage Regimen by and Concomitant Use of CYP2D6 or CYP3A Inhibitors Reduce dosage frequency of CERDELGA 84 mg to once daily in CYP2D6 EMs and IMs with or without hepatic impairment taking CYP2D6 or CYP3A inhibitors, as shown in Table 2. Table 2: Recommended Dosage of CERDELGA 84 mg Once Daily based on CYP2D6 Metabolizer,

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 (strong CYP3A inhibitors) with CERDELGA.

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).

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 3 presents the profile from the 9-month double-blind, randomized, placebo-controlled trial of 40 treatment-naive patients (Trial 1).

• Effect of Other Drugs on CERDELGA Coadministration of CERDELGA with: CYP2D6 or CYP3A inhibitors may increase eliglustat concentrations which may increase the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac interval. strong CYP3A inducers decrease eliglustat concentrations which may reduce CERDELGA efficacy. See Table 5 for prevention and management of interactions with drugs affecting CERDELGA. Use of CERDELGA is contraindicated, to be avoided, or may require dosage adjustment depending on the concomitant drug and CYP2D6 metabolizer status.
• Table 5: Prevention and Management Strategies of Drug Interactions Affecting CERDELGA Based on

Effect of CERDELGA on Other Drugs See Table 6 for clinically relevant interactions affecting P-gp or CYP2D6 substrates when coadministered with CERDELGA. Table 6: Prevention and Management Strategies of Drug Interactions Affecting Other Drugs Substrates for P-gp or CYP2D6 Clinical Impact Coadministration of CERDELGA may increase concentrations of drugs that are substrates for P-gp or CYP2D6 and may increase the risk of toxicity of these drugs. Prevention or Management Digoxin Monitor serum digoxin concentrations before initiating CERDELGA.

Other P-gp substrates or CYP2D6 substrates Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the concomitant drug and titrate to clinical effect.

Pregnancy Risk Summary Available data on CERDELGA use in pregnant women includes 20 pregnancies that occurred during the clinical development program and a small number of post-marketing case reports. These data are not sufficient to assess drug-associated risks major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies in pregnant rats administered oral eliglustat during organogenesis, a spectrum of various developmental abnormalities were observed at doses 6 times the recommended human dose.

No adverse developmental outcomes were observed with oral administration of eliglustat to pregnant rabbits at dose levels 10 times the recommended human dose. The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Disease-associated maternal and/or 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. Data 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) following administration of eliglustat during the period of organogenesis (gestation days 6 to 17 in the rat and 6 to 18 in the rabbit). 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-related effects on fetal rats were observed in association with signs of maternal toxicity. 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). Mild maternal toxicity was observed at the 100 mg/kg/day dose.

In a pre and postnatal development study in rats (dosed daily from gestation day 6 to postpartum day 21), 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).

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

CERDELGA is contraindicated in the following patients based on CYP2D6 metabolizer status due to the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac intervals. EMs Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor. Moderate or severe hepatic impairment.

Mild hepatic impairment taking a strong or moderate CYP2D6 inhibitor. Taking a strong CYP3A inhibitor. Any degree of hepatic impairment.

The highest eliglustat plasma concentration experienced to date occurred in a 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.

Hemodialysis is unlikely to be beneficial given that eliglustat has a large volume of distribution.