Version May 2024
Hemophilia A, severe: Note: Prior to valoctocogene roxaparvovec administration, perform testing for preexisting antibodies to adeno-associated virus serotype 5 (AAV5) and factor VIII inhibitors; do not administer in patients with positive antibody testing for AAV5 or factor VIII inhibitors. Assess ALT, AST, gamma-glutamyl transferase (GGT), alkaline phosphatase, total bilirubin, INR, as well as hepatic ultrasound and elastography for liver fibrosis. If there are radiological liver abnormalities and/or liver function test abnormalities, consider a hepatology consultation to assess eligibility for valoctocogene roxaparvovec therapy. Do not administer valoctocogene roxaparvovec in patients with infections (active acute or chronic uncontrolled), significant hepatic fibrosis, cirrhosis, or hypersensitivity to mannitol. Evaluate patients for general cardiovascular risk factors and risk for thrombosis prior to administration; consider prophylactic anticoagulation if indicated. Valoctocogene roxaparvovec–derived factor VIII activity levels may take several weeks to achieve a level sufficient for prevention of spontaneous bleeding; exogenous factor VIII or other hemostatic products may be needed during the first few weeks following infusion.
IV: 6 × 1013 vector genomes/kg (which is 3 mL/kg) as a single one-time dose (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
Hepatic impairment prior to treatment initiation: There are no dose adjustments provided in the manufacturer's labeling. If radiological liver abnormalities and/or liver function test abnormalities, consider a consultation with a hepatologist to assess eligibility for valoctocogene roxaparvovec therapy.
Hepatotoxicity following treatment: If ALT is ≥1.5 times baseline or above ULN, consider corticosteroid treatment.
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Prednisoneb oral dose |
Duration of therapy | |
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a In clinical studies, the median duration of corticosteroid therapy was 35 weeks (range: 3 to 120 weeks). The median duration of alternative immunosuppressive medication use was 26 weeks (range: 6 to 118 weeks). | ||
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b Corticosteroids equivalent to prednisone may also be used. Alternative immunosuppressive medications can be considered in the event of corticosteroid treatment failure, contraindication, or intolerance. | ||
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c Increase corticosteroid dose to a maximum of 1.2 mg/kg if ALT has not improved or continues to rise after 2 weeks (and after ruling out other causes of ALT elevation). | ||
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d Begin corticosteroid taper when ALT levels reach baseline. Individualize taper based on decline trend of ALT, patient's medical condition, and corticosteroid tolerance. | ||
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Starting corticosteroid dose |
60 mg/day |
2 weeksc |
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Corticosteroid tapering scheduled |
40 mg/day |
3 weeks |
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30 mg/day |
1 week | |
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20 mg/day |
1 week | |
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10 mg/day |
1 week | |
Infusion reactions: May stop or slow the infusion. If the infusion is stopped, restart at a lower rate (1 mL/minute) when the infusion reaction has resolved; consider maintaining at a previously tolerated rate for remainder of infusion. Consider corticosteroid, antihistamine administration, and/or other supportive management for infusion reaction management. Discontinue infusion for anaphylaxis.
Refer to adult dosing.
Infusion-related reactions and hypersensitivity reactions (including anaphylaxis) have been reported with valoctocogene roxaparvovec.
Risk factors:
• Infusion rate >4 mL/minute
Transaminase elevation, specifically increased serum alanine aminotransferase (ALT), has been reported with valoctocogene roxaparvovec and may reduce adeno-associated virus vector gene therapy efficacy. A majority of ALT elevations were low grade, though some were considered serious and/or associated with a decline in factor VII activity. In a clinical study, nearly all (96%) ALT elevations resolved with glucocorticoid initiation (Ref). No events met criteria for drug-induced liver injury.
Mechanism: Unknown; however, an inflammatory or immune-related response may be responsible in those occurring early post infusion (Ref).
Onset: Varied; the median time to elevation was 7 weeks (range 0.4 to 159 weeks) post infusion with a median elevation duration of 4 weeks.
Risk factors:
• Concomitant hepatotoxic medications including herbal products and nutritional supplements
• Alcohol consumption
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Endocrine & metabolic: Increased lactate dehydrogenase (57%)
Gastrointestinal: Nausea (31%)
Hematologic & oncologic: Increased clotting factor VIII (28%)
Hepatic: Increased gamma-glutamyl transferase (18%; >5 to 20 × ULN: 1%), increased serum alanine aminotransferase (81% to 96%; >5 to 20 × ULN: 8% to 9%), increased serum aspartate aminotransferase (69%; >5 to 20 × ULN: 7%), increased serum bilirubin (13%)
Nervous system: Fatigue (16%)
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (45%; >5 to 10 × ULN: 5%; >10 × ULN: 4%)
1% to 10%:
Dermatologic: Skin rash (1%)
Gastrointestinal: Abdominal pain (6%), diarrhea (4%), gastroenteritis (1%), vomiting (6%)
Hypersensitivity: Anaphylaxis (1%), hypersensitivity reaction (4%), infusion-related reaction (7%)
Nervous system: Dizziness (2%), headache (7%)
Frequency not defined:
Cardiovascular: Presyncope
Dermatologic: Maculopapular rash
Active infections, either acute (such as acute respiratory infections or acute hepatitis) or uncontrolled chronic (such as chronic active hepatitis B); known significant hepatic fibrosis (stage 3 or 4 on the Batts-Ludwig scale or equivalent) or cirrhosis; known hypersensitivity to mannitol.
Concerns related to adverse effects:
• Hepatocellular carcinogenicity: Liver-targeting adeno-associated virus vector DNA integration into the genome may be associated with the theoretical risk of hepatocellular carcinoma. Low levels of vector integration were found in liver and parotid gland tissue samples in a small number of patients treated with valoctocogene roxaparvovec. No valoctocogene roxaparvovec–associated carcinogenicity was observed in clinical studies. Risk factors for hepatocellular carcinoma include hepatitis B or C, metabolic dysfunction associated steatotic liver disease, chronic alcohol consumption, and/or metabolic dysfunction associated steatohepatitis. If a secondary malignancy occurs, contact the valoctocogene roxaparvovec manufacturer for instructions on collecting patient samples for testing.
• Thromboembolic events: Elevated factor VIII activity levels have occurred following valoctocogene roxaparvovec administration, which may increase the risk for venous and arterial thromboembolic events. In a clinical study of valoctocogene roxaparvovec, ~30% of patients had factor VIII elevations above ULN, with a median time to first occurrence of 14 weeks and median duration above ULN of 12 weeks. Patients with a history of venous or arterial thromboembolism or known history of thrombophilia were excluded from clinical trials of valoctocogene roxaparvovec. Consider prophylactic anticoagulation based on individual patient risk for thrombosis in relation to factor VIII activity levels above ULN.
Disease-related concerns:
• Factor VIII activity levels: Valoctocogene roxaparvovec–derived factor VIII activity levels may take several weeks to rise to a level sufficient for prevention of spontaneous bleeding. Continued routine prophylaxis support with exogenous factor VIII or other hemostatic products may be required during the first few weeks after valoctocogene roxaparvovec infusion. Exogenous factor VIII or other hemostatic products may also be required in case of surgery, invasive procedures, trauma, or bleeds if valoctocogene roxaparvovec–derived factor VIII activity is insufficient for adequate hemostasis. Perform testing for factor VIII inhibitors if plasma factor VIII levels decrease or if experiencing uncontrolled bleeding.
Concurrent drug therapy issues:
• Immunizations: Ensure vaccinations are up to date prior to valoctocogene roxaparvovec administration. Vaccination schedules may require adjustment due to possible concomitant immunosuppressive therapy; live vaccinations should not be administered during immunosuppressive therapy.
Other warnings/precautions:
• Appropriate use: Prior to valoctocogene roxaparvovec administration, perform testing for preexisting antibodies to adeno-associated virus serotype 5 (AAV5). Information on approved tests is available at http://www.fda.gov/CompanionDiagnostics.
• Concurrent therapy considerations: Concomitant medications may cause hepatotoxicity, decrease factor VIII activity, and/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. Patients should abstain from consuming alcohol for at least 1 year following valoctocogene roxaparvovec administration, as well as limit alcohol consumption thereafter.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, Intravenous [preservative free]:
Roctavian: Valoctocogene roxaparvovec-rvox 20 trillion VG/mL (1 ea)
No
Suspension (Roctavian Intravenous)
20000000000000VG/ML (per each): $0.00
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IV: Administer as an IV infusion through a peripheral venous catheter (do not use a central line or port) with an in-line 0.22-micron polyvinylidene fluoride filter with a polyvinyl chloride body (in-line filter should be added close to infusion site); do not administer as an IV push or bolus. Infuse valoctocogene roxaparvovec using a syringe infusion pump beginning at a rate of 1 mL/minute, which can be increased every 30 minutes by 1 mL/minute up to a maximum rate of 4 mL/minute; infusion times can range from 2 to 5 hours or longer depending on infusion volume, patient weight, infusion rate, and patient response. Syringe pump tubing and filter are initially primed (during preparation) with valoctocogene roxaparvovec; the infusion line may be primed with NS when replacing filters during infusion. Refer to filter instructions to determine the maximum recommended filtered fluid volume administered and replace filters as needed. Prime and flush filters with NS if replaced during infusion. Multiple syringes will be required for the dose. After completion of the final valoctocogene roxaparvovec syringe, flush tubing and filter with NS at the same infusion rate. Do not infuse valoctocogene roxaparvovec in the same IV line with any other medications.
If an infusion reaction occurs during valoctocogene roxaparvovec administration, decrease the rate or stop the infusion and provide supportive treatment; discontinue infusion for anaphylaxis. If the infusion is stopped, resume at a rate of 1 mL/minute and consider maintaining at the previously tolerated rate for the remainder of the infusion; complete infusion within 10 hours of initial product thaw. Administer in a setting with personnel and equipment immediately available for management of infusion reactions.
Monitor during infusion and for at least 3 hours after completion of valoctocogene roxaparvovec infusion. Maintain IV access during the observation period.
Dispose unused valoctocogene roxaparvovec and materials that may have come in contact with valoctocogene roxaparvovec according to local biosafety guidelines. Treat spills with a virucidal agent with proven activity against nonenveloped viruses.
Hemophilia A, severe: Treatment of severe hemophilia A (congenital factor VIII deficiency with factor VIII activity <1 IU/dL) without antibodies to adeno-associated virus serotype 5 (AAV5) in adults (as detected by an approved test).
Valoctocogene roxaparvovec may be confused with etranacogene dezaparvovec, nadofaragene firadenovec, onasemnogene abeparvovec, voretigene neparvovec.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Efavirenz: Valoctocogene Roxaparvovec may enhance the hepatotoxic effect of Efavirenz. Efavirenz may diminish the therapeutic effect of Valoctocogene Roxaparvovec. Risk X: Avoid combination
ISOtretinoin (Systemic): May diminish the therapeutic effect of Valoctocogene Roxaparvovec. Risk X: Avoid combination
Following administration of valoctocogene roxaparvovec, transgene DNA is detectable in semen. Patients should not donate semen for 6 months following the infusion of valoctocogene roxaparvovec. In addition, patients and their partners who could become pregnant should use effective contraception to prevent or postpone pregnancy for 6 months after valoctocogene roxaparvovec administration.
Animal reproduction studies have not been conducted. Valoctocogene roxaparvovec is not intended for use in people who could become pregnant.
It is not known if valoctocogene roxaparvovec is present in breast milk.
Prior to therapy: Testing for preexisting antibodies to adeno-associated virus serotype 5 (AAV5); factor VIII inhibitor titer testing; LFTs (AST, ALT, gamma-glutamyl transferase, alkaline phosphatase, total bilirubin); INR; liver ultrasound and elastography (for liver fibrosis). Assess risk for thromboembolism and cardiovascular risk factors prior to treatment.
During infusion: Monitor for signs/symptoms of infusion reaction (eg, urticaria, pruritus, rash, sneezing, coughing, shortness of breath, rhinorrhea, watery eyes, tingling throat, nausea, diarrhea, hypotension, tachycardia, presyncope, pyrexia, rigors, chills) during infusion and for at least 3 hours after completion of valoctocogene roxaparvovec infusion.
After therapy: Factor VIII activity and ALT levels as described below; factor VIII inhibitor testing post infusion if bleeding is not controlled or plasma factor VIII levels decrease. Conduct regular (annual) liver ultrasound and alpha-fetoprotein testing for 5 years after valoctocogene roxaparvovec in patients with risk factors for hepatocellular carcinoma (hepatitis B or C, metabolic dysfunction associated steatotic liver disease, chronic alcohol consumption, and/or metabolic dysfunction associated steatohepatitis).
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Recommended ALT a,b,c and Factor VIII Activityd Level Monitoring After Valoctocogene Roxaparvovec Administration | |
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Time frame |
Monitoring frequency |
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a If ALT is elevated, monitor AST and CPK as needed to rule out other causes of ALT elevation (eg, potentially hepatotoxic medications/agents, alcohol intake, strenuous exercise). | |
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b Consider repeat ALT testing within 24 to 48 hours to confirm ALT elevation prior to initiation of corticosteroid treatment. Use the same lab to measure ALT activity at baseline and over time to minimize variability of test results. | |
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c Monitor ALT weekly and as clinically indicated during corticosteroid treatment and tapering; continue monitoring until return to baseline. | |
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d Consider more frequent monitoring of factor VIII activity levels in patients with activity levels ≤5 IU/dL and evidence of bleeding. Use the same assay and reagents over time (different assays may impact test results). | |
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Weeks 1 to 25 |
Weekly |
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Weeks 26 to 52 (year 1) |
Every 1 to 2 weeks |
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Year 2 |
Every 3 months |
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After year 2 |
Every 6 months |
Valoctocogene roxaparvovec is an adeno-associated virus serotype 5 (AAV5)–based gene therapy vector (Ozelo 2022). It is 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, which results in hFVIII-SQ expression. The expressed hFVIII-SQ replaces the missing coagulation factor VIII required for effective hemostasis.
Onset of action: The majority (95%) of patients reached factor VIII activity levels of ≥5 IU/dL using the chromogenic substrate assay (CSA) within 5 months post infusion. Valoctocogene roxaparvovec–derived factor VIII activity levels may take several weeks to achieve a level sufficient for prevention of spontaneous bleeding.
Duration of action: Potentially transmissible vector DNA detectable in plasma up to 10 weeks after administration.
Distribution: Peak vector DNA concentrations observed in blood, followed by saliva, semen, stool, and urine.
Time to peak: Detectable peak concentrations of vector DNA in blood and all shedding matrices observed 1 to 9 days post administration.
Excretion: In clinical studies, patients treated with valoctocogene roxaparvovec had measurements below the lower limit of quantification (LLOQ) for vector DNA in semen by 36 weeks. The maximum time to levels below the limit of detection of potentially transmissible vector DNA in semen was 12 weeks. The maximum time to LLOQ measurements for urine, saliva, and stool were 8 weeks, 52 weeks, and 131 weeks, respectively.
Race/Ethnicity: In clinical studies of valoctocogene roxaparvovec, a trend of lower factor VIII activity levels was observed in Black patients when compared to patients of other races within the study population. Despite differences in factor VIII activity, annualized bleeding rates and factor VIII usage was similar across races. This observation was limited given small sample size, potential confounding factors, and multiple post hoc analyses. Given these limitations, this trend was insufficient to provide meaningful conclusions about the differences in response rates based on race.
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