Cyclosporine

Cyclosporine Manufacturers

• American Health Packaging
  

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  Cyclosporine | Johnson & Johnson Consumer Inc., Mcneil Consumer Healthcare Division

  

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  do not take more than directed the smallest effective dose should be used swallow whole; do not crush or chew drink a full glass of water with each dose adults and children 12 years and older 1 caplet every 12 hours do not take more than 2 caplets in 24 hours children under 12 years do not use

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• American Health Packaging
  

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  Cyclosporine | American Health Packaging

  

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  Cyclosporine Capsules USP NON-MODIFIED

  Cyclosporine Capsules USP (NON-MODIFIED) have decreased bioavailability in comparison to Neoral®* (cyclosporine capsules, USP) MODIFIED. Cyclosporine Capsules USP (NON-MODIFIED) and Neoral®* (cyclosporine capsules, USP) MODIFIED are not bioequivalent and cannot be used interchangeably without physician supervision.

  The initial oral dose of Cyclosporine Capsules USP NON-MODIFIED should be given 4 to 12 hours prior to transplantation as a single dose of 15 mg/kg. Although a daily single dose of 14 to 18 mg/kg was used in most clinical trials, few centers continue to use the highest dose, most favoring the lower end of the scale. There is a trend towards use of even lower initial doses for renal transplantation in the ranges of 10 to 14 mg/kg/day. The initial single daily dose is continued postoperatively for 1 to 2 weeks and then tapered by 5% per week to a maintenance dose of 5 to 10 mg/kg/day. Some centers have successfully tapered the maintenance dose to as low as 3 mg/kg/day in selected renal transplant patients without an apparent rise in rejection rate.

  (See Blood Level Monitoring below.)

  In pediatric usage, the same dose and dosing regimen may be used as in adults although in several studies, children have required and tolerated higher doses than those used in adults.

  Adjunct therapy with adrenal corticosteroids is recommended. Different tapering dosage schedules of prednisone appear to achieve similar results. A dosage schedule based on the patient’s weight started with 2.0 mg/kg/day for the first 4 days tapered to 1.0 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Another center started with an initial dose of 200 mg tapered by 40 mg/day until reaching 20 mg/day. After 2 months at this dose, a further reduction to 10 mg/day was made. Adjustments in dosage of prednisone must be made according to the clinical situation.

  Cyclosporine Capsules USP NON-MODIFIED should be administered on a consistent schedule with regard to time of day and relation to meals.

  Blood Level Monitoring

  Several study centers have found blood level monitoring of cyclosporine useful in patient management. While no fixed relationships have yet been established, in one series of 375 consecutive cadaveric renal transplant recipients, dosage was adjusted to achieve specific whole blood 24-hour trough levels of 100 to 200 ng/mL as determined by high-pressure liquid chromatography (HPLC).

  Of major importance to blood level analysis is the type of assay used. The above levels are specific to the parent cyclosporine molecule and correlate directly to the new monoclonal specific radioimmunoassays (mRIA-sp). Nonspecific assays are also available which detect the parent compound molecule and various of its metabolites. Older studies often cited levels using a nonspecific assay which were roughly twice those of specific assays. Assay results are not interchangeable and their use should be guided by their approved labeling. If plasma specimens are employed, levels will vary with the temperature at the time of separation from whole blood. Plasma levels may range from 1/2 to 1/5 of whole blood levels. Refer to individual assay labeling for complete instructions. In addition, Transplantation Proceedings (June 1990) contains position papers and a broad consensus generated at the Cyclosporine-Therapeutic Drug Monitoring conference that year. Blood level monitoring is not a replacement for renal function monitoring or tissue biopsies.

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• Physicians Total Care, Inc.
  

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  Cyclosporine | Physicians Total Care, Inc.

  

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  Cyclosporine Capsules USP MODIFIED, soft gelatin capsules, 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.

  The daily dose of Cyclosporine Capsules USP MODIFIED should always be given in two divided doses (BID). It is recommended that Cyclosporine Capsules USP MODIFIED be administered on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of cyclosporine, thus should be avoided.

  Newly Transplanted Patients

  The initial oral dose of Cyclosporine Capsules USP MODIFIED can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of Cyclosporine Capsules USP MODIFIED varies depending on the transplanted organ and the other immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients, the initial oral dose of Cyclosporine Capsules USP MODIFIED is the same as the initial oral dose of Sandimmune® (Cyclosporine Capsules USP). Suggested initial doses are available from the results of a 1994 survey of the use of Sandimmune® (Cyclosporine Capsules USP) in US transplant centers. The mean ±SD initial doses were 9±3 mg/kg/day for renal transplant patients (75 centers), 8±4 mg/kg/day for liver transplant patients (30 centers), and 7±3 mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses. The Cyclosporine Capsules USP MODIFIED dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration (see Blood Concentration Monitoring in Transplant Patients, below). If cyclosporine trough blood concentrations are used, the target range is the same for Cyclosporine Capsules USP MODIFIED as for Sandimmune® (Cyclosporine Capsules USP). Using the same trough concentration target range for Cyclosporine Capsules USP MODIFIED as for Sandimmune® (Cyclosporine Capsules USP) results in greater cyclosporine exposure when Cyclosporine Capsules USP MODIFIED is administered (see Pharmacokinetics, Absorption). Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Cyclosporine Capsules USP MODIFIED doses may be sufficient as maintenance therapy.

  Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage schedules of prednisone appear to achieve similar results. A representative dosage schedule based on the patient’s weight started with 2 mg/kg/day for the first 4 days tapered to 1 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical situation.

  Conversion from Sandimmune® (Cyclosporine Capsules USP) to Cyclosporine Capsules USP MODIFIED in Transplant Patients

  In transplanted patients who are considered for conversion to Cyclosporine Capsules USP MODIFIED from Sandimmune® (Cyclosporine Capsules USP), Cyclosporine Capsules USP MODIFIED should be started with the same daily dose as was previously used with Sandimmune® (Cyclosporine Capsules USP) (1:1 dose conversion). The Cyclosporine Capsules USP MODIFIED dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for Cyclosporine Capsules USP MODIFIED as for Sandimmune® (Cyclosporine Capsules USP) results in greater cyclosporine exposure when Cyclosporine Capsules USP MODIFIED is administered (see Pharmacokinetics, Absorption). Patients with suspected poor absorption of Sandimmune® (Cyclosporine Capsules USP) require different dosing strategies (see Transplant Patients with Poor Absorption of Sandimmune® (Cyclosporine Capsules USP), below). In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance.

  Until the blood trough concentration attains the pre-conversion value, it is strongly recommended that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to Cyclosporine Capsules USP MODIFIED. In addition, clinical safety parameters such as serum creatinine and blood pressure should be monitored every two weeks during the first two months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, the dosage of Cyclosporine Capsules USP MODIFIED must be adjusted accordingly.

  Transplant Patients with Poor Absorption of Sandimmune® (Cyclosporine Capsules USP)

  Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune® (Cyclosporine Capsules USP) may have poor or inconsistent absorption of cyclosporine from Sandimmune® (Cyclosporine Capsules USP). After conversion to Cyclosporine Capsules USP MODIFIED, patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to Cyclosporine Capsules USP MODIFIED, the cyclosporine blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to Cyclosporine Capsules USP MODIFIED at doses greater than 10 mg/kg/day. The dose of Cyclosporine Capsules USP MODIFIED should be titrated individually based on cyclosporine trough concentrations, tolerability, and clinical response. In this population the cyclosporine blood trough concentration should be measured more frequently, at least twice a week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes within the desired range.

  Rheumatoid Arthritis

  The initial dose of Cyclosporine Capsules USP MODIFIED is 2.5 mg/kg/day, taken twice daily as a divided (BID) oral dose. Salicylates, nonsteroidal anti-inflammatory agents, and oral corticosteroids may be continued (see WARNINGS and PRECAUTIONS, Drug Interactions). Onset of action generally occurs between 4 and 8 weeks. If insufficient clinical benefit is seen and tolerability is good (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5 to 0.75 mg/kg/day after 8 weeks and again after 12 weeks to a maximum of 4 mg/kg/day. If no benefit is seen by 16 weeks of therapy, Cyclosporine Capsules USP MODIFIED therapy should be discontinued.

  Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension elevations in serum creatinine (30% above patient’s pretreatment level) or clinically significant laboratory abnormalities (see WARNINGS and PRECAUTIONS).

  If dose reduction is not effective in controlling abnormalities or if the adverse event or abnormality is severe, Cyclosporine Capsules USP MODIFIED should be discontinued. The same initial dose and dosage range should be used if Cyclosporine Capsules USP MODIFIED is combined with the recommended dose of methotrexate. Most patients can be treated with Cyclosporine Capsules USP MODIFIED doses of 3 mg/kg/day or below when combined with methotrexate doses of up to 15 mg/week (see CLINICAL PHARMACOLOGY, Clinical Trials).

  There is limited long-term treatment data. Recurrence of rheumatoid arthritis disease activity is generally apparent within 4 weeks after stopping cyclosporine.

  Psoriasis

  The initial dose of Cyclosporine Capsules USP MODIFIED should be 2.5 mg/kg/day. Cyclosporine Capsules USP MODIFIED should be taken twice daily, as a divided (1.25 mg/kg BID) oral dose. Patients should be kept at that dose for at least 4 weeks, barring adverse events. If significant clinical improvement has not occurred in patients by that time, the patient’s dosage should be increased at 2 week intervals. Based on patient response, dose increases of approximately 0.5 mg/kg/day should be made to a maximum of 4 mg/kg/day.

  Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension, elevations in serum creatinine (≥ 25% above the patient’s pretreatment level), or clinically significant laboratory abnormalities. If dose reduction is not effective in controlling abnormalities, or if the adverse event or abnormality is severe, Cyclosporine Capsules USP MODIFIED should be discontinued (see Special Monitoring of Psoriasis Patients).

  Patients generally show some improvement in the clinical manifestations of psoriasis in 2 weeks. Satisfactory control and stabilization of the disease may take 12 to 16 weeks to achieve. Results of a dose-titration clinical trial with Cyclosporine Capsules USP MODIFIED indicate that an improvement of psoriasis by 75% or more (based on PASI) was achieved in 51% of the patients after 8 weeks and in 79% of the patients after 16 weeks. Treatment should be discontinued if satisfactory response cannot be achieved after 6 weeks at 4 mg/kg/day or the patient’s maximum tolerated dose. Once a patient is adequately controlled and appears stable the dose of Cyclosporine Capsules USP MODIFIED should be lowered, and the patient treated with the lowest dose that maintains an adequate response (this should not necessarily be total clearing of the patient). In clinical trials, cyclosporine doses at the lower end of the recommended dosage range were effective in maintaining a satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day may also be equally effective.

  Upon stopping treatment with cyclosporine, relapse will occur in approximately 6 weeks (50% of the patients) to 16 weeks (75% of the patients). In the majority of patients rebound does not occur after cessation of treatment with cyclosporine. Thirteen cases of transformation of chronic plaque psoriasis to more severe forms of psoriasis have been reported. There were 9 cases of pustular and 4 cases of erythrodermic psoriasis. Long-term experience with Cyclosporine Capsules USP MODIFIED in psoriasis patients is limited and continuous treatment for extended periods greater than one year is not recommended. Alternation with other forms of treatment should be considered in the long-term management of patients with this life long disease.

  Blood Concentration Monitoring in Transplant Patients

  Transplant centers have found blood concentration monitoring of cyclosporine to be an essential component of patient management. Of importance to blood concentration analysis are the type of assay used, the transplanted organ, and other immunosuppressant agents being administered. While no fixed relationship has been established, blood concentration monitoring may assist in the clinical evaluation of rejection and toxicity, dose adjustments, and the assessment of compliance.

  Various assays have been used to measure blood concentrations of cyclosporine. Older studies using a nonspecific assay often cited concentrations that were roughly twice those of the specific assays. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed. Current assay results are also not interchangeable and their use should be guided by their approved labeling. A discussion of the different assay methods is contained in Annals of Clinical Biochemistry 1994;31:420-446. While several assays and assay matrices are available, there is a consensus that parent-compound-specific assays correlate best with clinical events. Of these, HPLC is the standard reference, but the monoclonal antibody RIAs and the monoclonal antibody FPIA offer sensitivity, reproducibility, and convenience. Most clinicians base their monitoring on trough cyclosporine concentrations. Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring (1992) contains a broad discussion of cyclosporine pharmacokinetics and drug monitoring techniques. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.

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• Physicians Total Care, Inc.
  

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  Cyclosporine | Physicians Total Care, Inc.

  

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  Cyclosporine Capsules, USP NON-MODIFIED 

  Cyclosporine Capsules, USP (NON-MODIFIED) have decreased bioavailability in comparison to Neoral®* (cyclosporine capsules, USP) MODIFIED. Cyclosporine Capsules, USP (NON-MODIFIED) and Neoral®* (cyclosporine capsules, USP) MODIFIED are not bioequivalent and cannot be used interchangeably without physician supervision.

  The initial oral dose of Cyclosporine Capsules, USP NON-MODIFIED should be given 4 to 12 hours prior to transplantation as a single dose of 15 mg/kg. Although a daily single dose of 14 to 18 mg/kg was used in most clinical trials, few centers continue to use the highest dose, most favoring the lower end of the scale. There is a trend towards use of even lower initial doses for renal transplantation in the ranges of 10 to 14 mg/kg/day. The initial single daily dose is continued postoperatively for 1 to 2 weeks and then tapered by 5% per week to a maintenance dose of 5 to 10 mg/kg/day. Some centers have successfully tapered the maintenance dose to as low as 3 mg/kg/day in selected renal transplant patients without an apparent rise in rejection rate.

  (See Blood Level Monitoring below.)

  In pediatric usage, the same dose and dosing regimen may be used as in adults although in several studies, children have required and tolerated higher doses than those used in adults.

  Adjunct therapy with adrenal corticosteroids is recommended. Different tapering dosage schedules of prednisone appear to achieve similar results. A dosage schedule based on the patient’s weight started with 2.0 mg/kg/day for the first 4 days tapered to 1.0 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Another center started with an initial dose of 200 mg tapered by 40 mg/day until reaching 20 mg/day. After 2 months at this dose, a further reduction to 10 mg/day was made. Adjustments in dosage of prednisone must be made according to the clinical situation.

  Cyclosporine Capsules, USP NON-MODIFIED should be administered on a consistent schedule with regard to time of day and relation to meals.

  Blood Level Monitoring

  Several study centers have found blood level monitoring of cyclosporine useful in patient management. While no fixed relationships have yet been established, in one series of 375 consecutive cadaveric renal transplant recipients, dosage was adjusted to achieve specific whole blood 24-hour trough levels of 100 to 200 ng/mL as determined by high-pressure liquid chromatography (HPLC).

  Of major importance to blood level analysis is the type of assay used. The above levels are specific to the parent cyclosporine molecule and correlate directly to the new monoclonal specific radioimmunoassays (mRIA-sp). Nonspecific assays are also available which detect the parent compound molecule and various of its metabolites. Older studies often cited levels using a nonspecific assay which were roughly twice those of specific assays. Assay results are not interchangeable and their use should be guided by their approved labeling. If plasma specimens are employed, levels will vary with the temperature at the time of separation from whole blood. Plasma levels may range from 1/2 to 1/5 of whole blood levels. Refer to individual assay labeling for complete instructions. In addition, Transplantation Proceedings (June 1990) contains position papers and a broad consensus generated at the Cyclosporine-Therapeutic Drug Monitoring conference that year. Blood level monitoring is not a replacement for renal function monitoring or tissue biopsies.

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• Cardinal Health
  

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  Cyclosporine | Cardinal Health

  

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  Cyclosporine Capsules USP MODIFIED, soft gelatin capsules, 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.

  The daily dose of Cyclosporine Capsules USP MODIFIED should always be given in two divided doses (BID). It is recommended that Cyclosporine Capsules USP MODIFIED be administered on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of cyclosporine, thus should be avoided.

  Newly Transplanted Patients

  The initial oral dose of Cyclosporine Capsules USP MODIFIED can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of Cyclosporine Capsules USP MODIFIED varies depending on the transplanted organ and the other immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients, the initial oral dose of Cyclosporine Capsules USP MODIFIED is the same as the initial oral dose of Sandimmune® (Cyclosporine Capsules USP). Suggested initial doses are available from the results of a 1994 survey of the use of Sandimmune® (Cyclosporine Capsules USP) in US transplant centers. The mean ±SD initial doses were 9±3 mg/kg/day for renal transplant patients (75 centers), 8±4 mg/kg/day for liver transplant patients (30 centers), and 7±3 mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses. The Cyclosporine Capsules USP MODIFIED dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration (see Blood Concentration Monitoring in Transplant Patients, below). If cyclosporine trough blood concentrations are used, the target range is the same for Cyclosporine Capsules USP MODIFIED as for Sandimmune® (Cyclosporine Capsules USP). Using the same trough concentration target range for Cyclosporine Capsules USP MODIFIED as for Sandimmune® (Cyclosporine Capsules USP) results in greater cyclosporine exposure when Cyclosporine Capsules USP MODIFIED is administered (see Pharmacokinetics, Absorption). Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Cyclosporine Capsules USP MODIFIED doses may be sufficient as maintenance therapy.

  Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage schedules of prednisone appear to achieve similar results. A representative dosage schedule based on the patient’s weight started with 2 mg/kg/day for the first 4 days tapered to 1 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical situation.

  Conversion from Sandimmune® (Cyclosporine Capsules USP) to Cyclosporine Capsules USP MODIFIED in Transplant Patients

  In transplanted patients who are considered for conversion to Cyclosporine Capsules USP MODIFIED from Sandimmune® (Cyclosporine Capsules USP), Cyclosporine Capsules USP MODIFIED should be started with the same daily dose as was previously used with Sandimmune® (Cyclosporine Capsules USP) (1:1 dose conversion). The Cyclosporine Capsules USP MODIFIED dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for Cyclosporine Capsules USP MODIFIED as for Sandimmune® (Cyclosporine Capsules USP) results in greater cyclosporine exposure when Cyclosporine Capsules USP MODIFIED is administered (see Pharmacokinetics, Absorption). Patients with suspected poor absorption of Sandimmune® (Cyclosporine Capsules USP) require different dosing strategies (see Transplant Patients with Poor Absorption of Sandimmune® (Cyclosporine Capsules USP), below). In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance.

  Until the blood trough concentration attains the pre-conversion value, it is strongly recommended that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to Cyclosporine Capsules USP MODIFIED. In addition, clinical safety parameters such as serum creatinine and blood pressure should be monitored every two weeks during the first two months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, the dosage of Cyclosporine Capsules USP MODIFIED must be adjusted accordingly.

  Transplant Patients with Poor Absorption of Sandimmune® (Cyclosporine Capsules USP)

  Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune® (Cyclosporine Capsules USP) may have poor or inconsistent absorption of cyclosporine from Sandimmune® (Cyclosporine Capsules USP). After conversion to Cyclosporine Capsules USP MODIFIED, patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to Cyclosporine Capsules USP MODIFIED, the cyclosporine blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to Cyclosporine Capsules USP MODIFIED at doses greater than 10 mg/kg/day. The dose of Cyclosporine Capsules USP MODIFIED should be titrated individually based on cyclosporine trough concentrations, tolerability, and clinical response. In this population the cyclosporine blood trough concentration should be measured more frequently, at least twice a week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes within the desired range.

  Rheumatoid Arthritis

  The initial dose of Cyclosporine Capsules USP MODIFIED is 2.5 mg/kg/day, taken twice daily as a divided (BID) oral dose. Salicylates, nonsteroidal anti-inflammatory agents, and oral corticosteroids may be continued (see WARNINGS and PRECAUTIONS, Drug Interactions). Onset of action generally occurs between 4 and 8 weeks. If insufficient clinical benefit is seen and tolerability is good (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5 to 0.75 mg/kg/day after 8 weeks and again after 12 weeks to a maximum of 4 mg/kg/day. If no benefit is seen by 16 weeks of therapy, Cyclosporine Capsules USP MODIFIED therapy should be discontinued.

  Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension elevations in serum creatinine (30% above patient’s pretreatment level) or clinically significant laboratory abnormalities (see WARNINGS and PRECAUTIONS).

  If dose reduction is not effective in controlling abnormalities or if the adverse event or abnormality is severe, Cyclosporine Capsules USP MODIFIED should be discontinued. The same initial dose and dosage range should be used if Cyclosporine Capsules USP MODIFIED is combined with the recommended dose of methotrexate. Most patients can be treated with Cyclosporine Capsules USP MODIFIED doses of 3 mg/kg/day or below when combined with methotrexate doses of up to 15 mg/week (see CLINICAL PHARMACOLOGY, Clinical Trials).

  There is limited long-term treatment data. Recurrence of rheumatoid arthritis disease activity is generally apparent within 4 weeks after stopping cyclosporine.

  Psoriasis

  The initial dose of Cyclosporine Capsules USP MODIFIED should be 2.5 mg/kg/day. Cyclosporine Capsules USP MODIFIED should be taken twice daily, as a divided (1.25 mg/kg BID) oral dose. Patients should be kept at that dose for at least 4 weeks, barring adverse events. If significant clinical improvement has not occurred in patients by that time, the patient’s dosage should be increased at 2 week intervals. Based on patient response, dose increases of approximately 0.5 mg/kg/day should be made to a maximum of 4 mg/kg/day.

  Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension, elevations in serum creatinine (≥ 25% above the patient’s pretreatment level), or clinically significant laboratory abnormalities. If dose reduction is not effective in controlling abnormalities, or if the adverse event or abnormality is severe, Cyclosporine Capsules USP MODIFIED should be discontinued (see Special Monitoring of Psoriasis Patients).

  Patients generally show some improvement in the clinical manifestations of psoriasis in 2 weeks. Satisfactory control and stabilization of the disease may take 12 to 16 weeks to achieve. Results of a dose-titration clinical trial with Cyclosporine Capsules USP MODIFIED indicate that an improvement of psoriasis by 75% or more (based on PASI) was achieved in 51% of the patients after 8 weeks and in 79% of the patients after 16 weeks. Treatment should be discontinued if satisfactory response cannot be achieved after 6 weeks at 4 mg/kg/day or the patient’s maximum tolerated dose. Once a patient is adequately controlled and appears stable the dose of Cyclosporine Capsules USP MODIFIED should be lowered, and the patient treated with the lowest dose that maintains an adequate response (this should not necessarily be total clearing of the patient). In clinical trials, cyclosporine doses at the lower end of the recommended dosage range were effective in maintaining a satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day may also be equally effective.

  Upon stopping treatment with cyclosporine, relapse will occur in approximately 6 weeks (50% of the patients) to 16 weeks (75% of the patients). In the majority of patients rebound does not occur after cessation of treatment with cyclosporine. Thirteen cases of transformation of chronic plaque psoriasis to more severe forms of psoriasis have been reported. There were 9 cases of pustular and 4 cases of erythrodermic psoriasis. Long-term experience with Cyclosporine Capsules USP MODIFIED in psoriasis patients is limited and continuous treatment for extended periods greater than one year is not recommended. Alternation with other forms of treatment should be considered in the long-term management of patients with this life long disease.

  Blood Concentration Monitoring in Transplant Patients

  Transplant centers have found blood concentration monitoring of cyclosporine to be an essential component of patient management. Of importance to blood concentration analysis are the type of assay used, the transplanted organ, and other immunosuppressant agents being administered. While no fixed relationship has been established, blood concentration monitoring may assist in the clinical evaluation of rejection and toxicity, dose adjustments, and the assessment of compliance.

  Various assays have been used to measure blood concentrations of cyclosporine. Older studies using a nonspecific assay often cited concentrations that were roughly twice those of the specific assays. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed. Current assay results are also not interchangeable and their use should be guided by their approved labeling. A discussion of the different assay methods is contained in Annals of Clinical Biochemistry 1994;31:420-446. While several assays and assay matrices are available, there is a consensus that parent-compound-specific assays correlate best with clinical events. Of these, HPLC is the standard reference, but the monoclonal antibody RIAs and the monoclonal antibody FPIA offer sensitivity, reproducibility, and convenience. Most clinicians base their monitoring on trough cyclosporine concentrations. Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring (1992) contains a broad discussion of cyclosporine pharmacokinetics and drug monitoring techniques. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.

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• Watson Laboratories, Inc.
  

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  Cyclosporine | Actavis Pharma, Inc.

  

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  CYCLOSPORINE CAPSULES [MODIFIED] (SOFT GELATIN) and CYCLOSPORINE ORAL SOLUTION [MODIFIED]

  Cyclosporine capsules [MODIFIED] and cyclosporine oral solution [MODIFIED] have increased bioavailability in comparison to Sandimmune®* (cyclosporine capsules and cyclosporine oral solution). Cyclosporine [MODIFIED] and Sandimmune®* are not bioequivalent and cannot be used interchangeably without physician supervision.

  The daily dose of cyclosporine [MODIFIED] should always be given in two divided doses (b.i.d.). It is recommended that cyclosporine [MODIFIED] be administered on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of cyclosporine, thus should be avoided.

  Specific Populations
  Renal Impairment in Kidney, Liver and Heart Transplantation Cyclosporine undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatments (See CLINICAL PHARMACOLOGY). However, due to its nephrotoxic potential (See WARNINGS), careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated. (See WARNINGS and PRECAUTIONS)

  Renal Impairment in Rheumatoid Arthritis and Psoriasis Patients with impaired renal function should not receive cyclosporine (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS).

  Hepatic Impairment

  The clearance of cyclosporine may be significantly reduced in severe liver disease patients (See CLINICAL PHARMACOLOGY). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range. (See WARNINGS and PRECAUTIONS)

  Newly Transplanted Patients:

  The initial oral dose of cyclosporine [MODIFIED] can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of cyclosporine [MODIFIED] varies depending on the transplanted organ and the other immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients, the initial oral dose of cyclosporine [MODIFIED] is the same as the initial oral dose of Sandimmune®*. Suggested initial doses are available from the results of a 1994 survey of the use of Sandimmune®* in U.S. transplant centers. The mean ± SD initial doses were 9±3 mg/kg/day for renal transplant patients (75 centers), 8±4 mg/kg/day for liver transplant patients (30 centers), and 7±3 mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses. The cyclosporine [MODIFIED] dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration. (See Blood Concentration Monitoring in Transplant Patients, below.)

  If cyclosporine trough blood concentrations are used, the target range is the same for cyclosporine [MODIFIED] as for Sandimmune®*. Using the same trough concentration target range for cyclosporine [MODIFIED] as for Sandimmune®* results in greater cyclosporine exposure when cyclosporine [MODIFIED] is administered. (See Pharmacokinetics, Absorption.) Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower cyclosporine [MODIFIED] doses may be sufficient as maintenance therapy.

  Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage schedules of prednisone appear to achieve similar results. A representative dosage schedule based on the patient’s weight started with 2 mg/kg/day for the first 4 days tapered to 1 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical situation.

  Conversion from Sandimmune®* (cyclosporine to cyclosporine [MODIFIED] in Transplant Patients:

  In transplanted patients who are considered for conversion to cyclosporine [MODIFIED] from Sandimmune®*, cyclosporine [MODIFIED] should be started with the same daily dose as was previously used with Sandimmune®* (1:1 dose conversion). The cyclosporine [MODIFIED] dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for cyclosporine [MODIFIED] as for Sandimmune®* results in greater cyclosporine exposure when cyclosporine [MODIFIED] is administered. (See Pharmacokinetics, Absorption.) Patients with suspected poor absorption of Sandimmune®* require different dosing strategies. (See Transplant Patients with Poor Absorption of Sandimmune®*). In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance.

  Until the blood trough concentration attains the pre-conversion value, it is strongly recommended that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to cyclosporine [MODIFIED]. In addition, clinical safety parameters such as serum creatinine and blood pressure should be monitored every two weeks during the first two months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, the dosage of cyclosporine [MODIFIED] must be adjusted accordingly.

  Transplant Patients with Poor Absorption of Sandimmune®*:

  Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune®* may have poor or inconsistent absorption of cyclosporine from Sandimmune®*. After conversion to cyclosporine [MODIFIED], patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to cyclosporine [MODIFIED], the cyclosporine blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to cyclosporine [MODIFIED] at doses greater than 10 mg/kg/day. The dose of cyclosporine [MODIFIED] should be titrated individually based on cyclosporine trough concentrations, tolerability, and clinical response. In this population the cyclosporine blood trough concentration should be measured more frequently, at least twice a week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes within the desired range.

  Rheumatoid Arthritis:

  The initial dose of cyclosporine [MODIFIED] is 2.5 mg/kg/day, taken twice daily as a divided (b.i.d.) oral dose. Salicylates, nonsteroidal anti-inflammatory agents, and oral corticosteroids may be continued. (See WARNINGS and PRECAUTIONS: Drug Interactions.) Onset of action generally occurs between 4 and 8 weeks. If insufficient clinical benefit is seen and tolerability is good (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5 to 0.75 mg/kg/day after 8 weeks and again after 12 weeks to a maximum of 4 mg/kg/day. If no benefit is seen by 16 weeks of therapy, cyclosporine [MODIFIED] therapy should be discontinued.

  Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension, elevations in serum creatinine (>30% above patient’s pretreatment level) or clinically significant laboratory abnormalities. (See WARNINGS and PRECAUTIONS.)

  If dose reduction is not effective in controlling abnormalities or if the adverse event or abnormality is severe, cyclosporine [MODIFIED] should be discontinued. The same initial dose and dosage range should be used if cyclosporine [MODIFIED] is combined with the recommended dose of methotrexate. Most patients can be treated with cyclosporine [MODIFIED] doses of 3 mg/kg/day or below when combined with methotrexate doses of up to 15 mg/week. (See CLINICAL PHARMACOLOGY, CLINICAL TRIALS.)

  There is limited long-term treatment data. Recurrence of rheumatoid arthritis disease activity is generally apparent within 4 weeks after stopping cyclosporine.

  Psoriasis:

  The initial dose of cyclosporine [MODIFIED] should be 2.5 mg/kg/day. Cyclosporine [MODIFIED] should be taken twice daily, as a divided (1.25 mg/kg b.i.d.) oral dose. Patients should be kept at that dose for at least 4 weeks, barring adverse events. If significant clinical improvement has not occurred in patients by that time, the patient’s dosage should be increased at 2 week intervals. Based on patient response, dose increases of approximately 0.5 mg/kg/day should be made to a maximum of 4 mg/kg/day.

  Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension, elevations in serum creatinine (> 25% above the patient’s pretreatment level), or clinically significant laboratory abnormalities. If dose reduction is not effective in controlling abnormalities, or if the adverse event or abnormality is severe, cyclosporine [MODIFIED] should be discontinued.  (See Special Monitoring of Psoriasis Patients.)

  Patients generally show some improvement in the clinical manifestations of psoriasis in 2-weeks. Satisfactory control and stabilization of the disease may take 12 to 16 weeks to achieve. Results of a dose-titration clinical trial with cyclosporine [MODIFIED] indicate that an improvement of psoriasis by 75% or more (based on PASI) was achieved in 51% of the patients after 8 weeks and in 79% of the patients after 16 weeks. Treatment should be discontinued if satisfactory response cannot be achieved after 6 weeks at 4 mg/kg/day or the patient’s maximum tolerated dose. Once a patient is adequately controlled and appears stable the dose of cyclosporine [MODIFIED] should be lowered, and the patient treated with the lowest dose that maintains an adequate response (this should not necessarily be total clearing of the patient). In clinical trials, cyclosporine doses at the lower end of the recommended dosage range were effective in maintaining a satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day may also be equally effective.

  Upon stopping treatment with cyclosporine, relapse will occur in approximately 6 weeks (50% of the patients) to 16 weeks (75% of the patients). In the majority of patients rebound does not occur after cessation of treatment with cyclosporine. Thirteen cases of transformation of chronic plaque psoriasis to more severe forms of psoriasis have been reported. There were 9 cases of pustular and 4 cases of erythrodermic psoriasis. Long-term experience with cyclosporine [MODIFIED] in psoriasis patients is limited and continuous treatment for extended periods greater than one year is not recommended. Alternation with other forms of treatment should be considered in the long-term management of patients with this life long disease.

  Cyclosporine oral solution [MODIFIED] — Recommendations for Administration:

  To make cyclosporine oral solution [MODIFIED] more palatable, it should be diluted with orange or apple juice that is at room temperature.  Patients should avoid switching diluents frequently. Grapefruit juice affects metabolism of cyclosporine and should be avoided.  The combination of cyclosporine oral solution [MODIFIED] with milk can be unpalatable.  The effect of milk on the bioavailability of cyclosporine when administered as cyclosporine oral solution [MODIFIED] has not been evaluated.

  Take the prescribed amount of cyclosporine oral solution [MODIFIED] from the container using the dosing syringe supplied, after removal of the protective cover, and transfer the solution to a glass of orange or apple juice.  Stir well and drink at once.  Do not allow diluted oral solution to stand before drinking.  Use a glass container (not plastic).  Rinse the glass with more diluent to ensure that the total dose is consumed.  After use, dry the outside of the dosing syringe with a clean towel and replace the protective cover.  Do not rinse the dosing syringe with water or other cleaning agents.  If the syringe requires cleaning, it must be completely dry before resuming use.

  Blood Concentration Monitoring in Transplant Patients:

  Transplant centers have found blood concentration monitoring of cyclosporine to be an essential component of patient management. Of importance to blood concentration analysis are the type of assay used, the transplanted organ, and other immunosuppressant agents being administered. While no fixed relationship has been established, blood concentration monitoring may assist in the clinical evaluation of rejection and toxicity, dose adjustments, and the assessment of compliance.

  Various assays have been used to measure blood concentrations of cyclosporine. Older studies using a nonspecific assay often cited concentrations that were roughly twice those of the specific assays. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed. Current assay results are also not interchangeable and their use should be guided by their approved labeling. A discussion of the different assay methods is contained in Annals of Clinical Biochemistry 1994;31:420-446. While several assays and assay matrices are available, there is a consensus that parent-compound-specific assays correlate best with clinical events. Of these, HPLC is the standard reference, but the monoclonal antibody RIAs and the monoclonal antibody FPIA offer sensitivity, reproducibility, and convenience. Most clinicians base their monitoring on trough cyclosporine concentrations. Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring (1992) contains a broad discussion of cyclosporine pharmacokinetics and drug monitoring techniques. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.

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  Cyclosporine | Ivax Pharmaceuticals, Inc.

  

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  Cyclosporine Capsules USP MODIFIED, soft gelatin capsules, 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.

  The daily dose of Cyclosporine Capsules USP MODIFIED should always be given in two divided doses (BID). It is recommended that Cyclosporine Capsules USP MODIFIED be administered on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of cyclosporine, thus should be avoided.

  Specific Populations

  Renal Impairment in Kidney, Liver and Heart Transplantation

  Cyclosporine undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatments (see CLINICAL PHARMACOLOGY). However, due to its nephrotoxic potential (see WARNINGS), careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated (see WARNINGS and PRECAUTIONS).

  Renal Impairment in Rheumatoid Arthritis and Psoriasis

  Patients with impaired renal function should not receive cyclosporine (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS).

  Hepatic Impairment

  The clearance of cyclosporine may be significantly reduced in severe liver disease patients (see CLINICAL PHARMACOLOGY). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range (see WARNINGS and PRECAUTIONS).

  Newly Transplanted Patients

  The initial oral dose of Cyclosporine Capsules USP MODIFIED can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of Cyclosporine Capsules USP MODIFIED varies depending on the transplanted organ and the other immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients, the initial oral dose of Cyclosporine Capsules USP MODIFIED is the same as the initial oral dose of Sandimmune® (Cyclosporine Capsules USP). Suggested initial doses are available from the results of a 1994 survey of the use of Sandimmune® (Cyclosporine Capsules USP) in US transplant centers. The mean ± SD initial doses were 9 ± 3 mg/kg/day for renal transplant patients (75 centers), 8 ± 4 mg/kg/day for liver transplant patients (30 centers), and 7 ± 3 mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses. The Cyclosporine Capsules USP MODIFIED dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration (see Blood Concentration Monitoring in Transplant Patients, below). If cyclosporine trough blood concentrations are used, the target range is the same for Cyclosporine Capsules USP MODIFIED as for Sandimmune® (Cyclosporine Capsules USP). Using the same trough concentration target range for Cyclosporine Capsules USP MODIFIED as for Sandimmune® (Cyclosporine Capsules USP) results in greater cyclosporine exposure when Cyclosporine Capsules USP MODIFIED are administered (see Pharmacokinetics, Absorption). Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Cyclosporine Capsules USP MODIFIED doses may be sufficient as maintenance therapy.

  Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage schedules of prednisone appear to achieve similar results. A representative dosage schedule based on the patient’s weight started with 2 mg/kg/day for the first 4 days tapered to 1 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical situation.

  Conversion from Sandimmune® (Cyclosporine Capsules USP) to Cyclosporine Capsules USP MODIFIED in Transplant Patients

  In transplanted patients who are considered for conversion to Cyclosporine Capsules USP MODIFIED from Sandimmune® (Cyclosporine Capsules USP), Cyclosporine Capsules USP MODIFIED should be started with the same daily dose as was previously used with Sandimmune® (Cyclosporine Capsules USP) (1:1 dose conversion). The Cyclosporine Capsules USP MODIFIED dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for Cyclosporine Capsules USP MODIFIED as for Sandimmune® (Cyclosporine Capsules USP) results in greater cyclosporine exposure when Cyclosporine Capsules USP MODIFIED are administered (see Pharmacokinetics, Absorption). Patients with suspected poor absorption of Sandimmune® (Cyclosporine Capsules USP) require different dosing strategies (see Transplant Patients with Poor Absorption of Sandimmune® (Cyclosporine Capsules USP), below). In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance.

  Until the blood trough concentration attains the pre-conversion value, it is strongly recommended that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to Cyclosporine Capsules USP MODIFIED. In addition, clinical safety parameters such as serum creatinine and blood pressure should be monitored every two weeks during the first two months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, the dosage of Cyclosporine Capsules USP MODIFIED must be adjusted accordingly.

  Transplant Patients with Poor Absorption of Sandimmune® (Cyclosporine Capsules USP)

  Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune® (Cyclosporine Capsules USP) may have poor or inconsistent absorption of cyclosporine from Sandimmune® (Cyclosporine Capsules USP). After conversion to Cyclosporine Capsules USP MODIFIED, patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to Cyclosporine Capsules USP MODIFIED, the cyclosporine blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to Cyclosporine Capsules USP MODIFIED at doses greater than 10 mg/kg/day. The dose of Cyclosporine Capsules USP MODIFIED should be titrated individually based on cyclosporine trough concentrations, tolerability, and clinical response. In this population the cyclosporine blood trough concentration should be measured more frequently, at least twice a week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes within the desired range.

  Rheumatoid Arthritis

  The initial dose of Cyclosporine Capsules USP MODIFIED is 2.5 mg/kg/day, taken twice daily as a divided (BID) oral dose. Salicylates, non-steroidal anti-inflammatory agents, and oral corticosteroids may be continued (see WARNINGS and PRECAUTIONS, Drug Interactions). Onset of action generally occurs between 4 and 8 weeks. If insufficient clinical benefit is seen and tolerability is good (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5 to 0.75 mg/kg/day after 8 weeks and again after 12 weeks to a maximum of 4 mg/kg/day. If no benefit is seen by 16 weeks of therapy, Cyclosporine Capsules USP MODIFIED therapy should be discontinued.

  Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension elevations in serum creatinine (30% above patient’s pretreatment level) or clinically significant laboratory abnormalities (see WARNINGS and PRECAUTIONS).

  If dose reduction is not effective in controlling abnormalities or if the adverse event or abnormality is severe, Cyclosporine Capsules USP MODIFIED should be discontinued. The same initial dose and dosage range should be used if Cyclosporine Capsules USP MODIFIED are combined with the recommended dose of methotrexate. Most patients can be treated with Cyclosporine Capsules USP MODIFIED doses of 3 mg/kg/day or below when combined with methotrexate doses of up to 15 mg/week (see CLINICAL PHARMACOLOGY, Clinical Trials).

  There is limited long-term treatment data. Recurrence of rheumatoid arthritis disease activity is generally apparent within 4 weeks after stopping cyclosporine.

  Psoriasis

  The initial dose of Cyclosporine Capsules USP MODIFIED should be 2.5 mg/kg/day. Cyclosporine Capsules USP MODIFIED should be taken twice daily, as a divided (1.25 mg/kg BID) oral dose. Patients should be kept at that dose for at least 4 weeks, barring adverse events. If significant clinical improvement has not occurred in patients by that time, the patient’s dosage should be increased at 2 week intervals. Based on patient response, dose increases of approximately 0.5 mg/kg/day should be made to a maximum of 4 mg/kg/day.

  Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension, elevations in serum creatinine (≥ 25% above the patient’s pretreatment level), or clinically significant laboratory abnormalities. If dose reduction is not effective in controlling abnormalities, or if the adverse event or abnormality is severe, Cyclosporine Capsules USP MODIFIED should be discontinued (see Special Monitoring for Psoriasis Patients).

  Patients generally show some improvement in the clinical manifestations of psoriasis in 2 weeks. Satisfactory control and stabilization of the disease may take 12 to 16 weeks to achieve. Results of a dose-titration clinical trial with Cyclosporine Capsules USP MODIFIED indicate that an improvement of psoriasis by 75% or more (based on PASI) was achieved in 51% of the patients after 8 weeks and in 79% of the patients after 16 weeks. Treatment should be discontinued if satisfactory response cannot be achieved after 6 weeks at 4 mg/kg/day or the patient’s maximum tolerated dose. Once a patient is adequately controlled and appears stable the dose of Cyclosporine Capsules USP MODIFIED should be lowered, and the patient treated with the lowest dose that maintains an adequate response (this should not necessarily be total clearing of the patient). In clinical trials, cyclosporine doses at the lower end of the recommended dosage range were effective in maintaining a satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day may also be equally effective.

  Upon stopping treatment with cyclosporine, relapse will occur in approximately 6 weeks (50% of the patients) to 16 weeks (75% of the patients). In the majority of patients rebound does not occur after cessation of treatment with cyclosporine. Thirteen cases of transformation of chronic plaque psoriasis to more severe forms of psoriasis have been reported. There were 9 cases of pustular and 4 cases of erythrodermic psoriasis. Long-term experience with Cyclosporine Capsules USP MODIFIED in psoriasis patients is limited and continuous treatment for extended periods greater than one year is not recommended. Alternation with other forms of treatment should be considered in the long-term management of patients with this life long disease.

  Blood Concentration Monitoring in Transplant Patients

  Transplant centers have found blood concentration monitoring of cyclosporine to be an essential component of patient management. Of importance to blood concentration analysis are the type of assay used, the transplanted organ, and other immunosuppressant agents being administered. While no fixed relationship has been established, blood concentration monitoring may assist in the clinical evaluation of rejection and toxicity, dose adjustments, and the assessment of compliance.

  Various assays have been used to measure blood concentrations of cyclosporine. Older studies using a nonspecific assay often cited concentrations that were roughly twice those of the specific assays. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed. Current assay results are also not interchangeable and their use should be guided by their approved labeling. A discussion of the different assay methods is contained in Annals of Clinical Biochemistry 1994;31:420-446. While several assays and assay matrices are available, there is a consensus that parent-compound-specific assays correlate best with clinical events. Of these, HPLC is the standard reference, but the monoclonal antibody RIAs and the monoclonal antibody FPIA offer sensitivity, reproducibility, and convenience. Most clinicians base their monitoring on trough cyclosporine concentrations. Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring (1992) contains a broad discussion of cyclosporine pharmacokinetics and drug monitoring techniques. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.

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  Cyclosporine | X-gen Pharmaceuticals, Inc.

  

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  2.1 Dosing for Partial Onset Seizures

  Adults 16 Years and Older
  Initiate treatment with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg. There is no evidence that doses greater than 3000 mg/day confer additional benefit.

  Pediatric Patients
  1 Month to < 6 Months
  Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily). In the clinical trial, the mean daily dose was 35 mg/kg in this age group. The effectiveness of lower doses has not been studied.

  6 Months to < 4 Years
  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily). If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced. In the clinical trial, the mean daily dose was 47 mg/kg in this age group.

  4 Years to < 16 Years
  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced. In the clinical trial, the mean daily dose was 44 mg/kg. The maximum daily dose was 3000 mg/day.

  2.2 Dosing for Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

  Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Increase the dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied.

  2.3 Dosing for Primary Generalized Tonic-Clonic Seizures

  Adults 16 Years and Older
  Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Increase dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been adequately studied.

  Pediatric Patients Ages 6 to <16 Years
  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 20 mg/kg (10 mg/kg twice daily) to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.

  2.4 Switching from Oral Dosing

  When switching from oral levetiracetam, the initial total daily intravenous dosage of levetiracetam should be equivalent to the total daily dosage and frequency of oral levetiracetam.

  2.5 Switching to Oral Dosing

  At the end of the intravenous treatment period, the patient may be switched to Levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous administration.

  2.6 Preparation and Administration Instructions

  Levetiracetam injection is for intravenous use only and should be diluted in 100 mL of a compatible diluent prior to administration. If a smaller volume is required (e.g. pediatric patients), the amount of diluent should be calculated to not exceed a maximum levetiracetam concentration of 15 mg per mL of diluted solution.
  Consideration should also be given to the total daily fluid intake of the patient. Levetiracetam injection should be administered as a 15-minute IV infusion. One vial of levetiracetam injection contains 500 mg levetiracetam (500 mg/5 mL).

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Product with particulate matter or discoloration should not be used.

  Any unused portion of the levetiracetam injection vial contents should be discarded.

  Adults
  See Table 1 for the recommended preparation and administration of levetiracetam injection for adults to achieve a dose of 500 mg, 1000 mg, or 1500 mg.

  Table 1: Preparation And Administration Of Levetiracetam Injection for Adults

  Dose Withdraw Volume Volume of Diluent Infusion Time 500 mg  5 mL (5 mL vial) 100 mL 15 minutes 1000 mg 10 mL (two 5 mL vials) 100 mL 15 minutes 1500 mg 15 mL (three 5 mL vials) 100 mL 15 minutes

   For example, to prepare a 1000 mg dose, dilute 10 mL of levetiracetam injection in 100 mL of a compatible diluent and administer intravenously as a 15-minute infusion.

  Pediatric Patients
  When using levetiracetam injection for pediatric patients, dosing is weight-based (mg per kg).
  The following calculation should be used to determine the appropriate daily dose of levetiracetam injection for pediatric patients:

  equation 1

  2.7 Dosage Adjustments in Adult Patients with Renal Impairment

  Levetiracetam dosing must be individualized according to the patient’s renal function status. Recommended dosage adjustments for adults with renal impairment are shown in Table 2. Information is unavailable for dosage adjustments in pediatric patients with renal impairment. In order to calculate the dose recommended for adult patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated. To do this an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula:

  equation 2

   

  Then CLcr is adjusted for body surface area (BSA) as follows:

  equation 3

  Table 2: Dosage Adjustment Regimen for Adult Patients with Renal Impairment

  Group Creatinine Clearance
  (mL/min/1.73m​2​) Dosage (mg) Frequency  Normal > 80 500 to 1,500 Every 12 h Mild 50 to 80 500 to 1,000 Every 12 h Moderate 30 to 50 250 to 750 Every 12 h Severe < 30 250 to 500 Every 12 h ESRD patients using dialysis                   --     500 to 1,000*     Every 24 h* * Following dialysis, a 250 to 500 mg supplemental dose is recommended
  2.8 Compatibility and Stability

  Levetiracetam injection was found to be physically compatible and chemically stable when mixed with the following diluents and antiepileptic drugs for at least 24 hours and stored in polyvinyl chloride (PVC) bags at controlled room temperature 15-30°C (59-86°F).
  
  Diluents
  Sodium chloride (0.9%) injection, USP
  Lactated Ringer’s injection
  Dextrose 5% injection, USP

  Other Antiepileptic Drugs
  Lorazepam
  Diazepam
  Valproate sodium

  There is no data to support the physical compatibility of levetiracetam injection with antiepileptic drugs that are not listed above.

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  Cyclosporine | Hot Shots Nm, Llc Dba Midwest Positron Technology, Lc

  

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  Fludeoxyglucose F18 Injection emits radiation. Use procedures to minimize radiation exposure. Calculate the final dose from the end of synthesis (EOS) time using proper radioactive decay factors. Assay the final dose in a properly calibrated dose calibrator before administration to the patient [see Description(11.2)].

  2.1 Recommended Dose for Adults

  Within the oncology, cardiology and neurology settings, the recommended dose for adults is 5 – 10 mCi (185 – 370 MBq) as an intravenous injection.

  2.2 Recommended Dose for Pediatric Patients

  Within the neurology setting, the recommended dose for pediatric patients is 2.6 mCi, as an intravenous injection. The optimal dose adjustment on the basis of body size or weight has not been determined [see Use in Special Populations(8.4)].

  2.3 Patient Preparation To minimize the radiation absorbed dose to the bladder, encourage adequate hydration. Encourage the patient to drink water or other fluids (as tolerated) in the 4 hours before their PET study. Encourage the patient to void as soon as the imaging study is completed and as often as possible thereafter for at least one hour. Screen patients for clinically significant blood glucose abnormalities by obtaining a history and/or laboratory tests [see Warnings and Precautions(5.2)]. Prior to Fludeoxyglucose F 18 PET imaging in the oncology and neurology settings, instruct patient to fast for 4 – 6 hours prior to the drug’s injection. In the cardiology setting, administration of glucose-containing food or liquids (e.g., 50 – 75 grams) prior to Fludeoxyglucose F 18 Injection facilitates localization of cardiac ischemia. 2.4 Radiation Dosimetry

  The estimated human absorbed radiation doses (rem/mCi) to a newborn (3.4 kg), 1-year old (9.8 kg), 5-year old (19 kg), 10-year old (32 kg), 15-year old (57 kg), and adult (70 kg) from intravenous administration of Fludeoxyglucose F 18 Injection are shown in Table 1. These estimates were calculated based on human2 data and using the data published by the International Commission on Radiological Protection4 for Fludeoxyglucose 18F. The dosimetry data show that there are slight variations in absorbed radiation dose for various organs in each of the age groups. These dissimilarities in absorbed radiation dose are due to developmental age variations (e.g., organ size, location, and overall metabolic rate for each age group). The identified critical organs (in descending order) across all age groups evaluated are the urinary bladder, heart, pancreas, spleen, and lungs.

  Table 1. Estimated Absorbed Radiation Doses (rem/mCi) After Intravenous Administration of Fludeoxyglucose F 18 Injection * Organ Newborn
  (3.4 kg) 1-year old
  (9.8 kg) 5-year old
  (19 kg) 10-year old
  (32 kg) 15-year old
  (57 kg) Adult
  (70 kg) * MIRDOSE 2 software was used to calculate the radiation absorbed dose. Assumptions on the biodistribution based on data from Gallagher et al.1 and Jones et al.2 † The dynamic bladder model with a uniform voiding frequency of 1.5 hours was used. ‡ LLI = lower large intestine; § ULI = upper large intestine Bladder wall† 4.3 1.7 0.93 0.60 0.40 0.32 Heart wall 2.4 1.2 0.70 0.44 0.29 0.22 Pancreas 2.2 0.68 0.33 0.25 0.13 0.096 Spleen 2.2 0.84 0.46 0.29 0.19 0.14 Lungs 0.96 0.38 0.20 0.13 0.092 0.064 Kidneys 0.81 0.34 0.19 0.13 0.089 0.074 Ovaries 0.80 0.8 0.19 0.11 0.058 0.053 Uterus 0.79 0.35 0.19 0.12 0.076 0.062 LLI wall‡ 0.69 0.28 0.15 0.097 0.060 0.051 Liver 0.69 0.31 0.17 0.11 0.076 0.058 Gallbladder wall 0.69 0.26 0.14 0.093 0.059 0.049 Small intestine 0.68 0.29 0.15 0.096 0.060 0.047 ULI wall§ 0.67 0.27 0.15 0.090 0.057 0.046 Stomach wall 0.65 0.27 0.14 0.089 0.057 0.047 Adrenals 0.65 0.28 0.15 0.095 0.061 0.048 Testes 0.64 0.27 0.14 0.085 0.052 0.041 Red marrow 0.62 0.26 0.14 0.089 0.057 0.047 Thymus 0.61 0.26 0.14 0.086 0.056 0.044 Thyroid 0.61 0.26 0.13 0.080 0.049 0.039 Muscle 0.58 0.25 0.13 0.078 0.049 0.039 Bone surface 0.57 0.24 0.12 0.079 0.052 0.041 Breast 0.54 0.22 0.11 0.068 0.043 0.034 Skin 0.49 0.20 0.10 0.060 0.037 0.030 Brain 0.29 0.13 0.09 0.078 0.072 0.070 Other tissues 0.59 0.25 0.13 0.083 0.052 0.042 2.5 Radiation Safety – Drug Handling Use waterproof gloves, effective radiation shielding, and appropriate safety measures when handling Fludeoxyglucose F18 Injection to avoid unnecessary radiation exposure to the patient, occupational workers, clinical personnel and other persons. Radiopharmaceuticals should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radionuclides, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides. Calculate the final dose from the end of synthesis (EOS) time using proper radioactive decay factors. Assay the final dose in a properly calibrated dose calibrator before administration to the patient [see Description (11.2)]. The dose of Fludeoxyglucose F18 used in a given patient should be minimized consistent with the objectives of the procedure, and the nature of the radiation detection devices employed. 2.6 Drug Preparation and Administration Calculate the necessary volume to administer based on calibration time and dose. Aseptically withdraw Fludeoxyglucose F18 Injection from its container. Inspect Fludeoxyglucose F18 Injection visually for particulate matter and discoloration before administration, whenever solution and container permit. Do not administer the drug if it contains particulate matter or discoloration; dispose of these unacceptable or unused preparations in a safe manner, in compliance with applicable regulations. Use Fludeoxyglucose F 18 Injection within 12 hours from the EOS. 2.7 Imaging Guidelines Initiate imaging within 40 minutes following Fludeoxyglucose F 18 Injection administration. Acquire static emission images 30 – 100 minutes from the time of injection.

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  Cyclosporine | Eon Labs, Inc.

  

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  Cyclosporine capsules (modified) have increased bioavailability in comparison to Sandimmune®. Cyclosporine capsules (modified) and Sandimmune® are not bioequivalent and cannot be used interchangeably without physician supervision.

  The daily dose of cyclosporine capsules (modified) should always be given in two divided doses (BID). It is recommended that cyclosporine capsules (modified) be administered on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of cyclosporine, thus should be avoided.

  Newly Transplanted Patients

  The initial oral dose of cyclosporine capsules (modified) can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of cyclosporine capsules (modified) varies depending on the transplanted organ and the other immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients, the initial oral dose of cyclosporine capsules (modified) is the same as the initial oral dose of Sandimmune®. Suggested initial doses are available from the results of a 1994 survey of the use of Sandimmune® in US transplant centers. The mean ± SD initial doses were 9±3 mg/kg/day for renal transplant patients (75 centers), 8±4 mg/kg/day for liver transplant patients (30 centers), and 7±3 mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses. The cyclosporine capsules (modified) dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration (see DOSAGE AND ADMINISTRATION,Blood Concentration Monitoring in Transplant Patients, below). If cyclosporine trough blood concentrations are used, the target range is the same for cyclosporine capsules (modified) as for Sandimmune®. Using the same trough concentration target range for cyclosporine capsules (modified) as for Sandimmune® results in greater cyclosporine exposure when cyclosporine capsules (modified) are administered (see CLINICAL PHARMACOLOGY, Pharmacokinetics,Absorption).Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower cyclosporine capsules (modified) doses may be sufficient as maintenance therapy.

  Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage schedules of prednisone appear to achieve similar results. A representative dosage schedule based on the patient’s weight started with 2.0 mg/kg/day for the first 4 days tapered to 1.0 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical situation.

  Conversion from Sandimmune® to Cyclosporine Capsules (Modified) in Transplant Patients

  In transplanted patients who are considered for conversion to cyclosporine capsules (modified) from Sandimmune®, cyclosporine capsules (modified) should be started with the same daily dose as was previously used with Sandimmune® (1:1 dose conversion). The cyclosporine capsules (modified) dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for cyclosporine capsules (modified) as for Sandimmune® results in greater cyclosporine exposure when cyclosporine capsules (modified) are administered (see CLINICAL PHARMACOLOGY, Pharmacokinetics,Absorption). Patients with suspected poor absorption of Sandimmune® require different dosing strategies (see DOSAGE AND ADMINISTRATION,Transplant Patients with Poor Absorption of Sandimmune®, below). In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance.

  Until the blood trough concentration attains the pre-conversion value, it is strongly recommended that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to cyclosporine capsules (modified). In addition, clinical safety parameters such as serum creatinine and blood pressure should be monitored every two weeks during the first two months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, the dosage of cyclosporine capsules (modified) must be adjusted accordingly.

  Transplant Patients with Poor Absorption of Sandimmune®

  Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune® may have poor or inconsistent absorption of cyclosporine from Sandimmune®. After conversion to cyclosporine capsules (modified), patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to cyclosporine capsules (modified), the cyclosporine blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to cyclosporine capsules (modified) at doses greater than 10 mg/kg/day. The dose of cyclosporine capsules (modified) should be titrated individually based on cyclosporine trough concentrations, tolerability, and clinical response. In this population the cyclosporine blood trough concentration should be measured more frequently, at least twice a week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes within the desired range.

  Rheumatoid Arthritis

  The initial dose of cyclosporine capsules (modified) is 2.5 mg/kg/day, taken twice daily as a divided (BID) oral dose. Salicylates, nonsteroidal anti-inflammatory agents and oral corticosteroids may be continued (see WARNINGS and PRECAUTIONS, Drug Interactions). Onset of action generally occurs between 4 and 8 weeks. If insufficient clinical benefit is seen and tolerability is good (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5 mg/kg/day to 0.75 mg/kg/day after 8 weeks and again after 12 weeks to a maximum of 4 mg/kg/day. If no benefit is seen by 16 weeks of therapy, cyclosporine capsules (modified) therapy should be discontinued.

  Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension elevations in serum creatinine (30% above patient’s pretreatment level) or clinically significant laboratory abnormalities (see WARNINGS and PRECAUTIONS).

  If dose reduction is not effective in controlling abnormalities or if the adverse event or abnormality is severe, cyclosporine capsules (modified) should be discontinued. The same initial dose and dosage range should be used if cyclosporine capsules (modified) are combined with the recommended dose of methotrexate. Most patients can be treated with cyclosporine capsules (modified) doses of 3 mg/kg/day or below when combined with methotrexate doses of up to 15 mg/week (see CLINICAL PHARMACOLOGY, CLINICAL TRIALS).

  There is limited long-term treatment data. Recurrence of rheumatoid arthritis disease activity is generally apparent within 4 weeks after stopping cyclosporine.

  Psoriasis

  The initial dose of cyclosporine capsules (modified) should be 2.5 mg/kg/day. Cyclosporine capsules (modified) should be taken twice daily, as a divided (1.25 mg/kg BID) oral dose. Patients should be kept at that dose for at least 4 weeks, barring adverse events. If significant clinical improvement has not occurred in patients by that time, the patient’s dosage should be increased at 2-week intervals. Based on patient response, dose increases of approximately 0.5 mg/kg/day should be made to a maximum of 4.0 mg/kg/day.

  Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension, elevations in serum creatinine (≥25% above the patient’s pretreatment level), or clinically significant laboratory abnormalities. If dose reduction is not effective in controlling abnormalities or if the adverse event or abnormality is severe, cyclosporine capsules (modified) should be discontinued (see PRECAUTIONS, Special Monitoring for Psoriasis Patients).

  Patients generally show some improvement in the clinical manifestations of psoriasis in 2 weeks. Satisfactory control and stabilization of the disease may take 12 to 16 weeks to achieve. Results of a dose-titration clinical trial with cyclosporine capsules (modified) indicate that an improvement of psoriasis by 75% or more (based on PASI) was achieved in 51% of the patients after 8 weeks and in 79% of the patients after 16 weeks. Treatment should be discontinued if satisfactory response cannot be achieved after 6 weeks at 4 mg/kg/day or the patient’s maximum tolerated dose. Once a patient is adequately controlled and appears stable the dose of cyclosporine capsules (modified) should be lowered, and the patient treated with the lowest dose that maintains an adequate response (this should not necessarily be total clearing of the patient). In clinical trials, cyclosporine doses at the lower end of the recommended dosage range were effective in maintaining a satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day may also be equally effective.

  Upon stopping treatment with cyclosporine, relapse will occur in approximately 6 weeks (50% of the patients) to 16 weeks (75% of the patients). In the majority of patients rebound does not occur after cessation of treatment with cyclosporine. Thirteen cases of transformation of chronic plaque psoriasis to more severe forms of psoriasis have been reported. There were 9 cases of pustular and 4 cases of erythrodermic psoriasis. Long term experience with cyclosporine capsules (modified) in psoriasis patients is limited and continuous treatment for extended periods greater than one year is not recommended. Alternation with other forms of treatment should be considered in the long term management of patients with this life long disease.

  Blood Concentration Monitoring in Transplant Patients

  Transplant centers have found blood concentration monitoring of cyclosporine to be an essential component of patient management. Of importance to blood concentration analysis are the type of assay used, the transplanted organ, and other immunosuppressant agents being administered. While no fixed relationship has been established, blood concentration monitoring may assist in the clinical evaluation of rejection and toxicity, dose adjustments, and the assessment of compliance.

  Various assays have been used to measure blood concentrations of cyclosporine. Older studies using a nonspecific assay often cited concentrations that were roughly twice those of the specific assays. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed. Current assay results are also not interchangeable and their use should be guided by their approved labeling. A discussion of the different assay methods is contained in Annals of Clinical Biochemistry 1994;31:420-446. While several assays and assay matrices are available, there is a consensus that parent-compound-specific assays correlate best with clinical events. Of these, HPLC is the standard reference, but the monoclonal antibody RIAs and the monoclonal antibody FPIA offer sensitivity, reproducibility, and convenience. Most clinicians base their monitoring on trough cyclosporine concentrations. Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring (1992) contains a broad discussion of cyclosporine pharmacokinetics and drug monitoring techniques. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.

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