OCREVUS: Package Insert and Label Information (Page 4 of 5)

14.2 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.

Table 5 Key Clinical and MRI Endpoints in PPMS patients for Study 3

Endpoints	Study 3
	OCREVUS 600 mg (two 300 mg infusions two weeks apart every 24 weeks)	Placebo
	N=488	N=244
* Defined as an increase of 1.0 point or more from the baseline EDSS score for patients with baseline score of 5.5 or less, or an increase of 0.5 or more when the baseline score is more than 5.5
Clinical Outcomes
Proportion of patients with 12-week Confirmed Disability Progression *	32.9%	39.3%
Risk reduction	24%; p=0.0321
MRI Endpoints
Mean change in volume of T2 lesions, from baseline to Week 120 (cm3)	-0.39	0.79
	p<0.0001

* All patients in this analysis had a minimum of 120 weeks of follow-up. The primary analysis is based on all disability progression events accrued including 21 without confirmatory EDSS at 12 weeks.

Figure 2 Kaplan-Meier Plot of Time to Onset of Confirmed Disability Progression Sustained for at Least 12 Weeks with the Initial Event of Neurological Worsening Occurring During the Double-blind Treatment Period in Study 3*

(click image for full-size original)

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.

14.3 Safety Study of 2-Hour Infusions

The safety of the 2-hour OCREVUS infusion was evaluated in Study 4 (NCT03085810), a prospective, multicenter, randomized, double-blind, controlled, parallel arm substudy in patients with Relapsing-Remitting Multiple Sclerosis who were naïve to other non-steroid therapies for MS and did not experience a serious infusion reaction with any previous OCREVUS infusion. The first dose of OCREVUS was administered as two 300 mg infusions (600 mg total) separated by 14 days. After enrollment in the substudy, patients were randomized in a 1:1 ratio to receive infusions over approximately 3.5-hours or 2-hours, after appropriate premedication [see Dosage and Administration (2.2)] , every 24 weeks. The randomization was stratified by region and the dose at which patients were first randomized.

The primary endpoint of the substudy was the proportion of patients with infusion reactions occurring during or within 24 hours following the first randomized infusion of OCREVUS. The primary analysis was performed when 580 patients were randomized, at which time 469/579 (81%) of the treated patients had received only a single randomized infusion of OCREVUS. The proportions of patients with infusion reactions occurring during or within 24 hours following the first randomized infusion in this substudy were similar between the 2-hour and 3.5-hour infusion groups (24.4% versus 23.3%, respectively). Overall, in all randomized doses, 27.1% of the patients in the 2-hour infusion group and 25.0% of the patients in the 3.5-hour infusion group reported mild or moderate infusion reactions; two infusion reactions were severe in intensity, with one severe infusion reaction (0.3%) reported in one patient in each group in this substudy [see Warnings and Precautions (5.1)]. There were no life-threatening, fatal, or serious infusion reactions in this substudy.

16 HOW SUPPLIED/STORAGE AND HANDLING

OCREVUS (ocrelizumab) injection is a preservative-free, sterile, clear or slightly opalescent, and colorless to pale brown solution supplied as a carton containing one 300 mg/10 mL (30 mg/mL) single-dose vial (NDC 50242-150-01).

Store OCREVUS vials at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light. Do not freeze or shake.

17 PATIENT COUNSELING INFORMATION

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

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 [see Warnings and Precautions (5.1)].

Infection

Advise patients to contact their healthcare provider for any signs of infection during treatment or after the last dose [see Clinical Pharmacology (12.2)]. Signs include fever, chills, constant cough, or signs of herpes such as cold sore, shingles, or genital sores [see Warnings and Precautions (5.2)].

Advise patients that OCREVUS may cause reactivation of hepatitis B infection and that monitoring will be required if they are at risk [see Warnings and Precautions (5.2)].

Advise patients that herpes infections, including serious herpes infections affecting the central nervous system, skin, and eyes, have occurred during treatment with OCREVUS. Advise patients to promptly contact their healthcare provider if they experience any signs or symptoms of herpes infections including oral or genital symptoms, fever, skin rash, pain, itching, decreased visual acuity, eye redness, eye pain, headache, neck stiffness, or change in mental status [see Warnings and Precautions (5.2)].

Vaccination

Advise patients to complete any required live or live-attenuated vaccinations at least 4 weeks and, whenever possible, non-live vaccinations at least 2 weeks prior to initiation of OCREVUS. Administration of live-attenuated or live vaccines is not recommended during OCREVUS treatment and until B-cell recovery [see Warnings and Precautions (5.2)].

Progressive Multifocal Leukoencephalopathy

Inform patients that PML has occurred in patients who received OCREVUS. 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 healthcare provider 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 [see Warnings and Precautions (5.3)].

Malignancies

Advise patients that an increased risk of malignancy, including breast cancer, may exist with OCREVUS. Advise patients that they should follow standard breast cancer screening guidelines [see Warnings and Precautions (5.5)].

Immune-Mediated Colitis

Advise patients to promptly contact their healthcare provider if they experience any signs and symptoms of colitis, including diarrhea, abdominal pain, and blood in stool [see Warnings and Precautions (5.6)].

Contraception

Females of childbearing potential should use effective contraception while receiving OCREVUS and for 6 months after the last infusion of OCREVUS [see Clinical Pharmacology (12.3)].

Pregnancy Registry

Instruct patients that if they are pregnant or plan to become pregnant while taking OCREVUS they should inform their healthcare provider [see Use in Specific Populations (8.1)].

Encourage patients to enroll in the OCREVUS Pregnancy Registry if they become pregnant while taking OCREVUS [see Use in Specific Populations (8.1)].

OCREVUS^® [ocrelizumab]

Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990

OCREVUS is a registered trademark of Genentech, Inc.^© 2023 Genentech, Inc.

U.S. License No. 1048

This Medication Guide has been approved by the U.S. Food and Drug Administration							Revised: 8/2022
MEDICATION GUIDE
OCREVUS® (oak-rev-us)(ocrelizumab)injection, for intravenous use
What is the most important information I should know about OCREVUS?
OCREVUS can cause serious side effects, including: Infusion reactions: Infusion reactions are a common side effect of OCREVUS, which can be serious and may require you to be hospitalized. You will be monitored during your infusion and for at least 1 hour after each infusion of OCREVUS for signs and symptoms of an infusion reaction. Tell your healthcare provider or nurse if you get any of these symptoms:
	itchy skin rash hives tiredness coughing or wheezing		trouble breathing throat irritation or pain feeling faint fever redness on your face (flushing)		nausea headache swelling of the throat dizziness		shortness of breath fatigue fast heart beat
	These infusion reactions can happen for up to 24 hours after your infusion. It is important that you call your healthcare provider right away if you get any of the signs or symptoms listed above after each infusion.If you get infusion reactions, your healthcare provider may need to stop or slow down the rate of your infusion.
Infection: OCREVUS increases your risk of getting upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes infections. Infections are a common side effect, which can be serious. Tell your healthcare provider if you have an infection or have any of the following signs of infection including fever, chills, or a cough that does not go away. Signs of herpes infection include:
		cold sores shingles		genital sores skin rash		pain itching
Signs of a more serious herpes infection include:
		changes in vision eye redness or eye pain		severe or persistent headache stiff neck		confusion
Signs of infection can happen during treatment or after you have received your last dose of OCREVUS. Tell your healthcare provider right away if you have an infection. Your healthcare provider should delay your treatment with OCREVUS until your infection is gone.
	Hepatitis B virus (HBV) reactivation: Before starting treatment with OCREVUS, your healthcare provider will do blood tests to check for hepatitis B viral infection. If you have ever had hepatitis B virus infection, the hepatitis B virus may become active again during or after treatment with OCREVUS. Hepatitis B virus becoming active again (called reactivation) may cause serious liver problems including liver failure or death. Your healthcare provider will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop receiving OCREVUS. Weakened immune system: OCREVUS taken before or after other medicines that weaken the immune system could increase your risk of getting infections.
Progressive Multifocal Leukoencephalopathy (PML): PML is a rare brain infection that usually leads to death or severe disability, and has been reported with OCREVUS. Symptoms of PML get worse over days to weeks. It is important that you call your healthcare provider right away if you have any new or worsening neurologic signs or symptoms that have lasted several days, including problems with:
		thinking eyesight strength			balance weakness on 1 side of your body using your arms or legs
Decreased immunoglobulins: OCREVUS may cause a decrease in some types of immunoglobulins. Your healthcare provider will do blood tests to check your blood immunoglobulin levels. See “What are the possible side effects of OCREVUS?” for more information about side effects.
What is OCREVUS?
OCREVUS is a prescription medicine used to treat: 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.
It is not known if OCREVUS is safe and effective in children.
Who should not receive OCREVUS? Do not receive OCREVUS if you have an active hepatitis B virus (HBV) infection. Do not receive OCREVUS if you have had a life-threatening allergic reaction to OCREVUS. Tell your healthcare provider if you have had an allergic reaction to OCREVUS or any of its ingredients in the past. See “What are the ingredients in OCREVUS?“ for a complete list of ingredients in OCREVUS.
Before receiving OCREVUS, tell your healthcare provider about all of your medical conditions, including if you: have or think you have an infection. See “What is the most important information I should know about OCREVUS?“ have ever taken, take, or plan to take medicines that affect your immune system, or other treatments for MS. These medicines could increase your risk of getting an infection. have ever had hepatitis B or are a carrier of the hepatitis B virus. have a history of inflammatory bowel disease or colitis. have had a recent vaccination or are scheduled to receive any vaccinations. You should receive any required ‘live’ or ‘live-attenuated’ vaccines at least 4 weeks before you start treatment with OCREVUS. You should not receive ‘live’ or ‘live-attenuated’ vaccines while you are being treated with OCREVUS and until your healthcare provider tells you that your immune system is no longer weakened. When possible, you should receive any ‘non-live’ vaccines at least 2 weeks before you start treatment with OCREVUS. If you would like to receive any non-live (inactivated) vaccines, including the seasonal flu vaccine, while you are being treated with OCREVUS, talk to your healthcare provider. If you have a baby and you received OCREVUS during your pregnancy, it is important to tell your baby’s healthcare provider about receiving OCREVUS so they can decide when your baby should be vaccinated. are pregnant, think that you might be pregnant, or plan to become pregnant. It is not known if OCREVUS will harm your unborn baby. You should use birth control (contraception) during treatment with OCREVUS and for 6 months after your last infusion of OCREVUS. Talk with your healthcare provider about what birth control method is right for you during this time. Pregnancy Registry. There is a pregnancy registry for women who take OCREVUS during pregnancy. If you become pregnant while receiving OCREVUS, tell your healthcare provider right away. Talk to your healthcare provider about registering with the OCREVUS Pregnancy Registry. The purpose of this registry is to collect information about your health and your baby’s health. Your healthcare provider can enroll you in this registry by calling 1-833-872-4370 or visiting www.ocrevuspregnancyregistry.com. are breastfeeding or plan to breastfeed. It is not known if OCREVUS passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take OCREVUS.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How will I receive OCREVUS? OCREVUS is given through a needle placed in your vein (intravenous infusion) in your arm. Before treatment with OCREVUS, your healthcare provider will give you a corticosteroid medicine and an antihistamine to help reduce infusion reactions (make them less frequent and less severe). You may also receive other medicines to help reduce infusion reactions. See “What is the most important information I should know about OCREVUS?“ Your first full dose of OCREVUS will be given as 2 separate infusions, 2 weeks apart. Each infusion will last about 2 hours and 30 minutes. Your next doses of OCREVUS will be given as 1 infusion every 6 months. These infusions will last about 2 hours to 3 hours and 30 minutes depending on the infusion rate prescribed by your healthcare provider.
What are the possible side effects of OCREVUS?
OCREVUS may cause serious side effects, including: see “What is the most important information I should know about OCREVUS?“ risk of cancers (malignancies) including breast cancer. Follow your healthcare provider’s instructions about standard screening guidelines for breast cancer. Inflammation of the colon, or colitis: Tell your healthcare provider if you have any symptoms of colitis, such as: Diarrhea (loose stools) or more frequent bowel movements than usual Stools that are black, tarry, sticky or have blood or mucus Severe stomach-area (abdomen) pain or tenderness
These are not all the possible side effects of OCREVUS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of OCREVUS.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about OCREVUS that is written for health professionals.
What are the ingredients in OCREVUS?
Active ingredient: ocrelizumab.
Inactive ingredients: glacial acetic acid, polysorbate 20, sodium acetate trihydrate, trehalose dihydrate.
Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990
U.S. License No. 1048
For more information, go to www.OCREVUS.com or call 1-844-627-3887.

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):