St. John's Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since tacrolimus is a substrate for CYP3A4, there is the potential that the use of St. John's Wort in patients receiving Prograf could result in reduced tacrolimus levels.
In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14±6% vs. 7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance (0.036±0.008L/hr/kg vs. 0.053±0.010L/hr/kg) with concomitant rifampin administration.
Interaction studies with drugs used in HIV therapy have not been conducted. However, care should be exercised when drugs that are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A (e.g., ritonavir) are administered concomitantly with tacrolimus. Tacrolimus may effect the pharmacokinetics of other drugs (e.g. phenytoin) and increase their concentration. Grapefruit juice affects CYP3A-mediated metabolism and should be avoided (see DOSAGE AND ADMINISTRATION).
Other Drug Interactions
Immunosuppressants may affect vaccination. Therefore, during treatment with Prograf, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, and TY 21a typhoid.1
Carcinogenesis, Mutagenesis and Impairment of Fertility
An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin's lymphomas and carcinomas of the skin. As with other immunosuppressive therapies, the risk of malignancies in Prograf recipients may be higher than in the normal, healthy population. Lymphoproliferative disorders associated with Epstein-Barr Virus infection have been seen. It has been reported that reduction or discontinuation of immunosuppression may cause the lesions to regress.
No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.
Carcinogenicity studies were carried out in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found. The highest doses used in the mouse and rat studies were 0.8 - 2.5 times (mice) and 3.5 - 7.1 times (rats) the recommended clinical dose range of 0.1 - 0.2 mg/kg/day when corrected for body surface area.
No impairment of fertility was demonstrated in studies of male and female rats. Tacrolimus, given orally at 1.0 mg/kg (0.7 - 1.4X the recommended clinical dose range of 0.1 - 0.2 mg/kg/day based on body surface area corrections) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.3 - 4.6X the recommended clinical dose range based on body surface area correction), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.
Pregnancy: Category C
In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1.0 mg/kg during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions; these doses are equivalent to 0.5 - 1X and 1.6 - 3.3X the recommended clinical dose range (0.1 - 0.2 mg/kg) based on body surface area corrections. At the higher dose only, an increased incidence of malformations and developmental variations was also seen. Tacrolimus, at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally at 1.0 and 3.2 mg/kg (equivalent to 0.7 - 1.4X and 2.3 - 4.6X the recommended clinical dose range based on body surface area corrections) to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights.
No reduction in male or female fertility was evident.
There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. Prograf should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus.
Nursing Mothers
Since tacrolimus is excreted in human milk, nursing should be avoided.
Pediatric Patients
Experience with Prograf in pediatric kidney transplant patients is limited. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using Prograf. The two randomized active-controlled trials of Prograf in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to Prograf-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of Prograf to maintain blood trough concentrations of tacrolimus similar to adult patients (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS:
Liver Transplantation
The principal adverse reactions of Prograf are tremor, headache, diarrhea, hypertension, nausea, and renal dysfunction. These occur with oral and IV 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 posttransplant information from the U.S. study and from the European study is presented below. 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 below for the two controlled trials in liver transplantation:
LIVER TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN > 15% OF PROGRAF-TREATED PATIENTS
| U.S. STUDY (%) | EUROPEAN STUDY (%) | |||||
| Prograf (N=250) | CBIR (N=250) | Prograf (N=264) | CBIR (N=265) | |||
| Nervous System | ||||||
| Headache (see WARNINGS) | 64 | 60 | 37 | 26 | ||
| Tremor (see WARNINGS) | 56 | 46 | 48 | 32 | ||
| Insomnia | 64 | 68 | 32 | 23 | ||
| Paresthesia | 40 | 30 | 17 | 17 | ||
| Gastrointestinal | ||||||
| Diarrhea | 72 | 47 | 37 | 27 | ||
| Nausea | 46 | 37 | 32 | 27 | ||
| Constipation | 24 | 27 | 23 | 21 | ||
| LFT Abnormal | 36 | 30 | 6 | 5 | ||
| Anorexia | 34 | 24 | 7 | 5 | ||
| Vomiting | 27 | 15 | 14 | 11 | ||
| Cardiovascular | ||||||
| Hypertension (see PRECAUTIONS) | 47 | 56 | 38 | 43 | ||
| Urogenital | ||||||
| Kidney Function Abnormal (see WARNINGS) | 40 | 27 | 36 | 23 | ||
| Creatinine Increased (see WARNINGS) | 39 | 25 | 24 | 19 | ||
| BUN Increased (see WARNINGS) | 30 | 22 | 12 | 9 | ||
| Urinary Tract Infection | 16 | 18 | 21 | 19 | ||
| Oliguria | 18 | 15 | 19 | 12 | ||
| Metabolic and Nutritional | ||||||
| Hyperkalemia (see WARNINGS) | 45 | 26 | 13 | 9 | ||
| Hypokalemia | 29 | 34 | 13 | 16 | ||
| Hyperglycemia (see WARNINGS) | 47 | 38 | 33 | 22 | ||
| Hypomagnesemia | 48 | 45 | 16 | 9 | ||
| Hemic and Lymphatic | ||||||
| Anemia | 47 | 38 | 5 | 1 | ||
| Leukocytosis | 32 | 26 | 8 | 8 | ||
| Thrombocytopenia | 24 | 20 | 14 | 19 | ||
| Miscellaneous | ||||||
| Abdominal Pain | 59 | 54 | 29 | 22 | ||
| Pain | 63 | 57 | 24 | 22 | ||
| Fever | 48 | 56 | 19 | 22 | ||
| Asthenia | 52 | 48 | 11 | 7 | ||
| Back Pain | 30 | 29 | 17 | 17 | ||
| Ascites | 27 | 22 | 7 | 8 | ||
| Peripheral Edema | 26 | 26 | 12 | 14 | ||
| Respiratory System | ||||||
| Pleural Effusion | 30 | 32 | 36 | 35 | ||
| Atelectasis | 28 | 30 | 5 | 4 | ||
| Dyspnea | 29 | 23 | 5 | 4 | ||
| Skin and Appendages | ||||||
| Pruritus | 36 | 20 | 15 | 7 | ||
| Rash | 24 | 19 | 10 | 4 | ||
Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions below.
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 Prograf-treated kidney transplant patients are presented below:
KIDNEY TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN > 15% OF PROGRAF-TREATED PATIENTS
| Prograf (N=205) | CBIR (N=207) | |
| Nervous System | ||
| Tremor (see WARNINGS) | 54 | 34 |
| Headache (see WARNINGS) | 44 | 38 |
| Insomnia | 32 | 30 |
| Paresthesia | 23 | 16 |
| Dizziness | 19 | 16 |
| Gastrointestinal | ||
| Diarrhea | 44 | 41 |
| Nausea | 38 | 36 |
| Constipation | 35 | 43 |
| Vomiting | 29 | 23 |
| Dyspepsia | 28 | 20 |
| Cardiovascular | ||
| Hypertension (see PRECAUTIONS) | 50 | 52 |
| Chest Pain | 19 | 13 |
| Urogenital | ||
| Creatinine Increased (see WARNINGS) | 45 | 42 |
| Urinary Tract Infection | 34 | 35 |
| Metabolic and Nutritional | ||
| Hypophosphatemia | 49 | 53 |
| Hypomagnesemia | 34 | 17 |
| Hyperlipemia | 31 | 38 |
| Hyperkalemia (see WARNINGS) | 31 | 32 |
| Diabetes Mellitus (see WARNINGS) | 24 | 9 |
| Hypokalemia | 22 | 25 |
| Hyperglycemia (see WARNINGS) | 22 | 16 |
| Edema | 18 | 19 |
| Hemic and Lymphatic | ||
| Anemia | 30 | 24 |
| Leukopenia | 15 | 17 |
| Miscellaneous | ||
| Infection | 45 | 49 |
| Peripheral Edema | 36 | 48 |
| Asthenia | 34 | 30 |
| Abdominal Pain | 33 | 31 |
| Pain | 32 | 30 |
| Fever | 29 | 29 |
| Back Pain | 24 | 20 |
| Respiratory System | ||
| Dyspnea | 22 | 18 |
| Cough Increased | 18 | 15 |
| Musculoskeletal | ||
| Arthralgia | 25 | 24 |
| Skin | ||
| Rash | 17 | 12 |
| Pruritis | 15 | 7 |
Less frequently observed adverse reactions in both liver transplantion and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions shown below.
Less Frequently Reported Adverse Reactions
The following adverse events were reported in the range of 3% to less than 15% incidence in either liver or kidney transplant recipients who were treated with tacrolimus in the Phase 3 comparative trials.
NERVOUS SYSTEM: (see WARNINGS) abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, depression, dizziness, emotional lability, encephalopathy, hallucinations, hypertonia, incoordination, myoclonus, nervousness, neuropathy, psychosis, somnolence, thinking abnormal; SPECIAL SENSES: abnormal vision, amblyopia, ear pain, otitis media, tinnitus; GASTROINTESTINAL: anorexia, cholangitis, cholestatic jaundice, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastrointestinal hemorrhage, GGT increase, GI perforation, hepatitis, ileus, increased appetite, jaundice, liver damage, liver function test abnormal, oral moniliasis, rectal disorder, stomatitis; CARDIOVASCULAR: angina pectoris, chest pain, deep thrombophlebitis, abnormal ECG, hemorrhage, hypotension, postural hypotension, peripheral vascular disorder, phlebitis, tachycardia, thrombosis, vasodilatation; UROGENITAL: (see WARNINGS) albuminuria, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, oliguria, urinary frequency, urinary incontinence, 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, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactic dehydrogenase increase, weight gain; ENDOCRINE: (see PRECAUTIONS) Cushing's syndrome, diabetes mellitus; HEMIC/LYMPHATIC: coagulation disorder, ecchymosis, hypochromic anemia, leukocytosis, leukopenia, polycythemia, prothrombin decreased, serum iron decreased, thrombocytopenia; MISCELLANEOUS: abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, flu syndrome, generalized edema, hernia, peritonitis, photosensitivity reaction, sepsis; MUSCULOSKELETAL: arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis; RESPIRATORY: asthma, bronchitis, cough increased, lung disorder, pneumothorax, pulmonary edema, pharyngitis, pneumonia, respiratory disorder, rhinitis, sinusitis, voice alteration; SKIN: acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, hirsutism, skin discoloration, skin disorder, skin ulcer, sweating.