Brand name: Prograf

Active ingredient (generic name): Tacrolimus

Manufacturer: Astellas

Importer: Behestan Darou

Pharmacotherapeutic group: Calcineurin inhibitors

Pharmaceutical form: 0.5mg, 1mg & 5mg capsules

Pharmacodynamic:  

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.

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.

Pharmacokinetic:

Following oral administration of Prograf capsules peak concentrations (Cmax) of tacrolimus in blood are achieved in approximately 1 - 3 hours. In healthy subjects, the mean half-life in whole blood is approximately 43 hours.

Tacrolimus is widely metabolised in the liver, primarily by the cytochrome P450-3A4.

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.

 

Therapeutic indication:

Prophylaxis of transplant rejection in liver, kidney or heart allograft recipients.

Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal.

 

Dosage and administration:

Liver transplantation

Adults- Oral Prograf 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.

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.

Heart transplantation

Adults- Prograf can be used with antibody induction (allowing for delayed start of Prograf therapy) or alternatively in clinically stable patients without antibody induction.

Following antibody induction, oral Prograf 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.

Children- In patients without antibody induction, if Prograf 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.

Following antibody induction, if Prograf 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).

Kidney transplantation

Adults- Oral Prograf 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.

Children- An initial oral dose of 0.30mg/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.

 

Adverse reaction:

Undesirable effects are as following:

ischemic coronary artery disorders, tachycardia, anemia, leucopenia, thrombocytopenia, leukocytosis, red blood cell analyses abnormal, tremor, headache, seizures, disturbances in consciousness, paraesthesiae and dysaesthesias, peripheral neuropathies, dizziness, writing impaired, nervous system disorders , dyspnoea, parenchyma lung disorders, pleural effusion, pharyngitis, cough, nasal congestion and inflammations, diarrhea, nausea , pruritus, rash, alopecia, acne, sweating increased

Contraindication:

 

In case of Hypersensitivity to tacrolimus, other macrolides and any of the excipients, it is prohibited.

Pharmacokinetic interactions:

Concomitant use of medicinal products or herbal remedies known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease 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, Carbamazepine, phenytoin

 

 

Special warnings:

Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, has 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 Prograf therapy, or change of treatment to another immunosuppressive agent should be considered.

Patients treated with immunosuppressants, including Prograf 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.

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.

 

Pregnancy and lactation:

Due to the need of treatment, tacrolimus can be considered in pregnant women when there is no safer alternative and when the perceived benefit justifies the potential risk to the foetus.

Storage temperature:  

Room temperature (15-25 C)

 

         

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