Adverse reactions : תופעות לוואי

4.8     Undesirable effects

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


The most commonly reported adverse reactions (occurring in > 10% of patients) are tremor, renal impairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, hypertension and insomnia.

The frequency of adverse reactions is defined as follows: 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, undesirable effects are presented in order of decreasing seriousness.

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 Advagraf.

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, thrombocytopenia, leukopenia, red blood cell analyses abnormal, leukocytosis uncommon:        coagulopathies, pancytopenia, neutropenia, coagulation and bleeding analyses, abnormal, 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:     diabetes mellitus, hyperglycaemic conditions, hyperkalaemia common:          metabolic acidoses, other electrolyte abnormalities, hyponatraemia, fluid overload, hyperuricaemia, hypomagnesaemia, hypokalaemia, hypocalcaemia, appetite decreased, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia, hypophosphataemia uncommon:        dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia 
Psychiatric disorders very common:       insomnia common:            confusion and disorientation, depression, anxiety symptoms, hallucination, mental disorders, depressed mood, mood disorders and disturbances, nightmare uncommon:          psychotic disorder

Nervous system disorders very common:      headache, tremor

common:            nervous system disorders, seizures, disturbances in consciousness, peripheral neuropathies, dizziness, paraesthesias and dysaesthesias, writing impaired uncommon:          encephalopathy, central nervous system haemorrhages and cerebrovascular accidents, coma, speech and language abnormalities, paralysis and paresis, amnesia rare:              hypertonia very rare:         myasthenia not known:         posterior reversible encephalopathy syndrome (PRES) 
Eye disorders common:            eye disorders, vision blurred, photophobia 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:         heart failures, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias, cardiomyopathies, ventricular hypertrophy, palpitations rare:             pericardial effusion very rare:        Torsades de pointes

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

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

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

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

Skin and subcutaneous tissue disorders common:           rash, pruritus, 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, back pain, muscle spasms, pain in extremity uncommon:         joint disorders rare:             mobility decreased

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

Reproductive system and breast disorders uncommon:         dysmenorrhoea and uterine bleeding

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