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mechanism of action is Sphingosine 1-Phosphate Receptor Modulators [MoA]

Ponvory

(Ponesimod)

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Dosage & Administration

* Assessments are required prior to initiating PONVORY (

2.1 Assessments Prior to First Dose of PONVORY

Before initiation of treatment with PONVORY, assess the following:

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.

)

* Titration is required for treatment initiation (

2.2 Recommended Dosage

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)]

Table 1: Dose Titration Regimen
Titration Day	Daily Dose
Days 1 and 2	2 mg
Days 3 and 4	3 mg
Days 5 and 6	4 mg
Day 7	5 mg
Day 8	6 mg
Day 9	7 mg
Day 10	8 mg
Day 11	9 mg
Days 12, 13, and 14	10 mg

Maintenance	Daily Dose
Day 15 and thereafter	20 mg

If dose titration is interrupted, missed dose instructions must be followed

[see Dosage and Administration (2.4)]

)

* The recommended maintenance dosage is 20 mg taken orally once daily (

2.2 Recommended Dosage

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)]

Table 1: Dose Titration Regimen
Titration Day	Daily Dose
Days 1 and 2	2 mg
Days 3 and 4	3 mg
Days 5 and 6	4 mg
Day 7	5 mg
Day 8	6 mg
Day 9	7 mg
Day 10	8 mg
Day 11	9 mg
Days 12, 13, and 14	10 mg

Maintenance	Daily Dose
Day 15 and thereafter	20 mg

If dose titration is interrupted, missed dose instructions must be followed

[see Dosage and Administration (2.4)]

)

* First-dose monitoring is recommended for patients with sinus bradycardia, first- or second-degree [Mobitz type I] atrioventricular (AV) block, or a history of myocardial infarction or heart failure (

2.3 First Dose Monitoring in Patients with Certain Preexisting Cardiac Conditions

Because initiation of PONVORY treatment results in a decrease in heart rate (HR), 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

[see Warnings and Precautions (5.3)and Clinical Pharmacology (12.2)]

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)]

)

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Ponvory Prescribing Information

Warnings and Precautions (

5.1 Infections

Risk of Infections

PONVORY causes a dose-dependent reduction in peripheral lymphocyte count to 30–40% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues

[see Clinical Pharmacology (12.2)]

. PONVORY may therefore increase the susceptibility to infections. Life-threatening and rare fatal infections have been reported in association with other sphingosine 1-phosphate (S1P) receptor modulators.

In Study 1

[see Clinical Studies (14)]

, the overall rate of infections was comparable between the PONVORY-treated patients and those receiving teriflunomide 14 mg (54.2% vs 52.1%, respectively). PONVORY increased the risk of upper respiratory tract infections. Serious or severe infections occurred in 1.6% of PONVORY-treated patients compared to 0.9% of patients receiving teriflunomide 14 mg.

Before initiating treatment with PONVORY, results from a recent (i.e., within 6 months or after discontinuation of prior therapy) complete blood count including lymphocyte count should be reviewed.

Initiation of treatment with PONVORY should be delayed in patients with active infection until resolution. Lymphocyte counts returned to the normal range in 90% of patients within 1 week of stopping therapy in modeling studies

[see Clinical Pharmacology (12.2)]

. In Study 1, peripheral lymphocyte counts returned to normal range within 2 weeks after discontinuation of PONVORY, which was the first timepoint evaluated. Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for 1 to 2 weeks after discontinuation of PONVORY, vigilance for infection should be continued for 1 to 2 weeks after PONVORY is discontinued

[see Warnings and Precautions (5.12)].

In Study 1, the proportion of patients who experienced lymphocyte counts less than 0.2×10⁹/L was 3.2%. Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Consider interruption of treatment with PONVORY if a patient develops a serious infection.

Herpes Viral Infections

Cases of herpes viral infection have been reported in the development program of PONVORY; herpes simplex encephalitis and varicella zoster meningitis have been reported with other S1P receptor modulators.

In Study 1, the rate of herpetic infections was 4.8% for both PONVORY-treated patients and those receiving teriflunomide 14 mg. Patients without a healthcare professional confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating PONVORY

(see Vaccinations)

Cryptococcal Infections

Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with other S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. PONVORY treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. 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.

PML has been reported in patients treated with S1P receptor modulators and other multiple sclerosis (MS) therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptoms or magnetic resonance imaging (MRI) findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with PONVORY should be suspended until PML has been excluded.

If PML is confirmed, treatment with PONVORY should be discontinued.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient's condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

Prior and Concomitant Treatment with Anti-neoplastic, Immune-Modulating, or Immunosuppressive Therapies

Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be coadministered with caution because of the risk of additive immune system effects

[see Drug Interactions (7.1)]

Vaccinations

Patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating PONVORY treatment. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with PONVORY, following which initiation of treatment with PONVORY should be postponed for 4 weeks to allow the full effect of vaccination to occur.

No clinical data are available on the efficacy and safety of vaccinations in patients taking PONVORY. Vaccinations may be less effective if administered during PONVORY treatment.

If live

attenuated

vaccine immunizations are required, administer at least 1 month prior to initiation of PONVORY. Avoid the use of live

attenuated

vaccines during and for 1 to 2 weeks after treatment with PONVORY.

5.11 Severe Increase in Disability After Stopping PONVORY

Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping PONVORY treatment. Patients should be observed for a severe increase in disability upon PONVORY discontinuation and appropriate treatment should be instituted, as required.

After stopping PONVORY in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS)

[see Warnings and Precautions (5.1)]

)

08/2023

Assessments are required prior to initiating PONVORY (

2.1 Assessments Prior to First Dose of PONVORY
Before initiation of treatment with PONVORY, assess the following:
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.
)
Titration is required for treatment initiation (

2.2 Recommended Dosage
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)]
.
Table 1: Dose Titration Regimen
Titration Day Daily Dose
Days 1 and 2 2 mg
Days 3 and 4 3 mg
Days 5 and 6 4 mg
Day 7 5 mg
Day 8 6 mg
Day 9 7 mg
Day 10 8 mg
Day 11 9 mg
Days 12, 13, and 14 10 mg
Maintenance Daily Dose
Day 15 and thereafter 20 mg
If dose titration is interrupted, missed dose instructions must be followed
[see Dosage and Administration (2.4)]
.
)
The recommended maintenance dosage is 20 mg taken orally once daily (

2.2 Recommended Dosage
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)]
.
Table 1: Dose Titration Regimen
Titration Day Daily Dose
Days 1 and 2 2 mg
Days 3 and 4 3 mg
Days 5 and 6 4 mg
Day 7 5 mg
Day 8 6 mg
Day 9 7 mg
Day 10 8 mg
Day 11 9 mg
Days 12, 13, and 14 10 mg
Maintenance Daily Dose
Day 15 and thereafter 20 mg
If dose titration is interrupted, missed dose instructions must be followed
[see Dosage and Administration (2.4)]
.
)
First-dose monitoring is recommended for patients with sinus bradycardia, first- or second-degree [Mobitz type I] atrioventricular (AV) block, or a history of myocardial infarction or heart failure (
2.3 First Dose Monitoring in Patients with Certain Preexisting Cardiac Conditions
Because initiation of PONVORY treatment results in a decrease in heart rate (HR), 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
[see Warnings and Precautions (5.3)and Clinical Pharmacology (12.2)]
.
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)]
)

PONVORY is available as round, biconvex, film-coated tablets for oral use. PONVORY contains ponesimod in the following dosage strengths (see

Table 2: Dosage Form and Strengths for PONVORY
Tablet Strength	Tablet Color	Tablet Size	Tablet Debossing
2 mg	White	5.0 mm	"2" on one side and an arch on the other side.
3 mg	Red	5.0 mm	"3" on one side and an arch on the other side.
4 mg	Purple	5.0 mm	"4" on one side and an arch on the other side.
5 mg	Green	8.6 mm	"5" on one side and an arch and an "A" on the other side.
6 mg	White	8.6 mm	" 6 " on one side and an arch and an "A" on the other side.
7 mg	Red	8.6 mm	"7" on one side and an arch and an "A" on the other side.
8 mg	Purple	8.6 mm	"8" on one side and an arch and an "A" on the other side.
9 mg	Brown	8.6 mm	" 9 " on one side and an arch and an "A" on the other side.
10 mg	Orange	8.6 mm	"10" on one side and an arch and an "A" on the other side.
20 mg	Yellow	8.6 mm	"20" on one side and an arch and an "A" on the other side.

Table 2: Dosage Form and Strengths for PONVORY
Tablet Strength	Tablet Color	Tablet Size	Tablet Debossing
2 mg	White	5.0 mm	"2" on one side and an arch on the other side.
3 mg	Red	5.0 mm	"3" on one side and an arch on the other side.
4 mg	Purple	5.0 mm	"4" on one side and an arch on the other side.
5 mg	Green	8.6 mm	"5" on one side and an arch and an "A" on the other side.
6 mg	White	8.6 mm	" 6 " on one side and an arch and an "A" on the other side.
7 mg	Red	8.6 mm	"7" on one side and an arch and an "A" on the other side.
8 mg	Purple	8.6 mm	"8" on one side and an arch and an "A" on the other side.
9 mg	Brown	8.6 mm	" 9 " on one side and an arch and an "A" on the other side.
10 mg	Orange	8.6 mm	"10" on one side and an arch and an "A" on the other side.
20 mg	Yellow	8.6 mm	"20" on one side and an arch and an "A" on the other side.

Hepatic Impairment

: PONVORY is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B and C). (

8.6 Hepatic Impairment

No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A)

[see Clinical Pharmacology (12.3)]

PONVORY is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B and C, respectively), as the risk of adverse reactions may be greater

[see Clinical Pharmacology (12.3)]

)

PONVORY is contraindicated in 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
[see
5.2 Bradyarrhythmia and Atrioventricular Conduction Delays
Since initiation of PONVORY treatment results in a transient decrease in heart rate and atrioventricular (AV) conduction delays, an up-titration scheme must be used to reach the maintenance dosage of PONVORY (20 mg)
[see Dosage and Administration (2.2)and Clinical Pharmacology (12.2)]
.
Study 1 did not include patients who had:
A resting heart rate (HR) less than 50 beats per minute (bpm) on baseline electrocardiogram
Myocardial infarction or unstable ischemic heart disease in the last 6 months
Cardiac failure (New York Heart Association class III–IV) or presence of any severe cardiac disease
Cardiac conduction or rhythm disorders (including sino-atrial heart block, symptomatic bradycardia, atrial flutter or atrial fibrillation, ventricular arrhythmia, cardiac arrest) either in history or observed at screening
Mobitz Type II second degree AV block or higher-grade AV block observed at screening
QTcF interval greater than 470 ms (females) and greater than 450 ms (males) observed at screening
History of syncope associated with cardiac disorders
Uncontrolled systemic arterial hypertension
Reduction in Heart Rate
Initiation of PONVORY may result in a transient decrease in HR. In Study 1, bradycardia at treatment initiation and sinus bradycardia on ECG (defined as HR less than 50 bpm) occurred in 5.8% of PONVORY-treated patients compared to 1.6% of patients receiving teriflunomide 14 mg. After the first titration dose of PONVORY, the decrease in heart rate typically begins within an hour and reaches its nadir within 2–4 hours. The heart rate typically recovers to baseline levels 4–5 hours after administration. The mean decrease in heart rate on Day 1 of dosing was 6 bpm. With up-titration after Day 1, the post-dose decrease in heart rate is less pronounced. Bradycardia resolved in all patients in Study 1 without intervention and did not require discontinuation of PONVORY treatment. On Day 1, 3 patients treated with PONVORY had asymptomatic post-dose HR below or equal to 40 bpm; all 3 patients had baseline HRs below 55 bpm.
Atrioventricular Conduction Delays
Initiation of PONVORY treatment has been associated with transient atrioventricular conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration. In Study 1, the AV conduction delays manifested as first-degree AV block (prolonged PR interval on ECG), which occurred in 3.4% of PONVORY-treated patients and in 1.2% of patients receiving teriflunomide 14 mg. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, resolved without intervention, and did not require discontinuation of PONVORY treatment. In Study 1, second- and third-degree AV blocks were not reported in patients treated with PONVORY.
If treatment with PONVORY is considered, advice from a cardiologist should be sought for individuals:
With significant QT prolongation (QTc greater than 500 msec)
With atrial flutter/fibrillation or arrhythmia treated with Class Ia or Class III anti-arrhythmic drugs
[see Drug Interactions (7.2)]
With unstable ischemic heart disease, cardiac decompensated failure occurring more than 6 months prior to treatment initiation, history of cardiac arrest, cerebrovascular disease (TIA, stroke occurring more than 6 months prior to treatment initiation), or uncontrolled hypertension
With a history of Mobitz Type II second degree AV block or higher-grade AV block, sick-sinus syndrome, or sino-atrial heart block
[see Contraindications (4)]
Treatment Initiation Recommendations
Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present.
In all patients, a dose titration is recommended for initiation of PONVORY treatment to help reduce cardiac effects
[see Dosage and Administration (2.2)]
.
In patients with sinus bradycardia, first-or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset more than 6 months prior to initiation, first-dose monitoring is recommended
[see Dosage and Administration (2.1, 2.3)]
.
PONVORY is not recommended in patients with a history of cardiac arrest, cerebrovascular disease (e.g., TIA, stroke occurring more than 6 months prior to treatment initiation), uncontrolled hypertension, or severe untreated sleep apnea, since significant bradycardia may be poorly tolerated in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy.
Use of PONVORY in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring.
Experience with PONVORY is limited in patients receiving concurrent therapy with drugs that decrease heart rate (e.g., beta-blockers, non-dihydropyridine calcium channel blockers - diltiazem and verapamil, and other drugs that may decrease heart rate such as digoxin). Concomitant use of these drugs during PONVORY initiation may be associated with severe bradycardia and heart block. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring.
For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing PONVORY treatment. If the resting heart rate is greater than 55 bpm under chronic beta-blocker treatment, PONVORY can be introduced. If resting heart rate is less than or equal to 55 bpm, beta-blocker treatment should be interrupted until the baseline heart rate is greater than 55 bpm. Treatment with PONVORY can then be initiated and treatment with a beta-blocker can be reinitiated after PONVORY has been up-titrated to the target maintenance dosage
[see Drug Interactions (7.3)]
.
For patients taking other drugs that decrease heart rate, treatment with PONVORY should generally not be initiated without consultation from a cardiologist because of the potential additive effect on heart rate
[see Dosage and Administration (2.3)and Drug Interactions (7.2)]
.
Missed Dose During Treatment Initiation or Maintenance Treatment
If 4 or more consecutive daily doses are missed during treatment initiation or maintenance treatment, reinitiate Day 1 of the dose titration (new starter pack) and follow first-dose monitoring recommendations
[see Dosage and Administration (2.4)]
.
]
Have presence of Mobitz type II second-degree, third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless patient has a functioning pacemaker
[see
5.2 Bradyarrhythmia and Atrioventricular Conduction Delays
Since initiation of PONVORY treatment results in a transient decrease in heart rate and atrioventricular (AV) conduction delays, an up-titration scheme must be used to reach the maintenance dosage of PONVORY (20 mg)
[see Dosage and Administration (2.2)and Clinical Pharmacology (12.2)]
.
Study 1 did not include patients who had:
A resting heart rate (HR) less than 50 beats per minute (bpm) on baseline electrocardiogram
Myocardial infarction or unstable ischemic heart disease in the last 6 months
Cardiac failure (New York Heart Association class III–IV) or presence of any severe cardiac disease
Cardiac conduction or rhythm disorders (including sino-atrial heart block, symptomatic bradycardia, atrial flutter or atrial fibrillation, ventricular arrhythmia, cardiac arrest) either in history or observed at screening
Mobitz Type II second degree AV block or higher-grade AV block observed at screening
QTcF interval greater than 470 ms (females) and greater than 450 ms (males) observed at screening
History of syncope associated with cardiac disorders
Uncontrolled systemic arterial hypertension
Reduction in Heart Rate
Initiation of PONVORY may result in a transient decrease in HR. In Study 1, bradycardia at treatment initiation and sinus bradycardia on ECG (defined as HR less than 50 bpm) occurred in 5.8% of PONVORY-treated patients compared to 1.6% of patients receiving teriflunomide 14 mg. After the first titration dose of PONVORY, the decrease in heart rate typically begins within an hour and reaches its nadir within 2–4 hours. The heart rate typically recovers to baseline levels 4–5 hours after administration. The mean decrease in heart rate on Day 1 of dosing was 6 bpm. With up-titration after Day 1, the post-dose decrease in heart rate is less pronounced. Bradycardia resolved in all patients in Study 1 without intervention and did not require discontinuation of PONVORY treatment. On Day 1, 3 patients treated with PONVORY had asymptomatic post-dose HR below or equal to 40 bpm; all 3 patients had baseline HRs below 55 bpm.
Atrioventricular Conduction Delays
Initiation of PONVORY treatment has been associated with transient atrioventricular conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration. In Study 1, the AV conduction delays manifested as first-degree AV block (prolonged PR interval on ECG), which occurred in 3.4% of PONVORY-treated patients and in 1.2% of patients receiving teriflunomide 14 mg. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, resolved without intervention, and did not require discontinuation of PONVORY treatment. In Study 1, second- and third-degree AV blocks were not reported in patients treated with PONVORY.
If treatment with PONVORY is considered, advice from a cardiologist should be sought for individuals:
With significant QT prolongation (QTc greater than 500 msec)
With atrial flutter/fibrillation or arrhythmia treated with Class Ia or Class III anti-arrhythmic drugs
[see Drug Interactions (7.2)]
With unstable ischemic heart disease, cardiac decompensated failure occurring more than 6 months prior to treatment initiation, history of cardiac arrest, cerebrovascular disease (TIA, stroke occurring more than 6 months prior to treatment initiation), or uncontrolled hypertension
With a history of Mobitz Type II second degree AV block or higher-grade AV block, sick-sinus syndrome, or sino-atrial heart block
[see Contraindications (4)]
Treatment Initiation Recommendations
Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present.
In all patients, a dose titration is recommended for initiation of PONVORY treatment to help reduce cardiac effects
[see Dosage and Administration (2.2)]
.
In patients with sinus bradycardia, first-or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset more than 6 months prior to initiation, first-dose monitoring is recommended
[see Dosage and Administration (2.1, 2.3)]
.
PONVORY is not recommended in patients with a history of cardiac arrest, cerebrovascular disease (e.g., TIA, stroke occurring more than 6 months prior to treatment initiation), uncontrolled hypertension, or severe untreated sleep apnea, since significant bradycardia may be poorly tolerated in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy.
Use of PONVORY in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring.
Experience with PONVORY is limited in patients receiving concurrent therapy with drugs that decrease heart rate (e.g., beta-blockers, non-dihydropyridine calcium channel blockers - diltiazem and verapamil, and other drugs that may decrease heart rate such as digoxin). Concomitant use of these drugs during PONVORY initiation may be associated with severe bradycardia and heart block. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring.
For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing PONVORY treatment. If the resting heart rate is greater than 55 bpm under chronic beta-blocker treatment, PONVORY can be introduced. If resting heart rate is less than or equal to 55 bpm, beta-blocker treatment should be interrupted until the baseline heart rate is greater than 55 bpm. Treatment with PONVORY can then be initiated and treatment with a beta-blocker can be reinitiated after PONVORY has been up-titrated to the target maintenance dosage
[see Drug Interactions (7.3)]
.
For patients taking other drugs that decrease heart rate, treatment with PONVORY should generally not be initiated without consultation from a cardiologist because of the potential additive effect on heart rate
[see Dosage and Administration (2.3)and Drug Interactions (7.2)]
.
Missed Dose During Treatment Initiation or Maintenance Treatment
If 4 or more consecutive daily doses are missed during treatment initiation or maintenance treatment, reinitiate Day 1 of the dose titration (new starter pack) and follow first-dose monitoring recommendations
[see Dosage and Administration (2.4)]
.
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