Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
Prior to treatment initiation with ponesimod, an electrocardiogram (ECG) in all patients should be obtained to determine whether pre-existing conduction abnormalities are present. In patients with certain pre-existing conditions, first-dose monitoring is recommended (see below).
Initiation of ponesimod treatment may result in a transient decrease in heart rate (HR) and AV conduction delays (see sections 4.8 and 5.1), therefore an up-titration scheme must be used to reach the maintenance dose of ponesimod (20 mg) (see section 4.2).
After the first dose of ponesimod, the decrease in HR typically begins within an hour and reaches its nadir within 2-4 hours. The HR typically recovers to baseline levels 4-5 hours after administration. The mean decrease in HR on day 1 of dosing (2 mg) was 6 bpm. With up-titration after day 1, the decrease in HR is less pronounced with no further post-dose decrease in HR observed after day 3.
Caution should be applied when ponesimod is initiated in patients receiving treatment with a beta-blocker because of the additive effects on lowering heart rate; temporary interruption of the beta-blocker treatment may be needed prior to initiation of ponesimod (see section below and section 4.5).
For patients receiving a stable dose of a beta-blocker, the resting HR should be considered before introducing ponesimod treatment. If the resting HR is greater than 55 bpm under chronic beta-blocker treatment, ponesimod can be introduced. If resting HR is less than or equal to 55 bpm, beta-blocker treatment should be interrupted until the baseline HR is greater than 55 bpm. Treatment with ponesimod can then be initiated and treatment with a beta-blocker can be reinitiated after ponesimod has been up-titrated to the target maintenance dose (see section 4.5). Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod.
Because initiation of ponesimod treatment may result in a decrease in 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 section 5.1).
Administer the first dose of ponesimod 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 at the end of the 4-hour observation period.
Additional monitoring after 4-hours is recommended if any of the following abnormalities are present (even in the absence of symptoms), continue monitoring until the abnormality resolves:
If postdose 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.
determine overall benefit risk and the most appropriate monitoring strategy
Ponesimod causes a dose-dependent reduction in peripheral lymphocyte count to 30-40% of baseline values due to reversible sequestration of lymphocytes in lymphoid tissues. Ponesimod may therefore increase the risk of infections (see section 4.8). Life-threatening and rare fatal infections have been reported in association with sphingosine 1-phosphate (S1P) receptor modulators.
Before initiating treatment with ponesimod, results from a recent complete blood count (CBC) with differential (including lymphocyte count) (i.e., within 6 months or after discontinuation of prior therapy) should be reviewed. Assessments of CBC are also recommended periodically during treatment. Absolute lymphocyte counts <0.2 × 109/L, if confirmed, should lead to interruption of ponesimod therapy until the level reaches >0.8 × 109/L when re-initiation of ponesimod can be considered.
Initiation of treatment with ponesimod should be delayed in patients with severe active infection until resolution.
Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Suspension of treatment with ponesimod should be considered if a patient develops a serious infection.
In the development program, pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, were restored to normal within 1 week after discontinuation of ponesimod. In the OPTIMUM study, peripheral lymphocyte counts were restored to normal within 2 weeks after discontinuation of ponesimod, which was the first timepoint evaluated. Vigilance for signs and symptoms of infection should be continued for 1-2 weeks after ponesimod is discontinued (see below and section 4.8).
Cases of herpes viral infection have been reported in the development program of ponesimod (see section 4.8).
Patients without a healthcare professional confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV before initiating treatment. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ponesimod. The treatment with ponesimod should be delayed for 4 weeks after vaccination to allow the full effect of vaccination to occur. See Vaccinations section below.
Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with other S1P receptor modulators. No cases of CM have been reported in ponesimod-treated patients in the development program. 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. Ponesimod treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
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.
No cases of PML have been reported in ponesimod-treated patients in the development program; however, PML has been reported in patients treated with a S1P receptor modulator 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 ponesimod should be suspended until PML has been excluded. If confirmed, treatment with ponesimod should be discontinued.
In patients that are taking anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids), or if there is a history of prior use of these medicinal products, possible unintended additive immune system effects should be considered before initiating treatment with ponesimod (see section 4.5).
When switching from medicinal products with prolonged immune effects, the half-life and mode of action of these medicinal products must be considered in order to avoid unintended additive effects on the immune system while at the same time minimising risk of disease reactivation, when initiating ponesimod.
Pharmacokinetic/pharmacodynamic modeling indicates lymphocyte counts returned to the normal range in >90% of healthy subjects within 1 week of stopping ponesimod therapy (see section 5.1). In the development program, pharmacodynamic effects, such as lowering of peripheral lymphocyte counts, were restored to normal within 1 week after the last dose.
Use of immunosuppressants may lead to an additive effect on the immune system, and therefore caution should be applied up to 1 week after the last dose of ponesimod (see section 4.5).
No clinical data are available on the efficacy and safety of vaccinations in patients taking ponesimod. Vaccinations may be less effective if administered during ponesimod treatment.
Avoid the use of live attenuated vaccines while patients are taking ponesimod. If the use of live attenuated vaccine immunisation is required, ponesimod treatment should be paused from 1 week prior to 4 weeks after a planned vaccination (see section 4.5).
Ponesimod increases the risk of macular oedema (see section 4.8). An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients before starting treatment and again at any time if a patient reports any change in vision while on ponesimod therapy.
In the clinical trial experience in patients with all doses of ponesimod, the rate of macular oedema was 0.7%, the majority of patients had pre-existing risk factors or comorbid conditions. Most cases occurred within the first 6 months of therapy.
Ponesimod therapy should not be initiated in patients with macular oedema until resolution.
Continuation of ponesimod therapy in patients with macular oedema has not been evaluated. Patients who present with visual symptoms of macular oedema should be evaluated and, if confirmed, treatment with ponesimod should be discontinued. A decision on whether ponesimod should be re-initiated after resolution needs to take into account the potential benefits and risks for the individual patient.
Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular oedema during therapy with S1P receptor modulators. Therefore, these patients should have regular examinations of the fundus, including the macula, prior to treatment initiation with ponesimod and have follow-up evaluations while receiving therapy.
Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and reductions in diffusion lung capacity for carbon monoxide (DLCO) were observed in ponesimod-treated patients mostly occurring in the first month after treatment initiation (see section 4.8). Respiratory symptoms associated with ponesimod treatment can be reversed with administration of a short-acting beta2-agonist.
Ponesimod should be used with caution in patients with severe respiratory disease, pulmonary fibrosis and chronic obstructive pulmonary disease. Spirometry evaluation of respiratory function should be performed during therapy with ponesimod if clinically indicated.
Elevations of transaminases may occur in ponesimod-treated patients (see section 4.8). Recent (i.e., within last 6 months) transaminase and bilirubin levels should be reviewed before initiation of ponesimod therapy.
Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia, or jaundice and/or dark urine during treatment, should be monitored for hepatotoxicity. Ponesimod should be discontinued if significant liver injury is confirmed (for example, ALT exceeds 3-fold ULN and total bilirubin exceeds 2-fold ULN).
Although there are no data to establish that patients with pre-existing liver disease are at increased risk to develop elevated liver function test values when taking ponesimod, caution should be exercised when using ponesimod in patients with a history of significant liver disease (see section 4.2).
A mild reversible increase in blood pressure (mean change less than 3 mmHg) was observed in patients treated with ponesimod (see section 4.8). Blood pressure should be regularly monitored during treatment with ponesimod and managed appropriately.
As there is a potential risk of skin malignancies (see section 4.8), patients treated with ponesimod should be cautioned against exposure to sunlight without protection. These patients should not receive concomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy.
Based on animal studies, ponesimod may cause fetal harm. Due to the risk to the foetus, ponesimod is contraindicated during pregnancy and in women of childbearing potential not using effective contraception (see sections 4.3 and 4.6). Before initiation of treatment in women of childbearing potential, a negative pregnancy test result must be available (see section 4.6). Because it takes approximately 1 week to eliminate ponesimod from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 1 week after stopping ponesimod treatment.
Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a S1P receptor modulator. Such events have not been reported for ponesimod-treated patients in the development program. However, should a ponesimod-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider a MRI. Symptoms of PRES are usually reversible but may evolve into ischaemic stroke or cerebral haemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, ponesimod should be discontinued.
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 ponesimod treatment. Patients should be observed for a severe exacerbation or return of high disease activity upon ponesimod discontinuation and appropriate treatment should be instituted, as required (see above).
Ponvory contains lactose (see section 2). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
Ponesimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration (see section 4.4).
Ponesimod has not been studied in patients taking QT prolonging medicinal products (see section 4.4).
The negative chronotropic effect of co-administration of ponesimod and propranolol was evaluated in a dedicated pharmacodynamics safety study. The addition of ponesimod to propranolol at steady state has an additive effect on HR effect.
In a drug-drug interaction study, the up-titration regimen of ponesimod (see section 4.2) was administered to subjects receiving propranolol (80 mg) once daily at steady-state. Compared to ponesimod alone, the combination with propranolol after the first dose of ponesimod (2 mg) had a 12.4 bpm (90% CI: -15.6 to -9.1) decrease in mean hourly heart rate and at the first dose of ponesimod (20 mg) after up-titration a 7.4 bpm (90% CI: -10.9 to -3.9) decrease in mean hourly heart rate. No significant changes in pharmacokinetics of ponesimod or propranolol were observed.
Vaccinations may be less effective if administered while being treated with ponesimod and up to 1 week after its discontinuation (see section 4.4).
The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ponesimod treatment and up to 1 week after its discontinuation of treatment with ponesimod (see section 4.4).
Medicinal products that are inhibitors of major CYP or UGT enzymes are unlikely to impact the pharmacokinetics of ponesimod (see section 5.2).
Co-administration of ponesimod with strong inducers of multiple metabolic pathways of ponesimod (see section 5.2) may decrease the systemic exposure of ponesimod. It is unclear whether this decrease is clinically relevant.
Ponesimod is not a substrate of P-gp, BCRP, OATP1B1 or OATP1B3 transporters. Medicinal products that are inhibitors of these transporters are unlikely to impact the pharmacokinetics of ponesimod.
Ponesimod and its metabolites are unlikely to show any clinically relevant drug-drug interaction potential for CYP or UGT enzymes, or transporters (see section 5.2). Oral contraceptives Co-administration of ponesimod, with an oral hormonal contraceptive (containing 1 mg norethisterone/norethindrone and 35 mcg 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.
Interaction studies have only been performed in adults.
Ponvory is contraindicated in women of childbearing potential not using effective contraception (see section 4.3). Before initiation of Ponvory treatment in women of childbearing potential a negative pregnancy test result must be available, and women should be counselled on the potential for a serious risk to the foetus and the need for effective contraception during treatment with ponesimod. Since it takes approximately 1 week to eliminate ponesimod from the body after stopping treatment, the potential risk to the foetus may persist and women must use effective contraception during this period (see section 4.4).
Specific measures are also included in the Healthcare Professional checklist. These measures must be implemented before ponesimod is prescribed to female patients and during treatment.
When stopping ponesimod therapy for planning a pregnancy the possible return of disease activity should be considered (see section 4.4).
Ponvory is contraindicated during pregnancy (see section 4.3). Although there are no data from the use of ponesimod in pregnant women, studies in animals have shown reproductive toxicity (see section 5.3). If a woman becomes pregnant during treatment, ponesimod must be immediately discontinued. Medical advice should be given regarding the risk of harmful effects to the foetus associated with treatment (see section 5.3) and follow-up examinations should be performed.
Based on clinical experience in patients receiving another S1P receptor modulator, the use is associated with an increased risk of major congenital malformations.
It is unknown whether ponesimod or its metabolites are excreted in human milk. A study in lactating rats has indicated excretion of ponesimod in milk (see section 5.3). A risk to newborns/infants cannot be excluded. Ponvory should not be used during breast-feeding.
The effect of ponesimod on human fertility has not been evaluated. Data from preclinical studies do not suggest that ponesimod would be associated with an increased risk of reduced fertility (see section 5.3).
Ponvory has no or negligible influence on the ability to drive and use machines.
The most commonly reported adverse drug reactions are nasopharyngitis (19.7%), alanine aminotransferase increased (17.9%) and upper respiratory tract infection (11%).
Adverse reactions reported with ponesimod in controlled clinical trials and uncontrolled extension trials are ranked by frequency, with the most frequent reactions first. Frequencies were defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Table 2. Tabulated list of adverse reactions:
| System Organ Class (SOC) | Very common | Common | Uncommon |
|---|---|---|---|
| Infections and infestations | nasopharyngitis, upper respiratory tract infection | urinary tract infection, bronchitis, influenza, rhinitis, respiratory tract infection, respiratory tract infection viral, pharyngitis, sinusitis, viral infection, herpes zoster, laryngitis, pneumonia | |
| Blood and lymphatic system disorders | lymphopenia, lymphocyte count decreased | ||
| Psychiatric disorders | depression, insomnia, anxiety | ||
| Nervous system disorders | dizziness, hypoaesthesia, somnolence, migraine | ||
| Eye disorders | macular oedema | ||
| Ear and labyrinth disorders | vertigo | ||
| Cardiac disorders | bradycardia | ||
| Vascular disorders | hypertension | ||
| Respiratory, thoracic and mediastinal disorders | dyspnoea, cough | ||
| Gastrointestinal disorders | dyspepsia | dry mouth | |
| Musculoskeletal and connective tissue disorders | back pain, arthralgia, pain in extremity, ligament sprain | joint swelling | |
| General disorders and administration site conditions | fatigue, pyrexia, oedema peripheral, chest discomfort | ||
| Investigations | alanine aminotransferase increased | aspartate aminotransferase increased, hypercholesterolaemia, hepatic enzyme increased, C-reactive protein increased, transaminases increased, blood cholesterol increased | hyperkalaemia |
In the Phase 3 OPTIMUM study (see section 5.1), bradycardia at treatment initiation (sinus bradycardia/HR less than 50 bpm on ECG on day 1) occurred in 5.8% of ponesimod-treated patients compared to 1.6% of patients receiving teriflunomide 14 mg. Patients who experienced bradycardia were generally asymptomatic. Bradycardia resolved in all patients without intervention and did not require discontinuation of ponesimod treatment. On day 1, 3 patients treated with ponesimod had asymptomatic post-dose HR below or equal to 40 bpm; all 3 patients had baseline HRs below 55 bpm.
Initiation of ponesimod treatment has been associated with transient AV conduction delays that follow a similar temporal pattern as the observed decrease in HR during dose titration. The AV conduction delays manifested as first-degree AV block (prolonged PR interval on ECG), which occurred in 3.4% of ponesimod -treated patients and in 1.2% of patients receiving teriflunomide 14 mg in the OPTIMUM study. No second-degree AV blocks, Mobitz type I (Wenckebach), were observed in OPTIMUM. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, resolved without intervention, and did not require discontinuation of ponesimod treatment.
In the Phase 3 OPTIMUM study (see section 5.1), the overall rate of infections was comparable between the ponesimod-treated patients and those receiving teriflunomide 14 mg (54.2% vs 52.1% respectively). Nasopharyngitis and viral infections were more common in ponesimod-treated patients. Serious or severe infections occurred at a rate of 1.6% in ponesimod-treated patients compared to 0.9% of patients receiving teriflunomide 14 mg.
In OPTIMUM, the rate of herpetic infections was not different between the ponesimod-treated patients and those receiving teriflunomide 14 mg (4.8%).
In OPTIMUM, 3.2% of ponesimod-treated patients compared to none of the patients receiving teriflunomide 14 mg, experienced lymphocyte counts less than 0.2 × 109/L with values generally resolving to greater than 0.2 × 109/L while remaining on treatment with ponesimod.
In OPTIMUM, macular oedema was reported in 1.1% of ponesimod-treated patients compared to none of the patients receiving teriflunomide 14 mg.
In the OPTIMUM study, ALT increased to three and five times the upper limit of normal (ULN) in 17.3% and 4.6% of ponesimod-treated patients, respectively, compared to 8.3% and 2.5% of patients receiving, teriflunomide 14 mg, respectively. ALT increased eight times ULN in 0.7% ponesimod-treated patients compared to 2.1% in patients receiving teriflunomide 14 mg. The majority of elevations occurred within 6 or 12 months of starting treatment. ALT levels returned to normal after discontinuation of ponesimod. Most cases of ALT increases ≥3×ULN resolved on continued ponesimod treatment, and the remaining cases resolved upon treatment discontinuation. In clinical trials, ponesimod was discontinued if the elevation exceeded a 3-fold increase and the patient showed symptoms related to hepatic dysfunction.
In OPTIMUM, cases of seizures were reported in 1.4% of ponesimod-treated patients, compared to 0.2% in patients receiving teriflunomide 14 mg. It is not known whether these events were related to the effects of MS, to ponesimod, or to a combination of both.
Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) were observed in patients treated with ponesimod (see section 4.4). In OPTIMUM, a higher proportion of ponesimodtreated patients (19.4%) had a reduction of more than 20% from baseline in percent predicted FEV1 compared to 10.6% of patients receiving teriflunomide 14 mg. The reduction from baseline in percent predicted FEV1 at 2 years was 8.3% in ponesimod-treated patients compared to 4.4% in patients receiving teriflunomide 14 mg. The changes in FEV1 and DLCO appear to be partially reversible after treatment discontinuation. In the OPTIMUM study, 7 patients discontinued ponesimod because of pulmonary adverse events (dyspnoea). Ponesimod has been tested in MS patients with mild to moderate asthma or chronic obstructive pulmonary disease. The changes in FEV1 were similar in this subgroup compared with the subgroup of patients without baseline lung disorders.
In OPTIMUM, ponesimod-treated patients had an average increase of 2.9 mmHg in systolic blood pressure and 2.8 mmHg in diastolic blood pressure compared to 2.8 mmHg and 3.1 mmHg in patients receiving teriflunomide 14 mg, respectively. An increase in blood pressure with ponesimod was first detected after approximately 1 month of treatment initiation and persisted with continued treatment. The blood pressure values after ponesimod treatment discontinuation indicate reversibility. Hypertension was reported as an adverse reaction in 10.1% of ponesimod-treated patients and in 9.0% of patients receiving teriflunomide 14 mg.
In OPTIMUM, a case of malignant melanoma and two cases of basal cell carcinoma (0.4%) were reported in ponesimod-treated patients compared to one case of basal cell carcinoma (0.2%) in patients receiving teriflunomide 14 mg. An increased risk of cutaneous malignancies has been reported in association with another S1P receptor modulator.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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