Dosage Form: capsule
FULL PRESCRIBING INFORMATION
- Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression [see WARNINGS AND PRECAUTIONS (5.2)].
- Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see WARNINGS AND PRECAUTIONS (5.3, 5.4, 5.5)].
- Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Hecoria (tacrolimus) capsules. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [see WARNINGS AND PRECAUTIONS (5.1)]
Indications and Usage for Hecoria
Prophylaxis of Organ Rejection in Kidney Transplant
Hecoria (tacrolimus) capsules are indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney transplants. It is recommended that Hecoria be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see CLINICAL STUDIES ( 14.1)]. Therapeutic drug monitoring is recommended for all patients receiving Hecoria [see DOSAGE AND ADMINISTRATION (2.6 )].
Prophylaxis of Organ Rejection in Liver Transplant
Hecoria (tacrolimus) capsules are indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants. It is recommended that Hecoria be used concomitantly with adrenal corticosteroids [see CLINICAL STUDIES (14.2)]. Therapeutic drug monitoring is recommended for all patients receiving Hecoria [see DOSAGE AND ADMINISTRATION (2.6 )].
Limitations of Use
Hecoria (tacrolimus) capsules should not be used simultaneously with cyclosporine [see DOSAGE AND ADMINISTRATION (2.5 )].
Tacrolimus injection should be reserved for patients unable to take Hecoria orally [see DOSAGE AND ADMINISTRATION (2.1) and WARNINGS AND PRECAUTIONS(5.11)].
Use with sirolimus is not recommended in liver transplant. The safety and efficacy of Hecoria with sirolimus has not been established in kidney transplant [see WARNINGS AND PRECAUTIONS (5.12)].
Hecoria Dosage and Administration
Dosage in Adult Kidney, or Liver Transplant Patients
The initial oral dosage recommendations for adult patients with kidney, or liver transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of Hecoria (tacrolimus) capsules should be administered no sooner than 6 hours after transplantation in the liver transplant patients. In kidney transplant patients, the initial dose of Hecoria may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. For blood concentration monitoring details see DOSAGE AND ADMINISTRATION (2.6 ).
Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults
| Patient Population | Recommended Hecoria Initial Oral Dosage Note: daily doses should be administered as two divided doses, every 12 hours | Observed Tacrolimus Whole Blood Trough Concentrations |
Adult kidney transplant patients In combination with azathioprine | ||
| 0.2 mg/kg/day | month 1 to 3: 7 to 20 ng/mL month 4 to 12: 5 to 15 ng/mL | |
| In combination with MMF/IL-2 receptor antagonista | 0.1 mg/kg/day | month 1 to 12: 4 to 11 ng/mL |
| Adult liver transplant patients | 0.10 to 0.15 mg/kg/day | month 1 to 12: 5 to 20 ng/mL |
a In a second smaller trial, the initial dose of tacrolimus was 0.15 to 0.2 mg/kg/day and observed tacrolimus concentrations were 6 to 16 ng/mL during month 1 to 3 and 5 to 12 ng/mL during month 4 to 12 [see CLINICAL STUDIES (14.1)].
Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Hecoria dosages than the recommended initial dosage may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.
The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2).
| Time After Transplant | Caucasian n=114 | Black n=56 | ||
| Dose (mg/kg) | Trough Concentrations (ng/mL) | Dose (mg/kg) | Trough Concentrations (ng/mL) | |
| Day 7 | 0.18 | 12 | 0.23 | 10.9 |
| Month 1 | 0.17 | 12.8 | 0.26 | 12.9 |
| Month 6 | 0.14 | 11.8 | 0.24 | 11.5 |
| Month 12 | 0.13 | 10.1 | 0.19 | 11 |
Initial Dose – Injection
Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of Hecoria (tacrolimus) capsules. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of Hecoria, usually within 2 to 3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.
The observed trough concentrations described above pertain to oral administration of Hecoria (tacrolimus) capsules only; while monitoring Hecoria concentrations in patients receiving tacrolimus injection as a continuous IV infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated by the trough concentrations observed in patients on oral therapy.
The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney and liver transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.
Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection [see WARNINGS AND PRECAUTIONS (5.11)].
Dosage in Pediatric Liver Transplant Patients
The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see DOSAGE AND ADMINISTRATION (2.6 ). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.
| Patient Population | Recommended Hecoria Initial Oral Dosage Note: daily doses should be administered as two divided doses, every 12 hours | Observed Tacrolimus Whole Blood Trough Concentrations |
| Pediatric liver transplant patients | 0.15 to 0.20 mg/kg/day | Month 1 to 12: 5 to 20 ng/mL |
Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.
Experience in pediatric kidney transplantation patients is limited.
Dosage Adjustment in Patients with Renal Impairment
Due to its potential for nephrotoxicity, consideration should be given to dosing Hecoria (tacrolimus) capsules at the lower end of the therapeutic dosing range in patients who have received a liver transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.
In kidney transplant patients with post-operative oliguria, the initial dose of Hecoria should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery.
Dosage Adjustments in Patients with Hepatic Impairment
Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child Pugh ≥ 10) may require lower doses of Hecoria (tacrolimus) capsules. Close monitoring of blood concentrations is warranted.
The use of Hecoria in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see DOSAGE AND ADMINISTRATION (2.1 ), USE IN SPECIFIC POPULATIONS (8.7) and CLINICAL PHARMACOLOGY (12.3)].
Administration Instructions
It is recommended that patients initiate oral therapy with Hecoria (tacrolimus) capsules if possible.
Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 [see DOSAGE AND ADMINISTRATION (2.1, 2.2)]; for blood concentration monitoring details in kidney transplant patients [see DOSAGE AND ADMINISTRATION (2.1)].
It is important to take Hecoria consistently every day either with or without food because the presence and composition of food decreases the bioavailability of Hecoria [see CLINICAL PHARMACOLOGY (12.3)].
Patients should not eat grapefruit or drink grapefruit juice in combination with Hecoria [see DRUG INTERACTIONS (7.2)].
Hecoria should not be used simultaneously with cyclosporine. Hecoria or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated Hecoria or cyclosporine concentrations, dosing with the other drug usually should be further delayed.
In patients unable to take oral Hecoria (tacrolimus) capsules, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.
Therapeutic Drug Monitoring
Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Observed whole blood trough concentrations can be found in Table 1. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation.
The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure.
Methods commonly used for the assay of tacrolimus include high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer they should be deep frozen at -20° C. One study showed drug recovery >90% for samples stored at -20° C for 6 months, with reduced recovery observed after 6 months.
Dosage Forms and Strengths
Hecoria (tacrolimus) capsules are available in 0.5 mg, 1 mg, and 5 mg strengths.
Hecoria (tacrolimus) capsules, containing white to off white powder equivalent to 0.5 mg of anhydrous tacrolimus, are hard gelatin capsules with white opaque body and ivory cap. The body is imprinted “0.5 mg” and cap is imprinted “Hecoria” in black ink.
Hecoria (tacrolimus) capsules, containing white to off white powder equivalent to 1 mg of anhydrous tacrolimus, are hard gelatin capsules with white opaque body and brown cap. The body is imprinted “1 mg” and cap is imprinted “Hecoria” in black ink.
Hecoria (tacrolimus) capsules, containing white to off white powder equivalent to 5 mg of anhydrous tacrolimus, are hard gelatin capsules with white opaque body and orange cap. The body is imprinted “5 mg” and cap is imprinted “Hecoria” in black ink.
Contraindications
Hecoria (tacrolimus) capsules are contraindicated in patients with a hypersensitivity to tacrolimus. Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see ADVERSE REACTIONS (6)].
Warnings and Precautions
Management of Immunosuppression
Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use Hecoria (tacrolimus) capsules. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physicians responsible for maintenance therapy should have complete information requisite for the follow up of the patient [see BOX WARNING].
Lymphoma and Other Malignancies
Patients receiving immunosuppressants, including Hecoria (tacrolimus) capsules, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see BOX WARNING]. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.
As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Post transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children.
Serious Infections
Patients receiving immunosuppressants, including Hecoria (tacrolimus) capsules, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see BOX WARNING and WARNINGS AND PRECAUTIONS (5.4, 5.5)]. These infections may lead to serious, including fatal, outcomes. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.
Polyoma Virus Infections
Patients receiving immunosuppressants, including Hecoria (tacrolimus) capsules, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus-associated progressive multifocal leukoencephalopathy (PML) which have been observed in patients receiving tacrolimus [see ADVERSE REACTIONS (6.2)].
PVAN is associated with serious outcomes, including deteriorating renal function and kidney graft loss [see ADVERSE REACTIONS (6.2)]. Patient monitoring may help detect patients at risk for PVAN.
Cases of PML have been reported in patients treated with Hecoria. PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.
Reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.
Cytomegalovirus (CMV) Infections
Patients receiving immunosuppressants, including Hecoria (tacrolimus) capsules, are at increased risk of developing CMV viremia and CMV disease. The risk of CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease. Consideration should be given to reducing the amount of immunosuppression in patients who develop CMV viremia and/or CMV disease.
New Onset Diabetes After Transplant
Tacrolimus was shown to cause new onset diabetes mellitus in clinical trials of kidney and liver transplantation. New onset diabetes after transplantation may be reversible in some patients. Black and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using Hecoria (tacrolimus) capsules [see ADVERSE REACTIONS (6.1)].
Nephrotoxicity
Hecoria (tacrolimus) capsules, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity, particularly when used in high doses. Acute nephrotoxicity is most often related to vasoconstriction of the afferent renal arteriole, is characterized by increasing serum creatinine, hyperkalemia, and/or a decrease in urine output, and is typically reversible. Chronic calcineurin-inhibitor nephrotoxicity is associated with increased serum creatinine, decreased kidney graft life, and characteristic histologic changes observed on renal biopsy; the changes associated with chronic calcineurin-inhibitor nephrotoxicity are typically progressive. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy.
Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials, respectively [see ADVERSE REACTIONS (6.1)].
Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering Hecoria with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors (e.g., tenofovir) and protease inhibitors (e.g., ritonavir, indinavir). Similarly, care should be exercised when administering with CYP3A4 inhibitors such as antifungal drugs (e.g., ketoconazole), calcium channel blockers (e.g., diltiazem, verapamil), and macrolide antibiotics (e.g., clarithromycin, erythromycin, troleandomycin) which will result in increased tacrolimus whole blood concentrations due to inhibition of tacrolimus metabolism [see DRUG INTERACTIONS (7.3,7.4, 7.5, 7.6)].
Neurotoxicity
Hecoria (tacrolimus) capsules may cause a spectrum of neurotoxicities, particularly when used in high doses. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, and coma. Patients treated with tacrolimus have been reported to develop PRES. Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression.
Coma and delirium, in the absence of PRES, have also been associated with high plasma concentrations of tacrolimus. Seizures have occurred in adult and pediatric patients receiving Hecoria [see ADVERSE REACTIONS (6.1)].
Less severe neurotoxicities, include tremors, parathesias, headache, and other changes in motor function, mental status, and sensory function [see ADVERSE REACTIONS (6.1)] . Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment.
Hyperkalemia
Hyperkalemia has been reported with Hecoria (tacrolimus) capsule use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during Hecoria therapy [see ADVERSE REACTIONS (6.1)].
Hypertension
Hypertension is a common adverse effect of Hecoria (tacrolimus) capsules therapy and may require antihypertensive therapy [see ADVERSE REACTIONS (6.1)]. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see WARNINGS AND PRECAUTIONS (5.9)]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of Hecoria [see DRUG INTERACTIONS (7.5)].
Anaphylactic Reactions with Tacrolimus Injection
Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Tacrolimus injection should be reserved for patients who are unable to take tacrolimus capsules [see INDICATIONS AND USAGE (1.4)].
Patients receiving tacrolimus injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, the infusion should be stopped. An aqueous solution of epinephrine should be available at the bedside as well as a source of oxygen.
Use with Sirolimus
The safety and efficacy of Hecoria (tacrolimus) capsules with sirolimus has not been established in kidney transplant patients.
Use of sirolimus with tacrolimus in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT) and is not recommended [see INDICATIONS AND USAGE (1.4)].
Use with Strong Inhibitors and Inducers of CYP3A
Co-administration with strong CYP3A4-inhibitors (e.g., ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin) is not recommended without close monitoring of tacrolimus whole blood trough concentrations [see DRUG INTERACTIONS (7)].
Myocardial Hypertrophy
Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of Hecoria (tacrolimus) capsules should be considered [see ADVERSE REACTIONS (6.2)].
Immunizations
The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
Pure Red Cell Aplasia
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of Hecoria (tacrolimus) capsules should be considered [see ADVERSE REACTIONS (6.2)].
Adverse Reactions
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
- Lymphoma and Other Malignancies [see BOX WARNING, WARNINGS AND PRECAUTIONS (5.2)]
- Serious Infections [see BOX WARNING, WARNINGS AND PRECAUTIONS (5.3)]
- Polyoma Virus Infections [see BOX WARNING, WARNINGS AND PRECAUTIONS (5.4)]
- CMV Infections [see BOX WARNING, WARNINGS AND PRECAUTIONS (5.5)]
- New Onset Diabetes After Transplant [see WARNINGS AND PRECAUTIONS (5.6)]
- Nephrotoxicity [see WARNINGS AND PRECAUTIONS (5.7)]
- Neurotoxicity [see WARNINGS AND PRECAUTIONS (5.8)]
- Hyperkalemia [see WARNINGS AND PRECAUTIONS (5.9)]
- Hypertension [see WARNINGS AND PRECAUTIONS (5.10)]
- Myocardial Hypertrophy [see WARNINGS AND PRECAUTIONS (5.14)]
- Pure Red Cell Aplasia [see WARNINGS AND PRECAUTIONS (5.16)]
Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.
Kidney Transplant
The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression.
Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in trial where 205 patients received tacrolimus based immunosuppression and 207 patients received cyclosporine based immunosuppression. The trial population had a mean age of 43 years (mean±sd was 43±13 years on tacrolimus and 44±12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), Black (25%), Hispanic (12%) and Other (5%). The 12 month post-transplant information from this trial is presented below.
The most common adverse reactions ( ≥ 30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia and anemia.
Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below:
Tacrolimus /AZA (N=205) | Cyclosporine/AZA (N=207) | |
| Nervous System | ||
| Tremor | 54% | 34% |
| Headache | 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 | 50% | 52% |
| Chest Pain | 19% | 13% |
| Urogenital | ||
| Creatinine Increased | 45% | 42% |
| Urinary Tract Infection | 34% | 35% |
| Metabolic and Nutritional | ||
| Hypophosphatemia | 49% | 53% |
| Hypomagnesemia | 34% | 17% |
| Hyperlipemia | 31% | 38% |
| Diabetes Mellitus | 31% | 32% |
| Hyperkalemia | 24% | 9% |
| Hypokalemia | 22% | 25% |
| Hyperglycemia | 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% |
| Pruritus | 15% | 7% |
Two trials were conducted for tacrolimus -based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received tacrolimus (Group C, n=403), or one of two cyclosporine (CsA) regimens (Group A, n=384 and Group B, n=408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76), the distribution was 65% male, and the composition was 93% Caucasian. The 12 month post-transplant information from this trial is presented below.
Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below:
| Tacrolimus (Group C) | Cyclosporine (Group A) | Cyclosporine (Group B) | |
| (N=403) | (N=384) | (N=408) | |
| Diarrhea | 25% | 16% | 13% |
| Urinary Tract Infection | 24% | 28% | 24% |
| Anemia | 17% | 19% | 17% |
| Hypertension | 13% | 14% | 12% |
| Leukopenia | 13% | 10% | 10% |
| Edema Peripheral | 11% | 12% | 13% |
| Hyperlipidemia | 10% | 15% | 13% |
| Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C= Tac/MMF/CS/Daclizumab | |||
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