Chemical formula: C₂₉H₃₅F₃N₂O₃ Molecular mass: 516.605 g/mol PubChem compound: 44599207
Siponimod interacts in the following cases:
During treatment initiation siponimod should not be concomitantly used in patients receiving class Ia (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) anti-arrhythmic medicinal products, QT-prolonging medicinal products with known arrhythmogenic properties, heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem) or other substances that may decrease heart rate (e.g. ivabradine or digoxin) because of the potential additive effects on heart rate. No data are available for concomitant use of these medicinal products with siponimod. Concomitant use of these substances during treatment initiation may be associated with severe bradycardia and heart block. Because of the potential additive effect on heart rate, treatment with siponimod should generally not be initiated in patients who are concurrently treated with these substances. If treatment with siponimod is considered, advice from a cardiologist should be sought regarding the switch to non-heart-rate-lowering medicinal products or appropriate monitoring for treatment initiation.
The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during siponimod treatment and for up to 4 weeks after treatment.
Siponimod is metabolised primarily by cytochrome P450 2C9 (CYP2C9) (79.3%) and to a lesser extent by cytochrome P450 3A4 (CYP3A4) (18.5%). CYP2C9 is a polymorphic enzyme and the drug-drug interaction (DDI) effect in the presence of CYP3A or CYP2C9 perpetrator drugs is predicted to be dependent on the CYP2C9 genotype.
Because of a significant increase in exposure to siponimod, concomitant use of siponimod and medicinal products that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition is not recommended. This concomitant drug regimen can consist of a moderate CYP2C9/CYP3A4 dual inhibitor (e.g. fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate moderate or strong CYP3A4 inhibitor.
The co-administration of fluconazole (moderate CYP2C9/strong CYP3A4 inhibitor) 200 mg daily at steady state and a single dose of siponimod 4 mg in healthy volunteers with a CYP2C9*1*1 genotype led to a 2-fold increase in the area under the curve (AUC) of siponimod. According to evaluation of the drug interaction potential using physiologically based pharmacokinetic (PBPK) modelling, a maximum of a 2-fold increase in the AUC of siponimod is predicted across genotypes with any type of CYP3A4 and CYP2C9 inhibitors except for patients with a CYP2C9*2*2 genotype. In CYP2C9*2*2 patients, a 2.7-fold increase in the AUC of siponimod is expected in the presence of moderate CYP2C9/CYP3A4 inhibitors.
Siponimod is metabolised primarily by cytochrome P450 2C9 (CYP2C9) (79.3%) and to a lesser extent by cytochrome P450 3A4 (CYP3A4) (18.5%). CYP2C9 is a polymorphic enzyme and the drug-drug interaction (DDI) effect in the presence of CYP3A or CYP2C9 perpetrator drugs is predicted to be dependent on the CYP2C9 genotype.
Siponimod may be combined with most types of CYP2C9 and CYP3A4 inducers. However, because of an expected reduction in siponimod exposure, the appropriateness and possible benefit of the treatment should be considered when siponimod is combined:
A significant reduction of siponimod exposure (by up to 76% and 51%, respectively) is expected under these conditions according to evaluation of the drug interaction potential using PBPK modelling. The co-administration of siponimod 2 mg daily in the presence of 600 mg daily doses of rifampin (strong CYP3A4 and moderate CYP2C9 inducer) decreased siponimod AUCtau,ss and Cmax,ss by 57% and 45%, respectively, in CY2C9*1*1 subjects.
Caution should be exercised when siponimod is initiated in patients receiving beta blockers due to the additive effects on lowering heart rate. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
The negative chronotropic effect of co-administration of siponimod and propranolol was evaluated in a dedicated pharmacodynamic/safety study. The addition of propranolol on top of siponimod pharmacokinetic/pharmacodynamic steady state had less pronounced negative chronotropic effects (less than additive) in comparison to addition of siponimod on top of propranolol pharmacokinetic/pharmacodynamic steady state (additive HR effect).
A full course of vaccination with varicella vaccine is recommended for antibody-negative patients prior to commencing treatment with siponimod, following which initiation of treatment should be postponed for 1 month to allow the full effect of vaccination to occur.
The use of live attenuated vaccines should be avoided while patients are taking siponimod and for 4 weeks after stopping treatment.
Vaccinations may be less effective if administered during siponimod treatment. Discontinuation of treatment 1 week prior to planned vaccination until 4 weeks after is recommended. When stopping siponimod therapy for vaccination, the possible return of disease activity should be considered.
Siponimod has not been studied in combination with antineoplastic, immune-modulating or immunosuppressive therapies. Caution should be exercised during concomitant administration due to the risk of additive immune effects during such therapy and in the weeks after administration of any of these medicinal products is stopped.
When switching from other disease-modifying therapies, the half-life and mode of action of the other therapy must be considered to avoid an additive immune effect whilst at the same time minimising the risk of disease reactivation. A peripheral lymphocyte count (CBC) is recommended prior to initiating siponimod to ensure that immune effects of the previous therapy (i.e. cytopenia) have resolved.
Due to the characteristics and duration of alemtuzumab immune suppressive effects described in its product information, initiating treatment with siponimod after alemtuzumab is not recommended.
Siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.
Due to the characteristics and duration of alemtuzumab immune suppressive effects described in its product information, initiating treatment with siponimod after alemtuzmab is not recommended unless the benefits of treatment clearly outweigh the risks for the individual patient.
Macular oedema with or without visual symptoms was more frequently reported on siponimod (1.8%) than on placebo (0.2%) in the phase III clinical study. The majority of cases occurred within the first 3-4 months of therapy. An ophthalmological evaluation is therefore recommended 3-4 months after treatment initiation. As cases of macular oedema have also occurred on longer-term treatment, patients should report visual disturbances at any time while on siponimod therapy and an evaluation of the fundus, including the macula, is recommended.
Siponimod therapy should not be initiated in patients with macular oedema until resolution.
Siponimod should be used with caution in patients with a history of diabetes mellitus, uveitis or underlying/co-existing retinal disease due to a potential increase in the risk of macular oedema. It is recommended that these patients should undergo an ophthalmological evaluation prior to initiating therapy and regularly while receiving siponimod therapy to detect macular oedema.
Continuation of siponimod therapy in patients with macular oedema has not been evaluated. It is recommended that siponimod be discontinued if a patient develops macular oedema. A decision on whether or not siponimod should be re-initiated after resolution needs to take into account the potential benefits and risks for the individual patient.
Patients with hypertension uncontrolled by medication were excluded from participation in clinical studies and special care is indicated if patients with uncontrolled hypertension are treated with siponimod.
Hypertension was more frequently reported in patients on siponimod (12.6%) than in those given placebo (9.0%) in the phase III clinical study in patients with SPMS. Treatment with siponimod resulted in an increase of systolic and diastolic blood pressure starting early after treatment initiation, reaching maximum effect after approximately 6 months of treatment (systolic 3 mmHg, diastolic 1.2 mmHg) and staying stable thereafter. The effect persisted with continued treatment.
Blood pressure should be regularly monitored during treatment with siponimod.
A core pharmacodynamic effect of siponimod is a dose-dependent reduction of the peripheral lymphocyte count to 20-30% of baseline values. This is due to the reversible sequestration of lymphocytes in lymphoid tissues.
The immune system effects of siponimod may increase the risk of infections.
Before initiating treatment, a recent complete blood count (CBC) (i.e. within last 6 months or after discontinuation of prior therapy) should be available. Assessments of CBC are also recommended periodically during treatment. Absolute lymphocyte counts <0.2 × 109/l, if confirmed, should lead to dose reduction to 1 mg, because in clinical studies siponimod dose was reduced in patients with absolute lymphocyte counts <0.2 × 109/l. Confirmed absolute lymphocyte counts <0.2 × 109/l in a patient already receiving siponimod 1 mg should lead to interruption of siponimod therapy until the level reaches 0.6 × 109/l when re-initiation of siponimod can be considered.
Initiation of treatment should be delayed in patients with severe active infection until resolution. Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3 to 4 weeks after discontinuation, vigilance for infection should be continued throughout this period.
Patients should be instructed to report symptoms of infection to their physician promptly. Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Suspension of treatment with siponimod should be considered if a patient develops a serious infection.
A case of cryptococcal meningitis (CM) has been reported for siponimod. Cases of CM have been reported for another sphingosine 1-phosphate (S1P) receptor modulator. Patients with symptoms and signs consistent with CM should undergo prompt diagnostic evaluation. Siponimod treatment should be suspended until CM has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
No cases of progressive multifocal leukoencephalopathy (PML) have been reported for siponimod in the development programme; however, they have been reported for another S1P receptor modulator. Physicians should be vigilant for clinical symptoms or magnetic resonance imaging (MRI) findings that may be suggestive of PML. If PML is suspected, siponimod treatment should be suspended until PML has been excluded.
Cases of herpes viral infection (including one case of reactivation of varicella zoster virus [VZV] infection leading to varicella zoster meningitis) have been reported in the siponimod development programme. Patients without a physician-confirmed history of varicella or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before starting siponimod.
Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with siponimod.
In the phase III clinical study, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) three times the upper limit of normal (ULN) was observed in 5.6% of patients treated with siponimod 2 mg compared to 1.5% of patients who received placebo. In clinical studies treatment was discontinued if the elevation exceeded a 3-fold increase and the patient showed symptoms related to hepatic function or if the elevation exceeded a 5-fold increase. In the phase III clinical study, 1% of all discontinuations met one of these criteria.
Patients who develop symptoms suggestive of hepatic dysfunction should have liver enzymes checked and siponimod should be discontinued if significant liver injury is confirmed. Resumption of therapy will be dependent on whether or not another cause of liver injury is determined and on the benefits to the patient of resuming therapy versus the risks of recurrence of liver dysfunction.
Although there are no data to establish that patients with pre-existing liver disease are at increased risk of developing elevated liver function test values when taking siponimod, caution should be exercised in patients with a history of significant liver disease.
Initiation of siponimod treatment results in a transient decrease in heart rate, and a titration scheme to reach the maintenance dose on day 6 is therefore applied at the start of treatment.
After the first titration dose, the heart rate decrease starts within one hour and the day 1 decline is maximal at approximately 3 to 4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from day 1 (baseline) reached on day 5 to 6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on day 1, with the pulse declining on average 5 to 6 beats per minute (bpm). Post-dose declines on the following days are less pronounced. With continued dosing heart rate starts increasing after day 6 and reaches placebo levels within 10 days after treatment initiation.
Heart rates below 40 bpm were rarely observed. Patients who experienced bradycardia were generally asymptomatic. A few patients experienced mild to moderate symptoms including dizziness and non-cardiac chest pain, which resolved within 24 hours without intervention. If necessary, the decrease in heart rate induced by siponimod can be reversed by parenteral doses of atropine or isoprenaline.
Initiation of siponimod treatment has been associated with transient atrioventricular conduction delays that follow a similar temporal pattern to the observed decrease in heart rate during dose titration. The atrioventricular conduction delays manifested in most of the cases as first-degree atrioventricular (AV) blocks (prolonged PR interval on electrocardiogram). In clinical studies, second-degree AV blocks, usually Mobitz type I (Wenckebach), have been observed in less than 1.7% of patients at the time of treatment initiation. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours and did not require discontinuation of treatment.
As a precautionary measure, patients with the following cardiac conditions should be observed for a period of 6 hours after the first dose of siponimod for signs and symptoms of bradycardia:
In these patients, it is recommended that an electrocardiogram (ECG) is obtained prior to dosing and at the end of the observation period. If post-dose bradyarrhythmia or conduction-related symptoms occur or if ECG 6 hours post-dose shows new onset second-degree or higher AV block or QTc ≥500 msec, appropriate management should be initiated and observation continued until the symptoms/findings have resolved. If pharmacological treatment is required, monitoring should be continued overnight and 6-hour monitoring should be repeated after the second dose.
Due to the risk of serious cardiac rhythm disturbances or significant bradycardia, siponimod should not be used in patients with:
In such patients, treatment with siponimod should be considered only if the anticipated benefits outweigh the potential risks, and advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy.
A thorough QT study demonstrated no significant direct QT-prolonging effect and siponimod is not associated with an arrhythmogenic potential related to QT prolongation. Initiation of treatment may result in decreased heart rate and indirect prolongation of the QT interval during the titration phase. Siponimod was not studied in patients with significant QT prolongation (QTc >500 msec) or who were treated with QT-prolonging medicinal products. If treatment with siponimod is considered in patients with pre-existing significant QT prolongation or who are already being treated with QT-prolonging medicinal products with known arrhythmogenic properties, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy during treatment initiation.
Siponimod has not been studied in patients with arrhythmias requiring treatment with class Ia (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products. Class Ia and class III antiarrhythmic medicinal products have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of treatment results in decreased heart rate, siponimod should not be used concomitantly with these medicinal products during treatment initiation.
Experience is limited in patients receiving concurrent therapy with heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem) or other substances that may decrease heart rate (e.g. ivabradine or digoxin) as these medicinal products were not studied in patients receiving siponimod in clinical studies. Concomitant use of these substances during treatment initiation may be associated with severe bradycardia and heart block. Because of the potential additive effect on heart rate, treatment with siponimod should generally not be initiated in patients who are concurrently treated with these substances. In such patients, treatment with siponimod should be considered only if the anticipated benefits outweigh the potential risks.
If concomitant treatment with one of the above substances is considered during initiation of treatment with siponimod, advice from a cardiologist should be sought regarding the switch to a non-heart-rate-lowering medicinal product or appropriate monitoring for treatment initiation.
Bradyarrhythmic effects are more pronounced when siponimod is added to beta-blocker therapy. For patients receiving a stable dose of beta blocker, the resting heart rate should be considered before introducing treatment. If the resting heart rate is >50 bpm under chronic beta-blocker treatment, siponimod can be introduced. If resting heart rate is ≤50 bpm, then beta-blocker treatment should be interrupted until the baseline heart rate is >50 bpm. Treatment with siponimod can then be initiated and treatment with beta blocker can be re-initiated after siponimod has been up-titrated to the target maintenance dose.
There are no or limited amount of data available from the use of siponimod in pregnant women. Animal studies have demonstrated siponimod-induced embryotoxicity and foetotoxicity in rats and rabbits and teratogenicity in rats, including embryo-foetal deaths and skeletal or visceral malformations at exposure levels comparable to the human exposure at the daily dose of 2 mg. In addition, clinical experience with another sphingosine-1-phosphate receptor modulator indicated a 2-fold higher risk of major congenital malformations when administered during pregnancy compared with the rate observed in the general population.
Consequently, siponimod is contraindicated during pregnancy. Siponimod should be stopped at least 10 days before a pregnancy is planned. If a woman becomes pregnant while on treatment, siponimod must be discontinued. Medical advice should be given regarding the risk of harmful effects to the foetus associated with treatment and ultrasonography examinations should be performed.
It is unknown whether siponimod or its major metabolites are excreted in human milk. Siponimod and its metabolites are excreted in the milk of rats. Siponimod should not be used during breast-feeding.
Siponimod is contraindicated in women of childbearing potential not using effective contraception. Therefore, before initiation of treatment in women of childbearing potential a negative pregnancy test result must be available and counselling should be provided regarding serious risk to the foetus. Women of childbearing potential must use effective contraception during treatment and for at least ten days following the last dose of siponimod.
Specific measures are also included in the Physician Education Pack. These measures must be implemented before siponimod is prescribed to female patients and during treatment.
When stopping siponimod therapy for planning a pregnancy, the possible return of disease activity should be considered.
The effect of siponimod on human fertility has not been evaluated. Siponimod had no effect on male reproductive organs in rats and monkeys or on fertility parameters in rats.
Siponimod has no or negligible influence on the ability to drive and use machines. However, dizziness may occasionally occur when initiating therapy with siponimod. Therefore, patients should not drive or use machines during the first day of treatment initiation with siponimod.
The most common adverse drug reactions are headache (15%) and hypertension (12.6%).
Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse drug reaction is based on 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).
Common: Herpes zoster
Common: Melanocytic naevus
Common: Lymphopenia
Very common: Headache
Common: Dizziness, Seizure, Tremor
Common: Macular oedema
Common: Bradycardia, Atrioventricular block (first and second degree)
Very common: Hypertension
Common: Nausea, Diarrhoea
Common: Pain in extremity
Common: Oedema peripheral, Asthenia
Very common: Liver function test increased
Common: Pulmonary function test decreased
In the phase III clinical study in patients with SPMS the overall rate of infections was comparable between the patients on siponimod and those on placebo (49.0% versus 49.1%, respectively). However, an increase in the rate of herpes zoster infections was reported on siponimod (2.5%) compared to placebo (0.7%). In the extension part of the phase III clinical study, a case of cryptococcal meningitis (CM) has been reported.
Macular oedema was more frequently reported in patients receiving siponimod (1.8%) than in those given placebo (0.2%). Although the majority of cases occurred within 3 to 4 months of commencing siponimod, cases were also reported in patients treated with siponimod for more than 6 months. Some patients presented with blurred vision or decreased visual acuity, but others were asymptomatic and diagnosed on routine ophthalmological examination. The macular oedema generally improved or resolved spontaneously after discontinuation of treatment. The risk of recurrence after re-challenge has not been evaluated.
Initiation of siponimod treatment results in a transient decrease in heart rate and may also be associated with atrioventricular conduction delays. Bradycardia was reported in 6.2% of patients treated with siponimod compared to 3.1% on placebo and AV block in 1.7% of patients treated with siponimod compared to 0.7% on placebo.
The maximum decline in heart rate is seen in the first 6 hours post-dose.
A transient, dose-dependent decrease in heart rate was observed during the initial dosing phase and plateaued at doses ≥5 mg. Bradyarrhythmic events (AV blocks and sinus pauses) were detected with a higher incidence under siponimod treatment compared to placebo.
Most AV blocks and sinus pauses occurred above the therapeutic dose of 2 mg, with notably higher incidence under non-titrated conditions compared to dose titration conditions.
The decrease in heart rate induced by siponimod can be reversed by atropine or isoprenaline.
Increased hepatic enzymes (mostly ALT elevation) have been reported in MS patients treated with siponimod. In the phase III study in patients with SPMS, liver function test increases were more frequently observed in patients on siponimod (11.3%) than in those on placebo (3.1%), mainly due to liver transaminase (ALT/AST) and GGT elevations. The majority of elevations occurred within 6 months of starting treatment. ALT levels returned to normal within approximately 1 month after discontinuation of siponimod.
Hypertension was more frequently reported in patients on siponimod (12.6%) than in those given placebo (9.0%) in the phase III clinical study in patients with SPMS. Treatment with siponimod resulted in an increase of systolic and diastolic blood pressure starting early after treatment initiation, reaching maximum effect after approximately 6 months of treatment (systolic 3 mmHg, diastolic 1.2 mmHg) and staying stable thereafter. The effect persisted with continued treatment.
Seizures were reported in 1.7% of patients treated with siponimod compared to 0.4% on placebo in the phase III clinical study in patients with SPMS.
Minor reductions in forced expiratory volume in 1 second (FEV1) and in the diffusing capacity of the lung for carbon monoxide (DLCO) values were observed with siponimod treatment. At months 3 and 6 of treatment in the phase III clinical study in patients with SPMS, mean changes from baseline in FEV1 in the siponimod group were -0.1 L at each time point, with no change in the placebo group. These observations were slightly higher (approximately 0.15 L mean change from baseline in FEV1) in patients with respiratory disorders such as chronic obstructive pulmonary disease (COPD) or asthma treated with siponimod. On chronic treatment, this reduction did not translate into clinically significant adverse events and was not associated with an increase in reports of cough or dyspnoea.
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