Molecular mass: 460.97 g/mol PubChem compound: 11363176
Ponesimod interacts in the following cases:
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.
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. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod.
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 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.
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.
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.
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. 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.
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.
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.
Ponesimod is contraindicated during pregnancy. Although there are no data from the use of ponesimod in pregnant women, studies in animals have shown reproductive toxicity. 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 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. A risk to newborns/infants cannot be excluded. Ponesimod should not be used during breast-feeding.
Ponesimod is contraindicated in women of childbearing potential not using effective contraception. Before initiation of ponesimod 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.
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.
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.
Ponesimod 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, 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, 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. 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.
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