Data from FDA - Curated by EPG Health - Last updated 12 April 2018

Indication(s)

1 INDICATIONS AND USAGE OCREVUS is indicated for the treatment of adult patients with relapsing or primary progressive forms of multiple sclerosis. OCREVUS is a CD20-directed cytolytic antibody indicated for the treatment of patients with relapsing or primary progressive forms of multiple sclerosis (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS OCREVUS is contraindicated in patients with: Active HBV infection [see Dosage and Administration (2.6) and Warnings and Precautions (5.2)] A history of life-threatening infusion reaction to OCREVUS [see Warnings and Precautions (5.1)] Active hepatitis B virus infection (4) History of life-threatening infusion reaction to OCREVUS (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Infusion Reactions [see Warnings and Precautions (5.1)] Infections [see Warnings and Precautions (5.2)] Malignancies [see Warnings and Precautions (5.3)] The most common adverse reactions were: RMS (incidence ≥10% and > REBIF): upper respiratory tract infections and infusion reactions (6.1) PPMS (incidence ≥10% and > placebo): upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions 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 clinical practice. The safety of OCREVUS has been evaluated in 1311 patients across MS clinical studies, which included 825 patients in active-controlled clinical trials in patients with relapsing forms of MS (RMS) and 486 patients in a placebo-controlled study in patients with primary progressive MS (PPMS). Adverse Reactions in Patients with Relapsing Forms of MS In active-controlled clinical trials (Study 1 and Study 2), 825 patients with RMS received OCREVUS 600 mg intravenously every 24 weeks (initial treatment was given as two separate 300 mg infusions at Weeks 0 and 2) [see Clinical Studies (14.1)]. The overall exposure in the 96-week controlled treatment periods was 1448 patient-years. The most common adverse reactions in RMS trials (incidence ≥ 10%) were upper respiratory tract infections and infusion reactions. Table 2 summarizes the adverse reactions that occurred in RMS trials (Study 1 and Study 2). Table 2 Adverse Reactions in Adult Patients with RMS with an Incidence of at least 5% for OCREVUS and Higher than REBIF Adverse Reactions Studies 1 and 2 OCREVUS 600 mg IV Every 24 WeeksThe first dose was given as two separate 300 mg infusions at Weeks 0 and 2. (n=825) % REBIF 44 mcg SQ 3 Times per Week (n=826) % Upper respiratory tract infections 40 33 Infusion reactions 34 10 Depression 8 7 Lower respiratory tract infections 8 5 Back pain 6 5 Herpes virus- associated infections 6 4 Pain in extremity 5 4 Adverse Reactions in Patients with Primary Progressive MS In a placebo-controlled clinical trial (Study 3), a total of 486 patients with PPMS received one course of OCREVUS (600 mg of OCREVUS administered as two 300 mg infusions two weeks apart) given intravenously every 24 weeks and 239 patients received placebo intravenously [see Clinical Studies (14.2)]. The overall exposure in the controlled treatment period was 1416 patient-years, with median treatment duration of 3 years. The most common adverse reactions in the PPMS trial (incidence ≥ 10%) were upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections. Table 3 summarizes the adverse reactions that occurred in the PPMS trial (Study 3). Table 3 Adverse Reactions in Adult Patients with PPMS with an Incidence of at least 5% for OCREVUS and Higher than Placebo Adverse Reactions Study 3 OCREVUS 600 mg IV Every 24 WeeksOne dose of OCREVUS (600 mg administered as two 300 mg infusions two weeks apart) Placebo (n=486) % (n=239) % Upper respiratory tract infections 49 43 Infusion reactions 40 26 Skin infections 14 11 Lower respiratory tract infections 10 9 Cough 7 3 Diarrhea 6 5 Edema peripheral 6 5 Herpes virus associated infections 5 4 Laboratory Abnormalities Decreased Immunoglobulins OCREVUS decreased total immunoglobulins with the greatest decline seen in IgM levels. In MS clinical trials, there was no apparent association between immunoglobulin decrease and risk for serious infections. In the active-controlled (RMS) trials (Study 1 and Study 2), the proportion of patients at baseline reporting IgG, IgA, and IgM below the lower limit of normal (LLN) in OCREVUS-treated patients was 0.5%, 1.5%, and 0.1%, respectively. Following treatment, the proportion of OCREVUS-treated patients reporting IgG, IgA, and IgM below the LLN at 96 weeks was 1.5%, 2.4%, and 16.5%, respectively. In the placebo-controlled (PPMS) trial (Study 3), the proportion of patients at baseline reporting IgG, IgA, and IgM below the LLN in OCREVUS-treated patients was 0.0%, 0.2%, and 0.2%, respectively. Following treatment, the proportion of OCREVUS-treated patients reporting IgG, IgA, and IgM below the LLN at 120 weeks was 1.1%, 0.5%, and 15.5%, respectively. Decreased Neutrophil Levels In the PPMS clinical trial (Study 3), decreased neutrophil counts occurred in 13% of OCREVUS-treated patients compared to 10% in placebo patients. The majority of the decreased neutrophil counts were only observed once for a given patient treated with OCREVUS and were between LLN - 1.5 × 109/L and 1.0 × 109/L. Overall, 1% of the patients in the OCREVUS group had neutrophil counts less than 1.0 × 109/L and these were not associated with an infection. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to OCREVUS with the incidence of antibodies to other products may be misleading. Patients in MS trials (Study 1, Study 2, and Study 3) were tested at multiple time points (baseline and every 6 months post-treatment for the duration of the trial) for anti-drug antibodies (ADAs). Out of 1311 patients treated with OCREVUS, 12 (~1%) tested positive for ADAs, of which 2 patients tested positive for neutralizing antibodies. These data are not adequate to assess the impact of ADAs on the safety and efficacy of OCREVUS.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Hepatitis B virus screening is required before the first dose (2.1) Pre-medicate with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion (2.2) Administer OCREVUS by intravenous infusion Start dose: 300 mg intravenous infusion, followed two weeks later by a second 300 mg intravenous infusion (2.3) Subsequent doses: 600 mg intravenous infusion every 6 months (2.3) Must be diluted prior to administration (2.3, 2.6) Monitor patients closely during and for at least one hour after infusion (2.3, 2.5) 2.1 Assessments Prior to First Dose of OCREVUS Hepatitis B Virus Screening Prior to initiating OCREVUS, perform Hepatitis B virus (HBV) screening. OCREVUS is contraindicated in patients with active HBV confirmed by positive results for HBsAg and anti-HBV tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment [see Warnings and Precautions (5.2)]. Vaccinations Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all necessary immunizations according to immunization guidelines at least 6 weeks prior to initiation of OCREVUS [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)]. 2.2 Preparation Before Every Infusion Infection Assessment Prior to every infusion of OCREVUS, determine whether there is an active infection. In case of active infection, delay infusion of OCREVUS until the infection resolves [see Warnings and Precautions (5.2)]. Recommended Premedication Pre-medicate with 100 mg of methylprednisolone (or an equivalent corticosteroid) administered intravenously approximately 30 minutes prior to each OCREVUS infusion to reduce the frequency and severity of infusion reactions [see Warnings and Precautions (5.1)]. Pre-medicate with an antihistamine (e.g., diphenhydramine) approximately 30-60 minutes prior to each OCREVUS infusion to further reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered. 2.3 Recommended Dosage and Dose Administration Administer OCREVUS under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions such as serious infusion reactions. Initial dose: 300 mg intravenous infusion, followed two weeks later by a second 300 mg intravenous infusion. Subsequent doses: single 600 mg intravenous infusion every 6 months. Observe the patient for at least one hour after the completion of the infusion [see Warnings and Precautions (5.1)]. Table 1 Recommended Dose, Infusion Rate, and Infusion Duration for RMS and PPMS Amount and VolumeSolutions of OCREVUS for intravenous infusion are prepared by dilution of the drug product into an infusion bag containing 0.9% Sodium Chloride Injection, to a final drug concentration of approximately 1.2 mg/mL. Infusion Rate and DurationInfusion time may take longer if the infusion is interrupted or slowed [see Dosage and Administration (2.5)]. Initial Dose (two infusions) Infusion 1 300 mg in 250 mL Start at 30 mL per hour Increase by 30 mL per hour every 30 minutes Maximum: 180 mL per hour Duration: 2.5 hours or longer Infusion 2 (2 weeks later) 300 mg in 250 mL Subsequent Doses (one infusion) One infusion every 6 monthsAdminister the first Subsequent Dose 6 months after Infusion 1 of the Initial Dose. 600 mg in 500 mL Start at 40 mL per hour Increase by 40 mL per hour every 30 minutes Maximum: 200 mL per hour Duration: 3.5 hours or longer 2.4 Delayed or Missed Doses If a planned infusion of OCREVUS is missed, administer OCREVUS as soon as possible; do not wait until the next scheduled dose. Reset the dose schedule to administer the next sequential dose 6 months after the missed dose is administered. Doses of OCREVUS must be separated by at least 5 months [see Dosage and Administration (2.3)]. 2.5 Dose Modifications Because of Infusion Reactions Dose modifications in response to infusion reactions depends on the severity. Life-threatening Infusion Reactions Immediately stop and permanently discontinue OCREVUS if there are signs of a life-threatening or disabling infusion reaction [see Warnings and Precautions (5.1)]. Provide appropriate supportive treatment. Severe Infusion Reactions Immediately interrupt the infusion and administer appropriate supportive treatment, as necessary [see Warnings and Precautions (5.1)]. Restart the infusion only after all symptoms have resolved. When restarting, begin at half of the infusion rate at the time of onset of the infusion reaction [see Dosage and Administration (2.2)]. If this rate is tolerated, increase the rate as described in Table 1. This change in rate will increase the total duration of the infusion but not the total dose. Mild to Moderate Infusion Reactions Reduce the infusion rate to half the rate at the onset of the infusion reaction and maintain the reduced rate for at least 30 minutes [see Warnings and Precautions (5.1)]. If this rate is tolerated, increase the rate as described in Table 1. This change in rate will increase the total duration of the infusion but not the total dose. 2.6 Preparation and Storage of the Dilute Solution for Infusion Preparation OCREVUS must be prepared by a healthcare professional using aseptic technique. Visually inspect for particulate matter and discoloration prior to administration. Do not use the solution if discolored or if the solution contains discrete foreign particulate matter. Do not shake. Withdraw intended dose and further dilute into an infusion bag containing 0.9% Sodium Chloride Injection, to a final drug concentration of approximately 1.2 mg/mL. Withdraw 10 mL (300 mg) of OCREVUS and inject into 250 mL Withdraw 20 mL (600 mg) of OCREVUS and inject into 500 mL Do not use other diluents to dilute OCREVUS since their use has not been tested. The product contains no preservative and is intended for single use only. Storage of Infusion Solution Prior to the start of the intravenous infusion, the content of the infusion bag should be at room temperature. Use the prepared infusion solution immediately. If not used immediately, store up to 24 hours in the refrigerator at 2°C–8°C (36°F–46°F) and 8 hours at room temperature up to 25°C (77°F), which includes infusion time. In the event an intravenous infusion cannot be completed the same day, discard the remaining solution. No incompatibilities between OCREVUS and polyvinyl chloride (PVC) or polyolefin (PO) bags and intravenous (IV) administration sets have been observed. Administration Administer the diluted infusion solution through a dedicated line using an infusion set with a 0.2 or 0.22 micron in-line filter.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with use of OCREVUS in pregnant women. There are no data on B-cell levels in human neonates following maternal exposure to OCREVUS. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. OCREVUS is a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier. Following administration of ocrelizumab to pregnant monkeys at doses similar to or greater than those used clinically, increased perinatal mortality, depletion of B-cell populations, renal, bone marrow, and testicular toxicity were observed in the offspring in the absence of maternal toxicity [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Following intravenous administration of OCREVUS to monkeys during organogenesis (loading doses of 15 or 75 mg/kg on gestation days 20, 21, and 22, followed by weekly doses of 20 or 100 mg/kg), depletion of B-lymphocytes in lymphoid tissue (spleen and lymph nodes) was observed in fetuses at both doses. Intravenous administration of OCREVUS (three daily loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) to pregnant monkeys throughout the period of organogenesis and continuing through the neonatal period resulted in perinatal deaths (some associated with bacterial infections), renal toxicity (glomerulopathy and inflammation), lymphoid follicle formation in the bone marrow, and severe decreases in circulating B-lymphocytes in neonates. The cause of the neonatal deaths is uncertain; however, both affected neonates were found to have bacterial infections. Reduced testicular weight was observed in neonates at the high dose. A no-effect dose for adverse developmental effects was not identified; the doses tested in monkey are 2 and 10 times the recommended human dose of 600 mg, on a mg/kg basis. 8.2 Lactation Risk Summary There are no data on the presence of ocrelizumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Ocrelizumab was excreted in the milk of ocrelizumab-treated monkeys. Human IgG is excreted in human milk, and the potential for absorption of ocrelizumab to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for OCREVUS and any potential adverse effects on the breastfed infant from OCREVUS or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception Women of childbearing potential should use contraception while receiving OCREVUS and for 6 months after the last infusion of OCREVUS [see Clinical Pharmacology (12.3)]. 8.4 Pediatric Use Safety and effectiveness of OCREVUS in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of OCREVUS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Interactions

7 DRUG INTERACTIONS 7.1 Immunosuppressive or Immune-Modulating Therapies The concomitant use of OCREVUS and other immune-modulating or immunosuppressive therapies, including immunosuppressant doses of corticosteroids, is expected to increase the risk of immunosuppression. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with OCREVUS. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, consider the duration and mode of action of these drugs because of additive immunosuppressive effects when initiating OCREVUS [see Warnings and Precautions (5.2)].

More information

Category Value
Authorisation number BLA761053
Agency product number A10SJL62JY
Orphan designation No
Product NDC 50242-150
Date Last Revised 21-11-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1876380
Storage and handling Store OCREVUS vials at 2°C–8°C (36°F–46°F) in the outer carton to protect from light. Do not freeze or shake.
Marketing authorisation holder Genentech, Inc.