Complete Blood Count

Obtain a recent (i.e., within the last 6 months or after discontinuation of prior MS therapy) complete blood count (CBC), including lymphocyte count [see Warnings and Precautions (5.1)] .

Cardiac Evaluation

Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist should be sought and first-dose monitoring is recommended [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)] .

Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction [see Warnings and Precautions (5.2)] and Drug Interactions (7.2, 7.3)] .

Liver Function Tests

Obtain recent (i.e., within the last 6 months) transaminase and bilirubin levels [see Warnings and Precautions (5.4)] .

Ophthalmic Evaluation

Obtain an evaluation of the fundus, including the macula [see Warnings and Precautions (5.8)] .

Current or Prior Medications with Immune System Effects

If patients are taking anti-neoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with PONVORY [see Warnings and Precautions (5.1, 5.10) and Drug Interactions (7.1)] .

Vaccinations

Test patients for antibodies to varicella zoster virus (VZV) before initiating PONVORY; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with PONVORY [see Warnings and Precautions (5.1)] . If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of PONVORY.

Maintenance Dosage

After dose titration is complete (see Treatment Initiation) , the recommended maintenance dosage of PONVORY is 20 mg taken orally once daily starting on Day 15.

Administer PONVORY orally once daily. Swallow the tablet whole. PONVORY can be taken with or without food.

Treatment Initiation

A starter pack must be used for patients initiating treatment with PONVORY [see How Supplied/Storage and Handling (16.1)] . Initiate PONVORY treatment with a 14-day titration; start with one 2 mg tablet orally once daily and progress with the titration schedule as shown in Table 1 [see Warnings and Precautions (5.2)] .

If dose titration is interrupted, missed dose instructions must be followed [see Dosage and Administration (2.4)] .

First Dose 4-Hour Monitoring

Administer the first dose of PONVORY in a setting where resources to appropriately manage symptomatic bradycardia are available. Monitor patients for 4 hours after the first dose for signs and symptoms of bradycardia with a minimum of hourly pulse and blood pressure measurements. Obtain an ECG in these patients prior to dosing and at the end of the 4-hour observation period.

Additional Monitoring After 4-Hour Monitoring

If any of the following abnormalities are present after 4 hours (even in the absence of symptoms), continue monitoring until the abnormality resolves:

• The heart rate 4 hours post-dose is less than 45 bpm
• The heart rate 4 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 4 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 4 hours post-dose shows new onset second degree or higher AV block or QTc greater than or equal to 500 msec, initiate appropriate management, begin continuous ECG monitoring, and continue monitoring until the symptoms have resolved if no pharmacological treatment is required. If pharmacological treatment is required, continue monitoring overnight and repeat 4-hour monitoring after the second dose.

Advice from a cardiologist should be sought to determine the most appropriate monitoring strategy (which may include overnight monitoring) during treatment initiation, if treatment with PONVORY is considered in patients:

• With some preexisting heart and cerebrovascular conditions [see Warnings and Precautions (5.2)]
• With a prolonged QTc interval before dosing or during the 4-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 [see Warnings and Precautions (5.2) and Drug Interactions (7.2)]
• Receiving concurrent therapy with drugs that slow heart rate or AV conduction [see Drug Interactions (7.2, 7.3)]