Prograf

Tacrolimus.

0.5 mg cap: Each capsule contains 0.5mg tacrolimus.
1 mg cap: Each capsule contains 1mg tacrolimus.
5 mg cap: Each capsule contains 5mg tacrolimus.
Inj: Concentrate for solution for infusion contains tacrolimus 5 mg per 1 ml.
Excipients/Inactive Ingredients: Capsule content: Hypromellose, Croscarmellose sodium, Lactose monohydrate, Magnesium stearate.
Capsule shell: Titanium dioxide, Ferric iron oxide-Yellow (0.5 mg cap only), Ferric iron oxide-Red (5 mg cap only), Sodium Lauryl Sulfate, Gelatin.
Printing ink of capsule shell: 0.5 mg and 1 mg cap: Shellac, lecithin (soya), hydroxypropyl cellulose, simeticone, ferric oxide red (E 172).
5 mg cap: Shellac, titanium dioxide (E 171), propylene glycol.
Inj: Polyoxyethylene hydrogenated castor oil, Dehydrated alcohol.

Pharmacotherapeutic group: Immunosuppressants, calcineurin inhibitors. ATC code: L04AD02.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein (FKBP12) which is responsible for the intracellular accumulation of the compound. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete set of lymphokine genes.
Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both in vitro and in vivo experiments.
In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly 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, -3, and γ-interferon) and the expression of the interleukin-2 receptor.
Results from published data in other primary organ transplantation: Prograf has evolved into an accepted treatment as primary immunosuppressive medicinal product following pancreas, lung and intestinal transplantation. In prospective published studies tacrolimus was investigated as primary immunosuppressant in approximately 175 patients following lung, 475 patients following pancreas and 630 patients following intestinal transplantation. Overall, the safety profile of tacrolimus in these published studies appeared to be similar to what was reported in the large studies, where tacrolimus was used as primary treatment in liver, kidney and heart transplantation. Efficacy results of the largest studies in each indication are summarised as follows.
Lung transplantation: The interim analysis of a recent multicentre study discussed 110 patients who underwent 1:1 randomisation to either tacrolimus or ciclosporin. Tacrolimus was started as continuous intravenous infusion at a dose of 0.01 to 0.03 mg/kg/day and oral tacrolimus was administered at a dose of 0.05 to 0.3 mg/kg/day. A lower incidence of acute rejection episodes for tacrolimus-versus ciclosporin-treated patients (11.5% versus 22.6%) and a lower incidence of chronic rejection, the bronchiolitis obliterans syndrome (2.86% versus 8.57%), was reported within the first year after transplantation. The 1-year patient survival rate was 80.8% in the tacrolimus and 83% in the ciclosporin group.
Another randomised study included 66 patients on tacrolimus versus 67 patients on ciclosporin. Tacrolimus was started 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 and 71% in the ciclosporin group, the 2-year survival rates were 76% and 66%, respectively. Acute rejection episodes per 100 patient-days were numerically fewer in the tacrolimus (0.85 episodes) than in the ciclosporin group (1.09 episodes). Obliterative bronchiolitis developed in 21.7% of patients in the tacrolimus group compared with 38.0% of patients in the ciclosporin group (p = 0.025). Significantly more ciclosporin-treated patients (n = 13) required a switch to tacrolimus than tacrolimus-treated patients to ciclosporin (n = 2) (p = 0.02).
In an additional two-centre study, 26 patients were randomised to the tacrolimus versus 24 patients to the ciclosporin group. Tacrolimus was started as continuous intravenous infusion at a dose of 0.05 mg/kg/day and oral tacrolimus was administered at a dose of 0.1 to 0.3 mg/kg/day with subsequent dose adjustments to target trough levels of 12 to 15 ng/ml. The 1-year survival rates were 73.1% in the tacrolimus versus 79.2% in the ciclosporin group. Freedom from acute rejection was higher in the tacrolimus group at 6 months (57.7% versus 45.8%) and at 1 year after lung transplantation (50% versus 33.3%).
The three studies demonstrated similar survival rates. The incidences of acute rejection were numerically lower with tacrolimus in all three studies and one of the studies reported a significantly lower incidence of bronchiolitis obliterans syndrome with tacrolimus.
Pancreas transplantation: A multicentre study included 205 patients undergoing simultaneous pancreas-kidney transplantation who were randomised to tacrolimus (n=103) or to ciclosporin (n=102). The initial oral per protocol dose of tacrolimus was 0.2 mg/kg/day with subsequent dose adjustments to target trough levels of 8 to 15 ng/ml by Day 5 and 5 to 10 ng/mL after Month 6. Pancreas survival at 1 year was significantly superior with tacrolimus: 91.3% versus 74.5% with ciclosporin (p < 0.0005), whereas renal graft survival was similar in both groups. In total 34 patients switched treatment from ciclosporin to tacrolimus, whereas only 6 tacrolimus patients required alternative therapy.
Intestinal transplantation: Published clinical experience from a single centre on the use of tacrolimus for primary treatment following intestinal transplantation showed that the actuarial survival rate of 155 patients (65 intestine alone, 75 liver and intestine, and 25 multivisceral) receiving tacrolimus and prednisone was 75% at 1 year, 54% at 5 years, and 42% at 10 years. In the early years the initial oral dose of tacrolimus was 0.3 mg/kg/day. Results continuously improved with increasing experience over the course of 11 years. A variety of innovations, such as techniques for early detection of Epstein-Barr (EBV) and CMV infections, bone marrow augmentation, the adjunct use of the interleukin-2 antagonist daclizumab, lower initial tacrolimus doses with target trough levels of 10 to 15 ng/ml, and most recently allograft irradiation were considered to have contributed to improved results in this indication over time.
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 (C_max) 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 tacrolimus 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 C_max (50%), and an increase in t_max (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 C_max (15 to 38%), and an increase in t_max (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.
Toxicology: Preclinical safety data: The kidneys and the pancreas were the primary organs affected in toxicity studies performed in rats and baboons. In rats, tacrolimus caused toxic effects to the nervous system and the eyes. Reversible cardiotoxic effects were observed in rabbits following intravenous administration of tacrolimus.
When tacrolimus is administered intravenously as rapid infusion/bolus injection at a dose of 0.1 to 1.0 mg/kg, QTc prolongation has been observed in some animal species. Peak blood concentrations achieved with these doses were above 150 ng/mL which is more than 6-fold higher than mean peak concentrations observed with Prograf in clinical transplantation.
Embryofoetal toxicity was observed in rats and rabbits and was limited to doses that caused significant toxicity in maternal animals. In rats, female reproductive function including birth was impaired at toxic dosages and the offspring showed reduced birth weights, viability and growth.
A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats.

Prophylaxis of transplant rejection in liver, kidney or heart allograft recipients.
Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products.
0.5 mg and 1 mg cap: Rheumatoid arthritis which is not adequately responsive to conventional therapies.
Lupus nephritis (in a case where the effect of steroids is insufficient or administration of steroids is difficult because of their adverse reactions).

Transplantation: Prograf therapy requires careful monitoring by adequately qualified and equipped personnel. The medicinal product should only be prescribed, and changes in immunosuppressive therapy initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients.
Inadvertent, unintentional or unsupervised switching of immediate- or prolonged-release formulations of tacrolimus is unsafe. This can lead to graft rejection or increased incidence of side effects, including under- or over immunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist (see Precautions and Adverse Reactions). Following conversion to any alternative formulation, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained.
General considerations: The recommended initial dosages presented as follows are intended to act solely as a guideline. Prograf dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring (see as follows for recommended target whole blood trough concentrations). If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered.
Prograf can be administered intravenously or orally. In general, dosing may commence orally; if necessary, by administering the capsule contents suspended in water, via nasogastric tubing.
Prograf is routinely administered in conjunction with other immunosuppressive agents in the initial post-operative period. The Prograf dose may vary depending upon the immunosuppressive regimen chosen.
Posology: Dosage recommendations - Liver transplantation: Prophylaxis of transplant rejection - adults: Oral Prograf therapy should commence at 0.10 - 0.20 mg/kg/day administered as two divided doses (e.g. morning and evening). Administration should commence approximately 12 hours after the completion of surgery.
If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous therapy of 0.01 - 0.05 mg/kg/day should be initiated as a continuous 24-hour infusion.
Prophylaxis of transplant rejection - children: An initial oral dose of 0.30 mg/kg/day should be administered in two divided doses (e.g. morning and evening). If the clinical condition of the patient prevents oral dosing, an initial intravenous dose of 0.05 mg/kg/day should be administered as a continuous 24-hour infusion.
Dose adjustment during post-transplant period in adults and children: Prograf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Prograf monotherapy. Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.
Rejection therapy - adults and children: Increased Prograf doses, supplemental corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes. If signs of toxicity are noted (e.g. pronounced adverse reactions - see Adverse Reactions) the dose of Prograf may need to be reduced.
For conversion to Prograf, treatment should begin with the initial oral dose recommended for primary immunosuppression.
For information on conversion from ciclosporin to Prograf, see as follows under "Dose adjustments in specific patient populations".
Dosage recommendations - Kidney transplantation: Prophylaxis of transplant rejection - adults: Oral Prograf therapy should commence at 0.20 - 0.30 mg/kg/day administered as two divided doses (e.g. morning and evening). Administration should commence within 24 hours after the completion of surgery.
If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous therapy of 0.05 - 0.10 mg/kg/day should be initiated as a continuous 24-hour infusion.
Prophylaxis of transplant rejection - children: An initial oral dose of 0.30 mg/kg/day should be administered in two divided doses (e.g. morning and evening). If the clinical condition of the patient prevents oral dosing, an initial intravenous dose of 0.075 - 0.100 mg/kg/day should be administered as a continuous 24-hour infusion.
Dose adjustment during post-transplant period in adults and children: Prograf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Prograf-based dual-therapy. Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.
Rejection therapy - adults and children: Increased Prograf doses, supplemental corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes. If signs of toxicity are noted (e.g. pronounced adverse reactions - see Adverse Reactions) the dose of Prograf may need to be reduced.
For conversion to Prograf, treatment should begin with the initial oral dose recommended for primary immunosuppression.
For information on conversion from ciclosporin to Prograf, see as follows under "Dose adjustments in specific patient populations".
Dosage recommendations - Heart transplantation: Prophylaxis of transplant rejection - adults: Prograf can be used with antibody induction (allowing for delayed start of Prograf therapy) or alternatively in clinically stable patients without antibody induction.
Following antibody induction, oral Prograf therapy should commence at a dose of 0.075 mg/kg/day administered as two divided doses (e.g. morning and evening). Administration should commence within 5 days after the completion of surgery as soon as the patient's clinical condition is stabilised. If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous therapy of 0.01 to 0.02 mg/kg/day should be initiated as a continuous 24-hour infusion.
An alternative strategy was published where oral tacrolimus was administered within 12 hours post transplantation. This approach was reserved for patients without organ dysfunction (e.g. renal dysfunction). In that case, an initial oral tacrolimus dose of 2 to 4 mg per day was used in combination with mycophenolate mofetil and corticosteroids or in combination with sirolimus and corticosteroids.
Prophylaxis of transplant rejection - children: Prograf has been used with or without antibody induction in paediatric heart transplantation.
In patients without antibody induction, if Prograf therapy is initiated intravenously, the recommended starting dose is 0.03 - 0.05 mg/kg/day as a continuous 24-hour infusion targeted to achieve tacrolimus whole blood concentrations of 15 - 25 ng/ml. Patients should be converted to oral therapy as soon as clinically practicable. The first dose of oral therapy should be 0.30 mg/kg/day starting 8 to 12 hours after discontinuing intravenous therapy.
Following antibody induction, if Prograf therapy is initiated orally, the recommended starting dose is 0.10 - 0.30 mg/kg/day administered as two divided doses (e.g. morning and evening).
Dose adjustment during post-transplant period in adults and children: Prograf doses are usually reduced in the post-transplant period. Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.
Rejection therapy - adults and children: Increased Prograf doses, supplemental corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes.
In adult patients converted to Prograf, an initial oral dose of 0.15 mg/kg/day should be administered in two divided doses (e.g. morning and evening).
In paediatric patients converted to Prograf, an initial oral dose of 0.20 - 0.30 mg/kg/day should be administered in two divided doses (e.g. morning and evening).
For information on conversion from ciclosporin to Prograf, see as follows under "Dose adjustments in specific patient populations".
Dosage recommendations - Rejection therapy, other allografts: The dose recommendations for lung, pancreas and intestinal transplantation are based on limited prospective clinical trial data. In lung-transplanted patients Prograf has been used at an initial oral dose of 0.10 - 0.15 mg/kg/day, in pancreas-transplanted patients at an initial oral dose of 0.2 mg/kg/day and in intestinal transplantation at an initial oral dose of 0.3 mg/kg/day.
Dosage adjustments in specific patient populations: Patients with liver impairment: Dose reduction may be necessary in patients with severe liver impairment in order to maintain the blood trough levels within the recommended target range.
Patients with kidney impairment: As the pharmacokinetics of tacrolimus are unaffected by renal function, no dose adjustment should be required. However, owing to the nephrotoxic potential of tacrolimus careful monitoring of renal function is recommended (including serial serum creatinine concentrations, calculation of creatinine clearance and monitoring of urine output).
Paediatric population: In general, paediatric patients require doses 1½ - 2 times higher than the adult doses to achieve similar blood levels.
Older people: There is no evidence currently available to indicate that dosing should be adjusted in older people.
Conversion from ciclosporin: Care should be taken when converting patients from ciclosporin-based to Prograf-based therapy (see Precautions and Interactions). Prograf therapy should be initiated after considering ciclosporin blood concentrations and the clinical condition of the patient. Dosing should be delayed in the presence of elevated ciclosporin blood levels. In practice, Prograf therapy has been initiated 12 - 24 hours after discontinuation of ciclosporin. Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin might be affected.
Target whole blood trough concentration recommendations: Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient.
As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood including a semi-automated microparticle enzyme immunoassay (MEIA). Comparisons of concentrations from the published literature to individual values in clinical practice should be assessed with care and knowledge of the assay methods employed. In current clinical practice, whole blood levels are monitored using immunoassay methods.
Blood trough levels of tacrolimus should be monitored during the post-transplantation period. When dosed orally, blood trough levels should be drawn approximately 12 hours post-dosing, just prior to the next dose. The frequency of blood level monitoring should be based on clinical needs. As Prograf is a medicinal product with low clearance, adjustments to the dosage regimen may take several days before changes in blood levels are apparent. Blood trough levels should be monitored approximately twice weekly during the early post-transplant period and then periodically during maintenance therapy. Blood trough levels of tacrolimus should also be monitored following dose adjustment, changes in the immunosuppressive regimen, or following co-administration of substances which may alter tacrolimus whole blood concentrations (see Interactions).
Clinical study analysis suggests that the majority of patients can be successfully managed if tacrolimus blood trough levels are maintained below 20 ng/ml. It is necessary to consider the clinical condition of the patient when interpreting whole blood levels.
In clinical practice, whole blood trough levels have generally been in the range 5 - 20 ng/ml in liver transplant recipients and 10 - 20 ng/ml in kidney and heart transplant patients in the early post-transplant period. Subsequently, during maintenance therapy, blood concentrations have generally been in the range of 5 - 15 ng/ml in liver, kidney and heart transplant recipients.
Method of administration: Cap: It is recommended that the oral daily dose be administered in two divided doses (e.g. morning and evening). Capsules should be taken immediately following removal from the blister. Patients should be advised not to swallow the desiccant. The capsules should be swallowed with fluid (preferably water).
Capsules should generally be administered on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal, to achieve maximal absorption (see Pharmacology: Pharmacokinetics under Actions).
Inj: The concentrate should be used for intravenous infusion only after it is diluted with suitable carrier media.
The concentration of a solution for infusion should be within the range 0.004 - 0.100 mg/ml. The total volume of infusion during a 24-hour period should be in the range 20 - 500 ml.
The diluted solution should not be given as a bolus (see Instructions for use/handling under Cautions for Usage).
Duration of dosing: Cap: To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the duration of oral therapy can be given.
Inj: Patients should be converted from intravenous to oral medication as soon as individual circumstances permit. Intravenous therapy should not be continued for more than 7 days.
0.5 mg and 1 mg cap: Rheumatoid arthritis: For adults, usually, a dose of 3 mg as tacrolimus is orally administered, once daily after supper. In elderly patients, the dose starts with 1.5 mg, once daily after supper, and may be increased up to 3 mg, once daily, depending on the patient's symptoms.
In elderly patients with rheumatoid arthritis, it is recommended that the dose of tacrolimus be started with 1.5 mg, once daily for 4 weeks, and after confirming the safety, it is preferable to increase the dose to a maximum of 3 mg, once daily in case of insufficient response. Additionally, in order to avoid the development of adverse reactions, at the time of dosage increase, blood levels approximately 12 hours after administration should be monitored and the dosage should be adjusted. In order to avoid development of adverse reactions in patients with hepatic or renal disorders, it is recommended that the blood levels should be monitored periodically, and the dosage should be adjusted.
Lupus nephritis: For adults, usually, a dose of 3 mg as tacrolimus is orally administered, once daily after supper.
In order to avoid development of adverse reactions in patients with lupus nephritis, it is recommended that the blood levels be monitored monthly for 3 months after the start of tacrolimus therapy; thereafter, the blood levels approximately 12 hours after the administration should be monitored periodically, and the dosage should be adjusted. If this product does not improve the clinical signs of nephritis, such as urinary protein excretion, or the immunological findings after continuous treatment for 2 months, the treatment with this product should be discontinued, or the patient should be switched to another product. If treatment with this product is sufficiently effective, it is recommended that the dose should be reduced to the lowest level possible that will still allow the effect to be maintained.

Experience with overdosage is limited. Several cases of accidental overdosage have been reported; symptoms have included tremor, headache, nausea and vomiting, infections, urticaria, lethargy, increased blood urea nitrogen and elevated serum creatinine concentrations and increase in alanine aminotransferase levels.
No specific antidote to Prograf therapy is available. If overdosage occurs, general supportive measures and symptomatic treatment should be conducted.
Based on its high molecular weight, poor aqueous solubility, and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus will not be dialysable. In isolated patients with very high plasma levels, haemofiltration or -diafiltration have been effective in reducing toxic concentrations. In cases of oral intoxication, gastric lavage and/or the use of adsorbents (such as activated charcoal) may be helpful, if used shortly after intake.

Hypersensitivity to tacrolimus or other macrolides.
Hypersensitivity to any of the excipients listed in Description (in particular polyoxyethylene hydrogenated castor oil (HCO-60) or structurally related compounds for inj).

Transplantation: Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. This has led to serious adverse events, including graft rejection, or other side effects which could be a consequence of either under- or over-exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist (see Dosage & Administration and Adverse Reactions).
During the initial post-transplant period, monitoring of the following parameters should be undertaken on a routine basis: blood pressure, ECG, neurological and visual status, fasting blood glucose levels, electrolytes (particularly potassium), liver and renal function tests, haematology parameters, coagulation values, and plasma protein determinations. If clinically relevant changes are seen, adjustments of the immunosuppressive regimen should be considered.
Substances with potential for interaction: When substances with a potential for interaction (see Interactions) - particularly strong inhibitors of CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampicin, rifabutin) - are being combined with tacrolimus, tacrolimus blood levels should be monitored to adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure.
Herbal preparations containing St. John's Wort (Hypericum perforatum) or other herbal preparations should be avoided when taking Prograf due to the risk of interactions that lead to either a decrease in blood concentrations of tacrolimus and reduced clinical effect of tacrolimus, or an increase in blood concentrations of tacrolimus and risk of tacrolimus toxicity (see Interactions).
The combined administration of ciclosporin and tacrolimus should be avoided and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see Dosage & Administration and Interactions).
High potassium intake or potassium-sparing diuretics should be avoided (see Interactions).
Certain combinations of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the risk of these effects (see Interactions).
Vaccination: Immunosuppressants may affect the response to vaccination and vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided.
Gastrointestinal disorders: Gastrointestinal perforation has been reported in patients treated with tacrolimus. As gastrointestinal perforation is a medically important event that may lead to a life-threatening or serious condition, adequate treatments should be considered immediately after suspected symptoms or signs occur.
Since levels of tacrolimus in blood may significantly change during diarrhoea episodes, extra monitoring of tacrolimus concentrations is recommended during episodes of diarrhoea.
Cardiac disorders: Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been observed on rare occasions. Most cases have been reversible, occurring primarily in children with tacrolimus blood trough concentrations much higher than the recommended maximum levels. Other factors observed to increase the risk of these clinical conditions included pre-existing heart disease, corticosteroid usage, hypertension, renal or hepatic dysfunction, infections, fluid overload, and oedema. Accordingly, high-risk patients, particularly young children and those receiving substantial immunosuppression should be monitored, using such procedures as echocardiography or ECG pre- and post-transplant (e.g. initially at three months and then at 9-12 months). If abnormalities develop, dose reduction of Prograf therapy, or change of treatment to another immunosuppressive agent should be considered. Tacrolimus may prolong the QT interval and may cause Torsades de Pointes. Caution should be exercised in patients with risk factors for QT prolongation, including patients with a personal or family history of QT prolongation, congestive heart failure, bradyarrhythmias and electrolyte abnormalities. Caution should also be exercised in patients diagnosed or suspected to have Congenital Long QT Syndrome or acquired QT prolongation or patients on concomitant medications known to prolong the QT interval, induce electrolyte abnormalities or known to increase tacrolimus exposure (see Interactions).
Lymphoproliferative disorders and malignancies: Patients treated with Prograf have been reported to develop Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (see Adverse Reactions). Patients switched to Prograf therapy should not receive anti-lymphocyte treatment concomitantly. Very young (< 2 years), EBV-VCA-negative children have been reported to have an increased risk of developing lymphoproliferative disorders. Therefore, in this patient group, EBV-VCA serology should be ascertained before starting treatment with Prograf. During treatment, careful monitoring with EBV-PCR is recommended. Positive EBV-PCR may persist for months and is per se not indicative of lymphoproliferative disease or lymphoma.
As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
As with other potent immunosuppressive compounds, the risk of secondary cancer is unknown (see Adverse Reactions).
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 control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.
Eye disorders: Eye disorders, sometimes progressing to loss of vision, have been reported in patients treated with tacrolimus. Some cases have reported resolution on switching to alternative immunosuppression. Patients should be advised to report changes in visual acuity, changes in colour vision, blurred vision, or visual field defect, and in such cases, prompt evaluation is recommended with referral to an ophthalmologist as appropriate.
Infections including opportunistic infections: Patients treated with immunosuppressants, including Prograf are at increased risk for infections including opportunistic infections (bacterial, fungal, viral and protozoal) such as BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). Patients are also at an increased risk of infections with viral hepatitis (for example, hepatitis B and C reactivation and de novo infection, as well as hepatitis E, which may become chronic). 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 hepatic or renal function or neurological symptoms.
Prevention and management should be in accordance with appropriate clinical guidance.
Pure Red Cell Aplasia: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease or concomitant medications associated with PRCA.
Inj: If administered accidentally either arterially or perivasally, the reconstituted Prograf Concentrate for Solution for Infusion 5 mg/ml may cause irritation at the injection site.
Excipients: Cap: As Prograf contains lactose, special care should be taken in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
0.5 mg and 1 mg cap: The printing ink used to mark Prograf 0.5 mg and 1 mg capsules contains soya lecithin. In patients who are hypersensitive to peanut or soya, the risk and severity of hypersensitivity should be weighed against the benefit of using Prograf.
Inj: Prograf Concentrate for Solution for Infusion 5 mg/ml contains polyoxyethylene hydrogenated castor oil, which has been reported to cause anaphylactoid reactions. Caution is therefore necessary in patients who have previously received preparations containing polyoxyethylene castor oil derivatives either by intravenous injection or infusion, and in patients with an allergenic predisposition. The risk of anaphylaxis may be reduced by slow infusion of reconstituted Prograf Concentrate for Solution for Infusion 5 mg/ml or by the prior administration of an antihistamine. Patients should be closely observed during the first 30 minutes of infusion for possible anaphylactoid reaction.
The ethanol content (638 mg per ml) of Prograf Concentrate for Solution for Infusion 5 mg/ml should be taken into account.
Rheumatoid arthritis: 0.5 mg and 1 mg cap: For rheumatoid arthritis, treatment with this product should be limited to patients with persisting symptoms apparently attributable to the disease despite appropriate therapies with non-steroidal anti-inflammatory drugs or other antirheumatic drugs.
In patients with rheumatoid arthritis, this product should be prescribed only by physicians experienced in rheumatoid arthritis therapy. Before administration, physicians must explain the risks of treatment and the need of a long-term therapy to the patient, and ensure that the patient understands the information provided. If any abnormality is noted, the patient should be instructed to discontinue the product and contact the physician immediately for instructions.
Prograf should be administered with care in patients with rheumatoid arthritis-associated interstitial pneumonia (interstitial pneumonia may be aggravated) (see Adverse Reactions).
The safety of this product in children has not been established in rheumatoid arthritis (no clinical experiences).
The efficacy and safety of this product in combination with methotrexate, other antirheumatic drugs, or anti-TNF α drugs have not been established in patients with rheumatoid arthritis.
In rheumatoid arthritis, the safety of the use of this product in surgery such as artificial joint replacement has not been established.
Lupus nephritis: 0.5 mg and 1 mg cap: For lupus nephritis, the efficacy and safety of this product for patients in an acute phase with high disease activity has not been established.
For patients with lupus nephritis, this product should be prescribed by physicians experienced in lupus nephritis therapy.
Patients with lupus nephritis need special attention because the renal disorder may become aggravated as the lupus nephritis progresses.
Since patients with lupus nephritis are more likely to suffer from hyperlipidemia or hypertension, etc., which are considered to be risk factors for the development of the coronary artery disease associated with systemic erythematosus, the underlying disease, patients being treated with this product should also receive appropriate therapy for these coronary diseases.
The safety of this product in children has not been established in lupus nephritis (no clinical experiences).
In patients with lupus nephritis, creatinine clearance decreased after 28 weeks of treatment. There are only a few results from clinical trials in patients with lupus nephritis lasting longer than 28 weeks, and therefore the long-term safety of this product has not been established.
Effects on ability to drive and use machines: Cap: Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if Prograf is administered in association with alcohol.
Inj: Not relevant.

Pregnancy: Human data show that tacrolimus is able to cross the placenta. Limited data from organ transplant recipients show no evidence of an increased risk of adverse effects on the course and outcome of pregnancy under tacrolimus treatment compared with other immunosuppressive medicinal products. However, cases of spontaneous abortion have been reported. To date, no other relevant epidemiological data are available. Due to the need of treatment, tacrolimus can be considered in pregnant women when there is no safer alternative and when the perceived benefit justifies the potential risk to the foetus. In case of in utero exposure, monitoring of the newborn for the potential adverse effects of tacrolimus is recommended (in particular the effects on the kidneys). There is a risk for premature delivery (<37 week) as well as for hyperkalaemia in the newborn, which, however, normalizes spontaneously.
In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Breast-feeding: Human data demonstrate that tacrolimus is excreted into breast milk. As detrimental effects on the newborn cannot be excluded, women should not breast-feed whilst receiving Prograf.
Fertility: A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Transplantation: 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 as follows 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 as follows 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); not known (cannot be estimated from the available data).
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, including Prograf.
Neoplasms benign, malignant and unspecified (incl. cysts and polyps): 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, thrombotic microangiopathy.
Not known: pure red cell aplasia, agranulocytosis, haemolytic anaemia.
Immune system disorders: Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see Precautions).
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, 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 hypertonia.
Very rare: myasthenia.
Eye disorders: Common: vision blurred, photophobia, eye disorders.
Uncommon: cataract.
Rare: blindness.
Not known: optic neuropathy.
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.
Rare: pericardial effusion.
Very rare: Torsades de Pointes.
Vascular disorders: Very common: hypertension.
Common: haemorrhage, thromboembolic 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, acute and chronic pancreatitis, gastrooesophageal reflux disease, impaired gastric emptying, (peritonitis, blood amylase increased for inj).
Rare: subileus, pancreatic pseudocyst.
Hepatobiliary disorders: Common: 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 tissue 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 spasms, pain in extremity, back pain.
Uncommon: joint disorders.
Rare: mobility decreased.
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, body temperature perception disturbed.
Uncommon: multi-organ failure, influenza like illness, temperature intolerance, chest pressure sensation, feeling jittery, feeling abnormal.
Rare: thirst, fall, chest tightness, ulcer.
Very rare: fat tissue increased.
Not known: febrile neutropenia.
Investigations: Common: hepatic enzymes and function abnormalities, blood alkaline phosphatase increased, weight increased.
Uncommon: amylase increased, ECG investigations abnormal, heart rate and pulse investigations abnormal, weight decreased, blood lactate dehydrogenase increased.
Very rare: echocardiogram abnormal, electrocardiogram QT prolonged.
Injury, poisoning and procedural complications: Common: primary graft dysfunction.
Cap: Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. A number of associated cases of transplant rejection have been reported (frequency cannot be estimated from available data).
Description of selected adverse reactions: Pain in extremity has been described in a number of published case reports as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS). This typically presents as a bilateral and symmetrical, severe, ascending pain in the lower extremities and may be associated with supra-therapeutic levels of tacrolimus. The syndrome may respond to tacrolimus dose reduction. In some cases, it was necessary to switch to alternative immunosuppression.
0.5 mg and 1 mg cap: Rheumatoid arthritis: In the clinical studies conducted in Japan by the time of approval, the main adverse reactions or abnormal laboratory test values due to this product in 509 patients with rheumatoid arthritis (capsules 509) were abnormal renal function (20.8%, 105/506) including increased BUN (13.6%, 69/506), increased creatinine (9.3%, 47/506); gastrointestinal system disorders (14.8%, 75/508) including abdominal pain (3.7%, 19/508), diarrhea (2.6%, 13/508), and nausea (2.2%, 11/508); and impaired glucose tolerance (8.9%, 45/505) including increased HbA1C (6.6%, 33/498), and increased blood glucose (4.4%, 22/495).
In the post-marketing clinical study and surveillance, adverse reactions (including abnormalities in clinical laboratory findings) due to this product (capsules) were observed in 1,336 (38.1%) of 3,509 patients with rheumatoid arthritis. The major adverse reactions were white blood cell count increased 2.7% (96/3,509), NAG increased 2.2% (78/3,509), BUN increased 1.7% (58/3,509), nausea 1.5% (51/3,509), HbA1c increased 1.4% (50/3,509), diabetes mellitus 1.4% (50/3,509), diarrhoea 1.3% (47/3,509), renal impairment 1.3% (46/3,509), lymphocyte count decreased 1.3% (44/3,509), β₂ microglobulin urine increased 1.3% (44/3,509).
(Notification of the reexamination results in Japan: September 2013).
In patients with rheumatoid arthritis, interstitial pneumonia may occur (incidence ≥ 0.1%, < 5%*). Therefore, patients should be carefully observed, and if respiratory symptoms such as fever, cough, or dyspnea develop, the drug should be discontinued. Affected patients should be promptly examined by chest X-ray and CT scan, as well as blood testing, and appropriate measures, including administration of adrenocortical hormone, should be instituted, taking differential diagnosis of infection into consideration.
(*The incidence is based on the result for rheumatoid arthritis in the post-marketing clinical study and surveillance for Prograf in Japan.)
Lupus nephritis: The major adverse reactions or abnormalities in clinical laboratory findings due to this product in 65 patients with lupus nephritis (capsules 65) were increased urinary β₂-microglobulin (27.3%, 12/44), increased urinary NAG (22.2%, 14/63), nasopharyngitis (15.4%, 10/65), hyperuricemia (14.1%, 9/64), leukocytosis (14.1%, 9/64), increased creatinine (12.5%, 8/64), diarrhea (12.3%, 8/65), increased blood pressure (10.8%, 7/65), and hyperglycemia (10.9%, 7/64).

Metabolic interactions: Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of medicinal products or herbal remedies known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels.
It is therefore strongly recommended to closely monitor tacrolimus blood levels, as well as, QT prolongation (with ECG), renal function and other side effects, whenever substances which have the potential to alter CYP3A4 metabolism are used concomitantly and to interrupt or adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure (see Dosage & Administration and Precautions).
Inhibitors of metabolism: Clinically the following substances have been shown to increase tacrolimus blood levels: Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole, voriconazole, and isavuconazole, the macrolide antibiotic erythromycin, HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), HCV protease inhibitors (e.g. telaprevir, boceprevir, and the combination of ombitasvir and paritaprevir with ritonavir, when used with and without dasabuvir), or the CMV antiviral letermovir, the pharmacokinetic enhancer cobicistat, and the tyrosine kinase inhibitors nilotinib and imatinib. Concomitant use of these substances may require decreased tacrolimus doses in nearly all patients.
Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinylestradiol, omeprazole, nefazodone and (Chinese) herbal remedies containing extracts of Schisandra sphenanthera.
In vitro the following substances have been shown to be potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, troleandomycin.
Grapefruit juice has been reported to increase the blood level of tacrolimus and should therefore be avoided.
Lansoprazole and ciclosporin may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby increase tacrolimus whole blood concentrations.
Other interactions potentially leading to increased tacrolimus blood levels: Tacrolimus is extensively bound to plasma proteins. Possible interactions with other medicinal products known to have high affinity for plasma proteins should be considered (e.g., NSAIDs, oral anticoagulants, or oral antidiabetics).
Other potential interactions that may increase systemic exposure of tacrolimus include the prokinetic agent metoclopramide, cimetidine and magnesium-aluminium-hydroxide.
Inducers of metabolism: Clinically the following substances have been shown to decrease tacrolimus blood levels: Strong interactions have been observed with rifampicin, phenytoin or St. John's Wort (Hypericum perforatum) which may require increased tacrolimus doses in almost all patients. Clinically significant interactions have also been observed with phenobarbital. Maintenance doses of corticosteroids have been shown to reduce tacrolimus blood levels.
High dose prednisolone or methylprednisolone administered for the treatment of acute rejection have the potential to increase or decrease tacrolimus blood levels.
Carbamazepine, metamizole and isoniazid have the potential to decrease tacrolimus concentrations.
Effect of tacrolimus on the metabolism of other medicinal products: Tacrolimus is a known CYP3A4 inhibitor; thus concomitant use of tacrolimus with medicinal products known to be metabolised by CYP3A4 may affect the metabolism of such medicinal products.
The half-life of ciclosporin is prolonged when tacrolimus is given concomitantly. In addition, synergistic/additive nephrotoxic effects can occur. For these reasons, the combined administration of ciclosporin and tacrolimus is not recommended and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see Dosage & Administration and Precautions).
Tacrolimus has been shown to increase the blood level of phenytoin.
As tacrolimus may reduce the clearance of steroid-based contraceptives leading to increased hormone exposure, particular care should be exercised when deciding upon contraceptive measures.
Limited knowledge of interactions between tacrolimus and statins is available. Available data suggests that the pharmacokinetics of statins are largely unaltered by the co-administration of tacrolimus.
Animal data have shown that tacrolimus could potentially decrease the clearance and increase the half-life of pentobarbital and phenazone.
Mycophenolic acid. Caution should be exercised when switching combination therapy from ciclosporin, which interferes with enterohepatic recirculation of mycophenolic acid, to tacrolimus, which is devoid of this effect, as this might result in changes of mycophenolic acid exposure. Drugs which interfere with mycophenolic acid's enterohepatic cycle have potential to reduce the plasma level and efficacy of mycophenolic acid. Therapeutic drug monitoring of mycophenolic acid may be appropriate when switching from ciclosporin to tacrolimus or vice versa.
Other interactions which have led to clinically detrimental effects: Concurrent use of tacrolimus with medicinal products known to have nephrotoxic or neurotoxic effects may increase these effects (e.g., aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole + trimethoprim, NSAIDs, ganciclovir or aciclovir).
Enhanced nephrotoxicity has been observed following the administration of amphotericin B and ibuprofen in conjunction with tacrolimus.
As tacrolimus treatment may be associated with hyperkalaemia, or may increase pre-existing hyperkalaemia, high potassium intake, or potassium-sparing diuretics (e.g., amiloride, triamterene, or spironolactone) should be avoided (see Precautions).
Immunosuppressants may affect the response to vaccination and vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided (see Precautions).

Instructions for use/handling: Cap: To be used as directed. Patients should take the capsules immediately once they are taken out of the blister. In addition, patients should be cautioned not to swallow the desiccant sachet contained within the aluminium wrapper.
Inj: Prograf Concentrate for Solution for Infusion must not be injected undiluted.
Prograf Concentrate for Solution for Infusion should be diluted in 5% dextrose solution or physiological saline solution in polyethylene, polypropylene or glass bottles, but not in PVC containers (see Incompatibilities as follows). Only transparent and colourless solutions should be used.
The concentration of a solution for infusion should be within the range 0.004 - 0.100 mg/ml. The total volume of infusion during a 24-hour period should be in the range 20 - 500 ml.
The diluted solution should not be given as a bolus.
Any unused concentrate in an opened ampoule or unused reconstituted solution should be disposed of immediately to avoid contamination.
Incompatibilities: Cap: Tacrolimus is not compatible with PVC. Tubing, syringes and other equipment used to prepare or administer a suspension of Prograf capsule contents should not contain PVC.
Inj: When diluting, this medicinal product must not be mixed with other medicinal products except those mentioned previously.
Tacrolimus is absorbed by PVC plastics. Tubing, syringes and any other equipment used to prepare and administer Prograf Concentrate for Solution for Infusion 5 mg/ml should not contain PVC.
Tacrolimus is unstable under alkaline conditions. Combination of the reconstituted Prograf Concentrate for Solution for Infusion 5 mg/ml with other pharmaceutical products that produce a marked alkaline solution (e.g. aciclovir and ganciclovir) should be avoided.

Cap: Store in the original package. Store at or below 30°C. Hard capsules should be taken immediately following removal from the blister.
Inj: Store below 25°C. Protect from light.
Shelf life: Cap: Aluminium-wrapped blisters: 36 months.
After opening of the aluminium wrapper the capsules are stable for 12 months.
Inj: 24 months when protected from light and stored at temperatures up to 25°C.
After reconstitution, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Immunosuppressants / Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

L04AD02 - tacrolimus ; Belongs to the class of calcineurin inhibitors. Used as immunosuppressants.

P₁S₁S₃