Roctavian Prescribing Information

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 × 1013 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.

2.2 Preparation for Administration

2.3 Administration

• Administer ROCTAVIAN in a setting where personnel and equipment are immediately available to treat infusion-related reactions [see Warnings and Precautions (5.1)].
• Infuse the suspension through a suitable peripheral vein, using an infusion catheter with in-line filter and a programmable syringe pump.
• Start the infusion at a rate of 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. The infusion time depends on infusion volume, rate and patient response and can be, for example, 2 to 5 hours or longer for a patient weighing 100 kg.
• In the event of an infusion-related reaction during administration [see Warnings and Precautions (5.1)],
  • Decrease the infusion rate or stop the infusion.
  • Administer treatment as needed to manage infusion reaction.
  • If the infusion is stopped, restart the infusion at a rate of 1 mL/min and consider maintaining it at a previously tolerated level for the remainder of the infusion. If the infusion needs to be restarted, the infusion should be completed within 10 hours of initial drug product thaw.
  • Discontinue infusion for anaphylaxis.
• DO NOT administer ROCTAVIAN as an intravenous push or bolus.
• DO NOT infuse ROCTAVIAN in the same intravenous line with any other products.
• DO NOT use a central line or port.
• To ensure the patient receives the complete dose, after the content of the last ROCTAVIAN-containing syringe is infused, flush the infusion line with a sufficient volume of 0.9% Sodium Chloride Injection, USP, through the same tubing and filter, and at the same infusion rate.
• Maintain venous access during the subsequent observation period [see Warnings and Precautions (5.1)].

5.1 Infusion-Related Reactions

Infusion-related reactions, including hypersensitivity reactions and anaphylaxis, have occurred during and/or following ROCTAVIAN administration. Symptoms included one or more of the following: 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 completion of ROCTAVIAN infusion. Do not infuse the product faster than 4 mL/min [see Dosage and Administration (2.3)].

In the event of an infusion reaction, administration of ROCTAVIAN should be slowed or stopped. Restart at a lower rate after the infusion reaction has resolved. Discontinue infusion for anaphylaxis. Consider treatment with a corticosteroid, antihistamine, and other measures for management of an infusion reaction [see Dosage and Administration (2.3)].

5.2 Hepatotoxicity

Intravenous administration of a liver-directed AAV vector could lead to liver enzyme elevations (transaminitis), especially ALT elevation. Transaminitis is presumed to occur due to immune-mediated injury of transduced hepatocytes and may reduce the therapeutic efficacy of AAV-vector based gene therapy.

Majority of patients treated with ROCTAVIAN experienced ALT elevations. Most ALT elevations occurred within the first year following ROCTAVIAN administration, especially within the first 26 weeks, were low-grade, and resolved. The median time (range) to the first ALT elevation (defined as ALT ≥ 1.5 × baseline or above ULN) was 7 weeks (0.4, 159 weeks) and the median duration (range) was 4 weeks (0.1, 135 weeks). Some ALT elevations were associated with a decline in factor VIII activity.

The majority of the 112 patients in the clinical trial of ROCTAVIAN required corticosteroids for ALT elevation [see Adverse Reactions (6.1) and Clinical Studies (14)]. The median duration (range) of corticosteroid use was 35 weeks (3, 120 weeks). The median duration (range) of alternate immunosuppressive medications use was 26 weeks (6, 118 weeks). In 20 (18%) patients the duration of immunosuppression was > 1 year.

Monitor ALT and institute corticosteroid treatment in response to ALT elevations, as required. Monitor ALT and factor VIII activity levels weekly and, as clinically indicated, during corticosteroid therapy [see Dosage and Administration (2.3)]. Monitor for and manage adverse reactions secondary to corticosteroid therapy.

Since some ALT elevations have been attributed to alcohol consumption in clinical studies, patients should abstain from alcohol consumption for at least a year following ROCTAVIAN infusion and limit alcohol use thereafter. 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 [see Drug Interactions (7.0, 7.1, 7.2)]. Closely monitor concomitant medication use including herbal products and nutritional supplements and consider alternative medications in case of potential drug interactions.

5.3 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 following ROCTAVIAN administration. Thirty-eight (28%) patients experienced elevations of factor VIII above ULN with a median time to first occurrence of 14 weeks and a median total duration above ULN of 12 weeks.

An increase in factor VIII activity may increase the risk for venous and arterial thromboembolic events. There are no data in patients with a history of venous or arterial thromboembolism or known history of thrombophilia since such patients were excluded from clinical trials of ROCTAVIAN.

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.

5.4 Monitoring Laboratory Tests

5.5 Malignancy

The integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development.

ROCTAVIAN is composed of a non-replicating AAV5 vector whose DNA persists largely in episomal form. Low levels of vector integration were found following evaluation of liver samples from 5 patients and parotid gland tissue sample from 1 patient in clinical studies and liver samples from 12 nonhuman primates [see Clinical Pharmacology (12.2) and Nonclinical Toxicology (13.1)]. ROCTAVIAN can also insert into the DNA of other human body cells. No malignancies assessed as being likely related to ROCTAVIAN were observed in clinical studies.

Monitor patients with risk factors for hepatocellular carcinoma (e.g., hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age) with regular liver ultrasound (e.g., annually) and alpha-fetoprotein testing for 5 years following ROCTAVIAN administration [see Dosage and Administration (2.3)].

In the event that a malignancy occurs, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100 to obtain instructions on collecting patient samples for testing.

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 × 1013 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 6 lists laboratory abnormalities in patients treated with ROCTAVIAN.

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 administration.

Hepatotoxicity as defined by ALT ≥ 1.5 × baseline or ALT > ULN occurred in 107 of 112 (96%) patients. Nine (8%) patients had ALT between > 5-20 × ULN. One hundred (89%) patients had ALT elevations that occurred within the first 26 weeks, 74 (66%) patients had ALT elevations that occurred between weeks 27 to 52, and 72 (64%) patients had ALT elevations that occurred beyond 52 weeks after administration. Thirty-four of 112 (30%) patients had ALT elevations that were associated with a decline in factor VIII activity of ≥ 30%.

The majority of patients (82%, 92/112) required corticosteroids for one or more episodes of ALT elevation while 35% (39/112) required alternate immunosuppression. Seventy-six percent, 5%, and 1% of patients used corticosteroids within the first 26 weeks, weeks 27 to 52, and beyond 52 weeks respectively following ROCTAVIAN administration.

The most common (≥ 10%) adverse reactions from corticosteroid use (N = 92) included acne (34%), insomnia (27%), mood disorders (20%), cushingoid (20%), rash (18%), weight gain (16%), hypertension (12%), folliculitis (11%), abdominal pain (10%), and vision disorders (10%). Other clinically meaningful adverse events while on corticosteroid therapy included bone fracture (5%), impaired glucose tolerance (5%), herpes zoster (3%), oral candidiasis (3%), and adrenal insufficiency (1%). The most common adverse reactions from alternate immunosuppressant use (N = 39) included hypomagnesemia (15%) and diarrhea (10%). Infections requiring intravenous antimicrobial therapy occurred in 3 (3%) patients while on corticosteroid or other immunosuppressant therapy (N = 97).

One case of autoimmune hepatitis was reported during third year follow-up in a patient with history of hepatitis C and steatohepatitis.

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 × 1013 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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

ROCTAVIAN is not intended for administration in women.

8.4 Pediatric Use

The safety and effectiveness of ROCTAVIAN in pediatric patients have not been established.

8.5 Geriatric Use

A single patient ≥ 65 years of age was treated with ROCATVIAN in clinical studies. Clinical studies of ROCTAVIAN did not include sufficient numbers of patients aged 65 and over to determine whether the efficacy or safety differs compared to younger patients.

8.6 Human Immunodeficiency Virus (HIV) Positive Patients

In clinical studies, 3 HIV infected patients have been 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.

A single HIV infected patient treated with ROCTAVIAN developed hepatocellular injury that subsequently resolved and was attributed to concomitant administration with antiretroviral drug efavirenz [see Drug Interactions (7.2)].

8.7 Factor VIII Inhibitors

The safety and effectiveness of ROCTAVIAN in patients with prior or active factor VIII inhibitors have not been established [see Clinical Pharmacology (12.6)]. Patients with active factor VIII inhibitors should not take ROCTAVIAN.

After administration of ROCTAVIAN, patients should be monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests [see Warnings and Precautions (5.4)].

8.8 Hepatic Impairment

The safety and effectiveness of ROCTAVIAN in patients with hepatic impairment has not been 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. No dose adjustments can be recommended for patients with hepatic impairment.

8.9 Renal Impairment

The safety and effectiveness of ROCTAVIAN in patients with renal impairment has not been established. No dose adjustments can be recommended for patients with renal impairment.

12.1 Mechanism of Action

Valoctocogene roxaparvovec-rvox is an 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, which results in the expression of hFVIII-SQ. The expressed hFVIII-SQ replaces the missing coagulation factor VIII needed for effective hemostasis.

12.2 Pharmacodynamics

Following ROCTAVIAN infusion, vector DNA is processed in vivo to form full-length, episomal transgenes that increase circulating hFVIII-SQ up to 5 years.

Liver samples from 5 patients in clinical studies collected 0.5-4.1 years post-dose were analyzed. Vector integration into human genomic DNA was observed in all samples. No preferential integration of the vector and no clonal outgrowth of cells as a result of vector integration was observed. ROCTAVIAN can also insert into DNA of other human body cells; vector insertion into parotid gland DNA samples without associated clinical manifestations was observed in one patient treated with ROCTAVIAN.

12.3 Pharmacokinetics

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ROCTAVIAN or of other adeno-associated virus-based gene therapy products.

In clinical studies, all patients receiving treatment were required to screen negative for anti-AAV5 antibodies and negative (< 0.6 BU) for factor VIII inhibitors in a Nijmegen modified Bethesda assay following a lifetime minimum of 150 exposure days to factor VIII replacement therapy [see Use in Specific Populations (8.7)]. Following infusion of ROCTAVIAN, all patients remained negative for factor VIII inhibitors.

All patients seroconverted to anti-AAV5 antibody positive within 8 weeks of administration. Anti-AAV5 total antibody titers peaked by 36 weeks after administration with mean (SD) values of 12,528,983 (32,427,817), and remained stable until the last time point tested, Week 168 with mean (SD) values of 3,673,038 (3,344,713).

ROCTAVIAN-treated patients were tested for cellular immune responses against the AAV5 capsid and the factor VIII transgene product using an IFN-γ ELISpot assay. AAV5 capsid-specific cellular immune responses were detected beginning at Week 2 following dose administration and often declined or reverted to negative over the first 52 weeks in the majority of patients with available data. Incidence peaked at Week 2 with 67 of 96 patients (70%) testing positive in the IFN-γ ELISpot assay. This declined to 17 of 74 patients (23%) at Week 26, and 10 of 60 patients (17%) at Week 52.

Factor VIII-specific cellular responses were detected in 81 of 123 (65.9%) patients, often sporadically at a single time point and reverting to negative in most patients.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been conducted to evaluate the effects of ROCTAVIAN on carcinogenesis.

To evaluate vector integration, host genomic DNA was isolated from liver tissues obtained from nonhuman primates at 13 and 26 weeks following intravenous administration of ROCTAVIAN at dose levels of up to 5.4 × 1013 vg/kg. Vector DNA was mostly detected in the form of episomal DNA that was not integrated into the host genome. Vector integration events were observed at low frequencies and distributed throughout the host genome with no indication of clonal enrichment or preference to particular chromosomal locations, including genes associated with oncogenesis in humans [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.2)].

Since ROCTAVIAN vector DNA was detected in testes of adult male mice for at least 6 months following a single intravenous administration at dose level of 2.1 × 1014 vg/kg [see Clinical Pharmacology (12.3)], the potential for vertical transmission to offspring was studied in Rag2-/- immunodeficient mice. A single intravenous administration of ROCTAVIAN at a dose level of 6.7 × 1013 vg/kg into male immunodeficient mice that were mated 37 days later with naïve female mice did not result in adverse effects on fertility rates, pregnancy rates, and litter sizes. Quantitative polymerase chain reaction (qPCR) evaluation of liver tissues from the F1 pups did not detect the vector DNA.

13.2 Animal Toxicology and/or Pharmacology

A single intravenous administration of up to 2.1 × 1014 vg/kg of ROCTAVIAN in immunocompetent male mice with intact coagulation (CD1 mice), followed by an observation period of up to 26 weeks, showed dose-dependent toxicities in the heart, lung, thymus, and epididymis. At dose levels of 6.5 × 1013 vg/kg and higher, histopathologic findings in the heart included minimal to moderate epicardial hemorrhage, myocardial necrosis, fibrosis, inflammation, and vascular/perivascular necrosis, minimal to mild mesothelial hypertrophy/hyperplasia, fibroplasia, myocardial atrophy, and vascular/perivascular mixed cell infiltrates. Lung findings included moderate to marked hemorrhage, minimal to mild edema, vascular/perivascular necrosis, and mesothelial hypertrophy. Additional ROCTAVIAN-related findings included mild fibrosis, hemorrhage, and pigmented macrophages in the epididymis, and moderate to marked hemorrhage and hypocellularity of the thymus. ROCTAVIAN-related mortality, adverse clinical observations, and changes in gross pathology were observed at dose levels of 6.5 × 1013 vg/kg and higher, and were associated with fibrosis, hemorrhage, and necrosis in the heart.

In a toxicology study conducted in adult male nonhuman primates with a duration of 3 months, single intravenous administration of ROCTAVIAN at dose levels of 1.6 × 1013 vg/kg and 5.4 × 1013 vg/kg resulted in a dose-dependent prolongation of activated partial thromboplastin time (APTT). The transient APTT prolongation in a subset of nonhuman primates was temporally associated with an immune response to hFVIII-SQ protein. At 3 months post-administration, histopathology findings included minimal to mild mononuclear/mixed infiltration in the lungs.

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 × 1013 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 × 1013 vector genomes (vg).

16.2 Storage and Handling

Pre-Infusion Assessments

Inform patients that prior to dosing ROCTAVIAN the following will be necessary:

• Blood tests to look for factor VIII inhibitors and detect antibodies to AAV5. If these tests are positive, the patient will not be a candidate for ROCTAVIAN [see Dosage and Administration (2) and Use in Special Populations (12.6)].
• Liver health assessments, which include measuring liver function tests, liver ultrasound, and elastography or laboratory assessments for assessing hepatic fibrosis. If these tests are abnormal, the patient may not be a good candidate for ROCTAVIAN [see Dosage and Administration (2)].
• Assessment for suitability for corticosteroids and/or other immunosuppressive therapy. Inform patients that they may receive corticosteroids and/or other immunosuppressive agents for an extended period of time and communicate any risks associated with these therapies. The baseline assessment for suitability for immunosuppression may deem that the patient is not a good candidate for immunosuppression and hence not a good candidate for ROCTAVIAN [see Dosage and Administration (2, 2.3)].

Adverse Reactions During and After Infusion

• Inform patients that infusion reactions including anaphylaxis have occurred. Patients will be monitored during and for at least 3 hours after infusion [see Warnings and Precautions (5.1)].
• Educate patients on possible symptoms of infusion reactions during and after infusion and advise them to immediately inform medical staff if they experience such a reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. When discharging the patient, provide instructions on actions in case of a new or recurrent reaction and when to seek medical attention.

Importance of Liver Enzyme and Factor VIII Level Monitoring

• ROCTAVIAN can cause elevation of certain liver enzymes. Elevation in liver enzymes may be associated with decrease in factor VIII activity [see Warnings and Precautions (5.2)].
• Weekly blood test will be required for at least 26 weeks for monitoring this. Monitoring beyond this time is usually less frequent but depends on clinical situation, prior laboratory test results, and ongoing treatment with corticosteroids or other immunosuppressive therapy. [see Dosage and Administration (2.3)].

Use of Factor VIII Concentrates/Hemostatic Agents after Treatment with ROCTAVIAN

• 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 [see Dosage and Administration (2.3)].
• Advise patients that not all patients may respond to ROCTAVIAN and that currently it is not possible to predict who will respond and how long the treatment response will continue. Counsel patients, as necessary, on when they may need to re-instate prophylactic use of factor VIII concentrates/hemostatic agents [see Dosage and Administration (2.3)].

Corticosteroid Regimen and Alternate Immunosuppression

• Inform patients undergoing corticosteroid treatment to adhere to the regimen and about potential adverse reactions and necessary precautions [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].
• Advise patients that treatment with immunosuppressive agents other than corticosteroids may be required in case of intolerance, or adverse event from or failure of corticosteroid therapy [see Dosage and Administration (2.3)].

Hepatic Health

• Advise patients on how to maintain or improve hepatic health. Advise patients that they should abstain from consuming alcohol for at least one year after treatment and how much alcohol may be acceptable for them in the longer term [see Warnings and Precautions (5.2)].
• Advise patients not to use any medications, herbal products, or supplements without first confirming with a health professional that they are not hepatotoxic. Instruct patients that they or their healthcare professional contact you if use of a hepatotoxic agent appears unavoidable, to discuss potential alternatives and any implications for patient monitoring i.e., more frequent monitoring of liver enzymes and factor VIII activity may be needed [see Warnings and Precautions (5.2) and Drug Interactions (7)].

Thromboembolic Events

• Inform patients that elevated factor VIII activity above the upper limit of normal has occurred following ROCTAVIAN administration. Elevated factor VIII activity above the upper limit of normal may increase the risk of a thromboembolic event [see Warnings and Precautions (5.3)].
• As necessary, advise patients of their risk factors for thrombotic events and general cardiovascular risk factors, how to minimize their risk, how to recognize a thrombotic event and to seek immediate medical attention if they observe signs or symptoms that can indicate a thrombotic event [see Warnings and Precautions (5.3)].

Contraception and Semen Donation

• Advise patients that, after a male patient has been treated with ROCTAVIAN, the patient and/or his female partner must avoid pregnancy for a period of 6 months, and that male patients must not donate semen for a period of 6 months [see Use in Specific Populations (8.3)].
• Instruct patients on acceptable methods of contraception.

Blood, Organ, Tissue and Cell Donation

• Advise patients not to donate blood, organs, tissues, and cells for transplantation after treatment with ROCTAVIAN.

Repeat Treatment and Impact on Receiving Other AAV Gene Therapies

• Advise patients that ROCTAVIAN is a one-time treatment. Currently, treatment with ROCTAVIAN precludes the patient from receiving another gene therapy for hemophilia.

Malignancy

• Inform patients that since ROCTAVIAN is a liver-directed AAV therapy, there may be a theoretical risk of hepatocellular carcinoma. Patients with risk factors for hepatocellular carcinoma should be monitored regularly for 5 years with regular ultrasound and blood tests (alpha-fetoprotein). No malignancies assessed as being likely related to ROCTAVIAN treatment have been reported in clinical trials. Since the vector can insert into DNA of any cell, other malignancies may also occur [see Warnings and Precautions (5.5)].
• Advise patients to contact BioMarin Pharmaceutical Inc. (1-866-906-6100) if they are diagnosed with any malignancy [see Warnings and Precautions (5.5)].

Long-Term Follow-Up

• Inform patients that they should be enrolled in a 15-year registry to evaluate the long-term efficacy and safety of hemophilia treatments.