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Follow-up

The ROCTAVIAN follow-up plan1

  • A baseline assessment of liver function should be recorded
  • Monitor ALT weekly for at least the first 6 months, and institute corticosteroid treatment in response to ALT elevations as required. Continue to monitor ALT until it returns to baseline. Monitor Factor VIII activity levels, since ALT elevation may be accompanied by a decrease in Factor VIII activity
  • Consider more frequent monitoring in patients with Factor VIII activity levels ≤5 IU/dL and evidence of bleeding, taking into account the stability of Factor VIII levels since their previous measurement
  • Weekly monitoring is recommended, and is clinically indicated, during corticosteroid tapering1
  • Note: Agents that may reduce or increase the plasma concentration of corticosteroids (eg, agents that induce or inhibit cytochrome P450 3A4) can decrease the efficacy of the corticosteroid regimen or increase their side effects

*Monitoring of ALT should be accompanied by monitoring of AST and CPK, to rule out alternative causes for ALT elevations (including potentially hepatotoxic medications or agents, alcohol consumption, or strenuous exercise).

Managing hepatic reactions

ALT levels ≥1.5 x baseline or above the ULN1

  • Consider corticosteroid treatment using the schedule above
  • Patients should be evaluated for alternative causality (including potential hepatotoxic medications or agents, alcohol consumption, or strenuous exercise)
  • Consider repeating ALT laboratory testing within 24 to 48 hours and, if clinically indicated, perform additional tests to exclude alternative etiologies. In the absence of an alternative cause for the ALT elevation, a corticosteroid regimen should be promptly initiated
  • If ALT continues to rise or has not improved after 2 weeks, increase the corticosteroid dose up to a maximum of 1.2 mg/kg, after ruling out alternative causes for ALT elevation
  • Taper corticosteroids after ALT levels reach baseline. The taper may be individualized based on the trend of ALT decline, the patient’s medical condition, corticosteroid tolerance, and adverse reactions to corticosteroid therapy

Corticosteroids after Year 11

  • There is limited information regarding the benefit of starting a new corticosteroid course after the first year of ROCTAVIAN administration

Monitoring during corticosteroids1

  • Monitor for and manage adverse reactions from corticosteroid use
  • During corticosteroid treatment, monitor hepatic status and Factor VIII activity at least weekly

Alternative immunosuppressants1

  • Other immunosuppressive therapies (eg, tacrolimus, mycophenolate mofetil) may be considered if corticosteroids are contraindicated, ineffective, or there are adverse events secondary to corticosteroid use necessitating discontinuation

*Prednisone or equivalent dose of another corticosteroid.

Post-infusion bleed management

Manage your patient’s use of hemostatic agents following ROCTAVIAN1

  • Monitoring the patient’s Factor VIII activity level will indicate how well the patient is responding to ROCTAVIAN and allow you to assess the potential need for treatment with Factor VIII concentrates or hemostatic agents
  • Not all patients respond to ROCTAVIAN. Counsel patients, as necessary, on when they may need to re-instate prophylactic use of Factor VIII concentrates/hemostatic agents
  • Advise patients on tapering Factor VIII concentrates/hemostatic agents and, as necessary, on whether and how to continue or re-start their use, and on actions in case of invasive procedures, surgery, trauma, or bleeds and, currently, it is not possible to predict who will respond to treatment and how long treatment response will continue
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Reference:

  1. ROCTAVIAN™ (valoctocogene roxaparvovec-rvox). Prescribing Information. BioMarin Pharmaceutical Inc.; 2023

Indication and Important Safety Information

Contraindications: 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, and patients with known hypersensitivity to mannitol.
Infusion-related reactions including hypersensitivity reactions and anaphylaxis, have occurred. Monitor during and for at least 3 hours after ROCTAVIAN administration. Administer ROCTAVIAN in a setting where personnel and equipment are immediately available to treat infusion-related reactions. Discontinue infusion for anaphylaxis.
Hepatotoxicity: The safety and effectiveness of ROCTAVIAN in patients with hepatic impairment has not been established. Perform liver health assessments prior to administration. The majority of patients treated with ROCTAVIAN experienced ALT elevations and required corticosteroids for ALT elevation. Assess patient’s ability to receive corticosteroids and/or other immunosuppressive therapy that may be required for an extended period. Live vaccines should not be administered to patients while on immunosuppressive therapy.
Monitor ALT weekly for at least 26 weeks and as clinically indicated, during corticosteroid therapy and institute corticosteroid treatment in response to ALT elevations as required. Continue to monitor ALT until it returns to baseline. Monitor Factor VIII activity levels since ALT elevation may be accompanied by a decrease in Factor VIII activity. One case of autoimmune hepatitis was reported during third year follow-up in a patient with history of hepatitis C and steatohepatitis.
It is recommended that patients abstain from consuming alcohol for at least 1 year after administration and thereafter limit alcohol use. 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 or decrease the efficacy of the corticosteroid regimen or increase their side effects. Closely monitor concomitant medication use including herbal products and nutritional supplements and consider alternative medications in case of potential drug interactions.
Thromboembolic Events: Factor VIII activity above ULN has been reported following ROCTAVIAN infusion. Thromboembolic events may occur in the setting of elevated Factor VIII activity above ULN. Evaluate patients for risk of thrombosis including general cardiovascular risk factors before and after administration of ROCTAVIAN. Advise patients on their individual risk of thrombosis in relation to their Factor VIII activity levels above ULN and consider prophylactic anticoagulation. Advise patients to seek immediate medical attention for signs or symptoms indicative of a thrombotic event.
Factor VIII Inhibitors and Monitoring for Inhibitors. The safety and effectiveness of ROCTAVIAN in patients with prior or active Factor VIII inhibitors have not been established. Patients with active Factor VIII inhibitors should not take ROCTAVIAN. Following administration, monitor patients for Factor VIII inhibitors (neutralizing antibodies to Factor VIII). Test for Factor VIII inhibitors especially if bleeding is not controlled, or plasma Factor VIII activity levels decrease.
Monitor Factor VIII using the same schedule for ALT monitoring. It may take several weeks after ROCTAVIAN infusion before ROCTAVIAN-derived Factor VIII activity rises to a level sufficient for prevention of spontaneous bleeding episodes. Exogenous Factor VIII or other hemostatic products may also be required in case of surgery, invasive procedures, trauma, or bleeds. Consider more frequent monitoring in patients with Factor VIII activity levels ≤5 IU/dL and evidence of bleeding, taking into account the stability of Factor VIII levels since the previous measurement.
Factor VIII activity produced by ROCTAVIAN in human plasma is higher if measured with one-stage clotting assays compared to chromogenic substrate assays. When switching from hemostatic products prior to ROCTAVIAN treatment, physicians should refer to the relevant prescribing information to avoid the potential for Factor VIII activity assay interference during the transition period.
Malignancy: The integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development. ROCTAVIAN can also insert into the DNA of other human body cells. Monitor patients with risk factors for hepatocellular carcinoma (eg, hepatitis B or C, nonalcoholic fatty liver disease, chronic alcohol consumption, nonalcoholic steatohepatitis, advanced age) with regular liver ultrasound (eg, annually) and alpha-fetoprotein testing for 5 years following ROCTAVIAN administration. In the event that any malignancy occurs after treatment with ROCTAVIAN, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100.
Most Common Adverse Reactions: Most common adverse reactions (incidence ≥5%) were nausea, fatigue, headache, infusion-related reactions, vomiting, and abdominal pain. Most common laboratory abnormalities (incidence ≥10%) were ALT, AST, LDH, CPK, Factor VIII activity levels, GGT, and bilirubin >ULN. Patients also experienced adverse reactions from corticosteroid use.
Isotretinoin, Efavirenz, and HIV-Positive Patients. Isotretinoin is not recommended in patients who are benefiting from ROCTAVIAN. Efavirenz is not recommended in patients treated with ROCTAVIAN. Clinical studies of ROCTAVIAN did not include sufficient numbers of patients with HIV to determine whether the efficacy and safety differs compared to patients without HIV infection.
Females and Males of Reproductive Potential. ROCTAVIAN is not intended for administration in women. There are no data on the use of ROCTAVIAN in pregnant women or regarding lactation. For 6 months after administration of ROCTAVIAN, men of reproductive potential and their female partners must prevent or postpone pregnancy using an effective form of contraception, and men must not donate semen.
You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to BioMarin Pharmaceutical Inc. at 1-866-906-6100.

 

Please see additional safety information in the Prescribing Information.

 

Indication
ROCTAVIAN™ (valoctocogene roxaparvovec-rvox) is 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 detected by an FDA-approved test.