valoctocogene roxaparvovec (Rx)

Brand and Other Names:Roctavian

Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

suspension for IV infusion

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

Hemophilia A

Adeno-associated virus vector-based gene therapy indicated for severe hemophilia A (congenital factor VIII deficiency with factor VIII activity <1 IU/dL) in adults without pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test

6 x 1013 vector genomes (vg)/kg as a one-time IV infusion  

Calculating dose in milliliters (mL) and number of vials required

  • Patient dose volume in mL: Body weight in kg x 3 = dose in mL
  • Multiplication factor 3 represents the per kg dose (6 x 1013 vg/kg) divided by 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 minimum volume extractable from a vial (8 mL)
Example
  • Patient’s weight: 70 kg
  • 70 kg x 3 = 210 mL (dose in mL)
  • 210 mL/8 = 26.25, which rounds to 27 vials

Dosage Modifications

Renal impairment

  • All severities: No dosage adjustment can be recommended
  • Safety and effectiveness not established

Hepatic impairment

  • All severities: No dosage adjustment can be recommended
  • Safety and effectiveness not established
  • Clinical studies excluded patients with known hepatic cirrhosis, significant fibrosis (stage 3 or 4 on the Batts-Ludwig scale or equivalent), current hepatitis B or C, or history of hepatic malignancy

Dosing Considerations

Limited information available on safety and effectiveness in patients with HIV infection

Safety and effectiveness in patients with prior or active factor VIII inhibitors not established

Patient selection

  • Perform testing for pre-existing antibodies to AAV5 using FDA-approved companion diagnostic
  • Perform factor VIII inhibitor titer testing
    • Do NOT administer to patients who are positive for factor VIII inhibitor

Liver testing

  • Assess liver function tests (ALT, AST, GGT, ALP, total bilirubin and INR)
  • Ultrasound and elastography or laboratory assessments for liver fibrosis
  • If there are radiological liver abnormalities and/or liver function test abnormalities (ALT, AST, GGT, ALP or total bilirubin >1.25x ULN or INR ≥1.4), consider consulting a hepatologist to assess eligibility
  • Assess ability to receive corticosteroids and/or other immunosuppressive therapy that may be required for an extended period
  • Ensure that risks associated with immunosuppression are acceptable for each patient
  • Do NOT administer 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

Safety and efficacy not established

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Interactions

Interaction Checker

and valoctocogene roxaparvovec

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Contraindicated (0)

              Serious - Use Alternative (2)

              • efavirenz

                efavirenz decreases effects of valoctocogene roxaparvovec by pharmacodynamic antagonism. Avoid or Use Alternate Drug. 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. One HIV positive patient treated with valoctocogene roxaparvovec while on an antiretroviral therapy (ART) regimen consisting of efavirenz, lamivudine, and tenofovir experienced asymptomatic elevations of ALT, AST, and GGT and serum bilirubin at Week 4. The reaction resolved after the ART regimen was changed to a regimen without efavirenz. The patient later reverted to prophylactic use of factor VIII concentrates.

              • isotretinoin

                isotretinoin decreases effects of valoctocogene roxaparvovec by pharmacodynamic antagonism. Avoid or Use Alternate Drug. 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. One HIV positive patient treated with valoctocogene roxaparvovec while on an antiretroviral therapy (ART) regimen consisting of efavirenz, lamivudine, and tenofovir experienced asymptomatic elevations of ALT, AST, and GGT and serum bilirubin at Week 4. The reaction resolved after the ART regimen was changed to a regimen without efavirenz. The patient later reverted to prophylactic use of factor VIII concentrates.

              Monitor Closely (55)

              • allopurinol

                allopurinol and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • amiodarone

                amiodarone and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • azathioprine

                azathioprine and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • busulfan

                busulfan and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • carbamazepine

                carbamazepine and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • chlorpromazine

                chlorpromazine and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • clavulanate

                clavulanate and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • dantrolene

                dantrolene and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • diclofenac

                diclofenac and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • didanosine

                didanosine and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • dienogest/estradiol valerate

                dienogest/estradiol valerate and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • disulfiram

                disulfiram and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • drospirenone

                drospirenone and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • erythromycin base

                erythromycin base and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • erythromycin ethylsuccinate

                erythromycin ethylsuccinate and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • erythromycin lactobionate

                erythromycin lactobionate and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • erythromycin stearate

                erythromycin stearate and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • ethinylestradiol

                ethinylestradiol and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • floxuridine

                floxuridine and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • fluoxymesterone

                fluoxymesterone and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • flutamide

                flutamide and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • hydralazine

                hydralazine and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • ibuprofen

                ibuprofen and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • ibuprofen IV

                ibuprofen IV and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • infliximab

                infliximab and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • interferon alfa n3

                interferon alfa n3 and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • interferon beta 1a

                interferon beta 1a and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • interferon beta 1b

                interferon beta 1b and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • isoniazid

                isoniazid and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • ketoconazole

                ketoconazole and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • levonorgestrel oral

                levonorgestrel oral and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • levonorgestrel oral/ethinylestradiol/ferrous bisglycinate

                levonorgestrel oral/ethinylestradiol/ferrous bisglycinate and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • mercaptopurine

                mercaptopurine and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • methotrexate

                methotrexate and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • methyldopa

                methyldopa and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • minocycline

                minocycline and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • nevirapine

                nevirapine and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • nitrofurantoin

                nitrofurantoin and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • norgestrel

                norgestrel and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • oxymetholone

                oxymetholone and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • peginterferon alfa 2a

                peginterferon alfa 2a and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • phenytoin

                phenytoin and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • propylthiouracil

                propylthiouracil and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • pyrazinamide

                pyrazinamide and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • rifampin

                rifampin and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • simvastatin

                simvastatin and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • sulfadiazine

                sulfadiazine and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • sulfamethoxazole

                sulfamethoxazole and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • sulfasalazine

                sulfasalazine and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • sulfisoxazole

                sulfisoxazole and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • sulindac

                sulindac and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • telithromycin

                telithromycin and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • thioguanine

                thioguanine and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • ticlopidine

                ticlopidine and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              • valproic acid

                valproic acid and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.

              Minor (0)

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                Adverse Effects

                Note: Listed adverse reactions are for all severities unless otherwise indicated

                >10%

                ALT increases >ULN (81%)

                AST increases >ULN (69%)

                LDH increases >ULN (57%)

                CPK increases >ULN (45%)

                Nausea (31%)

                Factor VIII activity levels >ULN (28%)

                GGT increases >ULN (18%)

                Fatigue (16%)

                Bilirubin increases >ULN (13%)

                1-10%

                Headache (7%)

                Infusion-related reactions (7%)

                Vomiting (6%)

                Abdominal pain (6%)

                Headache (7%)

                Infusion-related reactions (7%)

                Vomiting (6%)

                Abdominal pain (6%)

                Diarrhea (4%)

                Dizziness (2%)

                Gastroenteritis (1%)

                Rash (1%)

                Infusion-related reactions, grade ≥3 (1%)

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                Warnings

                Contraindications

                Active infections (acute or uncontrolled chronic)

                Known significant hepatic fibrosis (stage 3 or 4 on Batts-Ludwig scale), or cirrhosis

                Hypersensitivity to mannitol

                Cautions

                Patients should abstain from alcohol consumption for at least a year following infusion and limit alcohol use thereafter

                An increase in factor VIII activity may increase risk for venous and arterial thromboembolic events

                Elevated factor VIII activity level above the ULN as measured by the chromogenic substrate assays (CSA), or 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, or 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 hr after completing infusion
                • Do not infuse faster than 4 mL/min
                • If infusion reaction occurs, slow or stop administration
                • Restart at a lower rate once 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 recommend
                  • 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 <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 (>5x ULN), and serum bilirubin (>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 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
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                Pregnancy & Lactation

                Pregnancy

                Not intended for females

                There are no data on use in pregnant females 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 females or can affect reproduction capacity

                Contraception for males 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 female partners must prevent or postpone pregnancy using an effective form of contraception, and men must not donate semen

                Lactation

                Not intended for females

                There is no information regarding drug presence in human milk, effects on breastfed infants, or effects on milk production

                Pregnancy Categories

                A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

                B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

                C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

                D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

                X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

                NA: Information not available.

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                Pharmacology

                Mechanism of Action

                Adeno-associated virus serotype 5 (AAV5)–based gene therapy vector, designed to introduce a functional copy of a transgene encoding the B-domain deleted SQ form of human coagulation factor VIII (hFVIII-SQ)

                Transcription of this transgene occurs within the liver, using a liver-specific promoter, resulting in expression of hFVIII-SQ

                Expressed hFVIII-SQ replaces missing coagulation factor VIII needed for effective hemostasis

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                Administration

                IV Incompatibilities

                Do not use infusion system components other than those described in IV compatibilities

                Do not mix or dilute with infusion solutions

                Do not infuse in same IV line with any other products

                IV Compatibilities

                Use 0.9% NaCl to prime and flush the infusion line

                Syringes: Polypropylene barrel with a synthetic rubber plunger tip

                Syringe cap: Polypropylene

                Infusion tubing (tubing extension should not exceed 40 inches): Polyethylene

                0.22-micron in-line filter: Polyvinylidene fluoride filter with polyvinyl chloride body

                Infusion catheter: Polyurethane-based polymer

                Stopcocks: Polycarbonate

                18- to 21-gauge sharp needles for extraction from vials: Stainless steel (do not use filter needles to extract from vials)

                IV Preparation

                General precautions

                • Do not expose drug to light of an ultraviolet radiation disinfection lamp
                • Prepare using aseptic technique
                • Wear gloves and safety glasses during preparation and administration
                • Treat spills with a virucidal agent with proven activity against non-enveloped viruses and blot using absorbent materials
                • Discard unused product and materials that are exposed to the drug in accordance with the local biosafety guidelines

                Thaw and inspect

                • Store vials in carton until ready to thaw
                • Drug is light sensitive
                • Thaw at room temperature; do not thaw or warm vials any other way (thawing time is ~ 2 hr)
                • Remove required number of vials from their cartons
                • Inspect vials for damage to the vial or cap; discard if damaged
                • Set vials upright
                • At room temperature, spread vials out evenly or place them in racks for optimal thawing
                • Visually confirm all vials have been thawed; there should be no visible ice
                • Very gently invert each vial 5x to mix to minimize foaming
                • Let suspension settle for ~5 minutes before continuing
                • Visually inspect the fully thawed vials; discard if suspension is not clear, not colorless to pale yellow, or contains visible particles
                • For microbiological safety, keep thawed suspension in vials until time for infusion

                Preparing syringes

                • Using 18- to 21-gauge sharp needles, slowly extract drug from vials into infusion-pump syringes
                • Number of syringes will depend on dose volume and syringe pump used
                • Prepare all infusion-pump syringes before administering
                • Contents of multiple vials may be combined into a single syringe

                Adding in-line filter and priming

                • Insert in-line filter close to infusion site
                • Prime tubing and filter
                • When replacing filters during infusion, use 0.9% NaCl, for priming and flushing

                IV Administration

                Do NOT administer as IV push or bolus

                Do NOT infuse in the same IV line with any other products

                Administer once as a single IV infusion in a setting where personnel and equipment are immediately available to treat infusion-related reactions

                Do NOT use a central line or port

                Infuse through a suitable peripheral vein, using an infusion catheter with in-line filter and a programmable syringe pump

                Infuse at initial rate of 1 mL/min; if tolerated, rate may increase q30min by 1 mL/min and should not exceed 4 mL/min

                Infusion time depends on infusion volume, rate, and patient response

                After completing infusion, flush infusion line with a sufficient volume of 0.9% NaCl, through the same tubing and filter, and at the same infusion rate

                Maintain venous access during subsequent observation period

                Infusion-related reactions

                • If an infusion-related reaction occurs during administration, decrease infusion rate or stop infusion
                • Administer treatment as needed to manage infusion reaction
                • If infusion was stopped, restart infusion at a rate of 1 mL/min and consider maintaining at a previously tolerated level for the remaining infusion
                • If restarting infusion, complete infusion within 10 hr of initial drug product thaw
                • Discontinue infusion for anaphylaxis

                Monitoring post-administration

                • Monitor AST and CPK as needed to rule out other causes for ALT elevations
                • Consider repeating ALT testing within 24-48 hr to confirm ALT elevation before initiating corticosteroid treatment
                • Monitoring parameters for ALT
                  • First 26 weeks: Monitor weekly
                  • Weeks 26-52 (Year 1): Monitor q1-2 weeks
                  • Year 2: Monitor q3 months
                  • After Year 2: Monitor q6 months
                • If ALT ≥1.5x baseline or above ULN, consider corticosteroid treatment
                • Recommended corticosteroid dosing
                  • NOTE: Use prednisone or equivalent dose of another corticosteroid
                  • Starting dose: 60 mg daily for 2 weeks; if ALT continues to increase or does not resolve after 2 weeks, increase corticosteroid dose up to a maximum of 1.2 mg/kg, after ruling out alternative causes for ALT elevation
                  • Tapering: 40 mg daily for 3 weeks, THEN 30 mg daily for 1 week, THEN 20 mg daily for 1 week, THEN 10 mg daily for 1 week
                  • Taper corticosteroids after ALT levels reach baseline; individualize taper based on trend of ALT decline, patient’s medical condition, corticosteroid tolerance, and adverse reactions to corticosteroid therapy
                  • Monitor ALT weekly, and as clinically indicated, during corticosteroid therapy
                  • Continue to monitor ALT until its return to baseline
                  • Monitor for and manage adverse reactions secondary to corticosteroid use
                  • Limited information on benefit of starting a corticosteroid course after first year of valoctocogene roxaparvovec administration
                  • Consider other immunosuppressive therapies (eg, tacrolimus, mycophenolate mofetil) if corticosteroids are contraindicated, ineffective, or discontinued due to corticosteroid-related reactions
                • Monitor factor VIII activity
                  • Monitor factor VIII activity using same schedule for ALT monitoring
                  • 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
                  • NOTE: It may take several weeks after infusion before drug-derived factor VIII activity rises to a level sufficient for prevention of spontaneous bleeding episodes
                  • Continued routine prophylaxis support with exogenous factor VIII or other hemostatic products used in managing hemophilia A may be needed during first few weeks after infusion
                  • Exogenous factor VIII or other hemostatic products may also be needed in case of surgery, invasive procedures, trauma, or bleeds if drug-derived factor VIII activity is deemed insufficient for adequate hemostasis in such situations
                  • Use of different assays may impact test results; therefore, use same assay and reagents to monitor patients over time, if feasible
                  • Use of exogenous factor VIII products before and after administering may impede assessment of drug-derived factor VIII activity
                  • Monitor for factor VIII inhibitors (neutralizing antibodies to factor VIII)
                  • Test for factor VIII inhibitors especially if bleeding is uncontrolled, or plasma factor VIII activity levels decrease
                  • Perform regular liver ultrasound (eg, annually) and alpha-fetoprotein (AFP) testing in patients with risk factors of hepatocellular carcinoma (eg, hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age)

                Storage

                Unopened product

                • Transport frozen at ≤ -60ºC (-76ºF)
                • Store upright at ≤ -60ºC (-76ºF)
                • Store vials in carton until ready to use
                • Protect from light

                During preparation and thawing

                • Thaw at room temperature, up to 25ºC (77ºF)
                • Once thawed, do NOT refreeze
                • Particles contains no preservative
                • If necessary, refrigerate intact vial (stopper not yet punctured) at 2-8ºC (36-46ºF) for up to 3 days, upright
                • Store at room temperature, up to 25ºC (77ºF), for up to 10 hr, including hold time in intact vial, preparation time for syringes, and duration of infusion
                • Do not expose to the light of an ultraviolet radiation disinfection lamp
                • Treat spills with a virucidal agent with proven activity against non-enveloped viruses, and blot using absorbent materials
                • Discard unused product and disposable materials that were exposed to drug in accordance with local guidance for pharmaceutical waste
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                Formulary

                FormularyPatient Discounts

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                The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

                Tier Description
                1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                NC NOT COVERED – Drugs that are not covered by the plan.
                Code Definition
                PA Prior Authorization
                Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
                QL Quantity Limits
                Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
                ST Step Therapy
                Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
                OR Other Restrictions
                Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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                Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.