HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`OCREVUS safely and effectively. See full prescribing information for
`OCREVUS.
`
`
`OCREVUSTM (ocrelizumab) injection, for intravenous use
`
`Initial U.S. Approval: 2017
`
`
`--------------------------- INDICATIONS AND USAGE ----------------------------
`
`OCREVUS is a CD20-directed cytolytic antibody indicated for the treatment
`of patients with relapsing or primary progressive forms of multiple sclerosis
`(1)
`
` ----------------------- 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
`o Start dose: 300 mg intravenous infusion, followed two weeks later by a
`
`
`
`second 300 mg intravenous infusion (2.3)
`o 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)
`
`
`
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS -----------------------
`
` Infusion reactions: Management recommendations for infusion reactions
`depend on the type and severity of the reaction. Permanently discontinue
`
`OCREVUS if a life-threatening or disabling infusion reaction occurs (2.3,
`
`5.1)
`
` Infections: Delay OCREVUS administration in patients with an active
`infection until the infection is resolved. Vaccination with live-attenuated or
`live vaccines is not recommended during treatment with OCREVUS and
`after discontinuation, until B-cell repletion (5.2)
`
`
` Malignancies: An increased risk of malignancy, including breast cancer,
`may exist with OCREVUS (5.3)
`
`
`
`
` ------------------------------ ADVERSE REACTIONS ------------------------------
`
`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)
`
`
`Revised: 3/2017
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
`
`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`
` Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS----------------------
`
`
` Injection: 300 mg/10 mL (30 mg/mL) in a single-dose vial. (3)
`
`
`
` ------------------------------ CONTRAINDICATIONS ------------------------------
`
` Active hepatitis B virus infection (4)
`
`
` History of life-threatening infusion reaction to OCREVUS (4)
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`8.1 Pregnancy
`
`
`
`
`8.2 Lactation
`1
`INDICATIONS AND USAGE
`
`
`
`
`8.3 Females and Males of Reproductive Potential
`2 DOSAGE AND ADMINISTRATION
`
`
`
`8.4 Pediatric Use
`2.1 Assessments Prior to First Dose of OCREVUS
`
`
`
`8.5 Geriatric Use
`
`2.2 Preparation Before Every Infusion
`
`
`
`2.3 Recommended Dosage and Dose Administration
`11 DESCRIPTION
`
`
`
`2.4 Delayed or Missed Doses
`12 CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`2.5 Dose Modifications Because of Infusion Reactions
`
`
`
`
`12.2 Pharmacodynamics
`2.6 Preparation and Storage of the Dilute Solution for Infusion
`
`
`
`
`12.3 Pharmacokinetics
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`13 NONCLINICAL TOXICOLOGY
`4 CONTRAINDICATIONS
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1
`Infusion Reactions
`14 CLINICAL STUDIES
`
`
`
`14.1 Relapsing Forms of Multiple Sclerosis (RMS)
`5.2
`Infections
`
`
`
`
`14.2 Primary Progressive Multiple Sclerosis (PPMS)
`5.3 Malignancies
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`17 PATIENT COUNSELING INFORMATION
`
`
`6.2
`Immunogenicity
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`7 DRUG INTERACTIONS
`
`listed
`7.1
`Immunosuppressive or Immune-Modulating Therapies
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`Reference ID: 4076448
`
`Biogen Exhibit 2173
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 18
`
`

`

`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`
`OCREVUS is indicated for the treatment of adult patients with relapsing or primary progressive forms of
`
`multiple sclerosis.
`DOSAGE AND ADMINISTRATION
`2
`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)].
`
`
`
`
`
`Reference ID: 4076448
`
`Page 2 of 18
`
`

`

`Table 1
`
`
`Recommended Dose, Infusion Rate, and Infusion Duration for RMS and PPMS
`
`Amount and Volume1
`
`
`
` Infusion Rate and Duration3
`
` Initial Dose
`
` (two infusions)
`
`
`Infusion 1
`
`Infusion 2
`(2 weeks later)
`
`Subsequent
`Doses
`(one infusion)
`
`
`One infusion
`every 6
` months2
`
`
` 300 mg
`
`
` in 250 mL
`
`300 mg
`
`
` in 250 mL
`
`600 mg
`
`
` in 500 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
`
`
` 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
`
`1 Solutions 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.
`
`
`2 Administer the first Subsequent Dose 6 months after Infusion 1 of the Initial Dose.
`
`3 Infusion time may take longer if the infusion is interrupted or slowed [see Dosage and Administration (2.5)].
`
`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.
`
`
`Reference ID: 4076448
`
`Page 3 of 18
`
`

`

`
`
`  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.
`DOSAGE FORMS AND STRENGTHS
`3
`
`Injection: 300 mg/10 mL (30 mg/mL) clear or slightly opalescent, and colorless to pale brown solution in a
`single-dose vial.
`
`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)]
`
`
`5 WARNINGS AND PRECAUTIONS
`
`Infusion Reactions
`5.1
`OCREVUS can cause infusion reactions, which can include pruritus, rash, urticaria, erythema, bronchospasm,
`throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia,
`
`fatigue, headache, dizziness, nausea, and tachycardia. In multiple sclerosis (MS) clinical trials, the incidence of
`infusion reactions in OCREVUS-treated patients [who received methylprednisolone (or an equivalent steroid)
`
`and possibly other pre-medication to reduce the risk of infusion reactions prior to each infusion] was 34 to 40%,
`with the highest incidence with the first infusion. There were no fatal infusion reactions, but 0.3% of
`
`OCREVUS-treated MS patients experienced infusion reactions that were serious, some requiring hospitalization.
`
`Observe patients treated with OCREVUS for infusion reactions during the infusion and for at least one hour
`after completion of the infusion. Inform patients that infusion reactions can occur up to 24 hours after the
`infusion.
`
`Reducing the Risk of Infusion Reactions and Managing Infusion Reactions
`Administer pre-medication (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to
`
`reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen)
`may also be considered [see Dosage and Administration (2.3)].
`
`
`
`
`Reference ID: 4076448
`
`Page 4 of 18
`
`

`

` Management recommendations for infusion reactions depend on the type and severity of the reaction [see
`
`Dosage and Administration (2.5)]. For life-threatening infusion reactions, immediately and permanently stop
`OCREVUS and administer appropriate supportive treatment. For less severe infusion reactions, management
`
` may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic
`
` treatment.
` Infections
`5.2
`
`A higher proportion of OCREVUS-treated patients experienced infections compared to patients taking REBIF
`or placebo. In RMS trials, 58% of OCREVUS-treated patients experienced one or more infections compared to
`52% of REBIF-treated patients. In the PPMS trial, 70% of OCREVUS-treated patients experienced one or more
`infections compared to 68% of patients on placebo. OCREVUS increased the risk for upper respiratory tract
`infections, lower respiratory tract infections, skin infections, and herpes-related infections [see Adverse
`Reactions (6.1)]. OCREVUS was not associated with an increased risk of serious infections in MS patients.
`
`Delay OCREVUS administration in patients with an active infection until the infection is resolved.
`
` Respiratory Tract Infections
`A higher proportion of OCREVUS-treated patients experienced respiratory tract infections compared to patients
`taking REBIF or placebo. In RMS trials, 40% of OCREVUS-treated patients experienced upper respiratory tract
`infections compared to 33% of REBIF-treated patients, and 8% of OCREVUS-treated patients experienced
`
`lower respiratory tract infections compared to 5% of REBIF-treated patients. In the PPMS trial, 49% of
`OCREVUS-treated patients experienced upper respiratory tract infections compared to 43% of patients on
`
`
`placebo and 10% of OCREVUS-treated patients experienced lower respiratory tract infections compared to 9%
`of patients on placebo. The infections were predominantly mild to moderate and consisted mostly of upper
`
`respiratory tract infections and bronchitis.
`
`Herpes
`In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in OCREVUS-
`treated patients than in REBIF-treated patients, including herpes zoster (2.1% vs. 1.0%), herpes simplex (0.7%
`vs. 0.1%), oral herpes (3.0% vs. 2.2%), genital herpes (0.1% vs. 0%), and herpes virus infection (0.1% vs. 0%).
`Infections were predominantly mild to moderate in severity. There were no reports of disseminated herpes.
`In the placebo-controlled (PPMS) clinical trial, oral herpes was reported more frequently in the OCREVUS-
`treated patients than in the patients on placebo (2.7% vs 0.8%).
`Progressive Multifocal Leukoencephalopathy (PML)
`PML is an opportunistic viral infection of the brain caused by the John Cunningham (JC) virus that typically only
`
`
`occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no
`cases of PML were identified in OCREVUS clinical trials, JC virus infection resulting in PML has been
`observed in patients treated with other anti-CD20 antibodies and other MS therapies and has been associated
`with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). At the first
`
`sign or symptom suggestive of PML, withhold OCREVUS and perform an appropriate diagnostic evaluation. MRI
`
`
`findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse,
`
`progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs,
`
`disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality
`
`
`changes.
`
`Hepatitis B Virus (HBV) Reactivation
`There were no reports of hepatitis B reactivation in MS patients treated with OCREVUS. Fulminant hepatitis,
`
`hepatic failure, and death caused by HBV reactivation have occurred in patients treated with other anti-CD20
`antibodies. Perform HBV screening in all patients before initiation of treatment with OCREVUS. Do not
`
`administer OCREVUS to patients with active HBV confirmed by positive results for HBsAg and anti-HB tests.
`
`
`
`Reference ID: 4076448
`
`Page 5 of 18
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`

`

`
`
`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.
`Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants
`When initiating OCREVUS after an immunosuppressive therapy or initiating an immunosuppressive therapy
`after OCREVUS, consider the potential for increased immunosuppressive effects [see Drug Interactions (7.1)
`and Clinical Pharmacology (12.1, 12.2)]. OCREVUS has not been studied in combination with other MS
`
` therapies.
` Vaccinations
`
` Administer all immunizations according to immunization guidelines at least 6 weeks prior to initiation of
`
` OCREVUS.
`The safety of immunization with live or live-attenuated vaccines following OCREVUS therapy has not been
`studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-
`cell repletion [see Clinical Pharmacology (12.2)].
`No data are available on the effects of live or non-live vaccination in patients receiving OCREVUS.
`5.3 Malignancies
`
` An increased risk of malignancy with OCREVUS may exist. In controlled trials, malignancies, including breast
`
` cancer, occurred more frequently in OCREVUS-treated patients. Breast cancer occurred in 6 of 781 females
`treated with OCREVUS and none of 668 females treated with REBIF or placebo. Patients should follow
`
`standard breast cancer screening guidelines.
`
`
`ADVERSE REACTIONS
`6
`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)]
`
`
`
`
`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
`
`
`
`
`Reference ID: 4076448
`
`Page 6 of 18
`
`

`

`
`
`
`Adverse Reactions
`
`
`Studies 1 and 2
`OCREVUS
`
`600 mg IV
`Every 24 Weeks1
`(n=825)
`%
`40
`34
`8
`8
`6
`6
`5
`
`REBIF
`
`44 mcg SQ
`3 Times per Week
`(n=826)
`%
`33
`10
`7
`5
`5
`4
`4
`
`Upper respiratory tract infections
`
`Infusion reactions
`Depression
`Lower respiratory tract infections
`Back pain
`Herpes virus- associated infections
`
`Pain in extremity
` 1 The first dose was given as two separate 300 mg infusions at Weeks 0 and 2.
`
` 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
`
`
`
`Study 3
`
` Placebo
`OCREVUS
`
`600 mg IV
`
`Every 24
`Weeks1
`
`
`(n=239)
`(n=486)
`%
`%
`
`49
`43
`Upper respiratory tract infections
`
`40
`26
`Infusion reactions
`14
`11
`Skin infections
`10
`9
`Lower respiratory tract infections
`7
`3
`Cough
`
`6
`5
`Diarrhea
`6
`5
`Edema peripheral
`
`5
`4
`Herpes virus associated infections
` 1 One dose of OCREVUS (600 mg administered as two 300 mg infusions two weeks apart)
`
`
`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.
`
`
`
`
`
`
`Adverse Reactions
`
`
`
`
`Reference ID: 4076448
`
`Page 7 of 18
`
`

`

`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 x 109/L and 1.0 x 109/L.
`
` Overall, 1% of the patients in the OCREVUS group had neutrophil counts less than 1.0 x 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.
`
`7
`DRUG INTERACTIONS
`
`Immunosuppressive or Immune-Modulating Therapies
`7.1
`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)].
`
`8
`USE IN SPECIFIC POPULATIONS
`
`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].
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`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.
`
`11 DESCRIPTION
`Ocrelizumab is a recombinant humanized monoclonal antibody directed against CD20-expressing B-cells.
`Ocrelizumab is a glycosylated immunoglobulin G1 (IgG1) with a molecular mass of approximately 145 kDa.
`OCREVUS (ocrelizumab) Injection for intravenous infusion is a preservative-free, sterile, clear or slightly
`opalescent, and colorless to pale brown solution supplied in single-dose vials. Each mL of solution contains 30
`mg ocrelizumab, glacial acetic acid (0.25 mg), polysorbate 20 (0.2 mg), sodium acetate trihydrate (2.14 mg),
`and trehalose dihydrate (40 mg) at pH 5.3.
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` 12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`The precise mechanism by which ocrelizumab exerts its therapeutic effects in multiple sclerosis is unknown, but
`is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes.
`Following cell surface binding to B lymphocytes, ocrelizumab results in antibody-dependent cellular cytolysis
`and complement-mediated lysis.
`
` 12.2 Pharmacodynamics
`For B-cell counts, assays for CD19+ B-cells are used because the presence of OCREVUS interferes with the
`CD20 assay. Treatment with OCREVUS reduces CD19+ B-cell counts in blood by 14 days after infusion. In
`clinical studies, B-cell counts rose to above the lower limit of normal (LLN) or above baseline counts between
`
` infusions of OCREVUS at least one time in 0.3% to 4.1% of patients. In a clinical study of 51 patients, the
` median time for B-cell counts to return to either baseline or LLN was 72 weeks (range 27-175 weeks) after the
`
`last OCREVUS infusion. Within 2.5 years after the last infusion, B-cell counts rose to either baseline or LLN
`in 90% of patients.
` 12.3 Pharmacokinetics
`
`Pharmacokinetics (PK) of OCREVUS in MS clinical studies fit a two compartment model with time-dependent
`
` clearance. The overall exposure at the steady-state (AUC over the 24 week dosing intervals) of OCREVUS was
`3,510 mcg/mL per day. In clinical studies in MS patients, maintenance doses of ocrelizumab were either
`
`600 mg every 6 months (RMS patients) or two 300 mg infusions separated by 14 days every 6 months (PPMS
`patients). The mean maximum concentration was 212 mcg/mL in patients with RMS (600 mg infusion) and 141
`mcg/mL in patients with PPMS (two 300 mg infusions administered within two weeks). The pharmacokinetics
`of ocrelizumab was essentially linear and dose proportional between 400 mg and 2000 mg.
`
`Distribution
`The population PK estimate of the central volume of distribution was 2.78 L. Peripheral volume and inter-
`compartment clearance were estimated at 2.68 L and 0.29 L/day, respectively.
`
`Elimination
`Constant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at 0.05 L/day, which
`
`declined with a half-life of 33