Valoctocogene Roxaparvovec-Rvox

FDA Drug Information • Also known as: Roctavian

Brand Names: Roctavian
Dosage Form: INJECTION, SUSPENSION
Product Type: DRUG FOR FURTHER PROCESSING

Description

11 DESCRIPTION ROCTAVIAN (valoctocogene roxaparvovec-rvox) is an adeno-associated virus (AAV) vector-based gene therapy product. ROCTAVIAN is replication-incompetent and consists of an AAV serotype 5 capsid containing a DNA sequence encoding the B-domain deleted SQ form of the human coagulation factor VIII (hFVIII-SQ). ROCTAVIAN is derived from naturally occurring adeno-associated virus and is produced using Sf9 insect cells and recombinant baculovirus technology. ROCTAVIAN is a sterile suspension for intravenous infusion. When thawed, the suspension is clear and colorless to pale yellow. Each vial of ROCTAVIAN contains an extractable volume of 8 mL of valoctocogene roxaparvovec-rvox at a concentration of 2 × 10 13 vector genomes (vg) per mL, and the following excipients: mannitol (20 mg/mL), poloxamer 188 (2.0 mg/mL), sodium chloride (8.2 mg/mL), sodium phosphate monobasic dihydrate (0.23 mg/mL), sodium phosphate dibasic dodecahydrate (3.05 mg/mL) and Water for Injection, USP. The pH of ROCTAVIAN is 6.9 to 7.8. The osmolarity of ROCTAVIAN is 364 to 445 mOsm/L. The product contains no preservative.

What Is Valoctocogene Roxaparvovec-Rvox Used For?

1 INDICATIONS AND USAGE ROCTAVIAN is an adeno-associated virus vector-based gene therapy indicated for the treatment of adults with severe hemophilia A (congenital factor VIII deficiency with factor VIII activity < 1 IU/dL) without antibodies to adeno-associated virus serotype 5 (AAV5) detected by an FDA-approved test. ROCTAVIAN is an adeno-associated virus vector-based gene therapy indicated for the treatment of adults with severe hemophilia A (congenital factor VIII deficiency with factor VIII activity < 1 IU/dL) without pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test. ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION For one-time single-dose intravenous use only. Treatment with ROCTAVIAN should be under the supervision of a physician experienced in the treatment of hemophilia and/or bleeding disorders. For one-time single-dose intravenous use only. ( 2 ) Perform baseline testing to select patients, including testing for pre-existing antibodies to adeno-associated virus serotype 5 (AAV5), factor VIII inhibitor presence, and liver health assessments. ( 2 ) The recommended dose of ROCTAVIAN is 6 × 10 13 vector genomes (vg) per kg of body weight. ( 2.1 ) Start the infusion at 1 mL/min. If tolerated, the rate may be increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min. ( 2.1 ) For Patient Selection Perform testing for pre-existing antibodies to AAV5 using the FDA approved companion diagnostic. DO NOT administer ROCTAVIAN to patients with a positive test for antibodies to AAV5. Information on FDA-approved tests for the detection of antibodies to AAV5 is available at: http://www.fda.gov/CompanionDiagnostics . Perform factor VIII inhibitor titer testing [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.6) ] . DO NOT administer ROCTAVIAN to a patient with a positive test for factor VIII inhibitor. Perform liver health assessments, which include: Liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total bilirubin and international normalized ration (INR)] Ultrasound and elastography or laboratory assessments for liver fibrosis In case of radiological liver abnormalities and/or liver function test abnormalities (ALT, AST, GGT, ALP or total bilirubin > 1.25 × ULN or INR ≥ 1.4), consider a consultation with a hepatologist to assess eligibility for ROCTAVIAN. Assess patient's ability to receive corticosteroids and/or other immunosuppressive therapy that may be required for an extended period [see Dosage and Administration (2.3) ] . Ensure that the risks associated with immunosuppression are acceptable for the individual patient. DO NOT administer ROCTAVIAN to patients with active acute or uncontrolled chronic infections, known significant hepatic fibrosis (stage 3 or 4 on the Batts-Ludwig scale or equivalent) or cirrhosis, or mannitol hypersensitivity [see Contraindications (4) and Use in Specific Populations (8.8) ] . 2.1 Dose The recommended dose of ROCTAVIAN is 6 × 10 13 vector genomes per kilogram (vg/kg) body weight, administered as a single intravenous infusion. ROCTAVIAN is administered using an infusion pump at a rate of 1 mL/min, which can be increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min. Calculating Dose in Milliliters (mL) and Number of Vials Required Patient dose volume in mL: Body weight in kg multiplied by 3 = dose in mL. The multiplication factor 3 represents the per kilogram dose (6 × 10 13 vg/kg) divided by the amount of vector genomes per mL of the ROCTAVIAN...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following adverse reactions are also discussed in other sections of the label: Infusion-Related Reactions [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence ≥ 5%) were nausea, fatigue, headache, infusion-related reactions, vomiting, and abdominal pain. ( 6 ) Most common laboratory abnormalities (incidence ≥ 10%) were ALT, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), factor VIII activity levels, gamma-glutamyl transferase (GGT) and bilirubin > ULN. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100, 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 cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in this section reflect the exposure of 134 adult patients with severe hemophilia A (defined as residual factor VIII activity ≤ 1 IU/dL) to a single dose of 6 × 10 13 vg/kg of body weight of ROCTAVIAN. Patients with detectable pre-existing antibodies to AAV5, active infections, history of thrombosis, immunosuppressive disorders, and liver dysfunction were excluded. All patients had a median follow-up of 162 weeks (range: 66 to 255 weeks) [see Clinical Studies (14) ] . The most common adverse reactions (≥ 5%) to ROCTAVIAN were nausea, fatigue, headache, infusion-related reactions, vomiting, and abdominal pain. The most common laboratory abnormalities (≥ 10%) to ROCTAVIAN were ALT, AST, LDH, CPK, factor VIII activity levels, GGT, and bilirubin > ULN. Non-laboratory adverse reactions (≥ 5%) to ROCTAVIAN are listed in Table 5. There were 6 serious adverse reactions related to ROCTAVIAN treatment including ALT elevation, presyncope, maculopapular rash, anaphylaxis, and hypersensitivity reaction. Table 5: Adverse Reactions in ≥ 5% Other adverse reactions include gastroenteritis (2 patients; 1%), rash (2 patients; 1%), diarrhea (6 patients; 4%), and dizziness (3 patients; 2%). of Patients Treated with ROCTAVIAN Adverse Reactions Number of Patients (%) N = 134 All Grades ≥ Grade 3 Nervous system disorders Headache 9 (7%) 0 (0%) Gastrointestinal disorders Nausea 42 (31%) 0 (0%) Vomiting 8 (6%) 0 (0%) Abdominal pain Includes abdominal discomfort, abdominal distension, abdominal tenderness, and abdominal pain upper. 8 (6%) 0 (0%) General disorders and administration site conditions Fatigue Includes fatigue, lethargy, and malaise. 21 (16%) 0 (0%) Infusion-related reactions Infusion-related reactions are not under a specific system organ class and include multiple symptoms that occurred during or within 6 hours after the end of infusion [see Warnings and Precautions (5.1) ]. 9 (7%) 2 (1%) Table 6 lists laboratory abnormalities in patients treated with ROCTAVIAN. Table 6: Laboratory Abnormalities in Patients Treated with ROCTAVIAN Laboratory Abnormalities Number of Patients (%) N = 134 ALT increases > ULN 109 (81%) AST increases > ULN 92 (69%) LDH increases > ULN 77 (57%) CPK increases > ULN 60 (45%) Factor VIII activity levels > ULN Patients with one or more instances of factor VIII activity levels > 170 IU/dL (ULN of the CSA used) or > 150 IU/dL (ULN of the OSA used) [see Warnings and Precautions (5.3) ] . 38 (28%) GGT increases > ULN 24 (18%) Bilirubin increases > ULN 18 (13%) Twelve (9%), 9 (7%) and 1 (1%) of patients experienced > 5-20 × ULN ALT, AST and GGT elevations, respectively. Seven (5%) patients and 5 (4%) patients experienced > 5-10 × ULN and > 10 × ULN CPK increases, respectively. Infusion-related reactions were observed in 9 patients (7%), including hypersensitivity reactions (4%) and anaphylaxis (1%), and have occurred during and/or following ROCTAVIAN...

Drug Interactions

7 DRUG INTERACTIONS Prior to ROCTAVIAN administration, the patient's existing medications should be reviewed to determine if they should be modified to prevent anticipated interactions described in this section. Concomitant medications should be monitored after ROCTAVIAN administration, and the need to change concomitant medications based on patient's hepatic status and risk should be evaluated. When a new medication is started, close monitoring of ALT and factor VIII activity levels (e.g., weekly to every 2 weeks for the first month) is recommended to assess potential effects on both levels. No in vivo interaction studies have been performed. 7.1 Isotretinoin In one patient, decreased factor VIII activity without ALT elevation was detected after starting treatment with systemic isotretinoin following ROCTAVIAN infusion. Factor VIII activity was 75 IU/dL at Week 60 and transiently decreased to < 3 IU/dL at Week 64, after initiating isotretinoin. After discontinuing isotretinoin at Week 72, factor VIII activity recovered to 46 IU/dL at Week 122. An in vitro study in human primary hepatocytes indicated that isotretinoin suppressed factor VIII transcription independent of hepatotoxicity, without impact on ALT, and expression was partially restored upon cessation of isotretinoin treatment. Isotretinoin is not recommended in patients who are benefiting from ROCTAVIAN. 7.2 Efavirenz One HIV positive patient treated with ROCTAVIAN at a dose of 4 × 10 13 vg/kg ROCTAVIAN while on an antiretroviral therapy regimen consisting of efavirenz, lamivudine, and tenofovir experienced asymptomatic elevations of ALT, AST, and GGT (> 5.0 × ULN) and serum bilirubin (> ULN and up to 1.5 × ULN) at Week 4 [see Use in Specific Populations (8.6) ] . The reaction resolved after the antiretroviral therapy regimen was changed to a regimen without efavirenz. The patient later reverted to prophylactic use of factor VIII concentrates. An in vitro study in human primary hepatocytes indicated that efavirenz suppressed factor VIII transcription independent of hepatotoxicity, and expression was not restored upon discontinuation of efavirenz. Efavirenz is not recommended in patients treated with ROCTAVIAN. 7.3 Interactions with Agents that May Reduce or Increase Plasma Concentrations of Corticosteroids Agents that may reduce or increase the plasma concentration of corticosteroids (e.g., agents that induce or inhibit cytochrome P450 3A4) can decrease the efficacy of the corticosteroid regimen or increase their side effects [see Dosage and Administration (2.3) ] . 7.4 Vaccinations Prior to ROCTAVIAN infusion, ensure up to date vaccinations. Individual vaccination schedules may need to be adjusted to accommodate concomitant immunosuppressive therapy [see Dosage and Administration (2.3) ] . Live vaccines should not be administered to patients while on immunosuppressive therapy.

Contraindications

4 CONTRAINDICATIONS Administration of ROCTAVIAN is contraindicated in: patients with active infections, either acute (such as acute respiratory infections or acute hepatitis) or uncontrolled chronic (such as chronic active hepatitis B) . patients with known significant hepatic fibrosis (stage 3 or 4 on the Batts-Ludwig scale or equivalent), or cirrhosis [see Dosage and Administration (2) ]. patients with known hypersensitivity to mannitol. Active infections, either acute or uncontrolled chronic. ( 4 ) Known significant hepatic fibrosis (stage 3 or 4), or cirrhosis. ( 4 ) Known hypersensitivity to mannitol. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary ROCTAVIAN is not intended for administration in women. There are no data on the use of ROCTAVIAN in pregnant women to inform a drug-associated risk of adverse developmental outcome. Animal reproduction and developmental toxicity studies have not been conducted with ROCTAVIAN. It is not known whether ROCTAVIAN can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects occurs in 2 to 4% of the general population and miscarriage occurs in 15 to 20% of clinically recognized pregnancies.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ROCTAVIAN (valoctocogene roxaparvovec-rvox) injection is supplied as a sterile, preservative-free, clear and colorless to pale yellow suspension for intravenous infusion. ROCTAVIAN contains 2 × 10 13 vector genomes (vg) per mL. Each carton of ROCTAVIAN (NDC 68135-927-48) contains one single-dose vial (NDC 68135-927-01) with an extractable volume of not less than 8 mL, containing 16 × 10 13 vector genomes (vg). 16.2 Storage and Handling Product as Packaged for Sale Transport frozen at ≤ -60°C (-76°F) Store upright at ≤ -60°C (-76°F). Store ROCTAVIAN vial in carton until ready to use. Protect ROCTAVIAN from light. During Preparation and Administration Thaw at room temperature, up to 25°C (77°F). After thawing, ROCTAVIAN can be held at room temperature for a maximum of 10 hours, including preparation and infusion times [see Dosage and Administration (2.2) ] . If necessary, an intact vial (stopper not yet punctured) that has been thawed can be stored refrigerated (2 to 8 °C) for up to 3 days, upright and protected from light (e.g., in the original carton). Do not expose ROCTAVIAN to the light of an ultraviolet radiation disinfection lamp. Once thawed, DO NOT REFREEZE. Treat spills of ROCTAVIAN with a virucidal agent with proven activity against non-enveloped viruses and blot using absorbent materials. Dispose of unused product and disposable materials that may have come in contact with ROCTAVIAN in accordance with local guidance for pharmaceutical waste.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.