Each capsule also contains the following excipients: Lactose, hydroxypropyl methylcellulose, croscarmellose sodium and magnesium stearate.
Tacrolimus has a chemical name of [3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]- 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone monohydrate.
Tacrolimus is an odorless and tasteless white crystalline powder. It is very hygroscopic and the compound is isolated from cultures of Streptomyces tsukabaensis, strain No. 9993. The drug binds strongly to polyvinyl chloride and polyurethane plastics.
Pharmacotherapeutic Group: Immunosuppressive agent.
Pharmacology: Mechanism of Action: Tacrolimus inhibits T-lymphocyte activation although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin and calcineurin is then formed, and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (eg, interleukin-2, γ interferon). The net result is the inhibition of T-lymphocyte activation (ie, immunosuppression).
Pharmacokinetics: Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus is 97.62%; its maximum blood concentration (Cmax) is 21.66 ng/mL and area under the curve (AUC0-t) is 146.46 ng·hr/mL and AUC0-inf is 259.08 ng·hr/mL. Tmax is 3.5 hrs and t½ is 13.21 hrs. The rate and the extent of tacrolimus absorption is greatest under fasted conditions. The plasma protein-binding of tacrolimus is approximately 99%. Tacrolimus is bound mainly to albumin and α1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors eg, hematocrit, temperature at the time of plasma separation, drug concentration and plasma protein concentration. Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-dimethyl tacrolimus.
As prophylaxis for organ rejection in patients receiving allogenic kidney or liver transplant. It is recommended that Seegraf should be used along with adrenal corticosteroids.
Adult Patients in Renal Transplantation: Recommended Initial Oral Dose: 0.2 mg/kg/day in 2 divided doses to be administered every 12 hrs. Whole blood concentration during month 1-3 should be maintained between 7-20 ng/mL, and 5-15 ng/mL during the 4th month and onwards. The first dose should be administered after the renal function has recovered (ie, serum creatinine <4 mg/dL). Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Seegraf dosages may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early posttransplant.
Adult Patients in Liver Transplantation: Recommended Dose: 0.1-0.15 mg/kg/day administered in 2 divided daily doses every 12 hrs. Most patients are stable when trough whole blood concentrations are maintained between 5-20 ng/mL. Long-term posttransplant patients often are maintained at low end of this target range.
Administration: The initial dose of Seegraf should be administered no sooner than 6 hrs after transplantation.
Administration/Replacement of Cyclosporine: Seegraf should be administered simultaneously with cyclosporine.
In switching over from cyclosporine to Seegraf, cyclosporine should be stopped for 24 hrs prior to switch over.
In patients who have received inadvertent overdosage of Seegraf, no adverse drug reactions have been reported compared from those reported in patients receiving therapeutic doses. General symptomatic care of vital signs should be undertaken. Gastric lavage may be performed immediately to avoid further absorption of the drug.
Hypersensitivity to tacrolimus or to any of the excipients of Seegraf.
Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Seegraf. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources.
As with other patients receiving immunosuppressants, patients receiving tacrolimus are at increased risk of developing lymphomas and other malignancies particularly of the skin. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, treatment with combined immunosuppressives should be used with caution. Hypertension is a common adverse effect of Seegraf therapy. Mild or moderate hypertension is more frequently reported than severe hypertension. Antihypertensive therapy may be required; the control of blood pressure can be accomplished with any of the common antihypertensive agents.
Use in pregnancy & lactation: Seegraf should be recommended only if the potential benefit justifies the potential risk to the foetus.
Since Seegraf is excreted in human milk, nursing should be avoided.
Use in children: Pediatric patients generally required higher doses of Seegraf to maintain blood trough concentrations of tacrolimus similar to adult patients.
Seegraf should be recommended only if the potential benefit justifies the potential risk to the foetus.
Since Seegraf is excreted in human milk, nursing should be avoided.
The principal adverse reactions of Seegraf are tremor, headache, diarrhea, hypertension, nausea and renal dysfunction. Diarrhea was sometimes associated with other gastrointestinal complaints eg, nausea and vomiting.
Hyperkalemia and hypomagnesemia have occurred in patients receiving tacrolimus therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy.
Myocardial hypertrophy has been reported in association with the administration of tacrolimus, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and intraventricular septum thickness. Hypertrophy has been observed in infants, children and adults. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In a group of 20 patients with pre- and posttreatment echocardiograms who showed evidence of myocardial hypertrophy, mean tacrolimus whole blood concentrations during the period prior to diagnosis of myocardial hypertrophy ranged from 11-53 ng/mL in infants (N=10, age 0.4-2 years), 4-46 ng/mL in children (N=7, age 2-15 years) and 11-24 ng/mL in adults (N=3, age 37-53 years). In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving Seegraf therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of Seegraf should be considered.
Due to potential additive or synergistic impairment for renal function, care should be taken when administering Seegraf with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, amphotericin B and cisplatin. Initial clinical experience with the co-administration of Seegraf and cyclosporine resulted in additive/synergistic nephrotoxicity. Patients switched from cyclosporine to Seegraf should receive the first Seegraf dose no sooner than 24 hrs after the last cyclosporine dose. Dosing may be delayed further in the presence of elevated cyclosporine levels. Since Seegraf is metabolized mainly by the CYP3A enzyme systems, substances known to inhibit these enzymes may decrease the metabolism of Seegraf with resultant increases in whole blood or plasma concentrations. Drugs known to increase to induce this enzyme systems may result in an increased metabolism of Seegraf and decreased whole blood or plasma concentrations. Monitoring of blood concentrations and appropriate dosage adjustments are essential when such drugs are used concomitantly.
Immunosuppressants may affect vaccination. Therefore, during treatment with Seegraf, vaccination may be less effective.
Reported drug interactions are as follows: Drugs that can Increase Seegraf Levels: Calcium-channel blockers, diltiazem, nicardipine, nifedipine, verapamil.
Antifungal Agents: Clotrimazole, fluconazole, itraconazole, ketoconazole.
Macrolide Antibiotics: Clarithromycin, erythromycin, troleandomycin.
Gastrointestinal Prokinetic Agents: Cisapride, metoclopramide.
Other Drugs: Bromocriptine, cimetidine, cyclosporine, danazol, ethinyl estradiol, methylprednisolone, omeprazole, protease inhibitors, nefazodone.
Drugs that can Reduce Seegraf Levels: Anticonvulsants: Carbamazepine, phenobarbital, phenytoin.
Antibiotics: Rifabutin, rifampin.
Herbal Preparation: St. John's wort.
Store in a cool, dry and dark place.
L04AD02 - tacrolimus ; Belongs to the class of calcineurin inhibitors. Used as immunosuppressants.
Cap 0.5 mg x 6 x 10's. 1 mg x 6 x 10's.
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