Glucosylceramide Synthase Inhibitor

Yargesa

Approved 6 Aug 2020OralCapsule

Indications

YARGESA is a glucosylceramide synthase inhibitor indicated as monotherapy for treatment of adult patients with mild/moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option ( 1.1 ).

1.1Type 1 Gaucher Disease

YARGESA is indicated as monotherapy for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to allergy, hypersensitivity, or poor venous access).

Contraindications

None None ( 4 )

Warnings and precautions

Peripheral neuropathy: Perform baseline and follow-up neurological evaluations at 6-month intervals in all patients ( 5.1 ).
Tremor: Reduce dose to ameliorate tremor or discontinue treatment if tremor does not resolve within days of dose reduction ( 5.2 ).
Diarrhea and weight loss: Evaluate for underlying gastrointestinal disease in patients who do not respond to usual interventions (e.g. diet modification) ( 5.3 ).
Reductions in Platelet count: Mild reductions in platelet counts without association with bleeding were observed in some patients. Monitoring of platelet counts is recommended. ( 5.4 )

5.1Peripheral Neuropathy

In clinical trials, cases of peripheral neuropathy have been reported in 3% of Gaucher‘s patients treated with miglustat capsules. All patients receiving miglustat capsules treatment should undergo baseline and repeat neurological evaluations at approximately 6-month intervals. Patients who develop symptoms of peripheral neuropathy such as pain, weakness, numbness and tingling should have a careful re-assessment of the risk/benefit of miglustat therapy, and cessation of treatment may be considered.

5.2Tremor Approximately 30%

of patients have reported tremor or exacerbation of existing tremor on treatment. These tremors were described as an exaggerated physiological tremor of the hands. Tremor usually began within the first month of therapy and in many cases resolved between 1 to 3 months during treatment. Reduce dose to ameliorate tremor or discontinue treatment if tremor does not resolve within days of dose reduction.

At a glance

Brand name: Yargesa
Active substance: miglustat
Pharmacologic class: Glucosylceramide Synthase Inhibitor, Enzyme Stabilizer
Route: Oral
Dosage form: Capsule
Applicant: Edenbridge Pharms
Status: Prescription
FDA approval: 6 Aug 2020
Application: ANDA209821-001

Indications

1.1Type 1 Gaucher Disease

Warnings and precautions

Peripheral neuropathy: Perform baseline and follow-up neurological evaluations at 6-month intervals in all patients ( 5.1 ).
Tremor: Reduce dose to ameliorate tremor or discontinue treatment if tremor does not resolve within days of dose reduction ( 5.2 ).
Diarrhea and weight loss: Evaluate for underlying gastrointestinal disease in patients who do not respond to usual interventions (e.g. diet modification) ( 5.3 ).
Reductions in Platelet count: Mild reductions in platelet counts without association with bleeding were observed in some patients. Monitoring of platelet counts is recommended. ( 5.4 )

5.1Peripheral Neuropathy

5.2Tremor Approximately 30%

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Based

on findings from animal reproduction studies, miglustat capsules may cause fetal harm when administered to a pregnant woman. Available data from postmarketing case reports with miglustat capsules use in pregnancy are insufficient to assess a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with symptomatic Type I Gaucher disease in pregnancy, including hepatosplenomegaly and thrombocytopenia (see Clinical Considerations).

Advise pregnant women of the potential risks to the fetus. In animal reproduction studies, miglustat was maternally toxic in rabbits at exposures near the expected human therapeutic dose and caused embryo-fetal toxicities in rats at doses twice the recommended human dose. No adverse developmental outcomes were observed with administration of miglustat to pregnant rats at dose levels 6 times the recommended human dose.

(see Data). The estimated background risk of major birth defects and miscarriage for 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 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and embryo-fetal risk Pregnancy may exacerbate existing Type 1 Gaucher disease symptoms or result in new disease manifestations.

Type 1 Gaucher disease 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 In female rats given miglustat by oral gavage at doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation day 17 (organogenesis), increased post implantation loss, decreased embryo-fetal survival and decreased fetal and pup weights were observed at doses greater than or equal to 60 mg/kg/day (greater than or equal to 2 times the human therapeutic dose on a mg/m 2 basis).

Miglustat was also administered to pregnant rats by oral gavage at doses of 20, 60, 180 mg/kg/day from gestation day 6 through lactation (postpartum day 20). Delayed and prolonged parturition with decreased live births were observed at doses greater than or equal to 60 mg/kg/day (greater than or equal to 2 times the human therapeutic dose on a mg/m 2 basis). In pregnant rabbits given miglustat by oral gavage at doses of 15, 30, 45 mg/kg/day during gestation days 6-18 (organogenesis), maternal toxicity, including maternal deaths (all doses), reduced food consumption (30 and 45 mg/kg/day), and decreased body weight gain (15 and 30 mg/kg/day), was observed.

The 15 mg/kg/day dose level was 0.97 times the human therapeutic dose on a mg/m 2 basis. A pre- and postnatal development study in rats, miglustat was administered by oral gavage at doses of 20, 60, 180 mg/kg/day from gestation day 6 through day 20 of lactation, decreased live births were observed in dams, as well as decreased body weight gain in the offspring at doses greater than or equal to 60 mg/kg/day (greater than or equal to 2 times the human therapeutic dose on a mg/m 2 basis).

There was no effect on behavioral and learning assessments, sexual maturation or reproductive performance of the offspring at doses up to 180 mg/kg/day (about 6 times the human therapeutic dose on a mg/m 2 basis).

Adverse reactions

The following serious adverse reactions are described below and elsewhere in the labeling:

Peripheral Neuropathy [ see Warnings and Precautions (5.1) ]
Tremor [ see Warnings and Precautions (5.2) ]
Diarrhea and weight loss [ see Warnings and Precautions (5.3) ]
Reductions in platelet count [ see Warnings and Precautions (5.4) ] The most common adverse reactions (incidence ≥ to 5%) are: diarrhea, weight loss, stomach pain, gas, nausea and vomiting, headache including migraine, tremor, leg cramps, dizziness, weakness, vision problems, thrombocytopenia, muscle cramps, back pain, constipation, dry mouth, heaviness in arms and legs, memory loss, unsteady walking, anorexia, indigestion, paresthesia, stomach bloating, stomach pain not related to food, and menstrual changes ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Edenbridge Pharmaceuticals, LLC at 1-877-381-3336 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 data described below reflect exposure of 80 patients with type 1 Gaucher disease in two open-label, uncontrolled, monotherapy trials, one open-label, active-controlled trial, and two extensions, who received miglustat capsules at doses ranging from 50 mg to 200 mg three times daily.

Patients were aged 18 to 69 years at first treatment. The population was evenly distributed by gender. The most common serious adverse reaction reported with miglustat capsules treatment in clinical trials was peripheral neuropathy [ see Warnings and Precautions (5.1) ]. The most commonly reported adverse reactions in patients treated with miglustat capsules (occurring in ≥ to 5%) that were considered related to miglustat capsules are shown in Tables 1 and 2. [ see Warnings and Precautions (5.2 , 5.3) ].

The most common adverse reactions requiring intervention were diarrhea and tremor. [ see Warnings and Precautions (5.2 , 5.3) ]. In two open-label, uncontrolled monotherapy trials, adult type 1 Gaucher disease patients were treated with miglustat capsules at a starting dose of 100 mg three times daily (dose range 100 to 200 mg three times daily) for up to 12 months in 28 patients [Study 1], or at a dose of 50 mg three times daily for up to 6 months in 18 patients [Study 2].

Table 1 below lists adverse reactions that occurred during the trials in ≥ to 5% of patients. Table 1: Adverse Reactions in greater than or equal to 5% of Patients in Two Open-Label, Uncontrolled Monotherapy Trials of miglustat capsules Incidence of adverse reactions Study 1 (starting dose 100mg three times daily) Study 2 (50mg three times daily) Patients entered in Study (n) 28 18 Body System – Preferred Term % of patients reporting % of patients reporting Gastrointestinal System Diarrhea 89 89 Flatulence 29 44 Abdominal Pain 18 50 Nausea 14 22 Vomiting 4 11 Bloating 0 6 Anorexia 7 0 Dyspepsia 7 0 Epigastric pain not food-related 0 6 Metabolic and Nutritional Disorders Weight Decrease 39 67 Central and Peripheral Nervous System Headache 21 22 Tremor 11 11 Dizziness 0 11 Leg cramps 4 11 Paresthesia 7 0 Migraine 0 6 Vision Disorders Visual Disturbance 0 17 Musculoskeletal Disorders Cramps 0 11 Platelet, Bleeding and Clotting Disorders Thrombocytopenia 7 6 Reproductive disorders, female Menstrual disorder 0 6 In an open-label, active-controlled study, 36 adult type 1 Gaucher disease patients were treated with miglustat capsules, imiglucerase, or miglustat capsules plus imiglucerase [Study 3] for up to 12 months.

Table 2 lists adverse reactions that occurred during the trial in greater than or equal to 5% of patients. Table 2: Adverse Reactions in greater than or equal to 5% of Patients in Open-Label Active Controlled Study Incidence of adverse reactions Miglustat capsules alone Imiglucerase alone Patients entered in Study (n) 12 12 Body System – Preferred Term % of patients reporting % of patients reporting Gastrointestinal System Diarrhea 100 0 Abdominal Pain 67 0 Flatulence 50 0 Constipation 8 0 Nausea 8 0 Dry Mouth 8 0 Body as Whole Pain 0 8 Generalized weakness 17 0 Abdominal distension 8 0 Back pain 8 0 Heaviness in limbs 8 0 Metabolic and Nutritional Disorders Weight Decrease 67 0 Central Peripheral Nervous System Tremor 17 0 Dizziness 8 0 Leg cramps 8 0 Unsteady gait 8 0 Psychiatric disorders Memory loss 8 0

Yargesa

Indications

1.1Type 1 Gaucher Disease

Contraindications

Warnings and precautions

5.1Peripheral Neuropathy

5.2Tremor Approximately 30%

At a glance

Two medicines in one question?

Yargesa

Indications

1.1Type 1 Gaucher Disease

Contraindications

Warnings and precautions

5.1Peripheral Neuropathy

5.2Tremor Approximately 30%

At a glance

Two medicines in one question?

5.3Diarrhea and Weight Loss Diarrhea

5.4Reductions in Platelet Count

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Based

Adverse reactions

6.1Clinical Trials Experience

Composition

Official product information