Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Summary of the safety profile
The most frequently reported adverse reactions in the teriflunomide treated (7 mg and 14 mg) patients were: headache (17.8%, 15.7%), diarrhoea (13.1%, 13.6%) increased ALT (13%, 15%), nausea (8%, 10.7%), and alopecia (9.8%, 13.5%). In general, headache, diarrhoea, nausea and alopecia, were mild to moderate, transient and infrequently led to treatment discontinuation.

Teriflunomide is the main metabolite of leflunomide. The safety profile of leflunomide in patients suffering from rheumatoid arthritis or psoriatic arthritis may be pertinent when prescribing teriflunomide in MS patients.

Tabulated list of adverse reactions

Teriflunomide was evaluated in atotal of 2,267 patients exposed to teriflunomide (1,155 on teriflunomide 7 mg and 1,112 on teriflunomide 14 mg) once daily for a median duration of about 672 days in four placebo-controlled studies (1,045 and 1,002 patients for teriflunomide 7 mg and 14 mg, respectively) and one active comparator study (110 patients in each of the teriflunomide treatment groups) in adult patients with relapsing forms of MS (Relapsing Multiple Sclerosis, RMS).




Listed below are the adverse reactions reported with AUBAGIO in placebo-controlled studies in adult patients, reported for teriflunomide 7 mg or14 mg from clinical studies in adult patients . 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). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

System organ          Very           Common            Uncommon          Rare      Very     Not known class          common                                                         rare Infections and                    Influenza,        Severe infections infestations                      Upper respiratory including sepsisa tractinfection,
Urinary tract infection,
Bronchitis,
Sinusitis,
Pharyngitis,
Cystitis,
Gastroenteritis viral,
Herpes virus infectionsb,
Tooth infection,
Laryngitis,
Tinea pedis
Blood and                         Neutropeniab,      Mild lymphatic                         Anaemia            thrombocytopenia system disorders                                     (platelets <100G/l) Immune system                     Mild allergic      Hyper-sensitivity disorders                         reactions          reactions
(immediateor delayed) including anaphylaxisand angioedema
Psychiatric                       Anxiety disorders
Nervous system      Headache      Paraesthesia,      Hyperaesthesia,
disorders                         Sciatica,          Neuralgia,
Carpal tunnel      Peripheral syndrome           neuropathy

Cardiac                           Palpitations disorders
Vascular                          Hypertensionb disorders
Respiratory,                                         Interstitial lung                         Pulmonary thoracic and                                         disease                                  hypertensio mediastinal                                                                                   n disorders
Gastrointestinal   Diarrhoea,     Abdominal pain     Pancreatitisb,c disorders           Nausea        upper,             Stomatitis
Vomiting,          Colitis
Toothache


System organ           Very           Common             Uncommon          Rare         Very   Not class               common                                                            rare      known 

Hepatobiliary       Alanine            Gamma-                               Acute               Drug- disorders           aminotransferas    glutamyltransfer                     hepatit             induced e (ALT)            ase (GGT)                            is                  liver injury increaseb          increaseb,                                               (DILI) Aspartate aminotransferas e increaseb



Metabolism and                                            Dyslipidaemia nutrition disorders
Skin and             Alopecia         Rash, Acne          Nail disorders, subcutaneous                                              Psoriasis tissue disorders                                          (including pustular)b,
Severe skin reactionsa
Musculoskeletal                       Musculoskeletal and connective                        pain,
tissue disorders                      Myalgia,
Arthralgia
Renal and urinary                     Pollakiuria disorders
Reproductive                          Menorrhagia system and breast disorders
General disorders                     Pain,
and                                   Astheniaa administration site conditions
Investigations                        Weight decrease,
Neutrophil count decreaseb,
White blood cell count decreaseb,
Blood creatine phosphokinase increased

Injury, poisoning                                         Post-traumatic and procedural                                            pain complications
 a: please refer to the detailed description section b: see section 4.4 c: frequency is “common” in children based on a controlled clinical study in paediatrics; frequency is “uncommon” in adults


     Description of selected adverse reactions
Alopecia
Alopecia was reported as hair thinning, decreased hair density, hair loss, associated or not with hair texture change, in 13.9% of patients treated with 14 mg teriflunomide versus 5.1% in patients treated with placebo.
Most cases were described as diffuse or generalised over the scalp (no complete hair loss reported) and occurred most often during the first 6 months and with resolution in 121 of 139 (87.1%) patients treated with teriflunomide 14 mg. Discontinuation because of alopecia was 1.3% in the teriflunomide 14 mg teriflunomide group, versus 0.1% in the placebo group.

Hepatic effects
During placebo-controlled studies in adult patients the following was detected: 
ALT increase (based on laboratory data) according to baseline status - Safety population in placebo- controlled studies
Placebo                  Teriflunomide 14 mg
(N=997)                  (N=1002)
>3 ULN                                        66/994 (6.6%)            80/999 (8.0%) >5 ULN                                        37/994 (3.7%)            31/999 (3.1%) >10 ULN                                       16/994 (1.6%)            9/999 (0.9%) >20 ULN                                       4/994 (0.4%)             3/999 (0.3%) ALT >3 ULN and TBILI >2 ULN                   5/994 (0.5%)             3/999 (0.3%) Mild increases in transaminase, ALT below or equal to 3-fold ULN were more frequently seen in teriflunomide-treated groups as compared to placebo. The frequency of elevations above 3-fold ULN and higher was balanced across treatment groups. These elevations in transaminase occurred mostly within the first 6 months of treatment and were reversible after treatment cessation. The recovery time varied between months and years.

Blood pressure effects
In placebo-controlled studies in adult patients the following was established: -      systolic blood pressure was >140 mm Hg in 19.9% of patients receiving 14 mg/day teriflunomide ascompared to 15.5% receiving placebo;
-      systolic blood pressure was >160 mm Hg in 3.8% of patients receiving 14 mg/day teriflunomide ascompared to 2.0% receiving placebo;
-      diastolic blood pressure was >90 mm Hg in 21.4% of patients receiving 14 mg/day teriflunomide ascompared to 13.6% receiving placebo.

Infections
In placebo-controlled studies in adult patients, no increase in serious infections was observed with teriflunomide 14 mg (2.7%) as compared to placebo (2.2%). Serious opportunistic infections occurred in 0.2% of each group. Severe infections including sepsis, sometimes fatal have been reported postmarketing.

Haematological effects
A mean decrease affecting white blood cell (WBC) count (<15% from baseline levels, mainly neutrophil and lymphocytes decrease) was observed in placebo-controlled trials with AUBAGIO in adult patients, although a greater decrease was observed in some patients. The decrease in mean count from baseline occurred during the first 6 weeks then stabilised over time while on-treatment but at decreased levels (less than a 15% decrease from baseline). The effect on red blood cell (RBC) (<2%) and platelet counts (<10%) was less pronounced.

Peripheral neuropathy
In placebo-controlled studies in adult patients, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), was reported more frequently in patients taking teriflunomide than in patientstaking placebo. In the pivotal, placebo-controlled studies, the incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.9% (17 patients out of 898) on 14 mg of teriflunomide, compared with 0.4% (4 patients out of 898) on placebo. Treatment was discontinued in 5 patients with peripheral neuropathy on teriflunomide 14 mg. Recovery following treatment discontinuation was reported in 4 of thesepatients.

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
There does not appear to be an increased risk of malignancy with teriflunomide in the clinical trial experience. The risk of malignancy, particularly lymphoproliferative disorders, is increased with use of some other agents that affect the immune system (class effect).

Severe skin reactions
Cases of severe skin reactions have been reported with teriflunomide post-marketing (see section 4.4).

Asthenia
In placebo-controlled studies in adult patients, frequencies for asthenia were 2.0%, 1.6% and 2.2% in the placebo,teriflunomide 7 mg and teriflunomide 14 mg group, respectively.
Psoriasis
In placebo-controlled studies, frequencies for psoriasis were 0.3%, 0.3% and 0.4% in the placebo, teriflunomide 7 mg and teriflunomide 14 mg group, respectively.

Gastrointestinal disorders
Pancreatitis has been reported infrequently in the post-marketing setting with teriflunomide in adults, including cases of necrotising pancreatitis and pancreatic pseudocyst. Pancreatic events may occur at any time during treatment with teriflunomide, which may lead to hospitalisation and/or require corrective treatment.


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 at https://sideeffects.health.gov.il/.