Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: Novartis SA (Pty) Ltd., Magwa Crescent West, Waterfall City, Johannesburg, 2090
A core pharmacodynamic effect of KIENDRA is a dose dependent reduction of peripheral lymphocyte count to 20 to 30 % of baseline values. This is due to the reversible sequestration of lymphocytes in lymphoid tissues.
The immune system effects of KIENDRA may increase the risk of infections.
Before initiating treatment with KIENDRA, a recent complete blood count (CBC) (i.e. within last 6 months or after discontinuation of prior therapy) should be available.
Initiation of treatment with KIENDRA 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 of KIENDRA, vigilance for infection should be continued throughout this period (see below: Stopping KIENDRA therapy).
Patients receiving KIENDRA should be instructed to report symptoms of infections to their medical practitioner. Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Suspension of treatment with KIENDRA, should be considered if a patient develops a serious infection.
Cryptococcal meningitis (CM) has been reported during KIENDRA use. Medical practitioners should be vigilant for clinical symptoms or signs of CM. Patients with such symptoms and signs should undergo prompt diagnostic evaluation. KIENDRA 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 KIENDRA, however, cases of PML have been reported for another S1P receptor modulator. Medical practitioners should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. If PML is suspected, KIENDRA 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 development programme of KIENDRA. 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 KIENDRA (see subsection Vaccination).
Initiation of treatment with KIENDRA should be delayed in patients with severe active infection (e.g. active TB and HIV patients with CD4 counts below 400 copies cells per mL) until resolution.
Anti-neoplastic, immune-modulating or immunosuppressive therapies (including corticosteroids) should be co-administered with caution due to the risk of additive immune system effects during such therapy (see section 4.4).
A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with KIENDRA, following which initiation of treatment with KIENDRA should be postponed for 1 month to allow the full effect of vaccination to occur (see section 4.8).
The use of live attenuated vaccines should be avoided while patients are taking KIENDRA and for 4 weeks after stopping KIENDRA treatment (see section 4.5).
Non-live attenuated vaccines may be less effective if administered during KIENDRA treatment. The decision whether to continue or pause the treatment with KIENDRA should be based on the benefit-risk assessment of the individual patient (section 4.4 subheading “Stopping therapy” and section 4.5)
Macular oedema (see section 4.8) with or without visual symptoms may occur during treatment with KIENDRA. The majority of cases occurred within the first 3 to 4 months of therapy. An ophthalmic evaluation is therefore recommended 3 to 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 KIENDRA therapy and an evaluation of the fundus, including the macula, is recommended.
Patients with a history of diabetes mellitus, uveitis and underlying/co-existing retinal diseases are at increased risk of macular oedema. It is recommended that patients with diabetes mellitus, uveitis or a history of retinal disorders undergo an ophthalmic evaluation prior to initiating KIENDRA therapy and have follow-up evaluations while receiving KIENDRA therapy.
Continuation of KIENDRA therapy in patients with macular oedema has not been evaluated. Patients with macular oedema should not start KIENDRA treatment and patients who develop macular oedema should stop KIENDRA. KIENDRA therapy should not be initiated in patients with macular oedema until resolution.
Since initiation of KIENDRA treatment results in a transient decrease in heart rate, an up-titration scheme to reach the maintenance dose of KIENDRA on day 6 is applied at treatment start (see section 4.2).
After the first titration dose, the heart rate decrease starts within an 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.
Patients who develop AV conduction problems and/or symptomatic bradycardia should be admitted to an appropriate healthcare facility with equipment to manage their condition. Initiation of KIENDRA treatment has been associated with atrioventricular conduction delays that follow a similar temporal pattern as 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). Second-degree AV blocks, usually Mobitz type I (Wenckebach), have been observed in less than 1.7 % of patients in clinical trials at the time of treatment initiation with KIENDRA. The conduction abnormalities typically were asymptomatic, resolved within 24 hours and did not require discontinuation of KIENDRA treatment.
As a precautionary measure, initiation of treatment in patients with:
Should post-dose bradydysrhythmia or conduction related symptoms occur or if ECG 6 hours post-dose show new onset second degree or higher AV block or QTc ≥500 msec, appropriate management should be initiated and observation should be 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, KIENDRA should not be used in patients with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino-atrial heart block. Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension or severe untreated sleep apnea, KIENDRA should not be used 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 KIENDRA 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.
A thorough QT study demonstrated no significant direct QT prolonging effect of KIENDRA and KIENDRA is not associated with a dysrhythmogenic potential related to QT prolongation. Initiation of KIENDRA treatment may result in decreased heart rate and indirect prolongation of the QT interval during the titration phase. KIENDRA was not studied in patients with significant QT prolongation (QTc >500 msec) or who were treated with QT prolonging medicines. If treatment with KIENDRA is considered in patients with pre-existing significant QT prolongation or who are treated with QT prolonging medicines with known dysrhythmogenic 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.
KIENDRA has not been studied in patients with dysrhythmias requiring treatment with Class Ia (e.g. quinidine, procainamide) or Class III anti-dysrhythmic medicines (e.g. amiodarone, sotalol). Class Ia and Class III medicines have been associated with cases of Torsades de Pointes in patients with bradycardia. Since initiation of KIENDRA treatment results in decreased heart rate, KIENDRA should not be used concomitantly with these medicines during treatment initiation.
Experience with KIENDRA is limited in patients receiving concurrent therapy with heart-rate lowering calcium channel blockers (such as verapamil or diltiazem), or other medicines that may decrease heart rate (e.g. ivabradine or digoxin). Concomitant use of these medicines during KIENDRA initiation may be associated with severe bradycardia and heart block. Because of the potential additive effect on heart rate, treatment with KIENDRA should generally not be initiated in patients who are concurrently treated with these medicines.
If concomitant treatment with KIENDRA of the above mentioned medicines is considered during initiation of treatment with KIENDRA, advice from a cardiologist should be sought regarding the switch to non- heart-rate lowering medicines or appropriate monitoring for treatment initiation.
Bradydysrhythmic effects are more pronounced when KIENDRA is added to beta-blocker therapy. For patients receiving a stable dose of beta-blocker, the resting heart rate should be considered before introducing KIENDRA treatment. If the resting heart rate is >50 bpm under chronic beta-blocker treatment, KIENDRA 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 KIENDRA can then be initiated and treatment with beta-blocker can be re-initiated after KIENDRA has been up-titrated to the target maintenance dose.
If a titration dose is missed on one day during the first 6 days of treatment or if 4 or more consecutive daily doses are missed during maintenance therapy, the same initial dose titration and monitoring recommendations should apply (see above “Treatment initiation recommendations” and section 4.2 posology and method of administration).
Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with KIENDRA. In the phase 3 clinical study, Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) three times upper limit of normal (ULN) were observed in 5.6% of patients treated with KIENDRA 2 mg compared to 1.5% of patients receiving placebo (see section 4.8 Undesirable effects). In clinical trials, KIENDRA was discontinued if the elevation exceeded a 3-fold increase and the patient showed symptoms related to hepatic function.
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 have liver enzymes checked and KIENDRA should be discontinued if significant liver injury is confirmed.
Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test (LFT) values when taking KIENDRA, caution should be exercised when using KIENDRA in patients with a history of significant liver disease.
Cases of basal cell carcinoma have been reported in patients treated with KIENDRA, particularly during longer exposure (see section 4.8). Cases of other skin malignancies, including melanoma, have also been reported in patients treated with KIENDRA and in patients on another S1P modulator. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer and patients with suspicious skin lesions. Patients treated with KIENDRA should be cautioned against exposure to sunlight without protection. These patients should not receive concomitant phototherapy with UV-B radiation or PUVA-photochemotherapy.
Blood pressure should be monitored during treatment with KIENDRA and managed appropriately.
Cases of posterior reversible encephalopathy syndrome (PRES) have been reported for sphingosine 1-phosphate (S1P) receptor modulator medicines. Should a patient on KIENDRA treatment develop any unexpected neurological or psychiatric symptoms/signs (e.g. cognitive deficits, behavioral changes, cortical visual disturbances or any other neurological cortical symptoms/signs or any symptom/sign suggestive of an increase of intracranial pressure) or accelerated neurological deterioration, the medical practitioner should promptly schedule a complete physical and neurological examination and should consider a magnetic resonance imaging (MRI).
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 minimizing risk of disease reactivation.
Due to the characteristics and duration of alemtuzumab immune suppressive effects described in its product information, initiating treatment with KIENDRA after alemtuzumab is not recommended.
Before initiation of treatment with KIENDRA, patients should be genotyped for CYP2C9 to determine the CYP2C9 metabolizer status. Patients homozygous for CYP2C9*3 (CYP2C9*3*3 genotype: approximately 0.3 to 0.4% of Caucasians and less in others) should not be treated with KIENDRA. Use of KIENDRA in these patients results in substantially elevated siponimod plasma levels.
The recommended maintenance dose of KIENDRA is 1 mg daily in patients with CYP2C9 *2*3 or *1*3 genotype to avoid an increased exposure to siponimod (see sections 4.2).
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 KIENDRA treatment.
Patients should be observed for a severe increase in disability upon KIENDRA discontinuation and appropriate treatment should be instituted, as required.
After stopping KIENDRA therapy siponimod remains in the blood for up to 10 days. Starting other therapies during this interval will result in concomitant exposure to siponimod.
Lymphocyte counts typically return to the normal range in the vast majority (90%) of SPMS patients within 10 days of stopping therapy. However, residual pharmacodynamics effects, such as lowering effects on peripheral lymphocyte count may persist for up to 3 to 4 weeks after the last dose. Use of immunosuppressants within this period may lead to an additive effect on the immune system and therefore caution should be applied 3 to 4 weeks after the last dose.
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take KIENDRA.
KIENDRA has not been studied in combination with anti-neoplastic, immune-modulating or immunosuppressive therapies. Caution should be used during concomitant administration due to the risk of additive immune effects during such therapy and in the weeks following stopping administration of any of these medicines (see section 4.4).
When switching from other disease modifying therapies, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimizing risk of disease reactivation.
Due to the characteristics and duration of alemtuzumab immune suppressive effects described in its product information, initiating treatment with KIENDRA after alemtuzumab is not recommended KIENDRA can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.
During treatment initiation KIENDRA should not be concomitantly used in patients receiving Class Ia (e.g. quinidine, procainamide), Class III anti-dysrhythmic medicines (e.g. amiodarone, sotalol), QT prolonging medicines with known dysrythmogenic properties, heart rate lowering calcium channel blockers (such as verapamil or diltiazem) or other medicines which may decrease heart rate (e.g. ivabradine or digoxin) because of the potential additive effects on heart rate. If treatment with KIENDRA is considered, advice from a cardiologist should be sought (see sections 4.3 and 4.4 Treatment initiation recommendations).
Caution should be applied when KIENDRA is initiated in patients receiving beta-blockers due to the additive effects on lowering heart rate (see sections 4.3 and 4.4 Treatment initiation recommendations). Beta-blocker treatment can be initiated in patients receiving stable doses of KIENDRA. The negative chronotropic effect of co-administration of siponimod and propranolol was evaluated in a dedicated PD/safety study. The addition of propranolol on top of siponimod PK/PD steady-state had less pronounced negative chronotropic effects (less than additive) in comparison to addition of siponimod on top of propranolol PK/PD steady state (additive HR effect).
The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during KIENDRA treatment and for up to 4 weeks after treatment with KIENDRA (see section 4.4 Vaccination).
Potential effects of siponimod on the immune response/immunogenicity of selected non-live attenuated vaccines were investigated in a dedicated study with two representative vaccines, a PPV-23 vaccine (T cell-independent vaccine) and a quadrivalent influenza vaccine (T cell-dependent vaccine). The study demonstrated that concomitant KIENDRA treatment does not compromise the efficacy of a PPV-23 vaccination and therefore no KIENDRA treatment pause is necessary. The efficacy of the influenza vaccination is not compromised if KIENDRA treatment is paused 1 week prior and until 4 weeks after vaccination. Shorter treatment pause from 10 days prior to 14 days after vaccination and concomitant KIENDRA treatment showed only modest impact on influenza vaccination efficacy with responder rates approximately 15% to 30% lower than on placebo (see section 4.4 – Vaccination).
Siponimod is primarily metabolised by cytochrome P450CYP2C9 (79.3%) and to a lesser extent by CYP3A4 (18.5%). CYP2C9 is a polymorphic enzyme and the medicine-medicine interaction effect in presence of CYP3A or CYP2C9 perpetrator medicines is predicted to be dependent on the CYP2C9 genotype.
Caution should be applied with concomitant use of KIENDRA with drugs that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition due to a clinically relevant increase in exposure to siponimod. This concomitant drug regimen can consist of moderate CYP2C9/CYP3A4 inhibitors (e.g. fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate moderate or strong CYP3A4 inhibitor. KIENDRA should be used with caution in patients with CYP2C9*2*2 genotype. Dosage adjustment to 1 mg daily may be considered in these patients as an approximately 2.7-fold increase of siponimod exposure is expected.
Caution should be applied with concomitant use of KIENDRA with medicine that cause moderate CYP2C9 and strong CYP3A4 induction because of a clinically relevant decrease in siponimod exposure. This concomitant drug regimen can consist of moderate CYP2C9/strong CYP3A4 dual inducers (e.g., rifampin or carbamazepine) or a moderate CYP2C9 inducer in combination with a separate strong CYP3A4 inducer. Caution is also needed with concomitant use of KIENDRA with moderate (e.g. modafinil) or strong CYP3A4 inducers for patients with CYP2C9*1/*3 and*2/*3 genotype.
Strong CYP3A4/moderate CYP2C9 inducers (e.g. carbamazepine) and moderate CYP3A4 inducers (e.g. modafinil) are expected to significantly reduce siponimod exposure by up to 76% and up to 51% respectively according to clinical medicine-medicine interaction studies and in silico evaluation of the medicine interaction potential.
Co-administration with siponimod did not reveal clinically relevant effects on the PK and PD of the combined ethinylestradiol and levonorgestrel oral contraceptive. Therefore the efficacy of the investigated oral contraceptive was maintained under siponimod treatment. No interaction studies have been performed with oral contraceptives containing other progestogens, however an effect of siponimod on the efficacy of oral contraceptives is not expected.
Since siponimod reduces blood lymphocyte counts via re-distribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilised to evaluate the lymphocyte subset status of a patient treated with KIENDRA.
Laboratory tests requiring the use of circulating mononuclear cells require large blood volumes due to reduction in the number of circulating lymphocytes.
KIENDRA is contraindicated during pregnancy or for use in women of child bearing potential, (see section 4.3).
Based on animal data and its mechanism of action KIENDRA may cause foetal harm when administered to a pregnant woman. Reproductive and developmental studies in pregnant rats and rabbits have demonstrated siponimod induced embryotoxicity and foetotoxicity in rats and rabbits and teratogenicity in rats. Increased incidences of post-implantation loss and foetal abnormalities (external, urogenital and skeletal) in rat and of embryo-foetal deaths, abortions and foetal variations (skeletal and visceral) in rabbit were observed following prenatal exposure to siponimod starting at a dose 2 times the exposure in humans at the highest recommended dose of 2 mg/day.
Pregnant women should be advised of a potential risk to the foetus if KIENDRA is used during pregnancy or if the patient becomes pregnant while taking this medicine.
The use of KIENDRA in women who have child bearing potential should only be considered when effective contraception (methods that result in less than 1% pregnancy rates) are being used during KIENDRA therapy and for at least ten days after stopping treatment with KIENDRA.
Women taking KIENDRA must not breastfeed their infants. See section 4.3.
In lactating rats dosed with a single oral dose of 10 mg/kg, siponimod and its metabolites passed into the milk.
There are no data regarding the effect of KIENDRA on fertility in humans.
Siponimod had no effect on male reproductive organs in rats and monkeys or fertility parameters in rats.
KIENDRA has no or negligible influence on the ability to drive and use machines. However, dizziness may occasionally occur when initiating therapy with KIENDRA. Therefore, patients should not drive or use machines during the first day of treatment initiation with KIENDRA (see section 4.4).
A total of 1,737 multiple sclerosis (MS) patients have been treated with siponimod in doses of at least 2 mg daily. These were included in study A2304, a phase 3, multicenter, randomised, double-blind, placebo-controlled study in patients with SPMS and study A2201, a phase 2, double-blind, randomised, multi-center, adaptive dose-ranging, placebo-controlled study in patients with relapsing-remitting MS (RRMS). Study A2304 randomised 1,651 SPMS patients 2:1 to receive either KIENDRA 2 mg once daily or placebo. Median treatment duration was 18 months (range 0 to 37 months). Study A2201 randomised a total of 297 RRMS patients to receive KIENDRA at once daily doses ranging from 0.25 mg to 10 mg or placebo for up to 6 months.
In study A2304 a higher percentage of siponimod than placebo patients completed the double-blinded part of the study medicine treatment (66.7% and 59.0%, respectively). The most common reasons for discontinuations in the siponimod and placebo groups were subject/guardian decisions (10.3% siponimod vs. 13.0% placebo), disease progression (9.1% for siponimod vs. 14.8% for placebo) and adverse events (8.5% siponimod vs. 5.1% placebo). The most common adverse medicine reactions in the siponimod 2 mg group (incidence ≥10%) in study A2304 were headache and hypertension.
Adverse medicine reactions from clinical trials have been defined primarily on the basis of the experience in study A2304 (Table 7-2) and are listed by MedDRA system organ class. Within each system organ class, the adverse medicine reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse medicine reaction is based on the following convention (CIOMS III): 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).
Table 2. List of adverse reactions:
| Adverse medicine reactions | Frequency category | |
|---|---|---|
| Infections and infestations | Herpes zoster* | common |
| Melanocytic naevus* | common | |
| Neoplasms benign, malignant and unspecified (incl. cysts and polyps) | Basal cell carcinoma** | common |
| Blood and lymphatic system disorders | Lymphopenia* | common |
| Nervous system disorders | Headache* | very common |
| Dizziness | common | |
| Seizure* | common | |
| Tremor* | common | |
| Eye disorders | Macular oedema* | common |
| Cardiac disorders | Bradycardia* | common |
| Atrioventricular block* (1st & 2nd degree) | common | |
| Vascular disorders | Hypertension* | very common |
| Gastrointestinal disorders | Nausea | common |
| Diarrhoea | common | |
| Musculoskeletal and connective tissue disorders | Pain in extremity* | common |
| General disorders and administration site conditions | Oedema peripheral* | common |
| Asthenia | common | |
| Investigations | Liver function test increased* | very common |
| Pulmonary function test decreased* | common | |
^ Core phase – Controlled pool
* Grouping of preferred terms (PTs) were considered for ADR frequency determination
** Adverse drug reactions from open-label extension part of the phase 3 study A2304
In the phase 3 clinical trial in patients with SPMS the overall rate of infections was comparable between the patients on siponimod and those on placebo (49.0% vs. 49.1% respectively). However, an increase in the rate of herpes zoster infections was reported on siponimod (2.5%) compared to placebo (0.7%) (see section 4.4). A case of cryptococcal meningitis was reported for KIENDRA (see section 4.4).
Macular oedema was more frequently reported in patients receiving siponimod (1.8%) than 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 to 12 months (see section 4.4 special warnings and precautions). Some patients presented with blurred vision or decreased visual acuity, but others were asymptomatic and diagnosed on routine ophthalmic examination. The macular oedema generally improved or resolved spontaneously after KIENDRA discontinuation. The risk of recurrence after re-challenge has not been evaluated. KIENDRA should not be restarted thereafter.
Initiation of siponimod treatment results in a decrease in heart rate and may also be associated with atrio-ventricular conduction delays (see section 4.4).
Increased hepatic enzymes (mostly ALT elevation) have been reported in MS patients treated with siponimod. In the phase 3 trial in patients with SPMS, liver function test increase were more frequently observed in 11.3% of patients on siponimod than in those on placebo (3.1%), mainly due to liver transaminase (ALT/AST/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 (see section 4.4).
Hypertension was more frequently reported in 12.6% of patients on siponimod than on placebo (9.0%) in the phase 3 clinical trial 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.
Cases of seizures were reported in 1.7% of patients treated with siponimod compared to 0.4% on placebo in the phase 3 clinical trial in patients with SPMS. It is not known whether these events were related to the effects of MS, to siponimod, or to a combination of both.
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 month 3 and month 6 of treatment in the phase 3 clinical trial in patients with SPMS, mean changes from baseline in the siponimod group were -0.1 L at each time point, with no change in the placebo group. 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 dyspnea.
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