Usual Adult Dose for Multiple Sclerosis

Treatment Initiation:
2 mg orally once a day on Day 1 and 2
3 mg orally once a day on Day 3 and 4
4 mg orally once a day on Day 5 and 6
5 mg orally once a day on Day 7
6 mg orally once a day on Day 8
7 mg orally once a day on Day 9
8 mg orally once a day on Day 10
9 mg orally once a day on Day 11
10 mg orally once a day on Days 12, 13, and 14

Maintenance Dose:
20 mg orally once a day starting on Day 15

Use: For the treatment of adult patients with relapsing forms of multiple sclerosis (MS), to
include clinically isolated syndrome, relapsing-remitting disease, and active secondary
progressive disease

Comments:

• Starter pack must be used for patients initiating treatment (14-day titration pack).
• Patients undergoing therapy initiation may develop a decrease in heart rate.
• Administer the first dose in a setting where resources to properly manage symptomatic bradycardia are available.
• First-dose 4-hour monitoring is recommended for patients with sinus bradycardia [HR less than 55 beats per minute (bpm)], first- or second-degree (Mobitz type I) AV block, or a history of myocardial infarction or heart failure occurring more than 6 months prior to treatment initiation and in stable condition.
• Interruption during treatment, especially during titration, is not recommended.
• Prior to therapy, obtain and review appropriate laboratory tests and medical examinations.
• Establish if patients are taking drugs that could slow heart rate or atrioventricular conduction before starting treatment.
• Consider possible unintended additive immunosuppressive effects before initiating treatment in patients taking or with prior use of anti-neoplastic, immunosuppressive, or immune-modulating therapies.
• Initiating this drug after treatment with alemtuzumab is not recommended.
• Assess vaccination status and test for antibodies to varicella zoster virus (VZV).

Renal Dose Adjustments

No adjustment recommended.

Liver Dose Adjustments

• Mild liver dysfunction (Child-Pugh A): No adjustment recommended.
• Moderate or severe liver dysfunction (Child-Pugh B or C): Not recommended.

Dose Adjustments

Reinitiating Therapy After Treatment Interruption:
If fewer than 4 consecutive doses are missed:

• During titration: Resume treatment with the first missed titration dose and resume the titration schedule at that dose and titration day.
• During maintenance: Resume treatment with the maintenance dosage.

• Treatment should be reinitiated with Day 1 of the titration regimen with a new treatment initiation pack and complete first-dose 4-hour cardiac monitoring as appropriate.

Precautions

CONTRAINDICATIONS:

• Patients who in the last 6 months, have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure.
• Patient who have presence of Mobitz type II second-degree, third-degree atrioventricular (AV) block, or sick sinus syndrome, or sino-atrial block, unless patient has a functioning pacemaker.

Dialysis

This drug has a high plasma protein binding (greater than 99%); therefore, dialysis is not expected to alter the total and unbound drug concentration, and no dose adjustments are anticipated based on these considerations.

Other Comments

Administration advice:

• Do not remove tablets from the blister until use.
• Tablets should be swallowed whole
• This drug may be taken with or without food.

• Store both Starter Pack and Maintenance Dose Bottle in the original package at 20C to 25C (68F to 77F); excursions permitted from 15C to 30C (59F to 86F)

• Assess laboratory tests including complete blood count with differential, liver function tests, and pregnancy testing in women of childbearing age.
• Perform ophthalmic and cardiac evaluations (i.e. electrocardiogram) to assess baseline function and anatomy, and whether pre-existing abnormalities are present.
• Review current and prior medication history, and for possible unintended additive immunosuppressive effects with other medications.
• Assess vaccination status and test patients for antibodies to VZV; VZV vaccination in antibody-negative patients is recommended prior to treatment with this drug.
• Administer live attenuated vaccines at least 1 month prior to initiation of this drug.

• Monitor patients for 4 hours after the first dose for signs and symptoms of bradycardia with at least hourly pulse and blood pressure measurements.
• Continue monitoring after the initial 4 hours if heart rate is less than 45 bpm, is at the lowest value post dose, or a new onset second-degree or higher AV block shows in the ECG, or monitoring until these abnormalities are resolved.
• Monitor for infection during treatment and for 1 to 2 weeks after the last dose.
• Monitor liver enzymes periodically during treatment.
• Monitor for blood pressure during treatment as appropriate.
• Monitor for suspicious skin lesions as appropriate, particularly in patients at risk for skin cancer.

• Read the FDA-approved patient labeling (Medication Guide).
• Initiation of this medication may cause a decrease in heart rate and cardiac monitoring may be required during the first dose.
• This drug may increase your risk for infection; notify your provider if you have any symptoms including fever, tiredness, body aches, chills, nausea, and/or vomiting.
• This medication may cause fetal harm; women of childbearing potential should use effective contraception during therapy and for 1 week after last dose.
• Avoid missed doses; interruption during treatment, especially during titration, is not recommended.
• In general, vaccines may be less effective while taking this medication.
• Avoid immunization with live attenuated vaccines during therapy and for 1 to weeks after treatment