ABRAMMUNE
ABRAMMUNE
Composition
Abrammune is a modified formula of cyclosporine (cyclosporine for microemulsion), available as capsules and oral solution. Each capsule contains 25, 50 or 100 mg cyclosporine. Each 1 ml liquid of Abrammune (oral solution) contains 100 mg cyclosporine.
Properties
Pharmacodynamics Cyclosporine is a potent, selective immunosuppressive agent that suppresses some humoral immunity and to a greater extent, cell-mediated immune reactions such as allograft rejection, delayed hypersensitivity and graft - vs - host disease. Cyclosporine targets mainly T-helper cell and to a lesser degree Lhe T-suppressor cell. Cyclosporine selectively and reversibly inhibits the immunocompetent lymphocytes in the G o and G 1 phase of the cell cycle. Cyclosporine inhibits lymphokine production and release including interleukin - 2 (T-cell growth factor TCGF). Cyclosporine does not cause bone marrow suppression, does not depress hemopoiesis, and has no effect on phagocytic function or tumor cells. Pharmacokinetics The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable. Abrammune capsules or oral solution is a formula of cyclosporine for micro-emulsion. Abrammune T max is 1.5 - 2.0 hrs, bioavailability is 58%. In blood, the distribution of Abrammune depends on concentration but is approximately: 33 - 47% in plasma (90% of which is bound to lipoproteins), 41 - 58% in erythrocytes, 5-12% in granulocytes, 4-9% in lymphocytes. Cyclosporine is extensively metabolized in the liver and to a lesser degree in the gastrointestinal tract and the kidney (metabolized by the cytochrome P-450 III enzyme). The terminal half-life ranged from 6.3 h in healthy volunteers to 20.4 h in patients with liver disease. Elimination is primarily biliary then into feces, with only 6% of the oral dose excreted in the urine (only 0 1 % of which is excreted as unchanged drug).
Indications
Solid Organ Transplantation - Prevention of graft rejection following kidney, liver, heart, combined heart-lung or pancreas allogeneic transplantation. - Treatment of transplant rejection in patients previously receiving other immunosuppressive agents. Non- Transplantation Nephrotic syndrome Abrammune can be used: - In adults and children with steroiddependent and steroid-resistant nephrotic syndrome in order to induce and maintain remissions. - Also, used to maintain steroid-induced remission allowing withdrawal of steroids. Rheumatoid arthritis, psoriasis, atopic dermatitis: Abrammune is indicated for treatment of severe cases when conventional treatment is ineffective or inappropriate. Endogenous uveitis - In active sight-threatening intermediate or posterior uveitis of non-infectious etiology where conventional therapy fails. - Behcet’s uveitis with repeated inflama- tory attacks involving the retina. Bone Marrow Transplantation - Prevention of graft rejection following bone marrow transplantation. - Prevention or treatment of graft-versus- host disease (GVHD).
Contraindications
Patients having hypersensitivity to cyclosporine. Side Effects They are usually dose-dependent and respond to dose reduction: Renal dysfunction'. Mostly in the form of functional changes that occur in the first few weeks of cyclosporine therapy. Rarely, on long term therapy, structural changes in the kidney may take place. Hepatic dysfunction, hypertrichosis, tremor, hypertension (especially in heart transplant patients), fatigue, burning sensation in the hands and feet (usually during the first week of therapy). Gingival hypertrophy, gastrointestinal disturbances (nausea, vomiting, abdominal pain, diarrhea). Headache, allergic rashes, mild anemia. Hyperkalemia, hyperuricemia, hypomagnesemia. Weight increase, edema, pancreatitis. Paresthesia, convulsions. Reversible dysmenorrhea or amenorrhea. Muscle cramps, muscle weakness. Especially in liver transplant patients, signs of encephalopathy, vision and movement disturbances and impaired consciousness. Thrombocytopenia associated with micro-angiopathic hemolytic anemia and renal failure. The incidence and distribution of malignancies and lymphoproliferative disorders on cyclosporine therapy are similar to conventional immunosup-pressive herapy.
Precautions
Pregnancy and Lactation Cyclosporine treatment imposes no increased risk of side effects on the course and outcome of pregnancy. Although successful pregnancies have been reported in women receiving cyclosporine, the drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. During cyclosporine therapy, lactating women should not breastfeed their babies since it is excreted in breast milk. In the Elderly and Children No particular problems have been reported following the use of cyclosporine in the elderly at the recommended dose. Children from 1 year of age have received cyclosporine in standard dosage with no particular problems. Abrammune with other immunosuppressants Although Abrammune (cyclosporine) should not be used with other immunosuppressive agents except corticosteroids, some centers combine cyclosporine with other immunosuppressive agents as aza- thioprine aiming at reducing the risk of cyclosporine-induced renal dysfunction. When Abrammune (cyclosporine) is used with other immunosuppressive agents, there is a risk of over - immunosuppression which can lead to increased susceptibility to infection and to development of lymphoma. Parameters that should be checked to follow-up safety during therapy - Kidney function: An increase in serum creatinine and urea may occur during the first few weeks of cyclosporine therapy denotes functional changes that are dose-dependant and reversible, usually responding to dose reduction by 25-50%. - Liver function - Cyclosporine levels in the blood, plasma or serum. - Blood pressure. If hypertension develops, appropriate antihypertensive treatment must be instituted. - Lipid profile: lipid determinations before treatment and after 1st month of therapy is advisable. - Serum potassium level should be monitored especially in patients with marked renal dysfunction. Patients on cyclosporine therapy should avoid intake of high dietary potassium, potas- sium-containing medications or potassium-sparing diuretics. - Serum uric acid level should be monitored especially in hyperuricemic patients. Abrammune and vaccination: During treatment with Abrammune, vaccination may be less effective and the live- attenuated vaccines should be avoided. Abrammune and exposure to light: During treatment, avoid excessive exposure to direct sunlight, UVB radiation or PUVA therapy. Special precaution with oral solution: The oral solution is preferably diluted with orange or apple juice or other soft drinks to improve the taste except grapefruit (which interferes with cytochrome P450 enzyme system). Storage Abrammune should be stored at a temperature between 15 - 30°C and should not be refrigerated. Drug Interactions Care should be taken when using Abrammune with: - Drugs known to have nephrotoxic effects: Aminoglycosides, amphotericin B, ciprofloxacin, melphalan, trimethoprim, diclofenac. - Lovastatin and colchicine to avoid increasing the potential of muscle pain and weakness. - Agents known to increase the plasma or whole blood levels of cyclosporine through competitive inhibition of hepatic enzymes involved in the metabolism and excretion of the drug (cytochrome P 450): Ketoconazole, macrolides as erythromycin, doxycycline, oral contraceptives. diltiazem. nifedipine, nicardipine, and verapamil. - Agents that decrease plasma or the whole blood levels of cyclosporine through induction of hepatic enzyme involved in the metabolism and excretion of the product (cytochrome P 450): Barbiturates, I.V. trimethoprim and I.V. sulfadimidine. - Corticosteroids: Cyclosporine reduces the clearance of prednisolone and high doses of methylprednisolone can increase the blood concentration of cyclosporine.
Dosage and Administration
The dosage of Abrammune as mentioned at each indication is the total daily dose which should be given in 2 divided doses: Solid Organ Transplantation Treatment with Abrammune should be initiated within 12 hours before surgery at a daily dose of 10-15 mg/kg to be maintained for 1-2 weeks postoperatively. Then, it is gradually reduced according to blood levels of cyclosporine until a maintenance dose of 2-6 mg/kg daily. When Abrammune is given with other immunosuppressants, as corticosteroids or as a part of triple or quadruple drug therapy . lower doses of 3-6 mg/kg daily may be used for the initial treatment. Graft-versus-Host Disease Mild and chronic graft-versus-host disease can develop after discontinuation of cyclosporine therapy. It can be treated by low doses of Abrammune. Non Transplantation Nephrotic syndrome Abrammune is used to induce remission Daily dose in children 6 mg/kg. Daily dose in adults 5 mg/kg. Abrammune could be used in combination with corticosteroids if the effect of cyclosporine alone is not satisfactory. The dose of Abrammune should be adjusted individually according to efficacy (proteinuria) and safety (serum creatinine). Abrammune is used to maintain remission: the dose of remission induction is slowly reduced to the lowest effective treatment. Psorasis To induce remission, the initial dose of Abrammune is 2.5 mg/kg daily. If there is no improvement, the dose can be increased up to 5 mg/kg daily. If no suffucient response of psoriatic lesion is obtained within 6 weeks on 5 mg/kg daily, cyclosporine should be discontinued. Initial dose of Abrammune can be 5 mg/kg daily in severe cases when rapid improvement is required. When Abrammune is used to maintain remission, the doses have to be titrated individually to the lowest effective dose. Hheumatoid arthritis For the first 6 weeks of treatment, the recommended dose of Abrammune is 3 mg/kg daily. - If the effect is insufficient, the dose can be gradually increased, as tolerability permits, to up to 5 mg/kg daily. - To reach full effectiveness, the duration of 12 weeks of therapy is required. For maintenance treatment, Abrammune has to be individualized according to tolerability to the lowest effective dose. Abrammune can be combined with low- dose corticosteroids and/or non-steroidal anti-inflammatory drugs. Abrammune in a dose of 2.5 mg/kg daily can be combined with low dose weekly methotrexate in patients with insufficient response to methotrexate alone. Bone Marrow Transplantation In most cases, the initial dose given on the day before the transplantation is preferred to be in the infusion form of cyclosporine lor 1-2 weeks post-trans- plant period. If oral form is used to initiate treatment, the dose is 12.5-15 mg/kg daily starting on the day before transplantation. Maintenance treatment should be continued for at least 3-6 months then the dose is gradually decreased till the complete withdrawal of the drug by 1 year after transplantation.
Packaging
ca: 25, 50, 100 mg x 50 (in 5 strips) sn: 50 ml (100 mg/ml with a calibrated measure).