Ocrevus

>10%

Upper respiratory tract infections (40-49%)

Infusion-related reactions (34-40%)

Skin infections (14%)

Decreased neutrophil counts (13%)

1-10%

Lower respiratory tract infections (8-10%)

Depression (8%) Cough (7%)

Back pain (6%)

Herpes virus-associated infections (5-6%)

Diarrhea (6%)

Peripheral edema (6%)

Pain in extremity (5%)

IV Compatibilities

0.9% NaCl

Polyvinyl chloride (PVC) bags and IV sets

Polyolefin (PO) bags and IV sets

IV Preparation

Visually inspect vial for particulate matter and discoloration; do not use if solution is discolored or contains discrete foreign particulate matter

Do not shake vial

Using aseptic technique, withdraw dose and further dilute into 0.9% NaCl infusion bag to final concentration of ~1.2 mg/mL (ie, 300 mg in 250-mL bag, 600 mg in 500-mL bag)

Product contains no preservative and is intended for single use only

Before starting the IV infusion, the content of the infusion bag should be at room temperature

Use the prepared infusion solution immediately or refrigerate (see Storage)

IV Administration

Administer the diluted infusion solution through a dedicated line using an infusion set with a 0.2 or 0.22 micron inline filter

Observe patient for infusion reactions during the infusion and for at least 1 hr after completion of the infusion; inform patients that infusion reactions can occur up to 24 hr after the infusion

See Dosage Modifications for instructions if infusion reaction occurs

Infection assessment

• Before every infusion, determine whether there is an active infection
• In case of active infection, delay infusion until the infection resolves

Premedication

• Methylprednisolone 100 mg IV (or an equivalent corticosteroid): Premedicate ~30 min before each ocrelizumab infusion to reduce the frequency and severity of infusion reactions
• Antihistamine (eg, diphenhydramine): Premedicate ~30-60 min before each ocrelizumab infusion to further reduce the frequency and severity of infusion reactions
• Antipyretic (eg, acetaminophen): Addition to the above medications may be considered

Infusion rate

• Initial dose (first 2 IV infusions)
  • Dilute 300 mg in 250 mL 0.9% NaCl to final concentration of ~1.2 mg/mL
  • Start IV at 30 mL/hr
  • Increase by 30 mL/hr q30min
  • Maximum rate: 180 mL/hr
  • Infusion duration: ≥2.5 hr
• Subsequent doses
  • Dilute 600 mg in 500 mL 0.9% NaCl to final concentration of ~1.2 mg/mL
  • Start IV at 40 mL/hr
  • Increase by 40 mL/hr q30min
  • Maximum rate: 200 mL/hr
  • Infusion duration: ≥3.5 hr

Delayed or missed dose

• If a planned infusion is missed, administer 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 must be separated by at least 5 months

Storage

Unopened vials

• Refrigerate at 2-8°C (36-46°F) in the outer carton to protect from light
• Do not freeze
• Do not shake

Diluted solution

• Refrigerated at 2-8°C (36-46°F): Up to 24 hr
• Room temperature up to 25°C (77°F): 8 hr (including infusion time)
• In the event an IV infusion cannot be completed the same day, discard the remaining solution

Ocrevus for PPMS is typically given as two intravenous (IV) infusions 14 days apart, which are administered every six months.

The dose of ocrelizumab used in the clinical trials was 300 mg for each infusion, or 600 mg every six months.

Ocrevus should be given by a skilled medical professional in a clinical setting.

Ocrevus Overdose

Because Ocrevus is administered in a medical facility by a trained healthcare worker, you are unlikely to experience an overdose.

But if you do suspect an overdose, contact a poison control center or emergency room immediately. You can get in touch with a poison control center at 800-222-1222.

Missed Dose of Ocrevus

If you miss a dose of Ocrevus, call your doctor for further instructions.

Call your doctor for instructions if you miss a dose of ocrelizumab.

Advise the patient to read the FDA-approved patient labeling (Medication Guide). 1

Infusion Reactions

Inform patients about the signs and symptoms of infusion reactions, and that infusion reactions can occur up to 24 hours after infusion. Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion reactions.1

Infection

Advise patients to contact their healthcare provider for any signs of infection during treatment or after the last dose. Signs include fever, chills, constant cough, or signs of herpes such as cold sore, shingles, or genital sores. 1

Advise patients that PML has happened with drugs that are similar to ocrelizumab and may happen with ocrelizumab. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that 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. 1

Advise patients that ocrelizumab may cause reactivation of hepatitis B infection and that monitoring will be required if they are at risk.1

Vaccination

Advise patients to complete any required vaccinations at least 6 weeks prior to initiation of ocrelizumab. Administration of live-attenuated or live vaccines is not recommended during ocrelizumab treatment and until B-cell recovery.1

Malignancies

Advise patients that an increased risk of malignancy, including breast cancer, may exist with ocrelizumab. Advise patients that they should follow standard breast cancer screening guidelines. 1

Pregnancy

Instruct patients that if they are pregnant or plan to become pregnant while taking ocrelizumab they should inform their healthcare provider. 1

In the U.S.

• Ocrevus

Available Dosage Forms:

• Solution

Therapeutic Class: Immune Modulator

Pharmacologic Class: Monoclonal Antibody

A nurse or other trained health professional will give you this medicine. This medicine is given through a needle placed into one of your veins.

This medicine needs to be given on a fixed schedule. If you miss a dose, call your doctor for instructions.

This medicine should come with a Medication Guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Ocrevus is indicated for the treatment of adult patients with relapsing or primary progressive forms of multiple sclerosis.

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)]

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)]

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).

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).

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.

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.

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.

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.

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)].

Pediatric Use

Safety and effectiveness of Ocrevus in pediatric patients have not been established.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been performed to assess the carcinogenic potential of Ocrevus.

No studies have been performed to assess the mutagenic potential of Ocrevus. As an antibody, Ocrevus is not expected to interact directly with DNA.

No effects on reproductive organs were observed in male monkeys administered ocrelizumab by intravenous injection (three loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) for 8 weeks. There were also no effects on estrus cycle in female monkeys administered ocrelizumab over three menstrual cycles using the same dosing regimen. The doses tested in monkey are 2 and 10 times the recommended human dose of 600 mg, on a mg/kg basis.

Relapsing Forms of Multiple Sclerosis (RMS)

The efficacy of Ocrevus was demonstrated in two randomized, double-blind, double-dummy, active comparator-controlled clinical trials of identical design, in patients with RMS treated for 96 weeks (Study1 and Study 2). The dose of Ocrevus was 600 mg every 24 weeks (initial treatment was given as two 300 mg IV infusions administered 2 weeks apart, and subsequent doses were administered as a single 600 mg IV infusion) and placebo subcutaneous injections were given 3 times per week. The dose of REBIF, the active comparator, was 44 mcg given as subcutaneous injections 3 times per week and placebo IV infusions were given every 24 weeks. Both studies included patients who had experienced at least one relapse within the prior year, or two relapses within the prior two years, and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.5. Patients with primary progressive forms of multiple sclerosis (MS) were excluded. Neurological evaluations were performed every 12 weeks and at the time of a suspected relapse. Brain MRIs were performed at baseline and at Weeks 24, 48, and 96.

The primary outcome of both Study 1 and Study 2 was the annualized relapse rate (ARR). Additional outcome measures included the proportion of patients with confirmed disability progression, the mean number of MRI T1 gadolinium (Gd)-enhancing lesions at Weeks 24, 48, and 96, and new or enlarging MRI T2 hyperintense lesions. Progression of disability was defined as an increase of 1 point or more from the baseline EDSS score attributable to MS when the baseline EDSS score was 5.5 or less, or 0.5 points or more when the baseline EDSS score was above 5.5. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit 12 weeks after the initial documentation of neurological worsening. The primary population for analysis of confirmed disability progression was the pooled population from Studies 1 and 2.

In Study 1, 410 patients were randomized to Ocrevus and 411 to REBIF; 11% of Ocrevus-treated and 17% of REBIF-treated patients did not complete the 96-week double-blind treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 37 years; 66% were female. The mean time from MS diagnosis to randomization was 3.8 years, the mean number of relapses in the previous year was 1.3, and the mean EDSS score was 2.8; 74% of patients had not been treated with a non-steroid therapy for MS in the 2 years prior to the study. At baseline, 40% of patients had one or more T1 Gd-enhancing lesions (mean 1.8).

In Study 2, 417 patients were randomized to Ocrevus and 418 to REBIF; 14% of Ocrevus-treated and 23% of REBIF-treated patients did not complete the 96-week double-blind treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 37 years; 66% were female. The mean time from MS diagnosis to randomization was 4.1 years, the mean number of relapses in the previous year was 1.3, and the mean EDSS score was 2.8; 74% of patients had not been treated with a non-steroid therapy for MS in the 2 years prior to the study. At baseline, 40% of Ocrevus-treated patients had one or more T1 Gd-enhancing lesions (mean 1.9).

In Study 1 and Study 2, Ocrevus significantly lowered the annualized relapse rate and the proportion of patients with disability progression confirmed at 12 weeks after onset compared to REBIF. Results for Study 1 and Study 2 are presented in Table 4 and Figure 1.

In exploratory subgroup analyses of Study 1 and Study 2, the effect of Ocrevus on annualized relapse rate and disability progression was similar in male and female patients.

Primary Progressive Multiple Sclerosis (PPMS)

Study 3 was a randomized, double-blind, placebo-controlled clinical trial in patients with PPMS. Patients were randomized 2:1 to receive either Ocrevus 600 mg or placebo as two 300 mg intravenous infusions 2 weeks apart every 24 weeks for at least 120 weeks. Selection criteria required a baseline EDSS of 3 to 6.5 and a score of 2 or greater for the EDSS pyramidal functional system due to lower extremity findings. Neurological assessments were conducted every 12 weeks. An MRI scan was obtained at baseline and at Weeks 24, 48, and 120.

In Study 3, the primary outcome was the time to onset of disability progression attributable to MS confirmed to be present at the next neurological assessment at least 12 weeks later. Disability progression occurred when the EDSS score increased by 1 point or more from the baseline EDSS if the baseline EDSS was 5.5 points or less, or by 0.5 points or more if the baseline EDSS was more than 5.5 points. In Study 3, confirmed disability progression also was deemed to have occurred if patients who had onset of disability progression discontinued participation in the study before the next assessment. Additional outcome measures included timed 25-foot walk, and percentage change in T2 hyperintense lesion volume.

Study 3 randomized 488 patients to Ocrevus and 244 to placebo; 21% of Ocrevus-treated patients and 34% of placebo-treated patients did not complete the trial. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 45; 49% were female. The mean time since symptom onset was 6.7 years, the mean EDSS score was 4.7, and 26% had one or more T1 Gd-enhancing lesions at baseline; 88% of patients had not been treated previously with a non-steroid treatment for MS. The time to onset of disability progression confirmed at 12 weeks after onset was significantly longer for Ocrevus-treated patients than for placebo-treated patients (see Figure 2). Results for Study 3 are presented in Table 5 and Figure 2.

In the overall population in Study 3, the proportion of patients with 20 percent worsening of the timed 25-foot walk confirmed at 12 weeks was 49% in Ocrevus-treated patients compared to 59% in placebo-treated patients (25% risk reduction).

In exploratory subgroup analyses of Study 3, the proportion of female patients with disability progression confirmed at 12 weeks after onset was similar in Ocrevus-treated patients and placebo-treated patients (approximately 36% in each group). In male patients, the proportion of patients with disability progression confirmed at 12 weeks after onset was approximately 30% in Ocrevus-treated patients and 43% in placebo-treated patients. Clinical and MRI endpoints that generally favored Ocrevus numerically in the overall population, and that showed similar trends in both male and female patients, included annualized relapse rate, change in T2 lesion volume, and number of new or enlarging T2 lesions.