Tacrolimus
Graficon® (Tacrolimus) a macrolide lactone with potent immunosuppressive activity, isolated from Streptomyces tsukubaensis.
Graficon®(Tacrolimus) a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Tacrolimus has an empirical formula of C44H69NO12, H2O and a formula weight of 822.05.
Mechanism of Action
Tacrolimus exerts potent inhibitory effect on T- lymphocyte activation. Tacrolimus binds to immunophilins FK506 binding proteins (FKBP-12) and a complex of FKBP-12, calcium, calmodulin and calcineurin is formed, inhibiting phosphatase activity of calcineurin.This prevents dephosphorylation and translocation of nuclear factor of activated T–cells (NF-AT) and inhibits transcription of early T-cell activation gene, Interleukin-2,Tumor Necrosis Factor(TNF-α) and proto-oncogenes; suppressing expression of IL-2 and IL-7 receptor. So this inhibits T-lymphocyte activation. Tacrolimus inhibits the mixed lymphocyte reaction, generation of cytotoxic T-cells and T-cell dependent B-cell activation. Due to intra subject variability of pharmacokinetics, individualized of dose regimen is necessary.
Absorption
The absorption of Tacrolimus after oral administration is incomplete and variable with absolute bioavailability of 17 ± 10% in adult renal transplantation, 22 ± 6% in adult liver transplantation and 18 ± 5% in healthy volunteers. Food appears to reduce the absorption and relative bioavailability of Tacrolimus.In most cases,Cmax is achieved after 0.5 to 1 hour. The overall mean time to Cmax is about 2 hrs.
Distribution
Tacrolimus is 72 – 99% plasma protein bound with a concentration range of 5-50 ng/ml. At concentration above 50 ng/ml,the plasma protein binding become saturable. Tacrolimus also binds to erythrocytes and lymphocytes. The distribution of Tacrolimus between whole blood and plasma depends on many factors, like hematocrit, temperature at the time of plasma separation, drug concentration and plasma protein concentration.
Metabolism
Tacrolimus is extensively metabolized by the mixed-function oxidase system,primarily the cytochrome P450 system (CYP3A).
Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsome is 13-demethyl Tacrolimus. In in-vitro studies, a 31-demethyl metabolite has been reported to have the same activity as Tacrolimus.
Excretion
In men, less than 1% of the dose administered is excreted unchanged in urine. After oral administration, fecal elimination was found to be 92.6 ± 30.7%, urinary elimination 2.3 ± 1.1% and the elimination half-life based on radioactivity was 31.9 ± 10.5 hours whereas it is 48.4 ± 12.3 hours based on Tacrolimus concentrations.
Special Population
Pediatric
Upon oral administration the mean AUC and Cmax are 337 ± 167 ng/hr/ml and 43.4 ± 27.9 ng/ml, respectively. The absolute bioavailability was 31 ± 21%. Pediatric patients need higher doses than adults to achieve similar Tacrolimus trough concentrations.
Renal and Hepatic Insufficiency
The mean clearance of Tacrolimus in patients with renal dysfunction is similar to that in normal volunteers. The mean clearance of Tacrolimus in patients with mild hepatic dysfunction is not substantially different from that in normal volunteers.
Race
A retrospective comparison of Black and Caucasian kidney transplant patients indicate that Black patients need higher doses of Tacrolimus to attain similar trough concentrations.
Gender
There is no effect of gender on pharmacokinetics of Tacrolimus in the renal transplant.
Indications and usage
Tacrolimus is indicated as prophylaxis for organ rejection in patients receiving allogenic renal or liver or heart transplants.
Contraindications
Tacrolimus is contraindicated in patients with hypersensitivity to Tacrolimus.
Warnings
- Administration of Tacrolimus may cause diabetes mellitus and may require treatment.
- Tacrolimus can cause neurotoxicity and nephrotoxicity when used in high doses.
- Tacrolimus should not be used simultaneously with Cyclosporine. Either of the two should be discontinued at least 24 hours prior to initiating the other.
- Patients should be monitored closely for the evaluation of rejection, toxicity, dose adjustments and compliance.
- Mild to moderate hyperkalemia may occur and may require frequent monitoring and treatment.
- Patients receiving Tacrolimus are at high risk of lymphomas, malignancies and infections due to over suppression of immune system. Therefore, combination immunosuppressant should be used with caution.
Precautions
Repeated laboratory tests like serum creatinine, potassium and fasting glucose to be assessed regularly. Routine monitoring of metabolic and hematologic systems should be performed as clinically warranted.
General
- Mild to moderate hypertension is common adverse effect.
- Anti-hypertensive therapy may be used in some patients.
- Patients with hepatic impairment: Lower dosage to be used in patients with compromised hepatic function.
- Patients with renal impairment: Lower dosage to be used in patients if graft is getting compromised.
- Hypertrophic cardiomyopathy: Hypertrophic cardiomyopathy has been observed in infants and children.
- Dose reduction or discontinuation of therapy is needed.
Pregnancy
There are no adequate and well-controlled studies in pregnant women. Tacrolimus should be used in pregnancy only if the benefits outweigh potential risks to fetus. Nursing Mothers Since Tacrolimus is excreted in human milk, nursing should be avoided. Drug/Food Interactions As Tacrolimus is metabolized by cytochrome P450 CYP3A enzyme, potential drug interactions are numerous.
Increased Tacrolimus Blood Concentration
Calcium channel blockers, Antifungal agents, Macrolide antibiotics, Corticosteroids, Cyclosporine, Prokinetic agents, Omeprazole, Bromocryptine, Protease inhibitors, etc., increase blood concentration of Tacrolimus. Monitoring of blood concentration of Tacrolimus and dosage adjustment is recommended.
Decreased Tacrolimus Blood Concentration
Anticonvulsants, Anticoagulants, Antacids, Rifabutin and Rifampicin decrease Tacrolimus blood concentration. Interaction studies with drugs used in HIV therapy has not been conducted.
Increased Renal Toxicity
Nephrotoxic drugs like Acyclovir, ACE inhibitors, Cisplatin, Aminoglycosides, Amphotericin B, Cyclosporine and NSAIDs has a potential for additive or synergistic toxicity with Tacrolimus. Care should be taken when these drugs are co-administered with Tacrolimus.
Vaccines
Tacrolimus may reduce the efficacy of vaccines and recipients of Tacrolimus should not receive live attenuated vaccines.
Food
Food decreases the rate and extent of absorption of Tacrolimus. Absorption of this drug is the greatest under fasting conditions. Grapefruit juice is reported to increase Tacrolimus blood through concentration and should be avoided.
Adverse Reactions
Tacrolimus shows adverse event common to other immunosuppresant therapy like neurotoxicity, nephrotoxicity, increased risk of infection and malignancy,diabetes mellitus and lymphoproliferative disorder related to Epstein-Barr virus. The most common adverse events reported are: Nervous system – Tremor, Headache, Paresthesia, Dizziness, Insomnia, Seizures, Coma and Delirium with high plasma concentrations of Tacrolimus Gastrointestinal – Diarrhea, Constipation, Nausea, Vomiting and Dyspepsia Cardiovascular – Hypertension and Chest Pain Urogenital – Creatinine increase and Urinary tract infection Metabolic and Nutritional – Hyperkalemia, Hyperglycemia(new onset post-transplant diabetes mellitus), Hyperlipidemia, Hypophosphatemia, Hypomagnesemia, Hyperglycemia Diabetes mellitus, Hypokalemia and Edema Hemic and Lymphatic – Anemia and Leukopenia Respiratory System – Dyspnea Musculoskeletal – Arthralgia and Back Pain Skin – Rash and Pruritus Miscellaneous – Infection, Peripheral edema, Asthenia, Abdominal Pain and Fever
Overdose and Treatment
There is very limited experience of Tacrolimus overdose. Acute over dose does not show any special adverse effect. However, it is expected that they shall be consistent with reported adverse effects of Tacrolimus. Overdose Management: It is expected that Tacrolimus is not dialysable to any significant extent. Though, the use of charcoal is reported, it is not supported by experience. General supportive measures and treatment of specific symptoms should be followed in all cases.
Presentation
Aluminium Foil pack of Graficon® 0.5mg in one strip 10 Capsules and 6 strips in a box.
Aluminium Foil pack of Graficon® 1mg in one strip 10 Capsules and 6 strips in a box.
Composition
Each hard gelatin Graficon® 0.5mg capsule contains Tacrolimus 0.5 mg I.P. Each hard gelatin Graficon® 1mg capsule contains Tacrolimus 1 mg I.P.
Indications
- Prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants.
- Treatment of refractory rejection in patients receiving allogeneic liver or kidney transplants.
- Treatment of active rheumatoid arthritis in adult patients for whom disease modifying anti-rheumatic drug (DMARD) therapy is ineffective or inappropriate.
Dosage
Renal Transplant : 0.1 to 0.2 mg/kg/day divided in two doses, administered every 12 hours before food
Liver Transplant : 0.1 to 0.15 mg/kg/day divided in two doses, administered every 12 hours before food
Heart Transplant : 0.075 mg/kg/day divided in two doses, administered every 12 hours before food
The dosage is adjusted based on the usage and dosage of concurant immunosuppressants, corticosteroids and induction agents used in soild organ transplants. A schematic monitoring of trough levels for Tacrolimus is done post-transplant to adjust the dosage which varies from patient to patient.
Benefits Of Graficon®
GRAFICON® (Tacrolimus) is a quality immunosuppressant manufactured at state of the art facility complying FDA, WHO-GMP regulations. Graficon®(Tacrolimus) is the mainstay in solid organ transplantation and has demonstrated less acute rejection rates and better graft survival in many studies.
Disclaimer:
This information is for registered medical practitioner only. Anyone other than medical practitioner should consult medical practitioner before using this product.