ocrelizumab

Ocrelizumab is a medication used in the treatment of adults with primary progressive and relapsing forms of multiple sclerosis (MS), an autoimmune disorder that affects the central nervous system. In multiple sclerosis, the body’s immune system, primarily the T-cells and B-cells mistakenly attack and damage the protective sheath (myelin) around the nerve fibers, affecting communication between nerve cells (neurons), and causing symptoms that include pain, fatigue, vision loss and other neuromuscular problems.

Although T-cells play a central role in multiple sclerosis, B-cells also play a major role by activating pro-inflammatory T-cells, and producing inflammatory proteins (cytokines) and generating autoantibodies against myelin. Ocrelizumab reduces the autoimmune activity in MS by specifically targeting and depleting the levels of immature and mature B-cells that express a surface protein (antigen) known as CD20.

Ocrelizumab is a second-generation immunoglobulin G1 (IgG1) monoclonal antibody produced in the laboratory using DNA recombinant technology. Ocrelizumab specifically binds to CD20, a unique antigen found on pre-B lymphocytes, and immature and mature B lymphocytes, and marks them for programmed cell death (apoptosis), which leads to the breakdown and death of these B-cells by killer T-cells, macrophages and the complement immune system.

Ocrelizumab spares other types of B-cells that do not express CD20, including stem cells and pro-B cells that turn into B-cells, and plasma cells that are differentiated B-cells, and hence has less effect, compared to older generation CD20 antagonist drugs, on the levels of IgG and IgM antibodies that fight infections. Ocrelizumab is administered as an intravenous infusion for over an hour or longer as required. Ocrelizumab is a humanized molecule and hence may elicit less immune response with repeated infusions, unlike antibodies produced in animal cell lines.

FDA-approved uses of ocrelizumab include:

• Primary progressive multiple sclerosis
• Relapsing forms of multiple sclerosis including:
  • Clinically isolated syndrome
  • Relapsing-remitting disease
  • Active secondary progressive disease

• Do not infuse ocrelizumab in patients with:
  • Active hepatitis B virus infection
  • History of life-threatening infusion reaction to ocrelizumab
• Ocrelizumab can cause infusion reactions, which may include pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, tachycardia and anaphylaxis.
  • Monitor patients during infusion and for at least one hour after completion of infusion.
  • Administer appropriate pre-medications such as antihistamines, antipyretics and corticosteroids to reduce frequency and severity of reactions.
  • If a patient develops moderate infusion reactions, interrupt infusion, reduce infusion rate and/or provide appropriate symptomatic treatment. If life-threatening infusion reactions occur, discontinue ocrelizumab permanently and institute appropriate supportive treatment.
  • Advise patients to be alert for infusion reactions, which can occur up to 24 hours after infusion, and report immediately.
• Ocrelizumab increases the risk for upper and lower respiratory tract infections, skin infections and herpes-related infections. The infections reported in trials were predominantly mild or moderate. Treat active infections before initiating ocrelizumab.
• There have been reports of serious herpes simplex and varicella zoster viral infections, including life-threatening central nervous system infections such as encephalitis and meningitis, intraocular infections, and disseminated skin and soft tissue infections. In case a patient develops serious herpes infections, provide appropriate treatment and withhold ocrelizumab until the infection is resolved.
• Ocrelizumab can reactivate hepatitis B virus (HBV) infection. Screen patients for HBV infection, and do not initiate treatment in patients with active infection confirmed by positive results for HBV surface antigen HbsAg and anti-HB tests. In patients negative for HbsAg and positive for HBV core antibody, consult a liver disease specialist before and during treatment with ocrelizumab.
• There have been reports of progressive multifocal leukoencephalopathy (PML) caused by JC virus in patients treated with ocrelizumab. PML is an opportunistic viral infection that affects the brain and typically occurs in immunocompromised patients. Monitor patients for neurological symptoms and, withhold ocrelizumab and evaluate the patient at the first sign of PML. If PML is confirmed, discontinue ocrelizumab permanently.
• Administer all vaccinations according to immunization guidelines before starting ocrelizumab treatment.
  • Live and live-attenuated vaccines should be administered at least 4 weeks before treatment, and inactivated vaccines, 2 weeks before treatment.
  • Ocrelizumab may interfere with the effectiveness of inactivated vaccines.
  • Safety of live and live-attenuated vaccines during or following ocrelizumab treatment has not been studied and are not recommended during treatment and until B-cell repletion back to baseline levels.
  • Do not administer live or live-attenuated vaccines to infants exposed to ocrelizumab in the uterus, until B-cell count is confirmed to be normal. Inactivated vaccines may be administered as scheduled, however, vaccine immune response must be assessed to confirm effectiveness.
• Depletion of B-cells can lower the levels of all types of antibodies (immunoglobulins), increasing the risk for serious infections. Monitor immunoglobulin levels during and after discontinuation of treatment until repletion of B-cells, especially in patients with recurrent infections. Consider discontinuing ocrelizumab in patients with serious opportunistic or recurrent infections and those who require treatment for prolonged low immunoglobulin levels (hypogammaglobulinemia).
• Ocrelizumab may increase the risk for malignancies, including breast cancer. Advise patients to follow standard breast cancer screening guidelines.
• Ocrelizumab treatment can lead to immune-mediated colitis, which can be severe in some cases, requiring hospitalization and surgical intervention. Monitor patients for signs and symptoms of immune-mediated colitis and treat promptly.

Common side effects of ocrelizumab include:

• Upper respiratory tract infections
• Lower respiratory tract infections
• Cough
• Infusion reactions
• Reduced level of neutrophil immune cells
• Decrease in serum immunoglobulin (particularly IgM)
• Skin infections including:
  • Herpes simplex
  • Varicella zoster
• Depression
• Diarrhea
• Swelling of extremities (peripheral edema)
• Back pain
• Limb pain

Less common side effects of ocrelizumab include:

• Malignant breast cancer
• Immune-mediated colon inflammation (colitis)
• Antibody development
• Painful ulcers on the skin (pyoderma gangrenosum)
• Reactivation of hepatitis B virus
• Ocular herpes simplex
• Herpes virus infection in the brain (herpes meningoencephalitis)
• Progressive multifocal leukoencephalopathy

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Solution for injection

• 30 mg/mL (10 mL single-dose vial)

Adult:

Multiple Sclerosis

• Indicated for adults with relapsing or primary progressive forms of multiple sclerosis
• Initial 2 doses: 300 mg intravenous (IV) once; repeat dose 2 weeks later
• Subsequent doses: 600 mg IV every 6 months

Dosage Modifications

Infusion reactions

• Dose modifications in response to infusion reactions depends on the severity
• Mild-to-moderate
  • Reduce infusion rate to half the rate at the onset of the infusion reaction and maintain the reduced rate for at least 30 minutes; if tolerated, may increase the rate
• Severe
  • Immediately interrupt infusion and administer appropriate supportive treatment, as necessary
  • Restart infusion once symptoms have resolved
  • When restarting, begin at half of the infusion rate at the time of onset of the infusion reaction; if tolerated, may increase the rate
• Life-threatening
  • Immediately stop and permanently discontinue ocrelizumab if there are signs of a life-threatening or disabling infusion reaction

Dosing Considerations

HBV screening

• Perform Hepatitis B virus (HBV) screening before initiating ocrelizumab
• Contraindicated with active HBV infection 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 positive] or are carriers of HBV [HBsAg positive], consult liver disease experts before starting and during treatment

Vaccinations

• 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 for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation for non-live vaccines

Serum immunoglobulins

• Before initiating treatment, test for quantitative serum immunoglobulins
• For patients with low serum immunoglobulins, consult immunology experts before initiating treatment

Pediatric:

• Safety and efficacy not established
• See Cautions for information regarding vaccinating infants born to mothers taking ocrelizumab

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Ocrelizumab has no known severe interactions with other drugs.
• Ocrelizumab has serious interactions with at least 43 different drugs.
• Ocrelizumab has moderate interactions with at least 44 different drugs.
• Ocrelizumab has no known mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There is no data on the developmental risks associated with use of ocrelizumab during pregnancy. Ocrelizumab is an immunoglobulin and immunoglobulins are known to cross the placenta.
• Transient peripheral depletion of B-cells and lymphocytopenia have been observed in infants whose mothers were exposed to other anti-CD20 antibodies during pregnancy, however, B-cell levels have not been studied in infants born to mothers who have received ocrelizumab, and the effects are unknown.
• Animal reproductive studies show ocrelizumab can cause fetal harm. Exposure of ocrelizumab to the fetus can cause B-cell depletion in the newborn infant, fetal and neonatal mortality, and kidney, bone marrow and testicular toxicity.
• Women of reproductive potential should use effective contraception during treatment with ocrelizumab and for 6 months after the last infusion.
• There is no information on the presence of ocrelizumab in breastmilk, or its effects on milk production and on the breastfed infant. Ocrelizumab was excreted in monkey milk. Human IgG is excreted in breastmilk. There is no information on the potential for ocrelizumab presence in breastmilk, its absorption and consequent B-cell depletion in the breastfed infant.
• Decision to breastfeed should be based on the mother’s clinical need for ocrelizumab, benefits of breastfeeding to the infant, and potential risk to the infant from exposure to the drug or underlying maternal condition.
• There is a pregnancy exposure registry that monitors pregnancy and fetal/neonatal/infant outcomes in women exposed to ocrelizumab (Ocrevus) during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-833-872-4370 or visiting www.ocrevuspregnancyregistry.com.

• Report immediately to your healthcare provider if you experience infusion reactions which may occur up to 24 hours after infusion. Symptoms include itching, rash, hives, redness, bronchospasm, throat irritation, mouth and throat pain, shortness of breath, throat swelling, flushing, low blood pressure, high temperature, fatigue, headache, dizziness, nausea, rapid heartbeat, and severe allergic reaction (anaphylaxis).
• Ocrelizumab can reactivate hepatitis B virus infection. You will need monitoring for reactivation of HBV during ocrelizumab therapy, if you have a history of HBV infection.
• Report immediately to your healthcare provider if, during treatment with ocrelizumab or after discontinuation, you develop:
  • Any signs of infection such as fever, chills and persistent cough.
  • Signs of herpes infections of the skin, eyes or central nervous system. Symptoms include oral or genital sores, shingles, rash, fever, pain, itching, eye symptoms, headache, neck pain and change in mental status.
  • Signs of JC virus infection that can affect the brain with symptoms that include progressive weakness on one side of the body, clumsiness of limbs, vision problems, confusion, changes in thinking and memory, and personality changes.
  • Symptoms of immune-mediated colitis such as diarrhea, abdominal pain and blood in stool.
• Complete all required live or live-attenuated vaccinations 4 weeks before and non-live vaccinations 2 weeks before ocrelizumab treatment. Do not take any live or live-attenuated vaccines during treatment and for several months after. Check with your physician before taking any scheduled vaccinations.
• Follow recommended guidelines for breast cancer screening. Ocrelizumab increases the risk for breast cancer.