Uses and Administration OF Tacrolimus in Kenya
Tacrolimus (Pangraf, Vingraf) is a potent macrolide (macrolactam) immunosuppressant derived from Streptomyces tsukubaensis, and has actions similar to those of cyclosporine (Arpimune). It is used to prevent or reverse rejection in patients receiving organ transplants in Kenya, as indicated by the cross-references given below, and has been tried in a few patients with refractory auto-immune or immune-mediated disorders. Tacrolimus is also applied topically in the management of moderate to severe atopic eczema.
The manufacturer recommends that oral tacrolimus should be taken consistently with respect to the timing of ingestion of food. (details below)
For transplantation, the initial dose recommended in the Kenya for liver graft recipients is 100 to 200 micrograms/kg daily by mouth, in 2 divided doses. The initial oral dose in kidney transplant patients is 150 to 300 micrograms/kg daily in 2 divided doses. Dosage should begin about 6 hours after completion of liver grafting and within 24 hours of a kidney transplant in Kenya. If the patient’s condition does not permit oral use, therapy may be commenced intravenously, by continuous 24-hour infusion: suggested initial doses are 10 to 50 micrograms/kg daily for liver transplants and 50 to 100 micrograms/kg daily for kidney transplants. In the USA, initial oral doses in patients with liver grafts are 100 to 150 micrograms/kg daily, in 2 divided doses, and in kidney grafts 200 micrograms/kg daily, in 2 divided doses. The recommended starting dose of intravenous tacrolimus is 30 to 50 micrograms/kg daily.
Dosage should be adjusted according to whole-blood or plasma trough concentrations in individual patients: it is suggested that most patients can be satisfactorily maintained at whole-blood concentrations below 20 nanograms/mL. Children generally require doses 1.5 to 2 times greater than those recommended in adults to achieve the same blood concentrations.
For the treatment of atopic eczema, where conventional therapies are ineffective or unsuitable, tacrolimus may be applied twice daily as a 0.03 or 0.1% ointment. Treatment should be continued for 1 week after resolution of signs and symptoms of the disease.
Adverse Effects and Precautions
Can A Breastfeeding Mother Take Tacrolimus.
YES! Tacrolimus concentrations were measured in milk from a liver transplant recipient on a dose of 0.1 mg/kg daily. The authors estimated that the infant would ingest only 0.06% (0.06 micrograms/kg daily) of the mother’s weight-adjusted dose. No adverse effects were noted in the infant at 2.5 months of age.
Effects of Tacrolimus on the blood.
Severe anaemia due to selective depression of erythropoiesis in a patient given tacrolimus resolved when tacrolimus was replaced with ciclosporin. More generalised bone marrow suppression, and post-transplant thrombotic microangiopathy have also been reported in some patients receiving Tacrolimus in Kenya.
Interactions of Tacrolimus with othe Drugs
Elevated plasma-tacrolimus concentrations have been reported in patients given clotrimazole, fluconazole, or voriconazole; a reduction in the dose of tacrolimus was likely to be necessary if it were given with an azole antifungal. A study involving tacrolimus and ketoconazole suggested that an increase in the oral bioavailability of tacrolimus from a mean of 14 to 30% when given with the azole was probably due to decreased cytochrome P450 isoenzyme CYP3A4 metabolism in the gut wall, or improved absorption due to inhibition of P-glycoprotein mediated efflux, rather than an effect on hepatic metabolism. Similarly, a 50% reduction in tacrolimus dosage was found to be necessary when the drug was given with itraconazole. It has been suggested that the interaction could be exploited to reduce the cost of immunosuppressant regimens in Kenya.
bromocriptine, calcium-channel blockers, cimetidine, some corticosteroids, ciclosporin, danazol, HIV-protease inhibitors, macrolide antibacterials, and metoclopramide, may produce increased blood concentrations of tacrolimus. The metabolism of tacrolimus may also be inhibited by grapefruit juice and concomitant use should be avoided. Equally, inducers of this enzyme system (such as carbamazepine, phenobarbital, phenytoin, and rifampicin) may reduce blood concentrations of tacrolimus. For a warning concerning the use of live vaccines in patients receiving immunosuppressants see Adverse Effects and Precautions. Facial flushing or skin irritation may occur if alcohol is consumed by patients using topical tacrolimus.
The cytochrome P450 isoenzyme subfamily CYP3A, and P-glycoprotein, are involved in the pharmacokinetic pathways of tacrolimus. Drugs known to interact with these systems will probably affect tacrolimus concentrations, primarily by influencing oral bioavailability rather than clearance. A study in vitro found that metabolism of tacrolimus by CYP3A in human liver microsomes was inhibited by bromocriptine, corticosterone, dexamethasone, ergotamine, erythromycin, ethinylestradiol, josamycin, ketoconazole, miconazole, midazolam, nifedipine, omeprazole, tamoxifen, troleandomycin, and verapamil. No effect on tacrolimus metabolism was seen with aspirin, amphotericin B, captopril, cefotaxime, ciprofloxacin, diclofenac, diltiazem, doxycycline, furosemide, glibenclamide, imipramine, lidocaine, paracetamol, prednisolone, progesterone, ranitidine, sulfamethoxazole, trimethoprim, or vancomycin.
Interactions of Tacrolimus with Antibacterials
Increased concentrations of tacrolimus in plasma have been reported with erythromycin; the interaction was accompanied by some evidence of nephrotoxicity. A similar interaction has been reported between tacrolimus and clarithromycin.
Treatment with rifampicin has been found to substantially decrease tacrolimus concentrations. A pharmacokinetic study found that rifampicin induces metabolism of tacrolimus in both the liver and intestine, probably by induction of the cytochrome P450 isoenzyme subfamily CYP3A and P-glycoprotein. Both metronidazole and chloramphenicol increased the blood concentrations of tacrolimus. This is probably due to inhibition of metabolism, and dosage reduction of the immunosuppressant may be necessary when either drug is given with tacrolimus.
Plasma concentrations of tacrolimus are also increased by quinupristin/dalfopristin.
Kenya: PANGRAF, VINGRAF Arg.: Prograf; Austral.: Prograf; Austria: Prograf; Protopic; Belg.: Prograft; Braz.: Prograf; Canad.: Prograf; Chile: Prograf; Denm.: Prograf; Fin.: Prograf; Fr.: Prograf; Ger.: Prograf; Gr.: Prograf; Hong Kong: Prograf; Hung.: Prograf; Irl.: Prograf; Protopic; Israel: Prograf; Ital.: Prograf; Jpn: Prograf; Protopic; Malaysia: Prograf; Mex.: Prograf; Norw.: Prograf; NZ: Prograf; Port.: Prograf; Protopic; S.Afr.: Prograf; Singapore: Prograf; Spain: Prograf; Protopic; Swed.: Prograf; Switz.: Prograf; Thai.: Prograf; UK: Prograf; Protopic; USA: Prograf; Protopic;