Adverse reactions : תופעות לוואי

4.8    Undesirable effects

The adverse drug reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medications.

Many of the adverse drug reactions stated below are reversible and/or respond to dose reduction. Oral administration appears to be associated with a lower incidence of adverse drug reactions compared with intravenous use. Adverse drug reactions are listed below in descending order by frequency of occurrence: very common (1/10); common (1/100, <1/10); uncommon (1/1,000, <1/100); rare (1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Infections and infestations
As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre- existing infections may be aggravated. Both generalised and localised infections can occur.
Cases of CMV infection, 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 Prograf.

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
Patients receiving immunosuppressive therapy are at increased risk of developing malignancies.
Benign as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin malignancies have been reported in association with tacrolimus treatment.
Blood and lymphatic system disorders common:         anaemia, leukopenia, thrombocytopenia, leukocytosis, red blood cell analyses abnormal uncommon:       coagulopathies, coagulation and bleeding analyses abnormal, pancytopenia, neutropenia, thrombotic microangiopathy rare:           thrombotic thrombocytopenic purpura, hypoprothrombinaemia not known:      pure red cell aplasia, agranulocytosis, haemolytic anaemia, febrile neutropenia 
Immune system disorders
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section 4.4).

Endocrine disorders rare:           hirsutism

Metabolism and nutrition disorders very common: hyperglycaemic conditions, diabetes mellitus, hyperkalaemia common:      hypomagnesaemia, hypophosphataemia, hypokalaemia, hypocalcaemia, hyponatraemia, fluid overload, hyperuricaemia, appetite decreased, metabolic acidoses, hyperlipidaemia, hypercholesterolaemia, hypertriglyceridaemia, other electrolyte abnormalities uncommon:    dehydration, hypoproteinaemia, hyperphosphataemia, hypoglycaemia 
Psychiatric disorders very common: insomnia common:      anxiety symptoms, confusion and disorientation, depression, depressed mood, mood disorders and disturbances, nightmare, hallucination, mental disorders uncommon:    psychotic disorder

Nervous system disorders very common: tremor, headache common:      seizures, disturbances in consciousness, paraesthesias and dysaesthesias, peripheral neuropathies, dizziness, writing impaired, nervous system disorders uncommon:    coma, central nervous system haemorrhages and cerebrovascular accidents, paralysis and paresis, encephalopathy, speech and language abnormalities, amnesia rare:        hypertonia very rare:   myasthenia not known:   posterior reversible encephalopathy syndrome (PRES)

Eye disorders common:         vision blurred, photophobia, eye disorders uncommon:       cataract rare:           blindness not known:      optic neuropathy

Ear and labyrinth disorders common:         tinnitus uncommon:       hypoacusis rare:           deafness neurosensory very rare:      hearing impaired


Cardiac disorders common:         ischaemic coronary artery disorders, tachycardia uncommon:       ventricular arrhythmias and cardiac arrest, heart failures, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations rare:           pericardial effusion very rare:      Torsades de pointes

Vascular disorders very common: hypertension common:      haemorrhage, thromboembolic and ischaemic events, peripheral vascular disorders, vascular hypotensive disorders uncommon:    infarction, venous thrombosis deep limb, shock

Respiratory, thoracic and mediastinal disorders common:         dyspnoea, parenchymal lung disorders, pleural effusion, pharyngitis, cough, nasal congestion and inflammations uncommon:       respiratory failures, respiratory tract disorders, asthma rare:           acute respiratory distress syndrome

Gastrointestinal disorders very common: diarrhoea, nausea common:      gastrointestinal inflammatory conditions, gastrointestinal ulceration and perforation, gastrointestinal haemorrhages, stomatitis and ulceration, ascites, vomiting, gastrointestinal and abdominal pains, dyspeptic signs and symptoms, constipation, flatulence, bloating and distension, loose stools, gastrointestinal signs and symptoms uncommon:    ileus paralytic, acute and chronic pancreatitis, gastrooesophageal reflux disease, impaired gastric emptying rare:        subileus, pancreatic pseudocyst

Hepatobiliary disorders common:         cholestasis and jaundice, hepatocellular damage and hepatitis, cholangitis rare:           hepatic artery thrombosis, venoocclusive liver disease very rare:      hepatic failure, bile duct stenosis

Skin and subcutaneous tissue disorders common:         pruritus, rash, alopecias, acne, sweating increased uncommon:       dermatitis, photosensitivity rare:           toxic epidermal necrolysis (Lyell’s syndrome) very rare:      Stevens-Johnson syndrome

Musculoskeletal and connective tissue disorders common:         arthralgia, muscle spasms, pain in extremity, back pain uncommon:       joint disorders rare:           mobility decreased

Renal and urinary disorders very common:         renal impairment common:              renal failure, renal failure acute, oliguria, renal tubular necrosis, nephropathy toxic, urinary abnormalities, bladder and urethral symptoms uncommon:            anuria, haemolytic uraemic syndrome very rare:           nephropathy, cystitis haemorrhagic


Reproductive system and breast disorders uncommon:        dysmenorrhoea and uterine bleeding

General disorders and administration site conditions common:          asthenic conditions, febrile disorders, oedema, pain and discomfort, body temperature perception disturbed uncommon:        multi-organ failure, influenza like illness, temperature intolerance, chest pressure sensation, feeling jittery, feeling abnormal rare:            thirst, fall, chest tightness, ulcer very rare:       fat tissue increased

Investigations very common: liver function tests abnormal common:      blood alkaline phosphatase increased, weight increased uncommon:    amylase increased, ECG investigations abnormal, heart rate and pulse investigations abnormal, weight decreased, blood lactate dehydrogenase increased very rare:   echocardiogram abnormal, electrocardiogram QT prolonged

Injury, poisoning and procedural complications common:          primary graft dysfunction

Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. A number of associated cases of transplant rejection have been reported (frequency cannot be estimated from available data).

Description of selected adverse reactions
Pain in extremity has been described in a number of published case reports as part of Calcineurin- Inhibitor Induced Pain Syndrome (CIPS). This typically presents as a bilateral and symmetrical, severe, ascending pain in the lower extremities and may be associated with supra-therapeutic levels of tacrolimus. The syndrome may respond to tacrolimus dose reduction. In some cases, it was necessary to switch to alternative immunosuppression.

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