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Cyclosporine Capsules USP MODIFIED, a systemic immunosuppressant, may increase the susceptibility to infection and the development of neoplasia. In kidney, liver, and heart transplant patients Cyclosporine Capsules USP MODIFIED may be administered with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma and other neoplasms may result from the increase in the degree of immunosuppression in transplant patients.
Cyclosporine Capsules USP MODIFIED has increased bioavailability in comparison to Sandimmune (Cyclosporine Capsules USP). Cyclosporine Capsules USP MODIFIED and Sandimmune (Cyclosporine Capsules USP) are not bioequivalent and cannot be used interchangeably without physician supervision. For a given trough concentration, cyclosporine exposure will be greater with Cyclosporine Capsules USP MODIFIED than with Sandimmune (Cyclosporine Capsules USP). If a patient who is receiving exceptionally high doses of Sandimmune (Cyclosporine Capsules USP) is converted to Cyclosporine Capsules USP MODIFIED, particular caution should be exercised. Cyclosporine blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking Cyclosporine Capsules USP MODIFIED to avoid toxicity due to high concentrations. Dose adjustments should be made in transplant patients to minimize possible organ rejection due to low concentrations. Comparison of blood concentrations in the published literature with blood concentrations obtained using current assays must be done with detailed knowledge of the assay methods employed.
Psoriasis patients previously treated with PUVA and to a lesser extent, methotrexate or other immunosuppressive agents, UVB, coal tar, or radiation therapy, are at an increased risk of developing skin malignancies when taking Cyclosporine Capsules USP MODIFIED.
Cyclosporine, the active ingredient in Cyclosporine Capsules USP MODIFIED, in recommended dosages, can cause systemic hypertension and nephrotoxicity. The risk increases with increasing dose and duration of cyclosporine therapy. Renal dysfunction, including structural kidney damage, is a potential consequence of cyclosporine, and therefore, renal function must be monitored during therapy.
Cyclosporine, the active principle in Cyclosporine Capsules USP MODIFIED, is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Mycelium sterilae.
The effectiveness of cyclosporine results from specific and reversible inhibition of immunocompetent lymphocytes in the G0- and G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine also inhibits lymphokine production and release including interleukin-2.
No effects on phagocytic function (changes in enzyme secretions, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo) have been detected in animals. Cyclosporine does not cause bone marrow suppression in animal models or man.
The relationship between administered dose and exposure (area under the concentration versus time curve, AUC) is linear within the therapeutic dose range. The intersubject variability (total, %CV) of cyclosporine exposure (AUC) when Cyclosporine Capsules USP MODIFIED or Sandimmune (Cyclosporine Capsules USP) is administered ranges from approximately 20% to 50% in renal transplant patients. This intersubject variability contributes to the need for individualization of the dosing regimen for optimal therapy (see DOSAGE AND ADMINISTRATION). Intrasubject variability of AUC in renal transplant recipients (%CV) was 9% to 21% for Cyclosporine Capsules USP MODIFIED and 19% to 26% for Sandimmune (Cyclosporine Capsules USP). In the same studies, intrasubject variability of trough concentrations (%CV) was 17% to 30% for Cyclosporine Capsules USP MODIFIED and 16% to 38% for Sandimmune (Cyclosporine Capsules USP).
Following oral administration of Cyclosporine Capsules USP MODIFIED, the time to peak blood cyclosporine concentrations (Tmax) ranged from 1.5 to 2 hours. The administration of food with Cyclosporine Capsules USP MODIFIED decreases the cyclosporine AUC and Cmax. A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before Cyclosporine Capsules USP MODIFIED administration decreased the AUC by 13% and Cmax by 33%. The effects of a low fat meal (667 kcal, 15 grams fat) were similar.
The effect of T-tube diversion of bile on the absorption of cyclosporine from Cyclosporine Capsules USP MODIFIED was investigated in eleven de novo liver transplant patients. When the patients were administered Cyclosporine Capsules USP MODIFIED with and without T-tube diversion of bile, very little difference in absorption was observed, as measured by the change in maximal cyclosporine blood concentrations from pre-dose values with the T-tube closed relative to when it was open: 6.941% (range -55% to 68%).
When diclofenac or methotrexate was coadministered with cyclosporine in rheumatoid arthritis patients, the AUC of diclofenac and methotrexate, each was significantly increased (see PRECAUTIONS, Drug Interactions). No clinically significant pharmacokinetic interactions occurred between cyclosporine and aspirin, ketoprofen, piroxicam, or indomethacin.
In the pediatric population, Cyclosporine Capsules USP MODIFIED also demonstrates an increased bioavailability as compared to Sandimmune (Cyclosporine Capsules USP). In 7 liver de novo transplant patients aged 1.4 to 10 years, the absolute bioavailability of Cyclosporine Capsules USP MODIFIED was 43% (range 30% to 68%) and for Sandimmune (Cyclosporine Capsules USP) in the same individuals absolute bioavailability was 28% (range 17% to 42%).
Study 2008 enrolled 144 patients with active RA and >6 active joints who had unsuccessful treatment courses of aspirin and gold or Penicillamine. Patients were randomized to 1 of 2 treatment groups (1) cyclosporine 2.5 to 5 mg/kg/day with adjustments after the first month to achieve a target trough level and (2) placebo. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 3.63 mg/kg/day. See graph below.
Study 654 enrolled 148 patients who remained with active joint counts of 6 or more despite treatment with maximally tolerated methotrexate doses for at least three months. Patients continued to take their current dose of methotrexate and were randomized to receive, in addition, one of the following medications: (1) cyclosporine 2.5 mg/kg/day with dose increases of 0.5 mg/kg/day at weeks 2 and 4 if there was no evidence of toxicity and further increases of 0.5 mg/kg/day at weeks 8 and 16 if a
Patients receiving Cyclosporine Capsules USP MODIFIED require frequent monitoring of serum creatinine (see DOSAGE AND ADMINISTRATION, Special Monitoring). Elderly patients should be monitored with particular care, since decreases in renal function also occur with age. If patients are not properly monitored and doses are not properly adjusted, cyclosporine therapy can be associated with the occurrence of structural kidney damage and persistent renal dysfunction.
An increase in serum creatinine and BUN may occur during Cyclosporine Capsules USP MODIFIED therapy and reflect a reduction in the glomerular filtration rate. Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated. The frequency and severity of serum creatinine elevations increase with dose and duration of cyclosporine therapy. These elevations are likely to become more pronounced without dose reduction or discontinuation.
Because Cyclosporine Capsules USP MODIFIED are not bioequivalent to Sandimmune (Cyclosporine Capsules USP), conversion from Cyclosporine Capsules USP MODIFIED to Sandimmune (Cyclosporine Capsules USP) using a 1:1 ratio (mg/kg/day) may result in lower cyclosporine blood concentrations. Conversion from Cyclosporine Capsules USP MODIFIED to Sandimmune (Cyclosporine Capsules USP) should be made with increased monitoring to avoid the potential of underdosing.
Based on the historical Sandimmune (Cyclosporine Capsules USP) experience with oral solution, nephrotoxicity associated with cyclosporine had been noted in 25% of cases of renal transplantation, 38% of cases of cardiac transplantation, and 37% of cases of liver transplantation. Mild nephrotoxicity was generally noted 2 to 3 months after renal transplant and consisted of an arrest in the fall of the pre-operative elevations of BUN and creatinine at a range of 35 to 45 mg/dL and 2 to 2.5 mg/dL respectively. These elevations were often responsive to cyclosporine dosage reduction.
More overt nephrotoxicity was seen early after transplantation and was characterized by a rapidly rising BUN and creatinine. Since these events are similar to renal rejection episodes, care must be taken to differentiate between them. This form of nephrotoxicity is usually responsive to cyclosporine dosage reduction.
Although specific diagnostic criteria which reliably differentiate renal graft rejection from drug toxicity have not been found, a number of parameters have been significantly associated with one or the other. It should be noted however, that up to 20% of patients may have simultaneous nephrotoxicity and rejection.
A form of a cyclosporine-associated nephropathy is characterized by serial deterioration in renal function and morphologic changes in the kidneys. From 5% to 15% of transplant recipients who have received cyclosporine will fail to show a reduction in rising serum creatinine despite a decrease or discontinuation of cyclosporine therapy. Renal biopsies from these patients will demonstrate one or several of the following alterations: tubular vacuolization, tubular microcalcifications, peritubular capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tubular atrophy. Though none of these morphologic changes is entirely specific, a diagnosis of cyclosporine-associated structural nephrotoxicity requires evidence of these findings.
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