1. Name Of The Medicinal Product
Modigraf 0.2 mg granules for oral suspension
Modigraf 1 mg granules for oral suspension
2. Qualitative And Quantitative Composition
Each sachet contains 0.2 mg tacrolimus (as monohydrate).
Excipient:
Each sachet contains 99.4 mg lactose monohydrate.
Each sachet contains 1 mg tacrolimus (as monohydrate).
Excipient:
Each sachet contains 497 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Granules for oral suspension.
White granules.
4. Clinical Particulars
4.1 Therapeutic Indications
Prophylaxis of transplant rejection in adult and paediatric, kidney, liver or heart allograft recipients.
Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult and paediatric patients.
4.2 Posology And Method Of Administration
This medicinal product should only be prescribed, and changes in immunosuppressive therapy initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients. Modigraf is a granular formulation of tacrolimus, for twice
Posology
The recommended initial doses presented below are intended to act solely as a guideline. Modigraf is routinely administered in conjunction with other immunosuppressive agents in the initial post
Careful and frequent monitoring of tacrolimus trough levels is recommended in the first 2 weeks post
Modigraf should not be switched with Advagraf as a clinically relevant difference in bioavailability between the two formulations cannot be excluded. In general, inadvertent, unintentional or unsupervised switching of immediate
Prophylaxis of kidney transplant rejection
Adults
Oral Modigraf therapy should commence at 0.20
If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous therapy of 0.05
Paediatric patients
An initial oral dose of 0.30mg/kg/day should be administered in 2 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 (with Prograf 5 mg/ml concentrate for solution for infusion) should be administered as a continuous 24
Dose adjustment during post
Tacrolimus doses are usually reduced in the post
Prophylaxis of liver transplant rejection
Adults
Oral Modigraf therapy should commence at 0.10
If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous therapy of 0.01
Paediatric patients
An initial oral dose of 0.30 mg/kg/day should be administered in 2 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 (with Prograf 5 mg/ml concentrate for solution for infusion) should be administered as a continuous 24
Dose adjustment during post
Tacrolimus doses are usually reduced in the post
Prophylaxis of heart transplant rejection
Adults
Modigraf can be used with antibody induction (allowing for delayed start of tacrolimus therapy) or alternatively in clinically stable patients without antibody induction.
Following antibody induction, oral Modigraf therapy should commence at a dose of 0.075 mg/kg/day administered as 2 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 (with Prograf 5 mg/ml concentrate for solution for infusion) should be initiated as a continuous 24
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.
Paediatric patients
Tacrolimus has been used with or without antibody induction in paediatric heart transplantation.
In patients without antibody induction, if tacrolimus therapy is initiated intravenously, the recommended starting dose is 0.03
Following antibody induction, if Modigraf therapy is initiated orally, the recommended starting dose is 0.10
Dose adjustment during post
Tacrolimus doses are usually reduced in the post
Conversion between Modigraf and Prograf tacrolimus formulations
In healthy subjects the systemic exposure to tacrolimus (AUC) for Modigraf was approximately 18% higher than that for Prograf capsules when administered as single doses. There are no safety data available on the use of Modigraf granules following a temporary switch from Prograf or Advagraf in critically ill patients.
Stable allograft recipients maintained on Modigraf granules, requiring conversion to Prograf capsules, should be converted on a 1:1 mg:mg total daily dose basis. If equal doses are not possible, the total daily dose of Prograf should be rounded
Similarly, for conversion of patients from Prograf capsules to Modigraf granules, the total daily Modigraf dose should preferably be equal to the total daily Prograf dose. If conversion on the basis of equal quantities is not possible, the total daily dose of Modigraf should be rounded down to the nearest total daily dose possible with sachets 0.2 mg and 1 mg.
The total daily dose of Modigraf granules should be administered in 2 equal doses. If equal doses are not possible, then the higher dose should be administered in the morning and the lower dose in the evening. Modigraf sachets must not be used partially.
Example: Total daily dose Prograf capsules given as 1 mg in the morning and 0.5 mg in the evening. Then give a total daily dose of Modigraf 1.4 mg divided as 0.8 mg in the morning and 0.6 mg in the evening.
Tacrolimus trough levels should be measured prior to conversion and within 1 week after conversion. Dose adjustments should be made to ensure that similar systemic exposure is maintained.
Conversion from ciclosporin to tacrolimus
Care should be taken when converting patients from ciclosporin
Treatment of allograft rejection
Increased tacrolimus doses, supplemental corticosteroid therapy, and introduction of short courses of mono
Treatment of allograft rejection after kidney or liver transplantation – adults and paediatric patients
For conversion from other immunosuppressants to twice daily Modigraf, treatment should begin with the initial oral dose recommended for primary immunosuppression.
Treatment of allograft rejection after heart transplantation therapy – adults and paediatric patients
In adult patients converted to Modigraf, an initial oral dose of 0.15 mg/kg/day should be administered in 2 divided doses (e.g. morning and evening).
In paediatric patients converted to tacrolimus, an initial oral dose of 0.20
Treatment of allograft rejection after transplantation of other allografts
The dose recommendations for lung, pancreas and intestinal transplantation are based on limited prospective clinical trial data with the Prograf formulation. Prograf has been used in lung
Dose adjustments in special populations
Hepatic 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.
Renal impairment
As the pharmacokinetics of tacrolimus are unaffected by renal function (see section 5.2), no dose adjustment is 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).
Race
In comparison to Caucasians, black patients may require higher tacrolimus doses to achieve similar trough levels.
Gender
There is no evidence that male and female patients require different doses to achieve similar trough levels.
Paediatric patients
In general, paediatric patients require doses 1½
Elderly patients
There is no evidence currently available to indicate that dosing should be adjusted in elderly patients.
Therapeutic drug monitoring
Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient aided by whole blood tacrolimus trough level monitoring.
As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood. 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. The relationship between tacrolimus trough levels (C12) and systemic exposure (AUC0) is similar between the 2 formulations Modigraf granules and Prograf capsules.
Blood trough levels of tacrolimus should be monitored during the post
Data from clinical studies 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
Method of administration
It is recommended that the oral daily dose of Modigraf be administered in 2 divided doses (e.g. morning and evening).
Tacrolimus therapy is generally initiated by the oral route. If necessary, tacrolimus dosing may commence by administering Modigraf granules suspended in water, via nasogastric tubing.
Modigraf granules 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 section 5.2).
The required dose is calculated from the weight of the patient, using the minimum number of sachets possible. Use 2 ml of water (at room temperature) per 1 mg tacrolimus to produce a suspension (up to a maximum of 50 ml, depending on body weight) in a cup. Do not use PVC containing materials (see section 6.2). Granules are added to the water and stirred. It is not advised to use any liquids or utensils to empty the sachets. The suspension can be drawn up via a syringe or swallowed directly by the patient. The taste is sweet due to the lactose. Thereafter the cup is rinsed once with the same quantity of water and the rinsings consumed by the patient. The suspension should be administered immediately after preparation.
In patients unable to take oral medicinal products during the immediate postth of the recommended oral dose for the corresponding indication.
4.3 Contraindications
Hypersensitivity to tacrolimus or to any of the excipients (see section 6.1).
Hypersensitivity to other macrolides.
4.4 Special Warnings And Precautions For Use
There are no safety data available on the use of Modigraf granules following a temporary switch from Prograf or Advagraf in critically ill patients.
Modigraf should not be switched with Advagraf as a clinically relevant difference in bioavailability between the two formulations cannot be excluded. Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate
During the initial post
When substances with a potential for interaction (see section 4.5) – particularly strong inhibitors of CYP3A4 (such as 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) should be avoided when taking Modigraf due to the risk of interactions that lead to decrease in blood concentrations of tacrolimus and reduced clinical effect of tacrolimus (see section 4.5).
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 sections 4.2 and 4.5).
High potassium intake or potassium
Certain combinations of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the risks of these effects (see section 4.5).
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.
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 with tacrolimus blood trough concentrations much higher than the recommended maximum levels. Other factors observed to increase the risk of these clinical conditions included preTorsades de Pointes. Caution should be exercised in patients with diagnosed or suspected Congenital Long QT Syndrome.
Lymphoproliferative disorders and malignancies
Patients treated with tacrolimus have been reported to develop EBVper se not indicative of lymphoproliferative disease or lymphoma.
As with other potent immunosuppressive compounds, the risk of secondary cancer is unknown (see section 4.8).
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.
Patients treated with immunosuppressants, including Modigraf, are at increased risk for 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 the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.
Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). If patients taking tacrolimus present with symptoms indicating PRES such as headache, altered mental status, seizures, and visual disturbances, a radiological procedure (e.g. MRI) should be performed. If PRES is diagnosed, adequate blood pressure and seizure control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.
Special populations
There is limited experience in non
Dose reduction may be necessary in patients with severe liver impairment (See section 4.2).
Modigraf granules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of substances known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels.
It is recommended to monitor tacrolimus blood levels whenever substance which have the potential to alter CYP3A4 metabolism or otherwise influence tacrolimus blood levels are used concomitantly, and to adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure (see sections 4.2 and 4.4).
CYP3A4 inhibitors potentially leading to increased tacrolimus blood levels
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 and voriconazole, the macrolide antibiotic erythromycin or HIV protease inhibitors (e.g. ritonavir). Concomitant use of these substances may require decreased tacrolimus doses in nearly all patients.
Pharmacokinetics studies have indicated that the increase in blood levels is mainly a result of increase in oral bioavailability of tacrolimus owing to the inhibition of gastrointestinal metabolism. Effect on hepatic clearance is less pronounced.
Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, danazol, ethinylestradiol, omeprazole and nefazodone.
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.
Lansoprazol and ciclosporin may potentially inhibit CYP3A4
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 prokinetic agents (such as metoclopramide and cisapride), cimetidine and magnesium
CYP3A4 inducers potentially leading to decreased tacrolimus blood levels
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
Tacrolimus has been shown to increase the blood level of phenytoin.
As tacrolimus may reduce the clearance of steroid
Limited knowledge of interactions between tacrolimus and statins is available. Clinical data suggest that the pharmacokinetics of statins are largely unaltered by the co
Animal data have shown that tacrolimus could potentially decrease the clearance and increase the half
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
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 section 4.4).
4.6 Pregnancy And Lactation
Pregnancy
Human data show that tacrolimus crosses the placenta. Limited data from organ transplant recipients show no evidence of an increased risk of adverse events on the course and outcome of pregnancy under tacrolimus treatment compared with other immunosuppressive medicinal products. To date, no other relevant epidemiological data are available. Tacrolimus treatment 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 events of tacrolimus is recommended (in particular effects on the kidneys).There is a risk for premature delivery (<37 week) (incidence of 66 of 123 births, i.e. 53.7%; however, data showed that the majority of the newborns had normal birth weight for their gestational age) as well as for hyperkalaemia in the newborn (incidence 8 of 111 neonates, i.e. 7.2%) which, however normalises spontaneously.
In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal toxicity (see section 5.3). Tacrolimus affected fertility in male rats (see section 5.3).
Lactation
Human data demonstrate that tacrolimus is excreted into breast milk. As detrimental effects on the newborn cannot be excluded, women should not breast
Fertility
A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if tacrolimus is administered in association with alcohol.
No studies on the effects of tacrolimus (Modigraf) on the ability to drive and use machines have been performed.
4.8 Undesirable Effects
The adverse reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medicinal products.
The most commonly reported adverse drug reactions (occurring in > 10% of patients) are tremor, renal impairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, hypertension and insomnia.
Many of the adverse reactions stated below are reversible and/or respond to dose reduction. The frequency of adverse reactions is defined as follows: very common (
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
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 Modigraf.
Neoplasms benign, malignant and unspecified (inl. cysts and polyps)
Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign as well as malignant neoplasms including EBV
Blood and lymphatic system disorders
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Immune system disorders
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section 4.4).
Endocrine disorders
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Metabolism and nutrition disorders
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Psychiatric disorders
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Nervous system disorders
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Eye disorders
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Ear and labyrinth disorders
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Cardiac disorders
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Vascular disorders
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Respiratory, thoracic and mediastinal disorders
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Gastrointestinal disorders
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Hepatobiliary disorders
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Skin and subcutaneous tissue disorders
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Musculoskeletal and connective tissue disorders
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Renal and urinary disorders
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Reproductive system and breast disorders
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General disorders and administration site conditions
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Injury, poisoning and procedural complications
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4.9 Overdose
Experience with overdose is limited. Several cases of accidental overdose have been reported with tacrolimus; symptoms have included tremor, headache, nausea and vomiting, infections, urticaria, lethargy and increases in blood urea nitrogen, serum creatinine concentrations and alanine aminotransferase levels.
No specific antidote to tacrolimus therapy is available. If overdose 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
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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 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
Clinical efficacy and safety of tacrolimus administered twice daily in other primary organ transplantation
In prospective published studies oral tacrolimus (given as Prograf capsules) 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 oral 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
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
In an additional 2
The 3 studies demonstrated similar survival rates. The incidences of acute rejection were numerically lower with tacrolimus in all 3 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
Intestinal transplantation
Published clinical experience from a single centre on the use of oral 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
5.2 Pharmacokinetic Properties
Absorption
In man, tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract. Available tacrolimus is generally rapidly absorbed.
Modigraf granules are an immediatemax) of tacrolimus in blood are on average achieved in approximately 2 to 2.5 hours.
Absorption of tacrolimus is variable. Results of a single dose bioequivalence study with adult healthy volunteers showed that Modigraf granules were approximately 20% more bioavailable than the Prograf capsules. Mean oral bioavailability of tacrolimus (investigated with the Prograf capsules formulation) is in the range of 20
Bile flow does not influence the absorption of tacrolimus and therefore treatment with Modigraf granules may commence orally.
In some patients, tacrolimus appears to be continuously absorbed over a prolonged period yielding a relatively flat absorption profile.
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
In stable liver transplant pati
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