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 as follows 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).
Common: ischaemic coronary artery disorders, tachycardia.
Uncommon: ventricular arrhythmias and cardiac arrest, heart failures, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations, ECG investigations abnormal, heart rate and pulse investigations abnormal.
Rare: pericardial effusion.
Very Rare: echocardiogram abnormal, electrocardiogram QT prolonged, Torsades de Pointes.
Blood and lymphatic system disorders:
Common: anaemia, leukopenia, thrombocytopenia, leukocytosis, red blood cell analyses abnormal.
Uncommon: coagulopathies, coagulation and bleeding analyses abnormal, pancytopenia, neutropenia.
Rare: thrombotic thrombocytopenic purpura, hypoprothrombinaemia, thrombotic microangiopathy.
Not Known: pure red cell aplasia, agranulocytosis, haemolytic anaemia.
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.
Very Rare: myasthenia.
Common: vision blurred, photophobia, eye disorders.
Not known: optic neuropathy.
Ear and labyrinth disorders:
Rare: deafness neurosensory.
Very rare: hearing impaired.
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.
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, amylase increased, gastrooesophageal reflux disease, impaired gastric emptying.
Rare: subileus, pancreatic pseudocyst.
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.
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.
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.
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 preexisting 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 Prograf.
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).
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.
Very common: hypertension.
Common: haemorrhage, thromboembolic and ischaemic events, peripheral vascular disorders, vascular hypotensive disorders.
Uncommon: infarction, venous thrombosis deep limb, shock.
General disorders and administration site conditions:
Common: asthenic conditions, febrile disorders, oedema, pain and discomfort, blood alkaline phosphatase increased, weight increased, body temperature perception disturbed.
Uncommon: multi-organ failure, influenza like illness, temperature intolerance, chest pressure sensation, feeling jittery, feeling abnormal, blood lactate dehydrogenase increased, weight decreased.
Rare: thirst, fall, chest tightness, ulcer.
Very rare: fat tissue increased.
Not known: febrile neutropenia.
Immune system disorders:
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see Precautions).
Common: hepatic enzymes and function abnormalities, cholestasis and jaundice, hepatocellular damage and hepatitis, cholangitis.
Rare: hepatitic artery thrombosis, venoocclusive liver disease.
Very rare: hepatic failure, bile duct stenosis.
Reproductive system and breast disorders:
Uncommon: dysmenorrhoea and uterine bleeding.
Very common: insomnia.
Common: anxiety symptoms, confusion and disorientation, depression, depressed mood, mood disorders and disturbances, nightmare, hallucination, mental disorders.
Uncommon: psychotic disorder.
Adverse reactions in patients with Lupus nephritis:
The major adverse reactions or abnormalities in clinical laboratory findings due to this product in 65 patients with lupus nephritis (capsules 65) were β2 microglobulin urine increased (27.3%, 12/44), urinary NAG increased (22.2%, 14/63), nasopharyngitis (15.4%, 10/65), hyperuricaemia (14.1%, 9/64), leukocytosis (14.1%, 9/64), creatinine increased (12.5%, 8/64), diarrhoea (12.3%, 8/65), blood pressure increased (10.8%, 7/65), and hyperglycaemia (10.9%, 7/64).
*: In isolated cases, pain in extremity has been reported as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS), which typically presents bilateral and symmetrical, severe, ascending pain in the lower extremities.