Valoctocogene Roxaparvovec

Valoctocogene Roxaparvovec is an adeno-associated virus vector-based gene therapy used for the treatment of adults with severe hemophilia A (congenital factor VIII deficiency with factor VIII activity less than 1 IU/dL) without pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test.severe hemophilia A.

• Valoctocogene Roxaparvovec is available under the following different brand names: Roctavian.

Common side effects of Valoctocogene Roxaparvovec include:

• nausea 
• fatigue
• headache
• infusion-related reactions 
• vomiting
• abdominal pain

Serious side effects of Valoctocogene Roxaparvovec include:

• hives
• difficulty breathing
• swelling of the face, lips, tongue, or throat.
• hepatotoxicity
• serious infusion-related reactions
• thromboembolic events

Rare side effects of Valoctocogene Roxaparvovec include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Suspension for IV infusion

• 2 × 1013 vector genomes (vg)/mL
• Each vial contains an extractable volume of not less than 8 mL (16 × 1013 vg)

Hemophilia A

Adult dosage

• 6 × 1013 vector genomes (vg)/kg as a one-time IV infusion  
• Calculating the dose in milliliters (mL) and number of vials required
• Patient dose volume in mL: Body weight in kg × 3 = dose in mL
• Multiplication factor 3 represents the per kg dose (6 ×1013 vg/kg) divided by the amount of vg/mL of suspension (2 × 1013 vg/mL)
• Number of vials to be thawed: Patient dose volume (mL) divided by 8 = Number of vials to thaw (round up to next whole vial)
• Division factor 8 represents the minimum volume extractable from a vial (8 mL)
• Example
  • Patient’s weight: 70 kg
    • 70 kg × 3 = 210 mL (dose in mL)
    • 210 mL/8 = 26.25, which rounds to 27 vials

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Valoctocogene Roxaparvovec has severe interactions with no other drugs
• Valoctocogene Roxaparvovec has serious interactions with the following drugs:
  • efavirenz
  • isotretinoin
• Valoctocogene Roxaparvovec has moderate interactions with at least 55 other drugs
• Valoctocogene Roxaparvovec has minor interactions with no other drugs

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, health questions, or concerns.

Contraindications

• Active infections (acute or uncontrolled chronic)
• Known significant hepatic fibrosis (stage 3 or 4 on the Batts-Ludwig scale), or cirrhosis
• Hypersensitivity to mannitol

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Valoctocogene Roxaparvovec?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Valoctocogene Roxaparvovec?”

Cautions

• Patients should abstain from alcohol consumption for at least a year following infusion and limit alcohol use after that
• An increase in factor VIII activity may increase the risk for venous and arterial thromboembolic events
• Elevated factor VIII activity level above the ULN, as measured by the chromogenic substrate assays (CSA), one-stage clotting assays (OSA), or both assays, has occurred
• Factor VIII activity above ULN reported following infusion; evaluate for thrombosis risk factors including cardiovascular risk factors before and after use and advise patients accordingly
• Monitor for factor VIII activity and factor VIII inhibitors
• Malignancy
  • Monitor for hepatocellular malignancy in patients with risk factors for hepatocellular carcinoma (eg, hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age) with regular ultrasound (eg, annually) and alpha-fetoprotein testing for 5 years after administration
  • If any malignancy occurs after treatment, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100
• Hepatoxicity
  • IV administration of a liver-directed AAV vector could lead to liver enzyme elevations (transaminitis), especially ALT elevation
  • Transaminitis may occur due to immune-mediated injury of transduced hepatocytes and may reduce the therapeutic efficacy of AAV-vector-based gene therapy
  • Concomitant medications may cause hepatotoxicity, decrease factor VIII activity, or change plasma corticosteroid levels which may impact liver enzyme elevation and/or factor VIII activity
  • Closely monitor concomitant medication use including herbal products and nutritional supplements, and consider alternative medications in case of potential drug interactions
• Infusion-related reaction
  • Infusion-related reactions, including hypersensitivity reactions and anaphylaxis, have occurred
  • Symptoms include urticaria, pruritus, rash, sneezing, coughing, dyspnea, rhinorrhea, watery eyes, tingling throat, nausea, diarrhea, hypotension, tachycardia, presyncope, pyrexia, rigors, and chills
  • Monitor patients during and for at least 3 hours after completing an infusion
  • Do not infuse faster than 4 mL/min
  • If an infusion reaction occurs, slow or stop administration
  • Restart at a lower rate once the infusion reaction has resolved
  • Discontinue infusion for anaphylaxis
  • Consider management of an infusion reaction with a corticosteroid, antihistamine, and other measures
• Drug interaction overview
  • Monitor concomitant medications after administering Valoctocogene Roxaparvovec, and adjust concomitant medications accordingly
  • If initiating a new medication, closely monitor ALT and factor VIII activity levels (eg, weekly to every 2 weeks for the first month) to assess potential effects on both levels
  • Isotretinoin
    • Not recommended
• Decreased factor VIII activity without ALT elevation was detected in one patient after starting treatment with systemic isotretinoin following valoctocogene Roxaparvovec infusion
• Factor VIII activity was 75 IU/dL at Week 60 and transiently decreased to less than 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
• Efavirenz
  • Not recommended
  • HIV-positive patient treated with valoctocogene Roxaparvovec while on an antiretroviral therapy regimen consisting of efavirenz, lamivudine, and tenofovir experienced asymptomatic elevations of ALT, AST, and GGT (more than 5x ULN), and serum bilirubin (more than ULN and up to 1.5x ULN) at week 4
  • Reaction resolved after stopping efavirenz
• Drugs affecting corticosteroid plasma concentration
  • Agents that may reduce or increase the plasma concentration of corticosteroids (eg, CYP3A4 inducers or inhibitors) can decrease the efficacy of corticosteroids or increase their toxicities
• Vaccinations
  • Do NOT administer live vaccines while on immunosuppressive therapy
  • Before infusion, ensure up-to-date vaccinations
  • Consider adjusting individual vaccination schedules to accommodate concomitant immunosuppressive therapy

Pregnancy and Lactation

• Not intended for women
• There are no data on use in pregnant women to inform a drug-associated risk of adverse developmental outcome
• Animal reproduction and developmental toxicity studies not conducted
• Unknown whether valoctocogene Roxaparvovec can cause fetal harm when administered to pregnant women or can affect reproduction capacity
• Contraception for men after administration
• In clinical studies, after administration, transgene DNA was detectable in semen
• In healthy mice, vector DNA detected in testes for at least 182 days after administration at a dose level of 2.1 x 1014 vg/kg
• For 6 months after administration, men of reproductive potential and their women partners must prevent or postpone pregnancy using an effective form of contraception, and men must not donate semen
• Lactation
• Not intended for women
• There is no information regarding the drug’s presence in human milk, its effects on breastfed infants, or milk production