DRUG INTERACTIONS

 

 Immunosuppressive or Immune-Modulating Therapies

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 

 

U.S. FDA APPROVED  DRUGS DURING 2017

 

Sr.No-  12

  

Name of the  Drug-        Ocrevus

 

Active Ingredient-          Ocrelizumab                                                                                                                                                                                                           Pharmacological Classification- 

 

                       To treat patients with relapsing and primary progressive

                        forms of multiple sclerosis

                                   

                                                                                                                           

Date of Approval-          03-28-2017

 

 (Ref- FDA approved List 2017)                                                                                                                                                                                                                                       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

 

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             

 

ADVERSE REACTIONS

 

The most common adverse reactions were: 

 RMS (incidence .10% and > REBIF): upper respiratory tract infections 

 and infusion reactions  

 

 PPMS (incidence .10% and > placebo): upper respiratory tract infections, 

  infusion reactions, skin infections, and lower respiratory tract infections

 

 CONTRAINDICATIONS

 

Active hepatitis B virus infection 

History of life-threatening infusion reaction to OCREVUS 

 

 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 

 

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 

 

Malignancies: 

 An increased risk of malignancy, including breast cancer, 

 may exist with OCREVUS 

 

 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

 

DOSAGE AND ADMINISTRATION 

 

Hepatitis B virus screening is required before the first dose .

Pre-medicate with methylprednisolone (or an equivalent corticosteroid)

 and an antihistamine (e.g., diphenhydramine) prior to each infusion.

 

 Administer OCREVUS by intravenous infusion

 Start dose: 300 mg intravenous infusion, followed two weeks later

 by a second 300 mg intravenous infusion 

 

 Subsequent doses: 600 mg intravenous infusion every 6 months.

 

Must be diluted prior to administration.  

Monitor patients closely during and for at least one hour after infusion.

 

 DOSAGE FORMS AND STRENGTHS

 

Injection: 300 mg/10 mL (30 mg/mL) in a single-dose vial. 

 

 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 

 

 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.

 

 Advise patients that PML has happened with drugs that are similar to 

 OCREVUS and may happen with 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 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 .

 

 Advise patients that OCREVUS may cause reactivation of hepatitis B infection

  and that monitoring will be required if they are at risk..

 

 Vaccination

 Advise patients to complete any required vaccinations at least 6 weeks prior to 

 initiation of OCREVUS. 

 

Administration of live-attenuated or live vaccines is not recommended during 

 OCREVUS treatment and until B-cell recovery..

 

 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.

 

Pregnancy

 Instruct patients that if they are pregnant or plan to become pregnant while 

 taking OCREVUS they should inform their healthcare provider 

 

OCREVUSTM [ocrelizumab]

Manufactured by: OCREVUS is a trademark of Genentech, Inc.

Genentech, Inc. ©2017 Genentech, Inc.

A Member of the Roche Group

1 DNA Way

South San Francisco, CA 94080-4990

U.S. License No. 1048

 

 CLINICAL PHARMACOLOGY

 

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.

 

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.

 

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 weeks. 

 The terminal elimination half-life was 26 days.

 

 Metabolism

The metabolism of OCREVUS has not been directly studied because 

  antibodies are cleared principally by catabolism.

 

 Specific Populations

 Renal impairment

 Patients with mild renal impairment were included in clinical trials. 

 No significant change in the pharmacokinetics of OCREVUS was 

  observed in those patients.

 

 Hepatic impairment

 Patients with mild hepatic impairment were included in clinical trials. 

 No significant change in the pharmacokinetics of OCREVUS was observed 

  in those patients.

 

 USE IN SPECIFIC POPULATIONS

 

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 

 

 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.

 

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.

 

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 .

 

4. Pediatric Use

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

 

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.