Multiple sclerosis

BOXED WARNING:

WARNING: HEPATIC INJURY INCLUDING AUTOIMMUNE HEPATITIS AND OTHER IMMUNE-MEDIATED DISORDERS

Hepatic Injury Including Autoimmune Hepatitis:
ZINBRYTA can cause severe liver injury including life-threatening events, liver failure, and autoimmune hepatitis. In clinical trials, 1 patient died due to autoimmune hepatitis. Liver injury, including autoimmune hepatitis, can occur at any time during treatment with ZINBRYTA, with cases reported up to 4 months after the last dose of ZINBRYTA.
ZINBRYTA is contraindicated in patients with pre-existing hepatic disease or hepatic impairment [see Contraindications (4) and Warnings and Precautions (5.1)].
Prior to starting ZINBRYTA, obtain serum transaminases (ALT and AST) and bilirubin levels [see Dosage and Administration (2.3)].
Test transaminase levels and total bilirubin monthly and assess before the next dose of ZINBRYTA. Follow transaminase levels and total bilirubin monthly for 6 months after the last dose of ZINBRYTA. In case of elevation in transaminases or total bilirubin, treatment interruption or discontinuation may be required [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].

Other Immune-Mediated Disorders:
In addition to autoimmune hepatitis, immune-mediated disorders such as skin reactions, lymphadenopathy, and non-infectious colitis can occur in patients treated with ZINBRYTA. Overall, serious immune-mediated conditions were observed in 5% of patients treated with ZINBRYTA [see Warnings and Precautions (5.2)].

If a patient develops a serious immune-mediated disorder, consider stopping ZINBRYTA and refer the patient to a specialist to ensure comprehensive diagnostic evaluation and appropriate treatment.

Some patients required systemic corticosteroids or other immunosuppressant treatment for autoimmune hepatitis or other immune-mediated disorders and continued this treatment after the last dose of ZINBRYTA [see Warnings and Precautions (5.1, 5.2)].

Because of the risks of hepatic injury, including autoimmune hepatitis, and other immune-mediated disorders, ZINBRYTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ZINBRYTA REMS Program [see Warnings and Precautions (5.3)].

Initial U.S. Approval:  2016

Mechanism of Action:
The precise mechanism by which daclizumab exerts therapeutic effects in multiple sclerosis is unknown but is presumed to involve modulation of IL-2 mediated activation of lymphocytes through binding to CD25, a subunit of the high-affinity IL-2 receptor.

INDICATIONS AND USAGE:
ZINBRYTA is an interleukin-2 receptor blocking antibody indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (MS). Because of its safety profile, the use of ZINBRYTA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.

DOSAGE AND ADMINISTRATION
Recommended dosage: 150 milligrams once monthly (2.1)
For subcutaneous use only (2.1)
Train patients in the proper technique for self-administration (2.2)
Conduct laboratory tests at baseline and at periodic intervals to monitor for early signs of potentially serious adverse reactions (2.3, 2.4).

HOW SUPPLIED:
DOSAGE FORMS AND STRENGTHS
Injection: 150 mg/mL solution in a single-dose prefilled syringe

INDICATIONS AND USAGE
AMPYRA™ (dalfampridine) is a potassium channel blocker indicated to improve walking in patients with multiple sclerosis (MS). This was demonstrated by an increase in walking speed

DOSAGE AND ADMINISTRATION
Maximum recommended dose: 10 mg twice daily (approximately 12 hours apart) with or without food.
Patients should not take double or extra doses if a dose is missed. No additional benefit was demonstrated at doses greater than 10 mg twice daily and adverse events, including seizures, were more frequent at higher doses.
Tablets should only be taken whole; do not divide, crush, chew, or dissolve.

Renal impairment: AMPYRA is contraindicated in patients with moderate or severe renal impairment; the risk of seizures in patients with mild renal impairment is unknown, but AMPYRA plasma levels in these patients may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures.

HOW SUPPLIED
AMPYRA (dalfampridine) extended release tablets, 10 mg are a film-coated, white to off-white, biconvex, oval shaped, non-scored tablets with flat edge. The tablets are identified by a debossed code "A10" on one side and are available in bottles of 60.

USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm. Pregnancy registry available.
Pediatric patients: Safety and effectiveness not established.
Hepatic impairment: Monitor patients with severe hepatic impairment closely, as GILENYA exposure is doubled, and risk of adverse reactions is greater.

DOSAGE AND ADMINISTRATION:
Recommended dose: 0.5 mg orally once daily, with or without food.

First Dose Monitoring:

• Observe all patients for signs and symptoms of bradycardia for at least 6 hours after first dose with hourly pulse and blood pressure measurement. Obtain ECG prior to dosing and at the end of the observation period.
• Patients who develop a heart rate <45 bpm, or a new onset 2nd degree or higher atrioventricular block should be monitored until resolution of the finding. Patients at lowest post-dose heart rate at the end of the observation period should be monitored until heart rate increases.
• In patients experiencing symptomatic bradycardia, begin continuous ECG monitoring until the symptoms have resolved; if pharmacological intervention is required to treat bradycardia, continuous ECG monitoring should continue overnight in a medical facility, and first-dose monitoring procedures should be repeated for the second dose.
• Patients at higher risk of symptomatic bradycardia or heart block because of a coexisting medical condition or certain concomitant medications should be observed overnight with continuous ECG monitoring .
• Patients with prolonged QTc interval at baseline or during the observation period, or taking drugs with known risk of torsades de pointes should be observed overnight with continuous ECG monitoring

DOSAGE FORMS AND STRENGTHS:
0.5 mg hard capsules.

CONTRAINDICATIONS:
Recent (within the last 6 months) occurrence of: myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III/IV heart failure.

History or presence of Mobitz Type II 2nd degree or 3rd degree AV block or sick sinus syndrome, unless patient has a pacemaker.

Baseline QTc interval ≥500 ms.

Treatment with Class Ia or Class III anti-arrhythmic drugs.

WARNINGS AND PRECAUTIONS

• Decrease in heart rate and/or atrioventricular conduction after first dose of GILENYA: Monitor patients
• Infections: GILENYA may increase the risk of infections. A recent CBC should be available before initiating treatment with GILENYA. Monitor for signs and symptoms of infection during treatment and for two months after discontinuation. Do not start GILENYA treatment in patients with active acute or chronic infections.
• Macular edema: Can occur with or without visual symptoms. An ophthalmologic evaluation should be performed before starting GILENYA and at 3-4 months after treatment initiation. Monitor visual acuity at baseline and during routine evaluations of patients. Patients with diabetes mellitus or a history of uveitis are at increased risk and should have regular ophthalmologic evaluations.
• Decrease in pulmonary function tests with GILENYA: Obtain spirometry and diffusion lung capacity for carbon monoxide (DLCO) when clinically indicated.
• Hepatic effects: GILENYA may increase liver transaminases. Recent liver enzyme results should be available before starting GILENYA. Assess liver enzymes if hepatic injury is suspected. Discontinue GILENYA if significant liver injury occurs
• Fetal risk: Women of childbearing potential should use effective contraception during and for 2 months after stopping GILENYA

ADVERSE REACTIONS
Most common adverse reactions (incidence ≥110% and > placebo): Headache, influenza, diarrhea, back pain, liver transaminase elevations and cough.

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
Ketoconazole: Monitor patients closely, as GILENYA exposure is increased by 70% during concomitant use with systemic ketoconazole, and risk of adverse reactions is greater.

Vaccines: Avoid live attenuated vaccines during, and for 2 months after stopping GILENYA treatment, due to risk of infection.

Because glatiramer acetate can modify immune functions, concerns exist about its potential to alter naturally occurring immune responses. Results of a limited battery of tests designed to evaluate this risk produced no finding of concern; nevertheless, there is no logical way to absolutely exclude this possibility.

INDICATIONS AND USAGE
COPAXONE® Injection is indicated for reduction of the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis.

CONTRAINDICATIONS
COPAXONE® Injection is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol.

WARNINGS
The only recommended route of administration of COPAXONE® Injection is the subcutaneous route. COPAXONE® Injection should not be administered by the intravenous route

Dosing (Adults): 
DOSAGE AND ADMINISTRATION

Recommended Dose:   COPAXONE is for subcutaneous use only. Do not administer intravenously. The dosing schedule depends on the product strength that is selected. The recommended doses are:

COPAXONE 20 mg per mL: administer once per day
    or
COPAXONE 40 mg per mL: administer three times per week and at least 48 hours apart

COPAXONE 20 mg per mL and COPAXONE 40 mg per mL are not interchangeable.

Instructions for Use:
Remove one blister-packaged prefilled syringe from the refrigerated carton. Let the prefilled syringe stand at room temperature for 20 minutes to allow the solution to warm to room temperature. Visually inspect the syringe for particulate matter and discoloration prior to administration. The solution in the syringe should appear clear, colorless to slightly yellow. If particulate matter or discoloration is observed, discard the syringe.

Areas for subcutaneous self-injection include arms, abdomen, hips, and thighs. The prefilled syringe is for single use only. Discard unused portions.

SUPPLIED:
Injection, solution [preservative free]:
20 mg per mL in a single-dose, prefilled syringe with a white plunger. For subcutaneous use only.

40 mg per mL in a single-dose, prefilled syringe with a blue plunger. For subcutaneous use only.

AVONEX® is intended for use under the guidance and supervision of a physician. Patients may self-inject only if their physician determines that it is appropriate and with medical follow-up, as necessary, after proper training in intramuscular injection technique. Sites for injection include the thigh or upper arm.

Reconstitution of AVONEX® Vials
Use appropriate aseptic technique during the preparation of AVONEX®. To reconstitute lyophilized AVONEX®, use a sterile syringe and MICRO PIN® to inject 1.1 mL of the supplied diluent, Sterile Water for Injection, USP, into the AVONEX® vial. Gently swirl the vial of AVONEX® to dissolve the drug completely. DO NOT SHAKE. The reconstituted solution should be clear to slightly yellow without particles. Inspect the reconstituted product visually prior to use. Discard the product if it contains particulate matter or is discolored. Each vial of reconstituted solution contains 30 mcg/1.0 mL Interferon beta-1a.

Withdraw 1.0 mL of reconstituted solution from the vial into a sterile syringe. Replace the cover on the MICRO PIN®, attach the sterile needle and inject the solution intramuscularly. The AVONEX® and diluent vials are for single-use only; unused portions should be discarded.

Using Avonex® Prefilled Syringes
The AVONEX® prefilled syringe should be held upright (cap faces up). Remove the cap by bending it at a 90°angle until it snaps free. Attach the needle and inject the solution intramuscularly. The AVONEX® prefilled syringe is for single-use only.

(Rebif®):
Dosing Information:   The recommended dose of REBIF is either 22 mcg or 44 mcg injected subcutaneously three times per week. REBIF should be administered, if possible, at the same time (preferably in the late afternoon or evening) on the same three days (e.g., Monday, Wednesday, and Friday) at least 48 hours apart each week.

Generally, patients should be started at 20% of the prescribed dose three times per week and increased over a 4-week period to the targeted dose, either 22 mcg three times per week (see Table 1) or 44 mcg three times per week (see Table 2). Patients prescribed a targeted dose of 22 mcg three times per week should use the prefilled syringes for titration.

A Titration Pack containing 6 doses of 8.8 mcg (0.2 mL) and 6 doses of 22 mcg (0.5 mL) is available for use during the titration period in both REBIF prefilled syringes and REBIF Rebidose autoinjectors.

Table 1: Titration Schedule for a 22 mcg Prescribed Dose*

*Use only prefilled syringes, not autoinjectors, to titrate to the 22 mcg Prescribed Dose

Table 2: Titration Schedule for a 44 mcg Prescribed Dose*

*Prefilled syringes or autoinjectors can be used to titrate to the 44 mcg Prescribed Dose

Important Administration Instructions
REBIF is intended for use under the guidance and supervision of a physician. It is recommended that physicians or qualified medical personnel train patients in the proper technique for self-administering subcutaneous injections using the prefilled syringe or injection device approved for use with REBIF. Injection depth of the REBIF Rebidose autoinjector is fixed at 8 mm; the health care provider should determine the injection technique.

The initial injection should be performed under the supervision of an appropriately qualified health care provider.

Appropriate instruction for self-injection or injection by another person should be provided to the patient or their caregiver, including careful review of the REBIF Medication Guide and the REBIF Rebidose autoinjector Instructions for Use that accompanies the product. Users should demonstrate competency in all aspects of the injection prior to independent use. If a patient is to self-administer REBIF, the physical and cognitive ability of that patient to self-administer and properly dispose of prefilled syringes or the REBIF Rebidose autoinjectors should be assessed. Patients with severe neurological deficits should not self-administer injections without assistance from a trained caregiver.

Advise patients and caregivers to:

• visually inspect REBIF for particulate matter and discoloration prior to administration
• use aseptic technique when administering REBIF
• rotate site of injection with each dose to minimize the likelihood of severe injection site reactions or necrosis
• use a puncture-resistant container for safe disposal of used needles, prefilled syringes and REBIF Rebidose autoinjectors
• do not re-use needles, syringes or REBIF Rebidose autoinjectors

Dosage adjustment in hepatic impairment: Rebif®: If liver function tests increase or in case of leukopenia: Decrease dose 20% to 50% until toxicity resolves

Administration
Avonex®: Must be administered by I.M. injection

Rebif®: Administer SubQ at the same time of day on the same 3 days each week (ie, late afternoon/evening Mon, Wed, Fri); rotate injection site

SUPPLIED:
(Rebif® ):
Injection: 8.8 mcg per 0.2 mL in a graduated, single-dose REBIF prefilled syringe
Injection: 22 mcg per 0.5 mL in a graduated, single-dose REBIF prefilled syringe
Injection: 44 mcg per 0.5 mL in a graduated, single-dose REBIF prefilled syringe
Injection: 8.8 mcg per 0.2 mL in a single-dose prefilled REBIF Rebidose autoinjector
Injection: 22 mcg per 0.5 mL in a single-dose prefilled REBIF Rebidose autoinjector
Injection: 44 mcg per 0.5 mL in a single-dose prefilled REBIF Rebidose autoinjector
Injection, solution: 8.8 mcg/0.2 mL (0.2 mL) [6 prefilled syringes; contains albumin]
Injection, solution: 22 mcg/0.5 mL (0.5 mL) [6 prefilled syringes; contains albumin]

Injection, powder for reconstitution (Avonex®): 33 mcg [6.6 million units; provides 30 mcg/mL following reconstitution] [contains albumin; packaged with SWFI, alcohol wipes, and access pin and needle]

Injection, solution (Avonex®): 30 mcg/0.5 mL (0.5 mL) [albumin free; prefilled syringe; syringe cap contains latex; packaged with alcohol wipes, gauze pad, and adhesive bandages]

Injection, solution [preservative free] (Rebif®): 22 mcg/0.5 mL (0.5 mL) [prefilled syringe; contains albumin]; 44 mcg/0.5 mL (0.5 mL) [prefilled syringe; contains albumin]

*Dosed every other day, subcutaneously

Reconstitution of the Lyophilized Powder
(a) Prior to reconstitution, verify that the vial containing lyophilized Betaseron is not cracked or damaged. Do not use cracked or damaged vials.

(b) To reconstitute lyophilized Betaseron for injection, attach the prefilled syringe containing the diluent (Sodium Chloride, 0.54% Solution) to the Betaseron vial using the vial adapter.

(c) Slowly inject 1.2 mL of diluent into the Betaseron vial.

(d) Gently swirl the vial to dissolve the lyophilized powder completely; do not shake. Foaming may occur during reconstitution or if the vial is swirled or shaken too vigorously. If foaming occurs, allow the vial to sit undisturbed until the foam settles.

(e) 1 mL of reconstituted Betaseron solution contains 0.25 mg of interferon beta-1b.

(f) After reconstitution, if not used immediately, refrigerate the reconstituted Betaseron solution at 2 to 8°C (35 to 46°F) and use within three hours. Do not freeze.

Important Administration Instructions
(a) Perform the first Betaseron injection under the supervision of an appropriately qualified healthcare professional. If patients or caregivers are to administer Betaseron, train them in the proper subcutaneous injection technique and assess their ability to inject subcutaneously to ensure the proper administration of Betaseron.

(b) Visually inspect the reconstituted Betaseron solution before use; discard if it contains particulate matter or is discolored.

(c) Keeping the syringe and vial adapter in place, turn the assembly over so that the vial is on top. Withdraw the appropriate dose of Betaseron solution. Remove the vial from the vial adapter before injecting Betaseron.

(d) Use safe disposal procedures for needles and syringes.

(e) Do not re-use needles or syringes.

(f) Advise patients and caregivers to rotate sites for subcutaneous injections to minimize the likelihood of severe injection site reactions, including necrosis or localized infection.

Premedication for Flu-like Symptoms
Concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with Betaseron use

SUPPLIED:
For injection: 0.3 mg lyophilized powder in a single use vial for reconstitution.

USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm.
Nursing Mothers: use EXTAVIA with caution.
Pediatric Use: Safety and efficacy not established in patients under 18 years of age.
Geriatric Use: Safety and efficacy not established in patients age 65 years or older.

DOSAGE AND ADMINISTRATION:
For subcutaneous use only.

The recommended dose is 0.25 mg injected subcutaneously every other day. Generally, start at 0.0625 mg (0.25 mL) subcutaneously every other day, and increase over a six week period to 0.25 mg (1 mL) every other day.

Instruct patients in the use of aseptic technique when administering Extavia.

DOSAGE FORMS AND STRENGTHS:
Lyophilized powder containing 0.3 mg of Interferon beta-1b, 15 mg Albumin (Human), USP, and 15 mg Mannitol, USP.

CONTRAINDICATIONS:
History of hypersensitivity to natural or recombinant interferon beta, Albumin (Human), USP, or any other component of the formulation.

WARNINGS AND PRECAUTIONS

• epression and suicide: advise patients to immediately report any symptom of depression and/or suicidal ideation; consider discontinuation of Extavia if depression occurs.
• Injection site necrosis: do not administer Extavia into affected area until it is fully healed; if multiple lesions occur, therapy should be discontinued until healing occurs.
• Injection site reactions.
• Anaphylaxis and other allergic reactions. 
• Flu-Like Symptom Complex.
• Leukopenia: monitor CBC.
• Liver enzymes abnormalities: monitor liver function tests.
• Monitor thyroid function tests every 6 months in patients with history of thyroid dysfunction.

ADVERSE REACTIONS
In controlled studies with interferon beta-1b, the most common adverse reactions (at least 2% more than placebo) were: Lymphopenia, neutropenia, leukopenia, lymphadenopathy, headache, insomnia, incoordination, hypertension, dyspnea, abdominal pain, increased liver enzymes, rash, skin disorder, hypertonia, myalgia, urinary urgency, metrorrhagia, impotence, injection site reaction, asthenia, flu-like symptom complex, pain, fever, chills, peripheral edema, chest pain, malaise, and injection site necrosis

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
No formal drug interaction studies have been conducted.

Initial U.S. Approval:  2017

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.

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:

HOW SUPPLIED:
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–8°C (36°F–46°F) in the outer carton to protect from light. Do not freeze or shake.

Initial U.S. Approval:  2014

Mechanism of Action: The mechanism by which PLEGRIDY exerts its effects in patients with multiple sclerosis is unknown.

INDICATIONS AND USAGE:  PLEGRIDY (peginterferon beta-1a) is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

HOW SUPPLIED:
Pen
Injection: 125 micrograms of PLEGRIDY per 0.5 mL of solution in a single-dose prefilled pen
Injection: Starter Pack containing 63 micrograms per 0.5 mL of solution in a single-dose prefilled pen and 94 micrograms per 0.5 mL solution in a single-dose prefilled pen

Prefilled Syringe
Injection: 125 micrograms of PLEGRIDY per 0.5 mL of solution in a single-dose prefilled syringe
Injection: Starter Pack containing 63 micrograms per 0.5 mL of solution in a single-dose prefilled syringe and 94 micrograms per 0.5 mL of solution in a single-dose prefilled syringe

Initial U.S. Approval:  2012

Mechanism of Action: Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. The exact mechanism by which teriflunomide exerts its therapeutic effect in multiple sclerosis is unknown but may involve a reduction in the number of activated lymphocytes in CNS.

INDICATIONS AND USAGE:  AUBAGIO is a pyrimidine synthesis inhibitor indicated for the treatment of patients with relapsing forms of multiple sclerosis

DOSAGE AND ADMINISTRATION
The recommended dose of AUBAGIO is 7 mg or 14 mg orally once daily. AUBAGIO can be taken with or without food.

Monitoring to assess safety:
Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see Warnings and Precautions (5.1)].
Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms of infection [see Warnings and Precautions (5.4)].
Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test or blood test for mycobacterium tuberculosis infection [see Warnings and Precautions (5.4)].
Check blood pressure before start of AUBAGIO treatment and periodically thereafter [see Warnings and Precautions (5.7)].

WARNINGS:
HEPATOTOXICITY and RISK OF TERATOGENICITY
See full prescribing information for complete boxed warning

CONTRAINDICATIONS:
Severe hepatic impairment
Pregnancy
Current leflunomide treatment

HOW SUPPLIED: 7 mg and 14 mg film-coated tablets