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 Takrosel 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.
Tacrolimus is absorbed by PVC plastics. Tubing, syringes and any other equipment used to prepare and administer Takrosel 5 mg/ml concentrate for solution for infusion should not contain PVC.
Tacrolimus is unstable under alkaline conditions. Combination of the reconstituted Takrosel 5 mg/ml concentrate for solution for infusion with other pharmaceutical products that produce a marked alkaline solution (e.g. aciclovir and ganciclovir) should be avoided.
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); 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 Takrosel.
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 |
| not known: | pure red cell aplasia, agranulocytosis, haemolytic anaemia |
| 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, 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 |
| rare: | pericardial effusion |
| very rare: | Torsades de Pointes |
| 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, acute and chronic pancreatitis, gastrooesophageal reflux disease, impaired gastric emptying |
| 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 limb, 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 |
| 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 |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
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 Takrosel 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.
Pharmacotherapeutic group: Calcineurin inhibitors, ATC code: L04AD02
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
Takrosel 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 below.
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 (Treede et al., 3rd ICI San Diego, US, 2004;Abstract 22).
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) (Keenan et al., Ann Thoracic Surg 1995;60:580).
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%) (Treede et al., J Heart Lung Transplant 2001;20:511).
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 (Bechstein et al., Transplantation 2004;77:1221).
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 (Abu-Elmagd et al., Ann Surg 2001;234:404).
Absorption
In man tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract. Following oral administration of Takrosel 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 tacrolimus is in the range of 20% - 25%.
After oral administration (0.30 mg/kg/day) to liver transplant patients, steady-state concentrations of Takrosel were achieved within 3 days in the majority of patients.
In healthy subjects, Takrosel 0.5 mg, Takrosel 1 mg and Takrosel 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 Takrosel 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 Takrosel 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 Takrosel.
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.
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 - 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 Takrosel 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.
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.
High potassium intake or potassium-sparing diuretics should be avoided.
Certain combinations of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the risk of these effects.
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 Takrosel 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.
Lymphoproliferative disorders and malignancies
Patients treated with Takrosel have been reported to develop Epstein-Barr Virus (EBV)-associated lymphoproliferative disorders. Patients switched to Takrosel 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 Takrosel. 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.
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.
Opportunistic infections
Patients treated with immunosuppressants, including Takrosel are at increased risk of opportunistic infections (bacterial, fungal, viral and protozoal). 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 patients with deteriorating renal function or neurological symptoms.
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.
If administered accidentally either arterially or perivasally, the reconstituted Takrosel 5 mg/ml concentrate for solution for infusion may cause irritation at the injection site.
Excipients
Takrosel 5 mg/ml concentrate for solution for infusion 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 Takrosel 5 mg/ml concentrate for solution for infusion 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 Takrosel 5 mg/ml concentrate for solution for infusion should be taken into account.
Not relevant.
Takrosel 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.
General considerations
The recommended initial dosages presented below are intended to act solely as a guideline. Takrosel dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring (see below for recommended target whole blood trough concentrations). If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered.
Takrosel 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.
Takrosel is routinely administered in conjunction with other immunosuppressive agents in the initial post-operative period. The Takrosel dose may vary depending upon the immunosuppressive regimen chosen.
Method of administration
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.
Duration of dosing
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.
Dosage recommendations - Liver transplantation
Prophylaxis of transplant rejection - adults
Oral Takrosel 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
Takrosel doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Takrosel 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 Takrosel 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 the dose of Takrosel may need to be reduced.
For conversion to Takrosel, treatment should begin with the initial oral dose recommended for primary immunosuppression.
For information on conversion from ciclosporin to Takrosel, see below under “Dose adjustments in specific patient populationsâ€.
Dosage recommendations - Kidney transplantation
Prophylaxis of transplant rejection - adults
Oral Takrosel 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
Takrosel doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Takrosel-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 Takrosel 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 the dose of Takrosel may need to be reduced.
For conversion to Takrosel, treatment should begin with the initial oral dose recommended for primary immunosuppression.
For information on conversion from ciclosporin to Takrosel, see below under “Dose adjustments in specific patient populationsâ€.
Dosage recommendations - Heart transplantation
Prophylaxis of transplant rejection - adults
Takrosel can be used with antibody induction (allowing for delayed start of Takrosel therapy) or alternatively in clinically stable patients without antibody induction.
Following antibody induction, oral Takrosel 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
Takrosel has been used with or without antibody induction in paediatric heart transplantation.
In patients without antibody induction, if Takrosel 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 Takrosel 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
Takrosel 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 Takrosel 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 Takrosel, 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 Takrosel, 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 Takrosel, see below under “Dose adjustments in specific patient populationsâ€.
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 Takrosel 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 patients
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 Takrosel-based therapy. Takrosel 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, Takrosel 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 Takrosel 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.
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.
Takrosel 5 mg/ml concentrate for solution for infusion must not be injected undiluted.
Takrosel 5 mg/ml concentrate for solution for infusion should be diluted in 5 % w/v glucose solution or physiological saline solution in polyethylene, polypropylene or glass bottles, but not in PVC containers. 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 in accordance with local requirements to avoid contamination.
