BRIEF SUMMARY

OLIPUDASE ALFA- Aug 2022)

Indn- To Treat Acid Sphingomyelinase deficiency 

Comp-  injection: 20 mg of olipudase alfa-rpcp as a lyophilized powder in a single-dose vial for reconstitution.   Consider pretreating with antihistamines, antipyretics, and/or corticosteroids.

  Adults: Recommended starting dose is 0.1 mg/kg administered as an intravenous infusion.

  Pediatrics: Recommended starting dose is 0.03 mg/kg administered as an intravenous infusion.

ADR- .

 Most common adverse reactions in pediatric patients (incidence =20%) are pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash, arthralgia, pruritus, fatigue and pharyngitis.

CONTRAINDICATIONS-                                                                                                    - None. 

WARNINGS-

 Infusion-Associated Reactions (IARs):   If severe IARs occur, discontinue  and initiate appropriate medical treatment.

 Elevated Transaminases:  Assess ALT and AST within one month prior to initiation of , within 72 hours prior to any infusion during dose escalation, or prior to the next scheduled  infusion upon resuming treatment following a missed dose.

 Risk of Fetal Malformations During Dosage Initiation or Escalation in Pregnancy:  dosage initiation or escalation, at any time during pregnancy, is not recommended as it may lead to elevated sphingomyelin metabolite levels that may increase the risk of fetal malformations.

Pat inform-

Hypersensitivity Reactions (Including Anaphylaxis) and Infusion-Associated Reactions (IARs) -                                                                                                    Advise the patient and caregiver that reactions related to the infusion may occur during and after treatment, including anaphylactic reactions, other serious or severe hypersensitivity reactions, and IARs.

Inform the patient and caregiver of the signs and symptoms of hypersensitivity reactions and IARs and to seek medical care should signs and symptoms occur

Embryo-Fetal Toxicity-  may cause embryo-fetal harm. Advise the pregnant female and females of reproductive potential of the potential risk to the fetus.

Advise a female patient and caregiver to inform their healthcare provider of a known or suspected pregnancy

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U.S.  APPROVED DRUGS SURING 2022                                        

Serial No 17

Name-                        XEPOZYME 

Active Ingredient -   Olipudase alfa

Pharmacological Classification- To Treat Acid Sphingomyelinase deficiency                                                                             

                                                                                                                                             Date of Approval-         8/31/2022   

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                              XENPOZYME TM safely and effectively.                                                                       See full prescribing information for XENPOZYME. XENPOZYME (olipudase alfa-rpcp) for injection, for intravenous use

Initial U.S. Approval: 2022

WARNING: SEVERE HYPERSENSITIVITY REACTIONS -                                           See full prescribing information for complete boxed warning.

Hypersensitivity Reactions Including Anaphylaxis                                                         • Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available. If a severe hypersensitivity reaction occurs, XENPOZYME should be discontinued immediately and appropriate medical treatment should be initiated.

INDICATIONS AND USAGE-

 XENPOZYME is a hydrolytic lysosomal sphingomyelin-specific enzyme indicated for treatment of non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients.

e risk of adverse reactions, and preparation and administration instructions. 

ADVERSE REACTIONS-

 • Most common adverse reactions in adult patients (incidence =10%) are headache, cough, diarrhea, hypotension and ocular hyperemia.

 • Most common adverse reactions in pediatric patients (incidence =20%) are pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash, arthralgia, pruritus, fatigue and pharyngitis.

CONTRAINDICATIONS-                                                                                                    - None. 

WARNINGS AND PRECAUTIONS-

 • See boxed warning. 

• Infusion-Associated Reactions (IARs):                                                                         If severe IARs occur, discontinue XENPOZYME and initiate appropriate medical treatment.

 • Elevated Transaminases:                                                                                    Assess ALT and AST within one month prior to initiation of XENPOZYME, within 72 hours prior to any infusion during dose escalation, or prior to the next scheduled XENPOZYME infusion upon resuming treatment following a missed dose.

 • Risk of Fetal Malformations During Dosage Initiation or Escalation in Pregnancy:                                                                                                            XENPOZYME dosage initiation or escalation, at any time during pregnancy, is not recommended as it may lead to elevated sphingomyelin metabolite levels that may increase the risk of fetal malformations.

Advise females of reproductive potential to use effective contraception during treatment and for 14 days after the last dose if XENPOZYME is discontinued.

DOSAGE AND ADMINISTRATION

• Prior to initiating treatment, verify pregnancy status in females of reproductive potential and obtain baseline transaminase levels.

 • Consider pretreating with antihistamines, antipyretics, and/or corticosteroids.

 • Adults: Recommended starting dose is 0.1 mg/kg administered as an intravenous infusion.

 • Pediatrics: Recommended starting dose is 0.03 mg/kg administered as an intravenous infusion.

 • See Full Prescribing Information for the recommended dose escalation and maintenance dosage, dosage modifications to reduce the risk of adverse reactions, and preparation and administration instructions. 

DOSAGE FORMS AND STRENGTHS-

 For injection: 20 mg of olipudase alfa-rpcp as a lyophilized powder in a single-dose vial for reconstitution. 

PATIENT COUNSELING INFORMATION-           

 Hypersensitivity Reactions (Including Anaphylaxis) and Infusion-Associated Reactions (IARs) -                                                                                                    Advise the patient and caregiver that reactions related to the infusion may occur during and after XENPOZYME treatment, including anaphylactic reactions, other serious or severe hypersensitivity reactions, and IARs.

Inform the patient and caregiver of the signs and symptoms of hypersensitivity reactions and IARs and to seek medical care should signs and symptoms occur

Embryo-Fetal Toxicity-                                                                                          XENPOZYME may cause embryo-fetal harm. Advise the pregnant female and females of reproductive potential of the potential risk to the fetus.

Advise a female patient and caregiver to inform their healthcare provider of a known or suspected pregnancy

 Advise a female of reproductive potential to use effective contraception during treatment and for 14 days after the last dose if XENPOZYME is discontinued.

Manufactured by: Genzyme Corporation 450 Water Street Cambridge, MA 02141 U.S. License Number: 1596

CLINICAL PHARMACOLOGY-

1. Mechanism of Action-                                                                                          ASMD is a lysosomal storage disease that results from reduced activity of the enzyme acid sphingomyelinase (ASM), caused by pathogenic variants in the sphingomyelin phosphodiesterase 1 gene. ASM degrades sphingomyelin to ceramide and phosphocholine.

The deficiency of ASM causes an intra-lysosomal accumulation of sphingomyelin (as well as cholesterol and other cell membrane lipids) in various tissues. XENPOZYME provides an exogenous source of ASM. XENPOZYME is not expected to cross the blood-brain barrier or modulate the CNS manifestations of ASMD.

2. Pharmacodynamics-                                                                                               Plasma Ceramide Levels Ceramide is elevated in plasma of adult and pediatric patients with ASMD. Plasma ceramide levels showed a transient increase after each administration (post infusion) of XENPOZYME.

3. Pharmacokinetics-                                                                                                      In adult patients with ASMD, the mean (SD) maximum plasma olipudase alfa-rpcp concentration (Cmax) and area under the concentration-time curve (AUC) at steady state were 30 (5) mcg/mL and 607 (120) mcg·h/mL, respectively, at the recommended maintenance dose of 3 mg/kg administered once every 2 weeks.

Distribution-                                                                                                                      The mean (SD) volume of distribution of olipudase alfa-rpcp was 13 (2) L in adult patients with ASMD.

Elimination-                                                                                                                   The mean (SD) clearance of olipudase alfa-rpcp was 0.33 (0.07) L/h and the mean half-life (t1/2) ranged from 32 to 38 hours in adult patients with ASMD.

Metabolism-                                                                                                                       The metabolic pathway of olipudase alfa-rpcp has not been characterized. Olipudase alfa-rpcp is expected to be metabolized into small peptides and amino acids via catabolic pathways.

Specific Populations-                                                                                             Pediatric Patients-                                                                                                           In pediatric patients (1.5 to 17.5 years of age) with ASMD, the mean (SD) Cmax was 24.3 (2.8) mcg/mL and the mean (SD) AUC was 449 (70) mcg·h/mL at the recommended maintenance dose of 3 mg/kg administered once every 2 weeks.

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USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                          Based on findings from animal reproduction studies, XENPOZYME may cause embryo-fetal harm when administered to a pregnant female. XENPOZYME dosage initiation or escalation, at any time during pregnancy, is not recommended as it may lead to elevated sphingomyelin metabolite levels that may increase the risk of fetal malformations..

There are no available data on XENPOZYME use in pregnant females to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Advise the pregnant female of the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, miscarriage, 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% to 4% and 15% to 20%, respectively 

2. Lactation Risk Summary-                                                                                      There are no data on the presence of olipudase alfa-rpcp in human milk, the effects on the breastfed infant, or the effects on milk production. Olipudase alfa-rpcp is present in animal milk. 

When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XENPOZYME and any potential adverse effects on the breastfed infant from XENPOZYME or from the underlying maternal condition

3. Females and Males of Reproductive Potential-                                                  XENPOZYME may cause embryo-fetal harm when administered during the first trimester of pregnancy [

Pregnancy Testing-                                                                                                      Verify the pregnancy status in females of reproductive potential prior to initiating XENPOZYME.

Contraception Females-                                                                                                  Advise females of reproductive potential to use effective contraception during treatment and for 14 days after the last dose if XENPOZYME is discontinued.

4. Pediatric Use-                                                                                                           The safety and effectiveness of XENPOZYME for the treatment of non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) have been established in pediatric patients down to birth

 Use of XENPOZYME for this indication is supported by evidence from an adequate, and wellcontrolled trial ) in adults with supportive efficacy, safety, and tolerability data in pediatric patients.

Compared to adults, a higher percentage of pediatric patients experienced treatment related serious adverse reactions, anaphylaxis, hypersensitivity reactions, and IARs that occurred within 24 hours of infusion 

5. Geriatric Use-                                                                                                              Of the total number of XENPOZYME-treated adult patients in these trials, 1 (3%) was 65 to 74 years of age, and none were 75 years of age and older..