DRUG INTERACTIONS(summary)

 • Vaccines: Avoid live attenuated vaccines during and for up to 1-2 weeks after treatment with PONVORY

 • Strong CYP3A4 and UGT1A1 Inducers: Coadministration with PONVORY is not recommended. 

BRIEF SUMMARY

PONESIMOD-(Mar 2021)

Indn-  To treat patients with relapsing forms of multiple  sclerosis

Comp-  Tablets: 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, and 20 

 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

ADR- Most common adverse reactions are upper respiratory tract infection, hepatic transaminase elevation, and hypertension.

CI-  Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker

WARNINGS-

 • Infections:  may increase the risk of infections. Obtain a complete blood count (CBC) before initiating treatment. Monitor for infection during treatment and for 1-2 weeks after discontinuation. Do not start  in patients with active infection. 

Pat nform-

Instruct patients to administer tablets whole.

Risk of Infections- Inform patients that they may have an increased risk of infections, some of which could be life-threatening, when taking  and for 1 to 2 weeks after stopping it, and that they should contact their doctor  if they develop symptoms of infection

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 13

Name of the Drug-    PONVORY

Active Ingredient -   Ponesimod

Pharmacological Classification-   To treat patients with relapsing forms of multiple                                                                sclerosis

                                                                                                                                               Date of Approval-          3/18/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                      PONVORY safely and effectively.                                                                                  See full prescribing information for PONVORY. PONVORYTM (ponesimod) tablets, for oral use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE

 PONVORY is a sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. (1) -----

DOSAGE AND ADMINISTRATION

 • Assessments are required prior to initiating PONVORY

 • Titration is required for treatment initiation

 • The recommended maintenance dosage is 20 mg taken orally once dail

 • 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

DOSAGE FORMS AND STRENGTHS

 Tablets: 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, and 20 mg

CONTRAINDICATIONS

 • In the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III/IV heart failure (4) • Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker (4) -------------

WARNINGS AND PRECAUTIONS

---------------------- • Infections: PONVORY may increase the risk of infections. Obtain a complete blood count (CBC) before initiating treatment. Monitor for infection during treatment and for 1-2 weeks after discontinuation. Do not start PONVORY in patients with active infection. (5.1

ADVERSE REACTIONS-

 Most common adverse reactions (incidence at least 10%) are upper respiratory tract infection, hepatic transaminase elevation, and hypertension.

CONTRAINDICATIONS

 • In the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III/IV heart failure

 • Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker

WARNINGS AND PRECAUTIONS

 • Infections: PONVORY may increase the risk of infections. Obtain a complete blood count (CBC) before initiating treatment. Monitor for infection during treatment and for 1-2 weeks after discontinuation. Do not start PONVORY in patients with active infection. 

• Bradyarrhythmia and Atrioventricular Conduction Delays: PONVORY may result in a transient decrease in heart rate; titration is required for treatment initiation.       Check an electrocardiogram (ECG) to assess for preexisting cardiac conduction abnormalities before starting PONVORY.                                                               Consider cardiology consultation for conduction abnormalities or concomitant use with other drugs that decrease heart rate. 

 • Respiratory Effects: May cause a decline in pulmonary function. Assess pulmonary function (e.g., spirometry) if clinically indicated.

 • Liver Injury: Discontinue if significant liver injury is confirmed. Obtain liver function tests before initiating PONVORY.

 • Increased Blood Pressure (BP): Monitor BP during treatment.

 • Cutaneous Malignancies: Periodic skin examination is recommended.

 • Fetal Risk: Women of childbearing potential should use effective contraception during and for 1 week after stopping PONVORY

 • Macular Edema: An ophthalmic evaluation is recommended before starting treatment and if there is any change in vision while taking PONVORY. Diabetes mellitus and uveitis increase the risk.

DOSAGE AND ADMINISTRATION

 • Assessments are required prior to initiating PONVORY

 • Titration is required for treatment initiation

 • The recommended maintenance dosage is 20 mg taken orally once dail

 • 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

DOSAGE FORMS AND STRENGTHS

 Tablets: 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, and 20 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide). 

Administration Tell patients not to discontinue PONVORY without first discussing this with the prescribing healthcare provider.

Advise patients to contact their healthcare provider if they accidently take more PONVORY than prescribed.

Instruct patients to administer tablets whole.

Risk of Infections Inform patients that they may have an increased risk of infections, some of which could be life-threatening, when taking PONVORY and for 1 to 2 weeks after stopping it, and that they should contact their healthcare provider if they develop symptoms of infection 

Advise patients that the use of some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with PONVORY, and PONVORY should be paused 1 week prior and until 4 weeks after a planned vaccination.

Recommend that patients postpone treatment with PONVORY for at least 1 month after VZV vaccination. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.

Cardiac Effects Advise patients that initiation of PONVORY treatment results in transient decrease in heart rate [see Warnings and Precautions (5.2)].

Inform patients that to reduce this effect, dose titration is required. Advise patients that dose titration is also required if 4 or more consecutive daily doses are missed during treatment initiation or maintenance treatment 

. Inform certain patients with certain preexisting cardiac conditions that they will need to be observed in the doctor's office or other facility for at least 4 hours after the first dose and after reinitiation if treatment is interrupted or discontinued for certain periods 

Respiratory Effects Advise patients that they should contact their healthcare provider if they experience new onset or worsening of dyspnea [see Warnings and Precautions (5.3)].

Liver Injury Inform patients that PONVORY may increase liver enzymes. Advise patient that they should contact their healthcare provider if they experience any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during treatment [see Warnings and Precautions (5.4)].

Cutaneous Malignancies Inform patients that the risk of basal cell carcinoma is increased with the use of PONVORY and that cases of melanoma and squamous cell carcinoma have been reported.

Advise patients that any suspicious skin lesions should be promptly evaluated. Advise patients to limit exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with high protection factor 

Pregnancy and Fetal Risk Inform patients that, based on animal studies, PONVORY may cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant.

Advise women of childbearing potential of the need for effective contraception during treatment with PONVORY and for one week after stopping PONVORY. Advise a female patient to immediately inform her healthcare provider if she is pregnant or planning to become pregnant [see Warnings and Precautions (5.7)].

Macular Edema Advise patients that PONVORY may cause macular edema, and that they should contact their healthcare provider if they experience any changes in their vision while taking PONVORY [see Warnings and Precautions (5.8)].

Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema is increased.

Posterior Reversible Encephalopathy Syndrome Advise patients to immediately report to their healthcare provider any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure.

Inform patients that delayed treatment could lead to permanent neurological sequelae 

Severe Increase in Disability After Stopping PONVORY Inform patients that severe increase in disability has been reported after discontinuation of another S1P receptor modulator like PONVORY.

Advise patients to contact their healthcare provider if they develop worsening symptoms of MS following discontinuation of PONVORY 

Immune System Effects After Stopping PONVORY Advise patients that PONVORY continues to have effects, such as lowering effects on peripheral lymphocyte count, for 1 to 2 weeks after the last dose 

Active ingredient made in Austria.

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 © 2021 Janssen Pharmaceutical Companies

 CLINICAL PHARMACOLOGY

1. Mechanism of Action -                                                                                            Ponesimod is a sphingosine 1-phosphate (S1P) receptor 1 modulator that binds with high affinity to S1P receptor 1. Ponesimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood.

The mechanism by which ponesimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

2 Pharmacodynamics-                                                                                                   Immune System In healthy volunteers, PONVORY induces a dose-dependent reduction of the peripheral blood lymphocyte count from a single dose of 5 mg onwards, with the greatest reduction observed 6 hours post-dose, caused by reversible sequestration of lymphocytes in lymphoid tissues.

Cardiac Electrophysiology-                                                                                              In a thorough QT study, daily administration of ponesimod doses of 40 mg and 100 mg (respectively 2- and 5-fold the recommended maintenance dose) until steady-state conditions were achieved resulted in prolongation of Fridericia-corrected QT (QTcF) intervals, with the maximum mean (upper bound of 90% two-sided confidence interval) at 11.8 ms (40 mg) and 16.2 ms (100 mg).

3. Pharmacokinetics-                                                                                                   Following ponesimod oral dosing, Cmax and AUC increased approximately dose-proportionally in the dose-range studied (1-75 mg).

Steady-state levels are approximately 2.0- to 2.6-fold greater than with a single dose, and are achieved following 3 days of administration of the maintenance dose of ponesimod.                                                                                                                        The pharmacokinetics of ponesimod are similar in healthy subjects and patients with multiple sclerosis, with 25% inter-subject variability across studies.

Absorption-                                                                                                                    The time to reach maximum plasma concentration of ponesimod is 2-4 hours post-dose. The absolute oral bioavailability of a 10 mg dose is 84%.

Food Effect -                                                                                                                      Food does not have a clinically relevant effect on ponesimod pharmacokinetics; therefore, PONVORY may be taken with or without food.

Distribution-                                                                                                                Following IV administration in healthy subjects, the steady-state volume of distribution of ponesimod is 160 L. Ponesimod is highly bound to plasma proteins (> 99%) and is mainly (78.5%) distributed in the plasma fraction of whole blood..

Metabolism-                                                                                                                   Ponesimod is extensively metabolized prior to excretion in humans, though unchanged ponesimod was the main circulating component in plasma.

Two inactive circulating metabolites, M12 and M13, have also been identified in human plasma. M13 and M12 are respectively about 20% and 6% of total drug-related exposure.

Excretion -                                                                                                                         After a single IV administration, the total clearance of ponesimod is 3.8 L/hour.

The elimination half-life after oral administration is approximately 33 hours. Following a single oral administration of 14C-ponesimod, 57% to 80% of the dose was recovered in feces (16% as unchanged ponesimod), and 10% to 18% in urine (no unchanged ponesimod).

Specific Populations-                                                                                                Renal Impairment-                                                                                                          No dose adjustment is necessary in patients with renal impairment. In adult subjects with moderate or severe renal impairment (estimated creatinine clearance [CrCl], as determined by the Cockroft-Gault, between 30-59 mL/min for moderate and <30 mL/min for severe), there were no significant changes in ponesimod Cmax and AUC, compared to subjects with normal renal function (CrCl>90 mL/min). The effect of dialysis on the PK of ponesimod has not been studied.

Hepatic Impairment -                                                                                                       In adult subjects with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B and C, respectively), no change in ponesimod Cmax was observed, but ponesimod AUC0-8 was increased by 1.3-, 2.0-, and 3.1-fold, respectively, compared to healthy subjects

Use in Specific Populations- 

Age-                                                                                                                                     Age (range: 17 to 65 years) was not identified to significantly influence the PK of ponesimod in population pharmacokinetics analyses. The effect of age (65 years of age and older) on the pharmacokinetics of ponesimod is unknown

Gender-                                                                                                                              Gender has no clinically significant influence on ponesimod pharmacokinetics.   

 Race -                                                                                                                             No clinically relevant pharmacokinetic differences were observed between Japanese and Caucasian subjects.

Drug Interaction Studies-

Beta-Blockers- In a drug-drug interaction study, the dose titration regimen of ponesimod] was administered to subjects receiving propranolol (80 mg) once daily at steady state. No significant changes in pharmacokinetics of ponesimod or propranolol were observed.

Compared to ponesimod alone, the combination of propranolol and the first dose of ponesimod (2 mg) led to a mean hourly heart rate decrease of 12.4 bpm (90% CI: -15.6 to -9.1).

Compared to ponesimod alone, propranolol administered in combination with the first maintenance dose of ponesimod (20 mg) led to a 7.4 bpm (90% CI: -10.9 to -3.9) mean hourly heart rate decrease.

Effect of Other Drugs on Ponesimod -

In vitro studies with human liver preparations indicate that metabolism of ponesimod occurs through multiple distinct enzyme systems, including multiple CYP450 (CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12), UGT (mainly UGT1A1 and UGT2B7), and non-CYP450 oxidative enzymes, without major contribution by any single enzyme.

 Effect of Ponesimod on Other Drugs-                                                                           In vitro investigations indicate that at the recommended dose of 20 mg once-daily, ponesimod and its metabolite M13 do not show any clinically relevant drug-drug interaction potential for CYP or UGT enzymes, or transporters.

Oral Contraceptives-                                                                                                 Coadministration of ponesimod with an oral hormonal contraceptive (containing 1 mg norethisterone/norethindrone and 35 µg ethinyl estradiol) showed no clinically relevant pharmacokinetic interaction with ponesimod.

Therefore, concomitant use of ponesimod is not expected to decrease the efficacy of hormonal contraceptives.

No interaction studies have been performed with oral contraceptives containing other progestogens; however, an effect of ponesimod on their exposure is not expected. 

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                       There are no adequate and well-controlled studies of PONVORY in pregnant women. In animal studies, administration of ponesimod during pregnancy produced adverse effects on development, including embryo lethality and fetal malformations, in the absence of maternal toxicity.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

2. Lactation Risk Summary-                                                                                              There are no data on the presence of PONVORY in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PONVORY and any potential adverse effects on the breastfed infant from PONVORY or from the underlying maternal condition.

3. Females and Males of Reproductive Potential

Contraception Females- Before initiation of PONVORY treatment, women of childbearing potential should be counseled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with PONVORY

Since it takes approximately one week to eliminate ponesimod from the body after stopping treatment, the potential risk to the fetus may persist, and women should use effective contraception during this period 

4. Pediatric Use-                                                                                                        Safety and effectiveness in pediatric patients have not been established.

5. Geriatric Use-                                                                                                                 Clinical studies of PONVORY did not include patients 65 years of age and over to determine whether they respond differently from younger subjects.

Use of PONVORY in elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy 

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

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

 OVERDOSAGE

Symptoms and Signs In patients with overdosage of PONVORY, especially upon initiation/reinitiation of treatment, it is important to observe for signs and symptoms of bradycardia as well as AV conduction blocks, which may include overnight monitoring.

Regular measurements of pulse rate and blood pressure are required, and ECGs should be performed

Treatment                                                                                                                   There is no specific antidote to ponesimod. Neither dialysis nor plasma exchange would result in meaningful removal of ponesimod from the body. The decrease in heart rate induced by PONVORY can be reversed by atropine.

In the event of overdose, PONVORY should be discontinued, and general supportive treatment given until clinical toxicity has been diminished or resolved.

It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose.