Usual Adult Dose for Multiple Sclerosis

CYP450 2C9 Genotype *1/*1, *1/*2, or *2/*2:

• Titration regimen: 0.25 mg orally once daily on Days 1 and 2, then 0.5 mg orally once daily on Day 3, then 0.75 mg orally once daily on Day 4, then 1.25 mg orally once daily on Day 5
• Maintenance dose: 2 mg orally once daily beginning on Day 6

NOTE: Use a starter pack for patients who will be titrated to the 2 mg maintenance dose.

CYP450 2C9 Genotype *1/*3 or *2/*3:

• Titration regimen: 0.25 mg orally once daily on Days 1 and 2, then 0.5 mg orally once daily on Day 3, then 0.75 mg orally once daily on Day 4
• Maintenance dose: 1 mg orally once daily beginning on Day 5

NOTE: Do not use the starter pack for patients who will be titrated to the 1 mg maintenance dose.

• If one titration dose is missed for more than 24 hours, therapy needs to be reinitiated with Day 1 of the titration regimen.

Comments:

• If one titration dose is missed for more than 24 hours, therapy needs to be reinitiated with Day 1 of the titration regimen.
• First-dose monitoring is recommended for patients with sinus bradycardia, first- or second-degree atrioventricular (AV) block, or a history of myocardial infarction or heart failure.
• Administer the first dose in a setting equipped to manage symptomatic bradycardia.
• Monitor patients for 6 hours after the first dose for bradycardia with hourly pulse and blood pressure measurements. Obtain an ECG in these patients at the end of Day 1.
• If any of the following abnormalities are present after 6 hours (even in the absence of symptoms), continue monitoring until the abnormality resolves: the heart rate 6 hours post dose is less than 45 bpm; the heart rate 6 hours post dose is at the lowest value post dose, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred; the ECG 6 hours post

dose shows new onset second-degree or higher AV block.

• If post dose symptomatic bradycardia, bradyarrhythmia, or conduction related symptoms occur, or if ECG 6 hours post dose shows new onset second degree or higher AV block or QTc greater than or equal to 500 msec, initiate management, begin continuous ECG monitoring, and continue monitoring until the symptoms have resolved if no treatment is required. If treatment is required, continue monitoring overnight and repeat 6-hour monitoring after the second dose.
• After the initial titration is complete, if treatment is interrupted for 4 or more consecutive daily doses, reinitiate therapy with Day 1 of the titration regimen; also complete first-dose monitoring in patients for whom it is recommended.

Use: For relapsing forms of multiple sclerosis (MS) including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults

Renal Dose Adjustments

No adjustment recommended.

Liver Dose Adjustments

No adjustment recommended.

Precautions

CONTRAINDICATIONS:

• Patients with a CYP450 2C9*3/*3 genotype.
• Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III or IV heart failure
• Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

This drug is 99.9% bound to plasma proteins; therefore, hemodialysis is not expected to alter the total and unbound concentration and no dose adjustments are recommended.

Other Comments

Administration advice:

• Before initiation of this drug, test patients to determine CYP450 2C9 genotype.
• Review results of a recent complete blood count (CBC).
• Obtain an evaluation of the fundus, including the macula.
• Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist and first-dose monitoring is recommended.
• Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction.
• If patients are taking antineoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible additive immunosuppressive effects before initiating this drug.
• Test for antibodies to varicella zoster virus (VZV) before initiating this drug. VZV vaccination of antibody-negative patients is recommended prior to therapy initiation.
• Obtain recent (i.e., within last 6 months) transaminase and bilirubin levels.
• Advice from a cardiologist should be sought to determine the best monitoring strategy (which may include overnight monitoring) during therapy initiation, if this drug is considered in patients with some preexisting heart and cerebrovascular conditions OR with a prolonged QTc interval before dosing or during the 6-hour observation, or at additional risk for QT prolongation, or on concurrent therapy with QT prolonging drugs with a known risk of Torsades de pointes OR receiving concurrent therapy with drugs that slow heart rate or AV conduction.

Storage requirements:

• Store unopened containers in a refrigerator at 2C to 8C (36F to 46F).
• Store the starter pack at 20C to 25C (68F to 77F) for up to 1 week after opening the blister. Store in original container.
• Store bottles at 20C to 25C (68F to 77F) for up to 1 month after opening the bottles.

Patient advice:

• Read the patient labeling before taking this drug.
• Do not discontinue this drug without first discussing it with the healthcare provider.
• Contact your healthcare provider immediately if you accidentally take more of this drug than prescribed.

Frequently asked questions

• What are the new drugs used for multiple sclerosis (MS)?