Prograf Adverse Reactions

Liver Transplantation: The principal adverse reactions of Prograf are tremor, headache, diarrhea, hypertension, nausea, and abnormal renal function. These occur with oral and intravenous administration of Prograf and may respond to a reduction in dosing. Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.
Hyperkalemia and hypomagnesemia have occurred in patients receiving Prograf therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy (see Warnings).
The incidence of adverse events was determined in two randomized comparative liver transplant trials among 514 patients receiving tacrolimus and steroids and 515 patients receiving a cyclosporine-based regimen (CBIR). The proportion of patients reporting more than one adverse event was 99.8% in the tacrolimus group and 99.6% in the CBIR group. Precautions must be taken when comparing the incidence of adverse events in the U.S. study to that in the European study. The 12-month post-transplant information from the U.S. study and from the European study is presented as follows. The two studies also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse events reported in ≥15% in tacrolimus patients (combined study results) are presented as follows for the two controlled trials in liver transplantation: See Table 16.

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Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under Less Frequently Reported Adverse Reactions as follows.
Kidney Transplantation: The most common adverse reactions reported were infection, tremor, hypertension, decreased renal function, constipation, diarrhea, headache, abdominal pain and insomnia.
Adverse events that occurred in ≥15% of kidney transplant patients treated with Prograf in conjunction with azathioprine are presented as follows: See Table 17.

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Adverse events that occurred in ≥10% of kidney transplant patients treated with Prograf in conjunction with MMF in Study 1^* are presented as follows: See Table 18.

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Adverse events that occurred in ≥15% of kidney transplant patients treated with Prograf in conjunction with MMF in Study 2 are presented as follows: See Table 19.

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Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under Less Frequently Reported Adverse Reactions shown as follows.
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).
(At the time of latest approval of indication: January 2007.)
Less Frequently Reported Adverse Reactions: The following adverse events were reported in the range of 3% to less than 15% incidence in either kidney, liver and/or heart transplant recipients who were treated with tacrolimus in clinical trials.
NERVOUS SYSTEM (see Warnings): abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, dizziness, elevated mood, emotional lability, encephalopathy, haemorrhagic stroke, hallucinations, headache, hypertonia, incoordination, insomnia, monoparesis, myoclonus, nerve compression, nervousness, neuropathy, paresthesia, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, writing impaired, brachial plexopathy, peripheral nerve lesion.
SPECIAL SENSES: abnormal vision, amblyopia, ear pain, otitis media, tinnitus.
GASTROINTESTINAL: anorexia, cholangitis, cholestatic jaundice, diarrhea, duodenitis, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI perforation, granulomatous liver disease, hepatitis, hepatocellular injury, ileus, increased appetite, jaundice, liver damage, liver function test abnormal, nausea, nausea and vomiting, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis, vomiting.
CARDIOVASCULAR: abnormal ECG, angina pectoris, cardiac fibrillation, cardiopulmonary failure, chest pain, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, tachycardia, thrombosis, vasodilatation.
UROGENITAL (see Warnings): albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, oliguria, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis.
METABOLIC/NUTRITIONAL: acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, BUN increased, dehydration, GGT increased, healing abnormal, hypercalcemia, hypercholesterolemia, hyperlipidemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactic dehydrogenase increase, weight gain.
ENDOCRINE (see Precautions): Cushing's syndrome, diabetes mellitus.
HEMIC/LYMPHATIC: coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, leukopenia, polycythemia, prothrombin decreased, serum iron decreased, thrombocytopenia.
MISCELLANEOUS: abdomen enlarged, abdominal pain, abscess, accidental injury, allergic reaction, asthenia, back pain, cellulitis, chills, fall, feeling abnormal, fever, flu syndrome, generalized edema, hernia, pain*, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer.
MUSCULOSKELETAL: arthralgia, joint disorder, mobility decreased, muscle spasms, myalgia, myasthenia, osteoporosis.
RESPIRATORY: asthma, bronchitis, cough increased, dyspnea, emphysema, hiccups, lung disorder, pharyngitis, pleural effusion, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration.
SKIN: acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, hirsutism, skin discoloration, skin disorder, skin ulcer, sweating.
*: 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.
Post Marketing: Post Marketing Adverse Events: The following adverse events have been reported from worldwide marketing experience with Prograf. Because these events are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, or (3) strength of causal connection to the drug.
There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving Prograf therapy (see Myocardial Hypertrophy under Precautions).
Other events include: Cardiovascular: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsades de pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation.
Gastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis haemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease, gastrointestinal perforation.
Hemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, haemolytic anemia, neutropenia, febrile neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic microangiopathy, thrombotic thrombocytopenic purpura, pure red cell aplasia (see Warnings).
Metabolic/Nutritional: Glycosuria, increased amylase including pancreatitis, weight decreased.
Miscellaneous: Feeling of body temperature change, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction.
Nervous System: Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope.
Respiratory: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure.
Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis.
Special Senses: Blindness, blindness cortical, optic neuropathy, hearing loss including deafness, photophobia.
Urogenital: Acute renal failure, cystitis haemorrhagic, haemolytic-uraemic syndrome, micturition disorder.
Infections and infestations: As it is well known for other potent immunosuppressive agents, patients receiving tacrolimus are at an increased risk for infections (viral, bacterial, fungal, and protozoal). The course of pre-existing infections may be aggravated. Overall, infections have been reported frequently in patients being treated with tacrolimus. Both generalised and localised infections can occur.