Data Sheet
PROGRAFTM
Tacrolimus
PROGRAF 0.5mg 1 mg, 5 mg Capsules
PROGRAF 5mg/mL Concentrated Injection
Molecular Formula: C44 H69NO12.H 20
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
In man tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract. Following oral administration of PROGRAF capsules peak concentrations (Cmax) of tacrolimus in blood are achieved in approximately 1 - 3 hours. In some patients, tacrolimus appears to be continuously absorbed over a prolonged period yielding a relatively flat absorption profile. The mean oral bioavailability of tarolimus is in the range of 20% - 25%.
After oral administration (0.30 mg/kg/day) to liver transplant patients, steady-state concentrations of PROGRAF were achieved within 3 days in the majority of patients.
In healthy subjects, PROGRAF 0.5 mg, PROGRAF 1 mg and PROGRAF 5 mg Capsules, hard have been shown to be bioequivalent, when administered as equivalent dose.
The rate and extent of absorption of tacrolimus is greatest under fasted conditions. The presence of food decreases both the rate and extent of absorption of tacrolimus, the effect being most pronounced after a high-fat meal. The effect of a high-carbohydrate meal is less pronounced.
In stable liver transplant patients, the oral bioavailability of PROGRAF was reduced when it was administered after a meal of moderate fat (34% of calories) content. Decreases in AUC (27%) and Cmax (50%), and an increase in tmax (173%) in whole blood were evident.
In a study of stable renal transplant patients who were administered PROGRAF immediately after a standard continental breakfast the effect on oral bioavailability was less pronounced. Decreases in AUC (2 to 12%) and Cmax (15 to 38%), and an increase in tmax (38 to 80%) in whole blood were evident.
Bile flow does not influence the absorption of PROGRAF.
A strong correlation exists between AUC and whole blood trough levels at steady-state. Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure.
Distribution and elimination
In man, the disposition of tacrolimus after intravenous infusion may be described as biphasic.
In the systemic circulation, tacrolimus binds strongly to erythrocytes resulting in an approximate 20:1 distribution ratio of whole blood/plasma concentrations. In plasma, tacrolimus is highly bound (> 98.8%) to plasma proteins, mainly to serum albumin and α-1-acid glycoprotein.
Tacrolimus is extensively distributed in the body. The steady-state volume of distribution based on plasma concentrations is approximately 1300 l (healthy subjects). Corresponding data based on whole blood averaged 47.6 l.
Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance (TBC) estimated from whole blood concentrations was 2.25 l/h. In adult liver, kidney and heart transplant patients, values of 4.1 l/h, 6.7 l/h and 3.9 l/h, respectively, have been observed. Paediatric liver transplant recipients have a TBC approximately twice that of adult liver transplant patients. Factors such as low haematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or corticosteroid-induced increased metabolism are considered to be responsible for the higher clearance rates observed following transplantation.
The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is approximately 43 hours. In adult and paediatric liver transplant patients, it averaged 11.7 hours and 12.4 hours, respectively, compared with 15.6 hours in adult kidney transplant recipients. Increased clearance rates contribute to the shorter half-life observed in transplant recipients.
Metabolism and biotransformation
Tacrolimus is widely metabolised in the liver, primarily by the cytochrome P450-3A4. Tacrolimus is also considerably metabolised in the intestinal wall. There are several metabolites identified. Only one of these has been shown in vitro to have immunosuppressive activity similar to that of tacrolimus. The other metabolites have only weak or no immunosuppressive activity. In systemic circulation only one of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to pharmacological activity of tacrolimus.
Excretion
Following intravenous and oral administration of 14C-labelled tacrolimus, most of the radioactivity was eliminated in the faeces. Approximately 2% of the radioactivity was eliminated in the urine. Less than 1% of unchanged tacrolimus was detected in the urine and faeces, indicating that tacrolimus is almost completely metabolised prior to elimination: bile being the principal route of elimination.
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 trough (12 hour) blood concentrations are maintained within the following range:
- Liver transplant: 5-20 ng/mL for the first 3 month, 5-15 ng/mL thereafter.
- Kidney transplant: 10-20 ng/mL for the first 3 months, 5-15 ng/mL thereafter
- Heart transplant: 10-20 ng/mL for the first 3 months , 5-15 ng/mL thereafter
- Lung transplant: 10-20 ng/mL for the first month, then 5-15 ng/mL thereafter
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.
Post Transplant Diabetes Mellitus (PTDM)
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.
Insulin-dependent post-transplant diabetes mellitus was reported in 13% (10/75) and 22% (29/132) of PROGRAF-treated heart transplant patients receiving mycophenolate mofetil or azathioprine and was reversible in 30% and 17% of these patients at one year post transplant, in the US and European randomised studies, respectively.
Neurotoxicity
Neurological and CNS disorders have been reported with PROGRAF therapy. Symptoms include tremor, headache, changes in motor function, sensory function or mental status, insomnia, seizures, coma and delirium. Patients experiencing such events should be carefully monitored. In cases of severe or worsening neurological disorder, adjustment of the immunosuppressive regimen should be considered.
Posterior reversible encephalopathy syndrome (PRES)
Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). If patients taking tacrolimus present with symptoms indicating PRES such as headache, altered mental status, seizures, and visual disturbances, a radiological procedure (e.g. MRI) should be performed. If PRES is diagnosed, adequate blood pressure and seizure control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.
Renal Impairment
PROGRAF can cause renal impairment charactered by increases in serum creatinine as a result of a reduced glomerular filtration rate, particularly when used in high doses. These changes have been observed to be dose dependent and improvement have been associated with reduced dosing. The mechanism leading to these changes is not fully understood. Use of PROGRAF with sirolimus in heart transplantation patients in a US study was associated with increased risk of renal function impairment, and is not recommended. Patients with impaired renal function should be monitored closely as the dosage of PROGRAF may need to be reduced.
Care should be taken in using tacrolimus with other nephrotoxic drugs. In particular, PROGRAF should not be used simultaneously with cyclosporin. PROGRAF or cyclosporin should be discontinued at least 24 hours prior to initiating the other. In the presence of elevated PROGRAF or cyclosporin concentrations, dosing with the other drug usually should be further delayed.
Anaphylaxis with IV Administration
PROGRAF Concentrated Injection contains PEG-60 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 PEG-60 Hydrogenated Castor Oil and in patients with an allergenic predisposition. Studies in the dog have show that the risk of anaphylaxis may be reduced by slow infusion of PROGRAF or by prior administration of an H1 antihistamine. PROGRAF capsules 1mg and 5mg do not contain PEG-60 Hydrogenated Castor Oil.
Hyperkalaemia
Mild to severe hyperkalemia was reported in patients treated with PROGRAF, especially in patients with renal impairment. Patients may require treatment, and should avoid high dietary potassium intake. Serum potassium levels should be monitored and potassium-sparing diuretics should not be used during PROGRAF therapy.
Malignancies
As with other potent immunosuppressive compounds, patients treated with PROGRAF are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Lymphoproliferative disorder (LPD) related to Epstein-Barr Virus (EBV) infection has been reported in immunosuppressed organ transplant recipients. 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.
Infections
Like other immunosuppressants, tacrolimus predisposes patients to the development of a variety of bacterial, fungal, parasitic and viral infections. Oversuppression of the immune system can also increase susceptibility to opportunistic infections, sepsis and fatal infections. Among these conditions are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.
Hypertension
Hypertension is a common adverse effect of PROGRAF therapy. Antihypertensive therapy may be required; the control of blood pressure can be accomplished with any of the common antihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium-sparing diuretics should be avoided. While calcium-channel blocking agents can be effective in treating Prograf-associated hypertension, care should be taken since interference with tacrolimus metabolism may require a dosage reduction.
Myocardial Hypertrophy
Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies have 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, e.g., with echocardiography or ECG. If abnormalities develop, dose reduction of PROGRAF therapy, or change of treatment to other immunosuppressive agent should be considered.
Conversion from cyclosporin
PROGRAF should not be administered concurrently with cyclosporin 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 cyclosporin and when converting patients from cyclosporin- to PROGRAF-based therapy. It is recommended that cyclosporin blood levels are monitored prior to the administration of PROGRAF. The most appropriate time to initiate PROGRAF therapy should be based upon information on cyclosporin blood levels and the clinical condition of the patient. Dosing may be delayed in the presence of elevated cyclosporin levels. Monitoring of cyclosporin blood levels should be continued following conversion as the clearance of cyclosporin may be affected. A 24 hour interval between stopping cyclosporin and starting PROGRAF has been commonly used.
Patients switched to PROGRAF rescue therapy should not be given anti-lymphocyte treatment concomitantly.
Driving / Operation of Machinery
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.
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 adverse drug reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medications.
Many of the adverse drug reactions stated below are reversible and/or respond to dose reduction. Oral administration appears to be associated with a lower incidence of adverse drug reactions compared with intravenous use. Adverse drug reactions are listed below in descending order by frequency of occurrence: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare ( <1/10,000, including isolated reports).
Infections and infestations
As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections may be aggravated. Both generalised and localised infections can occur.
Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, include tacrolimus.
Neoplasms benign, malignant and unspecified
Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin malignancies have been reported in association with tacrolimus treatment.
Blood and lymphatic system disorders
common: anaemia, leukopenia, thrombocytopenia, leukocytosis, red blood cell analyses abnormal
uncommon: coagulopathies, coagulation and bleeding analyses abnormal, pancytopenia, neutropenia
rare: thrombotic thrombocytopenic purpura, hypoprothrombinaemia
Immune system disorders
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus.
Endocrine disorders
rare: hirsutism
Metabolism and nutrition disorders
very common: hyperglycaemic conditions, diabetes mellitus, hyperkalaemia
common: hypomagnesaemia, hypophosphataemia, hypokalaemia, hypocalcaemia, hyponatraemia, fluid overload, hyperuricaemia, appetite decreased, anorexia, metabolic acidoses, hyperlipidaemia, hypercholesterolaemia, hypertriglyceridaemia, other electrolyte abnormalities
uncommon: dehydration, hypoproteinaemia, hyperphosphataemia, hypoglycaemia
Psychiatric disorders
very common: insomnia
common: anxiety symptoms, confusion and disorientation, depression, depressed mood, mood disorders and disturbances, nightmare, hallucination, mental disorders
uncommon: psychotic disorder
Nervous system disorders
very common: tremor, headache
common: seizures, disturbances in consciousness, paraesthesias and dysaesthesias, peripheral neuropathies, dizziness, writing impaired, nervous system disorders
uncommon: coma, central nervous system haemorrhages and cerebrovascular accidents, paralysis and paresis, encephalopathy, speech and language abnormalities, amnesia
rare: hypertonia
very rare: myasthenia
Eye disorders
common: vision blurred, photophobia, eye disorders
uncommon: cataract
rare: blindness
Ear and labyrinth disorders
common: tinnitus
uncommon: hypoacusis
rare: deafness neurosensory
very rare: hearing impaired
Cardiac disorders
common: ischaemic coronary artery disorders, tachycardia
uncommon: ventricular arrhythmias and cardiac arrest, heart failures, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations, ECG investigations abnormal, heart rate and pulse investigations abnormal, QT prolongation, Torsades de pointes.
rare: pericardial effusion
very rare: echocardiogram abnormal
Vascular disorders
very common: hypertension
common: haemorrhage, thrombembolic and ischaemic events, peripheral vascular disorders, vascular hypotensive disorders
uncommon: infarction, venous thrombosis deep limb, shock
Respiratory, thoracic and mediastinal disorders
common: dyspnoea, parenchymal lung disorders, pleural effusion, pharyngitis, cough, nasal congestion and inflammations
uncommon: respiratory failures, respiratory tract disorders, asthma
rare: acute respiratory distress syndrome
Gastrointestinal disorders
very common: diarrhoea, nausea
common: gastrointestinal inflammatory conditions, gastrointestinal ulceration and perforation, gastrointestinal haemorrhages, stomatitis and ulceration, ascites, vomiting, gastrointestinal and abdominal pains, dyspeptic signs and symptoms, constipation, flatulence, bloating and distension, loose stools, gastrointestinal signs and symptoms
uncommon: ileus paralytic, peritonitis, acute and chronic pancreatitis, blood amylase increased, gastrooesophageal reflux disease, impaired gastric emptying
rare: subileus, pancreatic pseudocyst
Hepatobiliary disorders
common: hepatic enzymes and function abnormalities, cholestasis and jaundice, hepatocellular damage and hepatitis, cholangitis
rare: hepatitic artery thrombosis, venoocclusive liver disease
very rare: hepatic failure, bile duct stenosis
Skin and subcutaneous disorders
common: pruritus, rash, alopecias, acne, sweating increased
uncommon: dermatitis, photosensitivity
rare: toxic epidermal necrolysis (Lyell's syndrome)
very rare: Stevens Johnson syndrome
Musculoskeletal and connective tissue disorders
common: arthralgia, muscle cramps, pain in limb, back pain
uncommon: joint disorders
Renal and urinary disorders
very common: renal impairment
common: renal failure, renal failure acute, oliguria, renal tubular necrosis, nephropathy toxic, urinary abnormalities, bladder and urethral symptoms
uncommon: anuria, haemolytic uraemic syndrome
very rare: nephropathy, cystitis haemorrhagic
Reproductive system and breast disorders
uncommon: dysmenorrhoea and uterine bleeding
General disorders and administration site conditions
common: asthenic conditions, febrile disorders, oedema, pain and discomfort, blood alkaline phosphatase increased, weight increased, body temperature perception disturbed
uncommon: multi-organ failure, influenza like illness, temperature intolerance, chest pressure sensation, feeling jittery, feeling abnormal, blood lactate dehydrogenase increased, weight decreased
rare: thirst, fall, chest tightness, mobility decreased, ulcer
very rare: fat tissue increased
Injury, poisoning and procedural complications
common: primary graft dysfunction
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. Use of PROGRAF with sirolimus in heart transplantation patients in a US study was associated with increased risk of renal function impairment, and is not recommended in de novo heart transplant patients. 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. |
| Dexamethasone | Induction of metabolism (>3-fold increase in metabolism in rats). | Increase tacrolimus dose as 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. |
| Agents that increase tacrolimus concentrations | ||
| Amphotericin B | In vitro inhibition of metabolism (8-20%) | Dose adjustment may be 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. |
| Cimetidine | Inhibition of metabolism (3-fold increase in blood concentration in rats. | 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 |
| Clotrimazole | Inhibition of metabolism (2- to 3-fold increase in trough plasma concentration in patients). | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| Cyclosporin | In vitro inhibition of metabolism (60%) | 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. |
| Diltiazem | Inhibition of metabolism (4-fold increase in blood concentrations in rats). | Monitor tacrolimus levels frequently and decrease dose as necessary. |
| 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. |
| 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. |
| 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. |
| Josamycin | Inhibition of metabolism (increased blood levels 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. |
| Nefazodone | Inhibition of metabolism (increased blood levels in patients) | Monitor tacrolimus levels frequently and decrease dose as necessary |
| Nelfinavir | Inhibition of metabolism (increased blood levels in patients) | Monitor tacrolimus levels frequently and decrease dose as necessary |
| Nicardipine | Inhibition of metabolism (increased blood levels in patients) | 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. |
| Omeprazole | Inhibition of metabolism (increased blood levels in patients) | Monitor tacrolimus levels frequently and decrease dose as necessary |
| Ritonavir | Inhibition of metabolism (increased blood levels in patients) | Monitor tacrolimus levels frequently and decrease dose as necessary |
| Saquinavir | Inhibition of metabolism (increased blood levels in patients) | 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. |
| Voriconazole | Inhibition of metabolism (increased blood levels in patients) | Monitor tacrolimus levels frequently and decrease dose as required for most patients |
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 30oC and Concentrated Injection below 25oC 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
Liver
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%).
Kidney
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%).
Heart
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.
Lung
In a prospective, 2-centre, open-label randomized trial, 74 lung transplant patients (aged 20-66 years old) were randomised to tacrolimus-based (n=37) and cyclosporin-based (n=37) immunosuppression. The drugs were given in combination with mycophenolate mofetil and corticosteroids. Tacrolimus was started immediately after transplantation as continuous intravenous infusion at a dose of 0.015mg/kg/day and oral tacrolimus was administered at a dose of 0.1 to 0.3mg/kg/day with subsequent dose adjustments to target trough levels of 12 to 15 ng/mL in the first month and 9 to 12 ng/mL thereafter. The 6-months and 1-year patient survival data was similar in both groups (89% vs 84% and 82% vs 71%, cyclosporin vs tacrolimus respectively). Freedom from acute rejection was comparable at 1 year, 35% in the cyclosporin group and 46% in the tacrolimus group.
Another prospective, randomised, open-label study included 66 patients on tacrolimus versus 67 patients on cyclosporin, aged 20 to 66 years old. The drugs were given in combination with azathioprine and corticosteroids. Tacrolimus was started 6 to 8 hours after transplantation as continuous intravenous infusion at a dose of 0.025 mg/kg/day and oral tacrolimus was administered at a dose of 0.15 mg/kg/day with subsequent dose adjustments to target trough levels of 10 to 20 ng/mL. The 1-year patient survival was 83% in the tacrolimus group and 71% in the cyclosporin group, the 2-year survival rates were 76% and 66%, respectively. The differences between groups were not statistically significant. Freedom from acute rejection after at least 37 weeks follow-up was also comparable (14% in the tacrolimus group and 11.5% in the cyclosporin group).
A number of published, open, uncontrolled studies have examined the use of tacrolimus in lung transplant patients who have developed refractory acute rejection or bronchiolitis obliterans syndrome while receiving cyclosporin-based immunosuppressive regimens. In these studies, conversion from cyclosporin to tacrolimus has been associated with improved clinical outcomes such as reduced frequency of further acute rejection episodes and stabilisation or improvement in declining FEV1 values.
Name and Address
Johnson & Johnson (New Zealand) Ltd,
Ground Floor, Ericsson House
105 Carlton Gore Road, Newmarket
Auckland, NEW ZEALAND
Distributed by: Janssen-Cilag Pty Ltd
PO Box 9222
Newmarket
Auckland, New Zealand
Tel: (09) 523 8700
Fax: (09) 523 1646
Date of Preparation
25 June 2009