Data Sheet
PROGRAFTM
Tacrolimus
PROGRAF 0.5mg 1 mg, 5 mg Capsules
PROGRAF 5mg/mL Concentrated Injection
Molecular Formula: C44H69NO12.H20
Molecular Weight: 822.05
Presentation
Capsules
Prograf capsules 0.5mg:light yellow, hard gelatine capsules with '0.5mg' and '[f]607 printed in red. Each capsule contains 0.5 mg tacrolimus.
Prograf capsules 1mg: white, hard gelatin capsules with '1 mg' and '[f]617' printed in red. Each capsule contains 1 mg tacrolimus.
Prograf capsules 5 mg: greyish-red, hard gelatine capsules with '5 mg' and '[f]657' printed in white. Each capsule contains 5 mg tacrolimus.
Prograf capsules are supplied as blister strips each containing 10 capsules packed within a protective aluminium wrapper. The 1 mg and 5 mg capsules should be stored below 30°C and the 0.5 mg capsules below 25°C. After opening the aluminium wrapper, Prograf capsules are stable for 12 months when stored at room temperature. The blister strips should be kept in a dry place and the capsules should be left in the blister until required for use.
Concentrated Injection
Prograf concentrate for infusion 5 mg/mL: colourless, clear, sterile liquid in transparent glass ampoules. Each mL of concentrate for infusion contains 5 mg tacrolimus together with PEG-60 hydrogenated castor oil and ethanol.
Prograf concentrate for infusion should be protected from light and stored below 25°C. Once an ampoule is opened, the contents should be used immediately. Following reconstitution in either 5% w/v glucose solution in polyethylene or glass containers or in 0.9% Sodium Chloride Injection in polyethylene containers, the resulting infusion mixture is stable for 24 hours.
Uses
Actions
Tacrolimus is an immunosuppressant. It is a macrolide lactone with potent in vitro and in vivo immunosuppressive activity. Studies suggest that tacrolimus inhibits the formation of cytotoxic lymphocytes which are regarded as being primarily responsible for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell proliferation, as well as the formation of lymphokines such as interleukins-2 and -3 and γ-interferon and the expression of the interleukin-2 receptor. At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein (FKBP) which is responsible for the intracellular accumulation of the compound. A complex of tacrolimus-FKBP-12, calcium, calmodulin and calcineurin is formed and the phosphatase activity of calcineurin inhibited.
Studies in animals and man have shown that Prograf is able to prevent and treat graft rejection following transplantation of the liver, kidney, and other solid organs.
Pharmacokinetics
Absorption of Prograf, following oral administration can be rapid (within 0.5 hours) or can occur continually over a prolonged period of time, resulting in a relatively flat absorption profile. The absorption of Prograf is reduced when taken with food, and it is recommended that capsules be taken on an empty stomach or at least an hour before a meal. The mean oral bioavailability was estimated to be approximately 20% in liver and kidney transplant patients. Bile does not influence the absorption of Prograf, and therefore commencement of therapy with an oral dose, and early conversions to oral therapy are both possible.
Prograf is highly bound to red blood cells and to plasma proteins and distribution is extensive. After oral administration, steady-state concentrations of Prograf were achieved within 3 days in most patients. The half-life of Prograf varies between 3.5 and 40.5 hours. In liver transplant patients, the elimination half-life based on the whole blood concentration averaged 11.7 hours. Renal clearance is less than 1 mL/min. Tacrolimus trough concentrations from 10 - 60 ng/mL measured at 10 - 12 hours post dose correlated well with the AUC plasma or whole blood. In 28 liver transplant patients the correlation coefficient was 0.94.
Prograf undergoes extensive hepatic first pass metabolism. Metabolites are primarily excreted via the bile. Less than 1% of unchanged tacrolimus is seen in the urine after intravenous or oral dosing. There is evidence that Prograf is metabolised in the gastrointestinal tract when given orally.
Indications
Primary immunosuppression in liver, kidney, pancreas, kidney-pancreas, lung or heart allograft recipients and rescue use in liver, kidney or other solid organ (heart, lung, pancreas or kidney-pancreas) transplantation, that has either failed conventional immunosuppressive agents, or where such agents are producing intolerable side effects.
Dosage and Administration
Adults
The dosage recommendations given below for oral and intravenous administration should act as a guideline. Prograf doses should be adjusted according to individual patient requirements.
Prograf is normally administered together with other immunosuppressive drugs. Prograf should not be given concurrently with ciclosporin.
If allograft rejection or adverse events occur, alteration of the immunosuppressive regimen should be considered.
Prograf concentrate for infusion should be diluted in 5% glucose solution in polyethylene or glass bottles or in 0.9% Sodium Chloride Injection in polyethylene bottles. The concentration of a solution for final infusion produced in this way should be in the range 0.004 - 0.1 mg/mL. The solution should not be given as a bolus.
Oral administration of Prograf should commence as soon as practicable. In some liver transplantation patients, therapy has commenced orally by administering the capsule contents suspended in water via an intranasal gastric tube.
It is recommended that the oral daily dose be taken in two divided doses. The capsules should be swallowed with fluid, preferably water. The capsules should be taken on an empty stomach or at least 1 hour before a meal to achieve maximal absorption.
Primary immunosuppression in liver, kidney, pancreas, lung or heart allograft recipients
LIVER: An initial intravenous dose of 0.01 - 0.05 mg/kg should be administered as a continuous infusion over a 24-hour period. Administration should start approximately 6 hours after the completion of surgery. When commencing oral therapy, an initial dose of 0.10 - 0.20 mg/kg/day should be administered in two divided doses.
KIDNEY, PANCREAS or KIDNEY-PANCREAS: An initial intravenous dose of 0.04 - 0.06 mg/kg should be administered as a continuous infusion over a 24-hour period. Administration should start approximately 6 hours after the completion of surgery. When commencing oral therapy, an initial dose of 0.15 - 0.30 mg/kg/day should be administered in two divided doses
HEART: An initial intravenous dose of 0.01 - 0.02 mg/kg should be administered as a continuous infusion over a 24-hour period. Administration should start no sooner than 6 hours after the completion of surgery. When commencing oral therapy, an initial dose of 0.075 mg/kg/day should be administered in two divided doses.
LUNG: An initial intravenous dose of 0.01 - 0.05 mg/kg should be administered as a continuous infusion over a 24-hour period. Administration should start no sooner than 6 hours after the completion of surgery. When commencing oral therapy, an initial dose of 0.10-0.30 mg/kg/day should be administered in two divided doses.
Allograft rejection either resistant to conventional immunosuppressive agents, or where such agents are producing intolerable side effects.
In these patients, PROGRAF treatment should begin with the initial dose recommended for primary immunosuppression in that particular allograft.
Elderly
Experience in the elderly is limited. There is no evidence presently available to suggest that doses should be altered in elderly patients.
Patients with Renal Impairment
No dose adjustment is required. However, careful monitoring of renal function is recommended (see 'Contra-indications').
Patients with Liver Impairment
Prograf is extensively metabolised by the liver. In patients with liver impairment, dose reduction is recommended.
Children
Higher mg/kg doses may be required in children compared with adult to achieve the same tacrolimus blood concentration. It is recommended that the initial intravenous dose if needed should be 0.05-0.06mg/kg/day. Initial oral doses should be 0.15-0.30mg/kg/day as two divided doses.
Monitoring Advice
Monitoring of tacrolimus WHOLE 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. 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 or liver function monitoring and tissue biopsies.
Various assays have been used to measure blood or plasma concentrations of tacrolimus. Comparison of the concentrations in published literature to patient concentrations should be made with care and knowledge of the assay methods employed.
The majority of patients (adults and children) can be successfully managed if the blood concentrations are maintained below 20 ng/mL. If the blood levels are below the limit of quantification of the assay and the patient's clinical condition is satisfactory then the dose should not be adjusted.
During the first months post-transplant, monitoring of the following parameters should be undertaken on a routine basis: blood pressure, ECG, visual status, blood glucose levels, electrolytes (particularly potassium), creatinine, BUN, urinary output, haematology parameters, coagulation values, and liver and renal function tests. If clinically relevant changes are seen, adjustment of the immunosuppressive regimen should be considered.
Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of PROGRAF. This should be considered when deciding upon a maintenance regimen.
Contraindications
Prograf is contra-indicated in patients hypersensitive to Tacrolimus or other macrolides, or to other ingredients of the capsules. Additionally, Prograf Concentrated Injection for infusion should not be used in patients known to be hypersensitive to polyoxyethylene hydrogenated castor oils.
Warnings and Precautions
Prograf therapy requires careful monitoring in hospital units equipped and staffed with adequate laboratory and supportive medical resources. The drug should only be prescribed, and changes in immunosuppressive therapy should be initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.
Use with caution in the following circumstances:
Neurological and CNS disorders have been reported with Prograf therapy. Patients experiencing such events should be carefully monitored. In cases of severe or worsening neurological disorder, adjustment of the immunosuppressive regimen should be considered.
Post transplant insulin dependent diabetes mellitus (PTDM - use of insulin for 30 or more consecutive days, with < 5 day gap, by patients without a prior history of insulin or non insulin-dependent diabetes mellitus) was reported in 20% (30/151) and 6% (17/281) of PROGRAF treated kidney transplant patients in the U.S. and European randomised trials respectively. The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these patients at one year and in 50% at two years post transplant. Black and Hispanic patients were found to be at increased risk of development of PTDM in the U.S. trial. The risk benefit ratio should be carefully considered before using tacrolimus in kidney transplant patients with a pre-transplant diabetic condition.
In liver transplantation PTDM was reported in 18% (42/239) and 11% (26/239) of PROGRAF treated patients and was reversible in 45% and 31% of these patients at one year post transplant in the U.S. and European randomised trials respectively.
Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies has been observed in a few cases in association with administration of Prograf. Most of these have been reversible, occurring primarily in patients having tacrolimus blood trough levels higher than the recommended level. Mean tacrolimus whole blood trough concentrations during the period prior to diagnosis of myocardial hypertrophy in 20 patients with pre and post treatment echo cardiograms ranged from 10.6 to 53.3 ng/mL in infants (N=10, age 0.4 to 2 years), 4.0 to 45.7 ng/mL in children (N=7, age 2 to 15 years) and 10.9 to 24.3 ng/mL in adults (N=3, age 37 to 45 years). Other factors observed to increase the risk of these clinical conditions are, for example, previously existing heart diseases, corticosteroid usage, hypertension, renal or hepatic dysfunction, and fluid overload. Accordingly high-risk patients should be monitored, eg, with echocardiography or ECG. If abnormalities develop, dose reduction of Prograf therapy, or change of treatment to other immunosuppressive agent should be considered.
Prograf may cause visual and neurological disturbances. Patients treated with Prograf who are affected by such disorders should not drive a car or operate dangerous machinery.
Prograf is extensively metabolised by the liver. In patients with liver impairment, dose reduction is recommended.
Check the following before use
Prograf should not be administered concurrently with ciclosporin as the half-life of the latter may be increased. Synergistic/additive nephrotoxic effects can also occur. Care should be taken when administering Prograf to patients who have previously received ciclosporin and when converting patients from ciclosporin to Prograf-based therapy. It is recommended that ciclosporin blood levels are monitored prior to the administration of Prograf. The most appropriate time to initiate Prograf therapy should be based upon information on ciclosporin blood levels and the clinical condition of the patient. Dosing may be delayed in the presence of elevated ciclosporin levels. Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin might be affected. A 24-hour interval between stopping ciclosporin and starting PROGRAF has been commonly used.
Patients switched to Prograf rescue therapy should not be given anti-lymphocyte treatment concomitantly.
As with other potent immunosuppressive compounds, patients treated with Prograf have been reported to develop EBV-associated lymphoproliferative disorders. In patients switched to Prograf, this may be attributable to over-immunosuppression before commencing therapy with this agent. Very young (<2 years), EBV-sero-negative children have been reported to have an increased risk of developing lymphoproliferative disorders. Therefore, in this patient group, EBV serology should be ascertained before starting treatment with Prograf. During treatment, careful monitoring is recommended.
Grapefruit juice has been reported to increase tacrolimus blood level. It is recommended that grapefruit juice be avoided (See Interaction).
Prograf concentrate for infusion contains polyoxyethylene hydrogenated castor oil, which has been reported to cause anaphylactoid reactions. These reactions consist of flushing of the face and upper thorax, acute respiratory distress with dyspnoea and wheezing, blood pressure changes and tachycardia. Caution is therefore necessary in patients who have previously received, by intravenous injection or infusion, preparations containing polyoxyethylated castor oil and in patients with an allergenic predisposition. Animal studies have shown that the risk of anaphylaxis may be reduced by slow infusion of Prograf or by the prior administration of an antihistamine. Prograf capsules 1 mg and 5 mg do not contain polyoxyethylene hydrogenated castor oil.
Carcinogenicity/Mutagenicity
In chronic, one-year toxicity studies (rats and baboons) and in long-term carcinogenicity studies (mouse, 18 months; rat, 24 months), no signs of a direct tumorigenic potential of Prograf were seen. However, as known from data with other immunosuppressive drugs, malignancies such as lymphomas and skin cancers can be expected in patients, and a low incidence has been observed.
Relevant in vitro and in vivo tests showed no signs of a mutagenic potential of Prograf.
Use in Pregnancy (Category C)
There are no adequate and well-controlled studies in pregnant women. The use of tacrolimus during pregnancy has been associated with neonatal hyperkalaemia and renal dysfunction. Prograf should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the foetus.
As Prograf may alter the metabolism of oral contraceptives, other forms of contraception should be used. It is advised that patients are counselled regarding the risks of becoming pregnant whilst receiving Prograf therapy. In animal studies (rats and rabbits), Prograf has been shown to be teratogenic at doses which also demonstrated maternal toxicity. Preclinical and human data show that the drug is able to cross the placenta.
Use in Lactation
Prograf is excreted into breast milk. It is therefore recommended that mothers should not breast-feed while receiving Prograf.
Lenticular degeneration of the eye was observed in rats treated orally with tacrolimus for at least 12 weeks.
Adverse Effects
The principal adverse reactions of Prograf are tremor, headache, diarrhoea, hypertension, nausea, and renal dysfunction. These occur with oral and intravenous administration of Prograf and may respond to a reduction in dosing. Diarrhoea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.
Hyperkalemia, hypomagnesemia and hyperuricemia have occurred in patients receiving Prograf therapy.
Hyperglycemia has been noted in many patients; some may require insulin therapy. (SEE WARNING AND PRECAUTIONS).
The incidence of adverse events was determined in two randomised, comparative, liver-transplant trials among 512 patients receiving tacrolimus and steroids and 511 patients receiving a ciclosporin 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 US study to that in the European study. Only adverse events occurring up to 12 months post transplant in the US study and up to 6 months in the European study are presented. 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.
| US Study (%) | European Study | |||
|---|---|---|---|---|
| Prograf (N=250) |
CBIR (N=250) |
Prograf (N=262) |
CBIR (N=261) |
|
| Nervous System | ||||
| Headache | 64 | 60 | 31 | 20 |
| Tremor | 56 | 46 | 44 | 30 |
| Insomnia | 64 | 68 | 29 | 21 |
| Paraesthesia | 40 | 30 | 15 | 13 |
Gastrointestinal |
||||
| Diarrhea | 72 | 47 | 32 | 23 |
| Nausea | 46 | 37 | 30 | 22 |
| Constipation | 24 | 27 | 19 | 20 |
| LFT Abnormal | 36 | 30 | 5 | 2 |
| Anorexia | 34 | 24 | 6 | 4 |
| Vomiting | 27 | 15 | 12 | 9 |
Cardiovascular |
||||
| Hypertension | 47 | 56 | 31 | 35 |
Urogenital |
||||
| Kidney Function Abnormal | 40 | 27 | 33 | 18 |
| Creatinine Increased | 39 | 25 | 19 | 16 |
| BUN Increased | 30 | 22 | 8 | 7 |
| Urinary Tract Infection | 16 | 18 | 19 | 18 |
| Oliguria | 18 | 15 | 16 | 8 |
Metabolic and Nutritional |
||||
| Hyperkalaemia | 45 | 26 | 10 | 7 |
| Hypokalaemia | 29 | 34 | 11 | 14 |
| Hyperglycaemia | 47 | 38 | 29 | 16 |
| Hypomagnesemia | 48 | 45 | 15 | 8 |
Haematologic and Lymphatic |
||||
| Anaemia | 47 | 38 | 4 | 1 |
| Leukocytosis | 32 | 26 | 8 | 7 |
| Thrombocytopenia | 24 | 20 | 10 | 14 |
Miscellaneous |
||||
| Abdominal Pain | 59 | 54 | 26 | 20 |
| Pain | 63 | 57 | 19 | 14 |
| Fever | 48 | 56 | 15 | 18 |
| Asthenia | 52 | 48 | 7 | 4 |
| Back Pain | 30 | 29 | 13 | 14 |
| Ascites | 27 | 22 | 5 | 6 |
| Peripheral Oedema | 26 | 26 | 10 | 11 |
Respiratory System |
||||
| Pleural Effusion | 30 | 32 | 32 | 29 |
| Atelectasis | 28 | 30 | 5 | 4 |
| Dyspnea | 29 | 23 | 3 | 2 |
Skin and Appendages |
||||
| Pruritus | 36 | 20 | 11 | 5 |
| Rash | 24 | 19 | 8 | 3 |
Common adverse events reported in tacrolimus - and ciclosporin treated
patients in the randomised US and European renal transplant trials are given
in the following table.
| U.S. Study | (%) | European Study | (%) | |
|---|---|---|---|---|
| PROGRAF (N=205) |
CBIR (N=207) |
PROGRAF (N=303) |
CBIR (N=145) |
|
| Nervous System | ||||
| Tremor | 54 | 34 | 35 | 12 |
| Headache | 44 | 38 | 20 | 14 |
| Insomnia | 32 | 30 | 24 | 26 |
| Paraesthesia | 23 | 16 | 6 | 3 |
| Dizziness | 19 | 16 | 4 | 4 |
| Gastrointestinal | ||||
| Diarrhea | 44 | 41 | 22 | 10 |
| Nausea | 38 | 36 | 17 | 16 |
| Constipation | 35 | 43 | 31 | 35 |
| Vomiting | 29 | 23 | 12 | 8 |
| Dyspepsia | 28 | 20 | 16 | 13 |
| Gum hyerplasia | 1 | 5 | 1 | 6 |
| Cardiovascular | ||||
| Hypertension | 50 | 52 | 37 | 39 |
| Chest Pain | 19 | 13 | 10 | 9 |
| Angina pectoris | 2 | 1 | 11 | 3 |
| Arrhythmia | 2 | 3 | 1 | 6 |
| Urogenital | ||||
| Creatinine Increased | 45 | 42 | 35 | 21 |
| Urinary Tract Infection | 34 | 35 | ||
| Metabolic and Nutritional | ||||
| Hypophosphataemia | 49 | 53 | 4 | 5 |
| Hypomagnesaemia | 34 | 17 | 4 | 1 |
| Hyperlipaemia | 31 | 38 | ||
| Hyperkalaemia | 31 | 32 | 21 | 16 |
| Diabetes mellitus | 24 | 9 | 11 | 2 |
| Hypokalaemia | 22 | 25 | 9 | 10 |
| Hyperglycaemia | 22 | 16 | 16 | 7 |
| Oedema | 18 | 19 | 7 | 13 |
| Haematologic and Lymphatic | ||||
| Anaemia | 30 | 24 | 18 | 17 |
| Leukocytosis | 15 | 17 | 17 | 15 |
| Miscellaneous | ||||
| Infection | 45 | 49 | 76 | 75 |
| Peripheral oedema | 36 | 48 | 16 | 16 |
| Asthenia | 34 | 30 | 7 | 4 |
| Adominal pain | 33 | 31 | 27 | 23 |
| Pain | 32 | 30 | 21 | 22 |
| Fever | 29 | 29 | 8 | 9 |
| Back pain | 24 | 20 | 7 | 10 |
| Respiratory System | ||||
| Dyspnea | 22 | 18 | 12 | 11 |
| Cough increased | 18 | 15 | 6 | 7 |
| Musculoskeletal | ||||
| Arthralgia | 25 | 24 | 9 | 10 |
| Skin | ||||
| Hirsuitism | 1 | 9 | 0 | 10 |
| Rash | 17 | 12 | 4 | 3 |
| Pruritus | 15 | 7 | 9 | 3 |
| Acne | 13 | 16 | 3 | 10 |
Common:
The following adverse events, not mentioned above, were reported with greater than 3% incidence in tacrolimus-treated patients.
Nervous System:
abnormal dreams, agitation, anxiety, confusion, convulsion, depression, dizziness, emotional lability, hallucinations, hypertonia, impaired consciousness including coma, incoordination, myoclonus, nervousness, neuropathy, psychosis, somnolence, thinking abnormal;
Special Senses:
abnormal vision, amblyopia, tinnitus;
Gastrointestinal:
cholangitis, cholestatic jaundice, dyspepsia, dysphasia, flatulence, gastrointestinal haemorrhage, GGT increase, GI perforation, hepatitis, ileus, increased appetite, jaundice, liver damage, oral moniliasis;
Cardiovascular:
chest pain, abnormal ECG, haemorrhage, hypotension, tachycardia;
Urogenital:
hematuria, kidney failure;
Metabolic Nutritional:
acidosis, alkaline phosphatase increased, alkalosis, bilirubinemia, healing abnormal, hyperlipemia, hyperphosphatemia, hyperuricemia, hypocalcaemia, hypophosphatemia, hyponatremia, hypoproteinimemia, AST (SGOT) increased, ALT (SGPT) increased;
Endocrine:
diabetes mellitus;
Haematologic/Lymphatic:
coagulation disorder, ecchymosis, hypochromic anaemia, leukopenia, prothrombin decreased;
Miscellaneous:
abdomen enlarged, abscess, chills, hemia, peritonitis, photosensitivity reaction;
Musculoskeletal:
arthralgia, generalised spasm, leg cramps, myalgia, myasthenia, osteoporosis; Respiratory: asthma, bronchitis, cough increased, lung disorder, pulmonary edema, pharyngitis, pneumonia, respiratory disorder, rhinitis, sinusitis, voice alteration;
Skin:
alopecia, herpes simplex, hirsutism, skin disorder, sweating.
Rare cases of ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, and in association with administration of Prograf have been observed.
Other adverse events reported have been pancreatitis, increased amylase, encephalopathy, thrombotic micoangiopathy, haemolytic uraemic syndrome, Stevens-Johnson syndrome, gastric ulcer, ventricular hypertrophy, and cardiomyopathy.
Interactions
Clinical data on drug interactions are limited. Clinical interactions have been noted with clotrimazole, ciclosporin, danazol, dexamethasone and methylprednisolone resulting in alterations in plasma or whole blood concentrations of these agents or of Prograf.
When considering co-administration of Prograf with other drugs the potential for exacerbation of toxic effects should be carefully considered. Care should be taken when using compounds known to have nephrotoxic effects, such as aminoglycosides, amphotericin B, co-trimozazole, gyrase inhibitors, NSAIDs and vancomycin. When Prograf is administered together with potentially neurotoxic substances such as ganciclovir or acyclovir, the neurotoxicity of these drugs may be enhanced. Tacrolimus has been shown to increase phenytoin blood levels. Hyperkalaemia has been reported in some patients receiving Prograf; where there is a risk of hyperkalaemia, potassium-sparing diuretics should be avoided. Care should also be taken when administering potassium supplements or other agents known to increase serum potassium levels.
During treatment with Prograf, vaccinations may be less effective and the use of live attenuated vaccines should be avoided.
Prograf is extensively metabolised via the hepatic microsomal cytochrome P-450 enzyme system. In particular, Prograf has shown a broad and powerful inhibitory effect on cytochrome P-450 3A4. Prograf may have an inducing or inhibitory effect on these enzymes and care should be taken when co-administering other drugs known to be metabolised by the cytochrome P-450 enzyme system.
Grapefruit juice has been reported to increase tacrolimus blood level. This is thought to be due to an inhibition by grapefruit juice of metabolism of tacrolimus by the cytochrome P450 enzyme systems. It is recommended that grapefruit juice be avoided.
Drug interactions of tacrolimus with other drugs
| Drug | Observations | Clinical Significance |
|---|---|---|
| Agents that decrease tacrolimus concentrations | ||
| Aluminium hydroxide | In vitro adsorbs tacrolimus (40% loss immediately). In patients no interaction | Change in dose not necessary. |
| Magnesium oxide | In vitro pH mediated degradation (complete loss in 1 hour. In patients no interaction. | Change in dose not necessary. |
| Sodium bicarbonate | In vitro pH mediated degradation (75% loss in 24 hours), in patients with decreased bioavailability (>50%). | Dose adjustment may be necessary. |
| Rifampicin (rifampin) | Induction of metabolism (50% decrease in trough plasma concentration in patients: >50% reduction in blood concentrations in rats). | Increase tacrolimus dose. |
| Dexamethasone | Induction of metabolism (>3-fold increase in metabolism in rats). | Increase tacrolimus dose as necessary. |
| Drug | Observations | Clinical Significance |
|---|---|---|
| Agents that increase tacrolimus concentrations | ||
| Erythromycin | Inhibition of metabolism (>4-fold increase in trough plasma concentrations in patients: 3- to 4-fold increase in blood concentrations in rats). | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| Clotrimazole | Inhibition of metabolism (2- to 3-fold increase in trough plasma concentration in patients). | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| Fluconazole | Inhibition of metabolism (2- to 3-fold increase in trough plasma concentration in patients: 10-fold increase in blood concentration in rats. | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| Danazol | Inhibition of metabolism (>5-fold increase in trough plasma concentration in patients: 3-fold increase in blood concentrations in rats). | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| Itraconazole | Inhibition of metabolism (2-fold increase in trough plasma concentration in patients: 2-fold increase in blood concentrations in rats). | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| Chloramphenicol | Inhibition of metabolism (3- to 4-fold increase in trough plasma concentrations in patients). | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| Ketoconazole | Inhibition of metabolism (2-fold increase in trough plasma concentrations in patients: 2-fold increase in blood concentrations in rats). | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| Diltiazem | Inhibition of metabolism (4-fold increase in blood concentrations in rats). | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| Nifedipine | In vitro inhibition of metabolism (60%). | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| Ciclosporin | In vitro inhibition of metabolism (60%) | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| Verapamil | Inhibition of metabolism (2-fold increase in blood concentrations in rats). | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| Cimetidine | Inhibition of metabolism (3-fold increase in blood concentration in rats. | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| Amphotericin B | In vitro inhibition of metabolism (8-20%) | Dose adjustment may be necessary. |
| Nefazodone | Inhibition of metabolism (increased blood levels in patients) | Monitor tacrolimus levels frequently and decrease dose as necessary |
| Sequinavir, Ritonavir Or Nalfinavir |
Inhibition of metabolism (increased blood levels in patients | Monitor tacrolimus levels frequently and decrease dose as necessary |
| Clarithromycin | Inhibition of metabolism (increased blood levels in patients) | Monitor tacrolimus levels frequently and decrease dose as necessary |
| Omeprazole | Inhibition of metabolism (increased blood levels in patients | Monitor tacrolimus levels frequently and decrease dose as necessary |
Theoretical interactions
Based on theoretical considerations or on results from in vitro and in vivo studies, the following drugs may increase tracrolimus blood concentrations:
Bromocriptine, cisapride, cortisone, dapsone, ergotamine, erythromycin, ethinyloestradiol, gestodene, josamycin, metoclopramide, metronidazole, miconazole, midazolam, nilvadipine, prednisolone, tamoxifen, triacetyloleandomycin.
Based on theoretical considerations or on results from in vitro and in vivo studies, the following drugs may decrease tracolimus blood concentrations:
Carbamazepine, isoniazid, metamizole, phenobarbitone, phenytoin, rifampicin, St John's Wort (Hypericum perforatum).
Effect of tacrolimus on the metabolism of other medicinal products
Conversely, Prograf has been shown to, or may inhibit the metabolism of the following: ciclosporin, cortisone, testosterone, pentobarbital, antipyrine, and steroid-based contraceptive agents. Particular care should therefore be exercised when deciding on contraceptive measures.
Protein binding considerations
Prograf is extensively bound to plasma proteins. Possible interactions with other drugs known to have high affinity to plasma proteins (eg NSAIDs, oral anticoagulants and oral antidiabetics) should be considered.
Agents that do not interact with tacrolimus
In in-vitro studies, no inhibitory effects on Prograf metabolism were observed with aspirin, captopril, cimetidine, ciprofloxacin, diclophenac, doxycycline, frusemide, glibenclamide, imipramine, lidocaine, paracetamol, progesterone, ranitidine, sulphamethoxazole, trimethoprim, and vancomycin. However, the lack of in vitro drug interactions does not necessarily exclude the possibility of such interactions occurring in vivo.
Overdosage
In acute oral and intravenous toxicity studies, mortalities were seen at or above the following doses; in adult rats 52x the recommended human oral dose; in immature rats 16x the recommended oral dose; and in adult rats 16x the recommended intravenous human dose (all based on body surface area corrections).
Experience of overdosage in humans is limited.
Early clinical experience (when initial induction doses were 2 -3 times greater than those currently recommended) suggested that symptoms of overdosage may include glucose intolerance, renal, neurological and cardiac disorders, hyperkalaemia and hypertension. Over immunosuppression may increase risk of severe infections.
Liver function clearly influences all pre- and post-operative pharmacokinetic variables. Patients with failing liver grafts or those switched from other immunosuppressive therapy to Prograf should be monitored carefully to avoid overdosage.
No specific antidote to Prograf therapy is available. If overdosage occurs, general supportive measures and symptomatic treatment should be conducted.
Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that Prograf will not be dialysable. Data on haemoperfusion are not available. In cases of oral intoxication, gastric lavage and/or the use of absorbents (such as activated charcoal) may be helpful.
Pharmaceutical Precautions
Prograf is incompatible with PVC plastics. Tubing, syringes, and other equipment used to administer Prograf should not contain PVC.
The shelf-life is thirty months for 1 and 5mg capsules and twenty-four months for 0.5mg capsules and Concentrated Injections. Capsules should be stored below 30°C and Concentrated Injection below 25°C and protected from light.
Medicine Classification
Prescription Medicine
Package Quantities
Prograf Capsules 0.5mg Cartons of 100 capsules
Prograf Capsules 1 mg Cartons of 100 capsules
Prograf Capsules 5 mg Cartons of 50 capsules
Prograf Concentrate for Infusion 5 mg/mL Cartons of 10 ampoules
Further Information
Clinical Trials
The efficacy and safety of a PROGRAF based immunosuppressive regimen following orthotopic liver transplantation was assessed in two prospective, randomised, non-blinded multicentre trials. The active control groups were treated with a ciclosporin based regimen. In a European trial, patients received a tacrolimus-steroid based regimen (n=264) or a ciclosporin-azathioprine-steroid (with or without anti-lymphocyte globulin) based regimen (n=265).
Equivalent graft survival (77.5 vs 72.69%) and patient survival (82.9 vs 77.5%) was seen. Significant reductions were seen in the tacrolimus treated patients for incidence of acute rejection (40.5 vs 49.8%), refractory acute rejection (0.8 vs 5.3%) and chronic rejection (1.5 vs 5.3%). In an American trial patients received a tacrolimus-steroid regimen (n=263) or a ciclosporin (mainly triple therapy) based regimen (n=266). Equivalent graft survival (82 vs 79%) and patient survival (88 vs 88%) rates were observed. Tacrolimus was associated with significant reductions in the incidence of acute rejection (68 vs 76%), steroid resistant rejection (19 vs 36%) and refractory rejection (3 vs 15%).
Two randomised, multicentre non-blinded comparative trials were performed in cadaveric kidney transplantation. In an American trial patients received a tacrolimus based (n=205) or ciclosporin based (n=207) regimen. All patients also received maintenance azathioprine and corticosteroids and an induction course of an antilymphocyte antibody preparation. Equivalent graft survival (91.2 vs 87.9%) and patient survival (95.6 vs 96.6%) was seen for the tacrolimus and ciclosporin treated patients respectively. A significantly reduced one year incidence rate of biopsy confirmed acute rejection (30.7 vs 46.4%), moderate to severe acute rejection (10.7 vs 26.6%) and use of antilymphocyte antibody preparation for treatment of rejection (10.7 vs 25.1%) was seen in the tacrolimus treated patients.
A European trial compared triple drug based immunosuppression with tacrolimus or ciclosporin centred regimens, with 303 and 145 patients randomised to the tacrolimus and ciclosporin arms respectively. Equivalent one year graft survival (82.5 vs 86.2%) and one year patient survival (93.0 vs 96.5%) rates were observed, but with significantly reduced one year acute rejection rate (32.3 vs 54.5%), rate of corticosteroid sensitive rejections (24.4 vs 42.1%) and rate of corticosteroid resistant rejections (10.2 vs 20.7%).
Two open-label, randomized, comparative studies evaluated the safety and efficacy of tacrolimus-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a Phase 3 study conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids and azathioprine in combination with tacrolimus or cyclosporine modified for 18 months. In a 3-arm study conducted in the US, 331 patients received corticosteroids and tacrolimus plus sirolimus, tacrolimus plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year.
The in European Phase 3 study, patient / graft survival at 18 months post-transplant was similar between treatment arms, 91.7% in the tacrolimus group and 89.2% in the cyclosporine group. In the US study, patient and graft survival at 12 months was similar with 93.5% survival in the tacrolimus plus MMF group and 86.1% survival in the cyclosporine modified plus MMF group. In the European study, the cyclosporine trough concentrations were above the pre-defined target range (ie 100-200 ng/mL) at Day 122 and beyond in 32-98% of the patients in the cyclosporine treatment arm, whereas the tacrolimus tough concentrations were within the pre-defined target range (ie. 5-15 ng/mL) in 74-86% of the patients in the tacrolimus treatment arm.
The US study contained a third arm of a combination regimen of sirolimus, 2mg per day, and full-dose tacrolimus; however, this regimen was associated with increased risk of wound healing complications, renal function impairment, and insulin dependent post transplant diabetes mellitus, and is not recommended.
Name and Address
Janssen-Cilag Pty Ltd.
PO Box 9222
Newmarket
Auckland 1
NEW ZEALAND
Telephone: Auckland 524-5012
Date of Preparation
06 February 2007