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Sandoz Private Ltd

Tacrolimus

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Trade Name(s): Renograf
Manufacturer: Sandoz Private Ltd
Source(s) of supply: Sandoz Philippines Corp
Pharmacologic classification: Immunosuppressant
Therapeutic indication: Prophylaxis
Dosage forms: 1mg Capsule

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Description

Description

Bioavailability and Pharmacokinetics

Pharmacotherapeutic group: Immunosuppressants, calcineurin inhibitors. ATC code: L04AD02.Pharmacology: Pharmacodynamics: Mechanism of action: 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 cytokine genes.Pharmacodynamic effects: 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-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. Clinical efficacy and safety: Results from clinical trials performed with once-daily tacrolimus: Liver transplantation: The efficacy and safety of tacrolimus prolonged-release and tacrolimus immediate-release, both in combination with corticosteroids, was compared in 471 de novo liver transplant recipients. 

The event rate of biopsy confirmed acute rejection within the first 24 weeks after transplantation was 32.6% in the tacrolimus prolonged-release group (N=237) and 29.3% in the tacrolimus immediate-release group (N=234). The treatment difference (prolonged-release - immediate-release) was 3.3% (95% confidence interval [-5.7%, 12.3%]). The 12-month patient survival rates were 89.2% for tacrolimus prolonged-release and 90.8% for tacrolimus immediate-release; in the tacrolimus prolonged-release arm 25 patients died (14 female, 11 male) and in the tacrolimus immediate-release arm 24 patients died (5 female, 19 male). 12-month graft survival was 85.3% for tacrolimus prolonged-release and 85.6% for tacrolimus immediate-release.Kidney transplantation: The efficacy and safety of tacrolimus prolonged-release and tacrolimus immediate-release, both in combination with mycophenolate mofetil (MMF) and corticosteroids, was compared in 667 de novo kidney transplant recipients. The event rate for biopsy-confirmed acute rejection within the first 24 weeks after transplantation was 18.6% in the tacrolimus prolonged-release group (N=331) and 14.9% in the tacrolimus immediate-release group (N=336). The treatment difference (prolonged-release - immediate-release) was 3.8% (95% confidence interval [-2.1%, 9.6%]).

The 12-month patient survival rates were 96.9% for tacrolimus prolonged-release and 97.5% for tacrolimus immediate release; in the tacrolimus prolonged-release arm 10 patients died (3 female, 7 male) and in the tacrolimus immediate-release arm 8 patients died (3 female, 5 male). 12-month graft survival was 91.5% for tacrolimus prolonged-release and 92.8% for tacrolimus immediate-release.Distribution: In man, the disposition of tacrolimus after intravenous infusion may be described as biphasic. In the systemic circulation, tacrolimus binds strongly to erythrocytes resulting in an approximate 20:1 distribution ratio of whole blood/plasma concentrations. In plasma, tacrolimus is highly bound (> 98.8%) to plasma proteins, mainly to serum albumin and α-1-acid glycoprotein. Tacrolimus is extensively distributed in the body. The steady-state volume of distribution based on plasma concentrations is approximately 1300 L (healthy subjects). Corresponding data based on whole blood averaged 47.6 L. Biotransformation: Tacrolimus is widely metabolized in the liver, primarily by the cytochrome P450-3A4. Tacrolimus is also considerably metabolized in the intestinal wall.

There are several metabolites identified. Only one of these has been shown in vitro to have immunosuppressive activity similar to that of tacrolimus.The other metabolites have only weak or no immunosuppressive activity. In systemic circulation only one of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to the pharmacological activity of tacrolimus.Elimination: Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance estimated from whole blood concentrations was 2.25 L/h. In adult liver, kidney and heart transplant patients, values of 4.1 L/h, 6.7 L/h and 3.9 L/h, respectively, have been observed. Factors such as low hematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or corticosteroid-induced increased metabolism, are considered to be responsible for the higher clearance rates observed following transplantation. The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is approximately 43 hours.

Dose range

Prophylaxis of kidney transplant rejection Initially 0.20-0.30 mg/kg once daily in the morning w/in 24 hr after the completion of surgery. Prophylaxis of liver transplant rejection Initially 0.10-0.20 mg/kg once daily in the morning approx 12-18 hr after the completion of surgery. Allograft rejection after kidney or liver transplantation Begin w/ the initial oral dose recommended in kidney & liver transplantation respectively for prophylaxis of transplant rejection. Allograft rejection after heart transplantation Adult 0.15 mg/kg once daily in the morning. Allograft rejection after transplantation of other allografts Lung-transplanted patient Initially 0.10-0.15 mg/kg daily. Pancreas-transplanted patients Initially 0.20 mg/kg daily. Intestinal transplantation Initially 0.30 mg/kg daily.

Known adverse effects and toxicities

Increased risk for infections (viral, bacterial, fungal, protozoal), aggravate preexisting infections, generalized & localized infections, BK virus associated w/ nephropathy, JC virus associated w/ progressive multifocal leukoencephalopathy; increased risk of developing malignancies, benign & malignant neoplasms including EBV-associated lymphoproliferative disorders & skin malignancies; allergic & anaphylactoid reactions. Hyperglycemic conditions, DM, hyperkalemia; insomnia; headache, tremor; HTN; diarrhea, nausea; renal impairment; abnormal LFTs. Anemia, leukopenia, thrombocytopenia, leukocytosis, abnormal RBC analyses; hypomagnesaemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, fluid overload, hyperuricemia, decreased appetite, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, other electrolyte abnormalities; anxiety symptoms, confusion & disorientation, depression, depressed mood, mood disorders & disturbances, nightmare, hallucination, mental disorders; nervous system disorders, seizures, disturbances in consciousness, peripheral neuropathies, dizziness, paresthesias & dysesthesia, impaired writing; blurred vision, photophobia, eye disorders; tinnitus; ischemic coronary artery disorders, tachycardia; hemorrhage, thromboembolic & ischemic events, peripheral vascular disorders, vascular hypotensive disorders; dyspnea, parenchymal lung disorders, pleural effusion, pharyngitis, cough, nasal congestion & inflammations; GI inflammatory conditions, GI ulceration & perforation, GI hemorrhages, stomatitis & ulceration, ascites, vomiting, GI & abdominal pains dyspeptic signs & symptoms, constipation, flatulence, bloating & distension, loose stools, GI signs & symptoms; bile duct disorders, hepatocellular damage & hepatitis, cholestasis & jaundice; pruritus, rash, alopecia, acne, increased sweating; arthralgia, back pain, muscle spasms, pain in extremity; renal failure, acute renal failure, oliguria, renal tubular necrosis, toxic nephropathy, urinary abnormalities, bladder & urethral symptoms; asthenic conditions, febrile disorders, edema, pain & discomfort, disturbed body temp perception; increased blood alkaline & wt; primary graft dysfunction.

Special precautions

Graft rejection or other side effects which could be a consequence of either under- or overexposure to tacrolimus. Prophylaxis of transplant rejection in adult heart allograft recipients. Suspected symptoms or signs of GI perforation. Cardiomyopathies may occur. May prolong the QT interval & cause Torsades de Pointes. Patients w/ risk factors for QT prolongation including those w/ personal or family history of QT prolongation, CHF, bradyarrhythmias & electrolyte abnormalities; diagnosed or suspected to have congenital long QT syndrome or acquired QT prolongation, or on concomitant medications known to prolong the QT interval, induce electrolyte abnormalities or known to increase exposure. Development of EBV-associated lymphoproliferation disorders or posterior reversible encephalopathy syndrome. Limit exposure to sunlight & UV light due to risk of malignant skin changes. Eye disorders (sometimes progressive to loss of vision). Increased risk for infections including opportunistic infections eg, BK virus associated nephropathy & JC virus associated progressive multifocal leukoencephalopathy; viral hepatitis. Pure red cell aplasia.

Non-Caucasian patients & patients at elevated immunological risk (eg, retransplantation, evidence of panel reactive Abs). Monitor BP, ECG, neurological & visual status, fasting blood glucose levels, electrolytes (particularly K), liver & renal function tests, haematology parameters, coagulation values, & plasma protein determinations during the initial post-transplant period; blood level conc during episodes of diarrhea. Monitor high-risk patients receiving substantial immunosuppression using echocardiography or ECG pre- & post-transplant (eg, initially at 3 mth & then at 9-12 mth) & reduce dose if abnormalities develop. Combination w/ strong CYP3A4 inhibitors (eg, telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers (eg, rifampicin, rifabutin); w/ medicinal products known to have nephrotoxic or neurotoxic effects; immunosuppressives eg, antilymphocytic Abs (eg, basiliximab, daclizumab). Avoid herbal prep containing St. John's wort or other herbal prep; ciclosporin; high K intake or K-sparing diuretics; live attenuated vaccines. May enhance visual & neurological disturbance w/ alcohol. Severe liver impairment. Reduced sperm counts & motility in male. Pregnancy. Do not use during lactation. Not recommended for use in childn <18 yr.
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