Adverse reactions : תופעות לוואי

4.8   Undesirable effects
Summary of the safety profile

The most commonly reported adverse reactions (> 5%) in controlled periods of the adult MS and UC clinical studies are nasopharyngitis, alanine aminotransferase (ALT) increased, and gamma-glutamyl transferase (GGT) increased.

The most common adverse reactions leading to discontinuation were related to liver enzyme elevations (1.1%) in the MS clinical studies. Liver enzyme elevations leading to discontinuation occurred in 0.4% of patients, in UC controlled clinical studies.
The overall safety profile was similar for patients with multiple sclerosis and ulcerative colitis.

Tabulated list of adverse reactions

The adverse reactions observed in patients treated with ozanimod in MS and UC clinical studies and from post-marketing experience including spontaneous case reports are listed below by system organ class (SOC) and frequency for all adverse reactions. Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Frequencies are defined as: 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).



Table 2:         Summary of adverse reactions reported

SOC                                      Frequency                    Adverse reaction 
Very common                  Nasopharyngitis
Pharyngitis, respiratory tract infection viral,
Infections and
Common                       urinary tract infection*, herpes zoster, herpes infestations simplex
Rare                         Progressive multifocal leukoencephalopathy Blood and lymphatic
Very common                  Lymphopenia system disorders
Alanine aminotransferase increased, gamma-
Common                       glutamyl transferase increased, blood bilirubin Hepatobiliary disorders                                               increased Rare                         Liver injury****
Immune system disorders                  Uncommon                     Hypersensitivity (including rash and urticaria*) Nervous system disorders                 Common                       Headache Eye disorders                            Uncommon                     Macular oedema** Cardiac disorders                        Common                       Bradycardia* Vascular disorders                       Common                       Hypertension*†, orthostatic hypotension General disorders and administration site                      Common                       Peripheral oedema conditions

Investigations                           Common                       Pulmonary function test abnormal*** * At least one of these adverse reactions was reported as serious
† Includes hypertension, essential hypertension, and blood pressure increased (see section 4.4).
** for patients with pre-existing factors (see section 4.4)
*** including pulmonary function test decreased, spirometry abnormal, forced vital capacity decreased, carbon monoxide diffusing capacity decreased, forced expiratory volume decreased
**** Adverse reactions from post-marketing reports


Description of selected adverse reactions
Elevated hepatic enzymes
In MS clinical studies, elevations of ALT to 5-fold the upper limit of normal (ULN) or greater occurred in 1.6% of patients treated with ozanimod 0.92 mg and 1.3% of patients on IFN β-1a IM.
Elevations of 3-fold the ULN or greater occurred in 5.5% of patients on ozanimod and 3.1% of patients on IFN β-1a IM. The median time to elevation 3-fold the ULN was 6 months. The majority (79%) continued treatment with ozanimod with values returning to < 3-fold the ULN within approximately 2-4 weeks. Ozanimod was discontinued for a confirmed elevation greater than 5-fold the ULN. Overall, the discontinuation rate due to elevations in hepatic enzymes was 1.1% of MS patients on ozanimod 0.92 mg and 0.8% of patients on IFN beta-1a IM.

In UC clinical studies, during the induction period, elevations of ALT to 5-fold the ULN or greater occurred in 0.9% of patients treated with ozanimod 0.92 mg and 0.5% of patients who received placebo, and in the maintenance period elevations occurred in 0.9% and no patients, respectively. In the induction period, elevations of ALT to 3-fold the ULN or greater occurred in 2.6% of UC patients treated with ozanimod 0.92 mg and 0.5% of patients who received placebo, and in the maintenance period elevations occurred in 2.3% and no patients, respectively. In controlled and uncontrolled UC clinical studies, the majority (96%) of patients with ALT greater than 3-fold the ULN continued treatment with ozanimod with values returning to less than 3-fold the ULN within approximately 2 to 4 weeks.
Overall, the discontinuation rate due to elevations in hepatic enzymes was 0.4% of patients treated with ozanimod 0.92 mg, and none in patients who received placebo in the controlled UC clinical studies.

Severe liver injury has been reported in a post-marketing setting (see section 4.4).

Bradyarrhythmia
After the initial dose of ozanimod 0.23 mg, the greatest mean reduction from baseline in sitting/ supine HR occurred at Hour 5 on day 1 (decrease of 1.2 bpm in MS clinical studies and 0.7 bpm in the UC clinical studies), returning towards baseline at Hour 6. With continued dose escalation, there were no clinically relevant HR decreases.

In MS clinical studies, bradycardia was reported in 0.5% of patients treated with ozanimod versus 0% of patients treated with IFN β-1a IM on the day of treatment initiation (Day 1). After Day 1, the incidence of bradycardia was 0.8% on ozanimod versus 0.7% on IFN β-1a IM. (see section 5.1).
Patients who experienced bradycardia were generally asymptomatic. Heart rates below 40 beats per minute were not observed.

In MS clinical studies, first-degree atrioventricular block was reported in 0.6% (5/882) of patients treated with ozanimod versus 0.2% (2/885) treated with IFN β-1a IM. Of the cases reported with ozanimod, 0.2% were reported on Day 1 and 0.3% were reported after Day 1.

In UC clinical studies, during the induction period, bradycardia was reported on the day of treatment initiation (Day 1), in 0.2% of patients treated with ozanimod and none in patients treated with placebo. After Day 1 bradycardia was reported in 0.2% of patients treated with ozanimod. During the maintenance period, bradycardia was not reported.

Increased blood pressure
In MS clinical studies, patients treated with ozanimod had an average increase of approximately 1-2 mm Hg in systolic pressure over IFN β-1a IM, and approximately 1 mm Hg in diastolic pressure over IFN β-1a IM. The increase in systolic pressure was first detected after approximately 3 months of treatment initiation and remained stable throughout treatment.
Hypertension-related events (hypertension, essential hypertension, and blood pressure increased) were reported as an adverse reaction in 4.5% of patients treated with ozanimod 0.92 mg and in 2.3% of patients treated with IFN β-1a IM.

In UC clinical studies, during the induction period, patients treated with ozanimod had an average increase of 1.4 mm Hg in systolic pressure over placebo (3.7 vs 2.3 mm Hg) and 1.7 mm Hg in diastolic pressure over placebo (2.3 vs 0.6 mm Hg). During the maintenance period, patients treated with ozanimod had an average increase of 3.6 mm Hg in systolic pressure over placebo (5.1 vs 1.5 mm Hg) and 1.4 mm Hg in diastolic pressure over placebo (2.2 vs 0.8 mm Hg).

Hypertension was reported as an adverse reaction in 1.2% of patients treated with ozanimod 0.92 mg and none in patients treated with placebo in the induction period. In the maintenance period, hypertension was reported in 2.2% of patients in each treatment arm. Hypertensive crisis was reported in two patients receiving ozanimod, who recovered without treatment interruption, and one patient receiving placebo.

Blood lymphocyte count reduction
In MS clinical studies, 3.3% of patients and in UC controlled clinical studies, 3% of patients experienced lymphocyte counts less than 0.2 x 109/L with values generally resolving to greater than 0.2 x 109/L while remaining on treatment with ozanimod.

Infections
In MS clinical studies, the overall rate of infections (35%) with ozanimod 0.92 mg was similar to IFN β-1a IM. The overall rate of serious infections was similar between ozanimod (1%) and IFN β-1a IM (0.8%) in MS clinical studies.

In UC clinical studies, during the induction period, the overall rate of infections and rate of serious infections in patients treated with ozanimod or placebo were similar (9.9% vs. 10.7% and 0.8% vs.
0.4%, respectively). During the maintenance period, the overall rate of infections in patients treated with ozanimod was higher than in patients treated with placebo (23% vs. 12%) and the rate of serious infections was similar (0.9% vs. 1.8%).

Ozanimod increased the risk of herpes infections, upper respiratory tract infections and urinary tract infections.

Herpetic infections
In MS clinical studies, herpes zoster was reported as an adverse reaction in 0.6% of patients treated with ozanimod 0.92 mg and in 0.2% of patients on IFN β-1a IM.

In UC clinical studies, herpes zoster was reported in 0.4% of patients who received ozanimod 0.92 mg and none in patients who received placebo in the induction period. In the maintenance period, herpes zoster was reported in 2.2% of patients who received ozanimod 0.92 mg and in 0.4% of patients who received placebo. None were serious or disseminated.

Respiratory system
Minor dose-dependent reductions in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were observed with ozanimod treatment. At months 3 and 12 of treatment in MS clinical studies, median changes from baseline in FEV1 (FVC) in the ozanimod 0.92 mg group were - 0.07 L and -0.1 L (-0.05 L and – 0.065 L), respectively, with smaller changes from baseline in the IFN ß-1a group (FEV1: -0.01 L and -0.04 L, FVC: 0.00 L and -0.02 L).

Similar to MS clinical studies, small mean reductions in pulmonary function tests were observed with ozanimod relative to placebo (FEV1 and FVC) during UC clinical studies, in the induction period.
There were no further reductions with longer term treatment with ozanimod in the maintenance period and these small changes in pulmonary function tests were reversible in patients re-randomised to placebo.

Reporting of suspected adverse reactions

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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/.