Ocrevus

OCREVUS is indicated for the treatment of:

• Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults
• Primary progressive MS, in adults

• Before initiating OCREVUS, screen for Hepatitis B virus and obtain serum quantitative immunoglobulins, aminotransferases, alkaline phosphatase, and bilirubin (
  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)]

  .

  Serum Immunoglobulins

  
  
  Prior to initiating OCREVUS, perform testing for quantitative serum immunoglobulins

  [see Warnings and Precautions (5.4)]

  . For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with OCREVUS.

  Vaccinations

  Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of OCREVUS for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of OCREVUS for non-live vaccines

  [see Warnings and Precautions (5.2)and Clinical Pharmacology (12.2)]

  .

  Liver Function Tests

  Prior to initiating OCREVUS, obtain serum aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), alkaline phosphatase, and bilirubin levels

  [see Warnings and Precautions (5.7)]

  .
  )
• Pre-medicate with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion (
  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.
  )
• Administer OCREVUS by intravenous infusion
  • Start dose: 300 mg intravenous infusion, followed two weeks later by a second 300 mg intravenous infusion (
    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) every 6 months)Administer the first Subsequent Dose 6 months after Infusion 1 of the Initial Dose.	Option 1 Infusion of approximately 3.5 hours duration	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
    	OR
    	Option 2 (If no prior serious infusion reaction with any previous OCREVUS infusion) [see Adverse Reactions (6.1)and Clinical Studies (14.3)] . Infusion of approximately 2 hours duration	600 mg in 500 mL	Start at 100 mL per hour for the first 15 minutes Increase to 200 mL per hour for the next 15 minutes Increase to 250 mL per hour for the next 30 minutes Increase to 300 mL per hour for the remaining 60 minutes Duration: 2 hours or longer
    )
  • Subsequent doses: 600 mg intravenous infusion every 6 months (
    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) every 6 months)Administer the first Subsequent Dose 6 months after Infusion 1 of the Initial Dose.	Option 1 Infusion of approximately 3.5 hours duration	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
    	OR
    	Option 2 (If no prior serious infusion reaction with any previous OCREVUS infusion) [see Adverse Reactions (6.1)and Clinical Studies (14.3)] . Infusion of approximately 2 hours duration	600 mg in 500 mL	Start at 100 mL per hour for the first 15 minutes Increase to 200 mL per hour for the next 15 minutes Increase to 250 mL per hour for the next 30 minutes Increase to 300 mL per hour for the remaining 60 minutes Duration: 2 hours or longer
    )
• Must be diluted prior to administration (
  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) every 6 months)Administer the first Subsequent Dose 6 months after Infusion 1 of the Initial Dose.	Option 1 Infusion of approximately 3.5 hours duration	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
  	OR
  	Option 2 (If no prior serious infusion reaction with any previous OCREVUS infusion) [see Adverse Reactions (6.1)and Clinical Studies (14.3)] . Infusion of approximately 2 hours duration	600 mg in 500 mL	Start at 100 mL per hour for the first 15 minutes Increase to 200 mL per hour for the next 15 minutes Increase to 250 mL per hour for the next 30 minutes Increase to 300 mL per hour for the remaining 60 minutes Duration: 2 hours or longer
  ,
  2.6 Preparation and Storage of the Dilute Solution for Infusion

  Preparation

  OCREVUS must be prepared by a healthcare professional using aseptic technique. A sterile needle and syringe should be used to prepare the diluted infusion solution.

  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 to 8°C (36°F to 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.
  )
• Monitor patients closely during and for at least one hour after infusion (
  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) every 6 months)Administer the first Subsequent Dose 6 months after Infusion 1 of the Initial Dose.	Option 1 Infusion of approximately 3.5 hours duration	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
  	OR
  	Option 2 (If no prior serious infusion reaction with any previous OCREVUS infusion) [see Adverse Reactions (6.1)and Clinical Studies (14.3)] . Infusion of approximately 2 hours duration	600 mg in 500 mL	Start at 100 mL per hour for the first 15 minutes Increase to 200 mL per hour for the next 15 minutes Increase to 250 mL per hour for the next 30 minutes Increase to 300 mL per hour for the remaining 60 minutes Duration: 2 hours or longer
  ,
  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. If this rate is tolerated, increase the rate as described in Table 1

  [see Dosage and Administration (2.3)]

  . 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

  [see Dosage and Administration (2.3)]

  . This change in rate will increase the total duration of the infusion but not the total dose.
  )

Injection: 300 mg/10 mL (30 mg/mL) clear or slightly opalescent, and colorless to pale brown solution in a single-dose vial.

• Pregnancy: Based on animal data, may cause fetal harm (
  8.1 Pregnancy

  Risk Summary

  OCREVUS is a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier. There are no adequate data on the developmental risk associated with use of OCREVUS in pregnant women. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. B-cell levels in infants following maternal exposure to OCREVUS have not been studied in clinical trials. The potential duration of B-cell depletion in such infants, and the impact of B-cell depletion on vaccine safety and effectiveness, is unknown

  [see Warnings and Precautions (5.2)]

  .

  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.
  )