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.
Many of the adverse reactions stated as follows are reversible and/or respond to dose reduction. 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 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:
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.
Rare: thrombotic thrombocytopenic purpura, hypoprothrombinaemia, thrombotic microangiopathy.
Not known: pure red cell aplasia, agranulocytosis, haemolytic anaemia.
Immune system disorders:
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see Precautions).
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.
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.
Very rare: myasthenia.
Common: eye disorders, vision blurred, photophobia.
Not known: optic neuropathy.
Ear and labyrinth disorders:
Rare: deafness neurosensory.
Very rare: hearing impaired.
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.
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.
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.
Common: bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice.
Rare: venoocclusive liver disease, hepatitic 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.
Not known: febrile neutropenia.
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.