Adverse reactions : תופעות לוואי

4.8    Undesirable effects

The following undesirable effects cover adverse drug reactions from clinical trials: 
Malignancies
Patients receiving immunosuppressive regimens involving combinations of drugs, including MPA, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4). Lymphoproliferative disease or lymphoma developed in 2 de novo (0.9%) patients and in 2 maintenance patients (1.3%) receiving Myfortic for up to 1 year.
Non-melanoma skin carcinomas occurred in 0.9% of de novo and 1.8% of maintenance patients receiving Myfortic for up to 1 year; other types of malignancy occurred in 0.5% of de novo and 0.6% of maintenance patients.

Opportunistic infections
All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load (see section 4.4). The most common opportunistic infections in de novo renal transplant patients receiving Myfortic with other immunosuppressants in controlled clinical trials of renal transplant patients followed for 1 year were cytomegalovirus (CMV), candidiasis and herpes simplex. CMV infection (serology, viraemia or disease) was reported in 21.6% of de novo and in 1.9% of maintenance renal transplant patients.

Older people
Elderly patients may generally be at increased risk of adverse drug reactions due to immunosuppression.

Other adverse drug reactions
Table 1 below contains adverse drug reactions possibly or probably related to Myfortic reported in the controlled clinical trials in renal transplant patients, in which Myfortic was administered together with ciclosporin microemulsion and corticosteroids at a dose of 1,440 mg/day for 12 months. It is compiled according to MedDRA system organ class.

Adverse reactions are listed according to the following categories:
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 1
Infections and infestations
Very common:        Viral, bacterial and fungal infections
Common:             Upper respiratory tract infections, pneumonia
Uncommon:           Wound infection, sepsis*, osteomyelitis*

Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon:          Skin papilloma*, basal cell carcinoma*,
Kaposi´s sarcoma*, lymphoproliferative disorder, squamous cell carcinoma*

Blood and lymphatic system disorders
Very common:      Leukopenia
Common:           Anaemia, thrombocytopenia
Uncommon:         Lymphopenia*, neutropenia*, lymphadenopathy*

Metabolism and nutrition disorders
Very common:       Hypocalcemia, hypokalemia, hyperuricemia
Common:             Hyperkalemia, hypomagnesemia

Uncommon:           Anorexia, hyperlipidaemia, diabetes mellitus*, hypercholesterolaemia*, hypophosphataemia
Psychiatric disorders
Very Common:      Anxiety
Uncommon:         Abnormal dreams*, delusional perception*, insomnia* Nervous system disorders
Common:           Dizziness, headache
Uncommon:         Tremor
Eye disorders
Uncommon:         Conjunctivitis*, vision blurred*
Cardiac disorders
Uncommon:         Tachycardia, ventricular extrasystoles
Vascular disorders
Very common:      Hypertension
Common:           Hypotension
Uncommon:         Lymphocele*

Respiratory, thoracic and mediastinal disorders

Common:             Cough, dyspnoea
Uncommon:           Interstitial lung disease, pulmonary congestion*, wheezing*, pulmonary oedema*



Gastrointestinal disorders
Very common:      Diarrhoea
Common:           Abdominal distension, abdominal pain, constipation, dyspepsia, flatulence, gastritis, nausea, vomiting
Uncommon:         Abdominal tenderness, gastrointestinal haemorrhage, eructation, halitosis*, ileus*, lip ulceration*, oesophagitis*, subileus*, tongue discolouration*, dry mouth*, gastro-oesophageal reflux disease*, gingival hyperplasia*, pancreatitis, parotid duct obstruction*, peptic ulcer*, peritonitis*
Hepato-biliary disorders
Common:            Liver function tests abnormal
Skin and subcutaneous tissue disorders
Common             Acne, pruritus
Uncommon:          Alopecia
Musculoskeletal and connective tissue disorders
Very Common:      Arthralgia
Common            Myalgia
Uncommon:         Arthritis*, back pain*, muscle cramps
Renal and urinary disorders
Common:           Blood creatinine increased
Uncommon:         Haematuria*, renal tubular necrosis*, urethral stricture Reproductive system and breast disorders
Uncommon:         Impotence*
General disorders and administration site conditions
Common:           Asthenia, Fatigue, oedema peripheral, pyrexia
Uncommon:         Influenza like illness, oedema lower limb*, pain, rigors*, thirst*,weakness* Injury, poisoning and procedural complications
Uncommon:         Contusion*

* event reported in a single patient (out of 372) only.

Note: renal transplant patients were treated with 1,440 mg Myfortic daily up to one year. A similar profile was seen in the de novo and maintenance transplant population although the incidence tended to be lower in the maintenance patients.

Adverse drug reactions from post-marketing experience:

Blood and lymphatic system disorders: Agranulocytosis
Immune system disorders: Hypersensitivity reactions (including anaphylaxis) 
Skin and subcutaneous tissue disorders: Rash

General disorders and administration site conditions:
De novo purine synthesis inhibitors-associated acute inflammatory syndrome with frequency uncommon has been described from post-marketing experience as a paradoxical proinflammatory reaction associated with mycophenolate mofetil and mycophenolic acid, characterised by fever, arthralgia, arthritis, muscle pain and elevated inflammatory markers.
Literature case reports showed rapid improvement following discontinuation of the medicinal product.

The following additional adverse reactions are attributed to MPA derivatives as a class effect: 

Infections and infestations:
Serious, life-threatening infections, including meningitis, infectious endocarditis, tuberculosis, and atypical mycobacterial infection. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Myfortic (see section 4.4).

Blood and lymphatic system disorders:
Neutropenia, pancytopenia.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives (see section 4.4).

Immune system disorders:
Hypogammaglobulinaemia has been reported in patients receiving Myfortic in combination with other immunosuppressants.

Respiratory, thoracic and mediastinal disorders:
There have been isolated reports of interstitial lung disease in patients treated with Myfortic in combination with other immunosuppressants. There have also been reports of bronchiectasis in combination with other immunosuppressants.

Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with MPA derivatives. These changes are not associated with impaired neutrophil function. These changes may suggest a ‘left shift’ in the maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that receive Myfortic.

Gastrointestinal disorders:
Colitis, CMV gastritis, intestinal perforation, gastric ulcers, duodenal ulcers.

Pregnancy, puerperium and perinatal conditions:
Cases of spontaneous abortion have been reported in patients exposed to mycophenolate mainly in the first trimester (see section 4.6).

Congenital disorders:
Congenital malformations have been observed post-marketing in children of patients exposed to mycophenolate in combination with other immunosuppressants (see section 4.6).


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 and to Novartis using the following email address: safetydesk.israel@novartis.com