Prograf Adverse Reactions

Transplantation: 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 as follows 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).
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 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.
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).
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 hypertonia.
Very rare: myasthenia.
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, (peritonitis, blood amylase increased for inj).
Rare: subileus, pancreatic pseudocyst.
Hepatobiliary disorders: Common: cholestasis and jaundice, hepatocellular damage and hepatitis, cholangitis.
Rare: hepatitic 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.
Not known: febrile neutropenia.
Investigations: Common: hepatic enzymes and function abnormalities, 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.
Cap: 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.
0.5 mg and 1 mg cap: Rheumatoid arthritis: In the clinical studies conducted in Japan by the time of approval, the main adverse reactions or abnormal laboratory test values due to this product in 509 patients with rheumatoid arthritis (capsules 509) were abnormal renal function (20.8%, 105/506) including increased BUN (13.6%, 69/506), increased creatinine (9.3%, 47/506); gastrointestinal system disorders (14.8%, 75/508) including abdominal pain (3.7%, 19/508), diarrhea (2.6%, 13/508), and nausea (2.2%, 11/508); and impaired glucose tolerance (8.9%, 45/505) including increased HbA1C (6.6%, 33/498), and increased blood glucose (4.4%, 22/495).
In the post-marketing clinical study and surveillance, adverse reactions (including abnormalities in clinical laboratory findings) due to this product (capsules) were observed in 1,336 (38.1%) of 3,509 patients with rheumatoid arthritis. The major adverse reactions were white blood cell count increased 2.7% (96/3,509), NAG increased 2.2% (78/3,509), BUN increased 1.7% (58/3,509), nausea 1.5% (51/3,509), HbA1c increased 1.4% (50/3,509), diabetes mellitus 1.4% (50/3,509), diarrhoea 1.3% (47/3,509), renal impairment 1.3% (46/3,509), lymphocyte count decreased 1.3% (44/3,509), β₂ microglobulin urine increased 1.3% (44/3,509).
(Notification of the reexamination results in Japan: September 2013).
In patients with rheumatoid arthritis, interstitial pneumonia may occur (incidence ≥ 0.1%, < 5%*). Therefore, patients should be carefully observed, and if respiratory symptoms such as fever, cough, or dyspnea develop, the drug should be discontinued. Affected patients should be promptly examined by chest X-ray and CT scan, as well as blood testing, and appropriate measures, including administration of adrenocortical hormone, should be instituted, taking differential diagnosis of infection into consideration.
(*The incidence is based on the result for rheumatoid arthritis in the post-marketing clinical study and surveillance for Prograf in Japan.)
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 increased urinary β₂-microglobulin (27.3%, 12/44), increased urinary NAG (22.2%, 14/63), nasopharyngitis (15.4%, 10/65), hyperuricemia (14.1%, 9/64), leukocytosis (14.1%, 9/64), increased creatinine (12.5%, 8/64), diarrhea (12.3%, 8/65), increased blood pressure (10.8%, 7/65), and hyperglycemia (10.9%, 7/64).