Usual Adult Dose for Organ Transplant - Rejection Prophylaxis

FOR PATIENTS AT LOW TO MODERATE IMMUNOLOGIC RISK:
Dosing by body weight:

• Less than 40 kg:

Loading dose: 3 mg/m2 on day 1
Maintenance: 1 mg/m2 once daily

• Greater than or equal to 40 kg:

Loading dose: 6 mg orally on day 1
Maintenance: 2 mg orally once daily

IN PATIENTS AT HIGH IMMUNOLOGIC RISK (defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high-panel reactive antibodies [PRA; peak PRA level greater than 80%]):

• For patients receiving sirolimus with cyclosporine:

Loading Dose: Up to 15 mg on day one post-transplantation
Maintenance Dose: Beginning on day 2, an initial maintenance dose of 5 mg/day should be given. A trough level should be obtained between days 5 and 7, and the daily dose of sirolimus should be adjusted thereafter.

• Antibody induction therapy may be used.

Comments:

• It is recommended that this sirolimus be used in a regimen with cyclosporine and corticosteroids.
• Sirolimus should be taken consistently with or without food.
• Once the sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring.

MAINTENANCE THERAPY AFTER WITHDRAWAL OF CYCLOSPORINE:

• Cyclosporine withdrawal is not recommended in high-immunological risk patients. Following 2 to 4 months of combined therapy, withdrawal of cyclosporine may be considered in low-to-moderate risk patients. Cyclosporine should be discontinued over 4 to 8 weeks, and a necessary increase in the dosage of sirolimus (up to 4-fold) should be anticipated due to removal of metabolic inhibition by cyclosporine and to maintain adequate immunosuppressive effects. -Dose-adjusted trough target concentrations are typically 16 to 24 ng/mL for the first year post-transplant and 12 to 20 ng/mL thereafter (measured by chromatographic methodology).

Use:

• As an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplant.

Usual Adult Dose for Pulmonary Lymphangioleiomyomatosis

• Initial dose: 2 mg/day
• Sirolimus whole blood trough concentrations should be measured in 10 to 20 days, with dosage adjustment to maintain concentrations between 5 and 15 ng/mL.

Comment:

• This drug should be taken consistently with or without food.

General Use:

• For the treatment of patients with lymphangioleiomyomatosis

Usual Pediatric Dose for Organ Transplant - Rejection Prophylaxis

FOR PATIENTS AT LOW TO MODERATE IMMUNOLOGIC RISK:
Greater than or equal to 13 years of age:
Dosing by body weight:

• Less than 40 kg:

Loading dose: 3 mg/m2 on day 1
Maintenance: 1 mg/m2 once daily

• Greater than or equal to 40 kg:

Loading dose: 6 mg orally on day 1
Maintenance: 2 mg orally once daily

Use:

• As an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplant.

Renal Dose Adjustments

No dosage adjustment is necessary in loading or maintenance dose. However, adjustment of the regimen (including discontinuation of therapy) should be considered when used concurrently with cyclosporine and elevated or increasing serum creatinine is noted.

Liver Dose Adjustments

Loading dose: No adjustment required
Maintenance dose:

• Mild-to-moderate hepatic impairment: Reduce maintenance dose by approximately 33%
• Severe hepatic impairment: Reduce maintenance dose by approximately 50%

Dose Adjustments

• Sirolimus dosages should be adjusted to maintain trough concentrations within the desired range based on risk and concomitant therapy. Maximum daily dose: 40 mg. The dosage should be adjusted at intervals of 7 to 14 days to account for the long half-life of sirolimus. In general, dose proportionality may be assumed. The new sirolimus dose equals current dose multiplied by (target concentration/current concentration).
• If a large dose increase is required, consider loading dose calculated as:

Loading dose equals (new maintenance dose minus current maintenance dose) multiplied by 3.

• Maximum dose in one day: 40 mg
• If the required dose is greater than 40 mg (due to loading dose), then the dose should be divided over 2 days. Serum concentrations should not be used as the sole basis for dosage adjustment. Clinical signs/symptoms, tissue biopsy, and laboratory parameters should also be monitored.

Precautions

US BOXED WARNINGS:

• IMMUNOSUPPRESSION: Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use this drug for prophylaxis of organ rejection in patients receiving renal transplants.
• USE IS NOT RECOMMENDED IN LIVER OR LUNG TRANSPLANT PATIENTS: The safety and efficacy of this drug as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended:
• Liver Transplantation: Excess mortality, graft loss, and hepatic artery thrombosis
• Lung Transplantation: Bronchial anastomotic dehiscence

NARROW THERAPEUTIC INDEX:

• This drug should be considered a narrow therapeutic index (NTI) drug as small differences in dose or blood concentrations may lead to serious therapeutic failures or adverse drug reactions.

Recommendations:

• Generic substitution should be done cautiously, if at all, as current bioequivalence standards are generally insufficient for NTI drugs.
• Additional and/or more frequent monitoring should be done to ensure receipt of an effective dose while avoiding unnecessary toxicities.

The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant population has not been established.

Safety and efficacy have not been established in patients less than 13 years old, or in pediatric (less than 18 years) renal transplant patients considered at high-immunologic risk.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• This drug should be administered as soon as possible after transplantation.
• Tablets should be swallowed whole and not crushed, chewed, or split.
• This drug should be taken consistently with or without food. Patients unable to take the oral tablets should be prescribed the oral solution.
• It is recommended that this drug be taken 4 hours after administration of cyclosporine.
• This drug should not be taken with grapefruit juice.

General:

• The oral solution may develop a slight haze when refrigerated; however, this does not affect the quality of the drug and may be remedied by allowing the bottle to stand at room temperature and then shaking gently until the haze disappears.
• The 24 hour trough concentration ranges recommended by the manufacturer are based on chromatographic methods and are not interchangeable with immunoassay methods.
• The oral solution should not be emptied into a plastic, paper or polystyrene cup. The dosing syringe should be used to withdraw the prescribed dose from the bottle, emptied from the syringe into a glass container with at least 60 mL of water or orange juice, stirred vigorously, and then drunk immediately. The glass container should then be refilled with at least 120 mL of water or orange juice, stirred vigorously, and drunk immediately. A new dosing syringe should be used for each dose. The oral solution produces a white to off-white dispersion when it is mixed with water or orange juice.
• The tablets and oral solution are not bioequivalent due to differences in absorption. However, clinical equivalence has been demonstrated at the 2 mg dose level.
• It is recommended that sirolimus be taken 4 hours after administration of cyclosporine oral solution and/or cyclosporine capsules.
• The sirolimus dose should be individualized, to obtain whole blood trough levels of 4 to 12 ng/mL.
• In patients at low to moderate immunological risk, it is recommended that this drug be used initially in a regimen with cyclosporine and corticosteroids. Cyclosporine should be withdrawn 2 to 4 months after transplantation and the sirolimus dose should be increased to reach recommended blood concentrations.
• The safety and efficacy of cyclosporine withdrawal in high risk patients have not been adequately studied and therefore is not recommended. This high risk group includes patients with Banff grade III acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis dependent, or with serum creatinine greater than 4.5 mg/dL, black patients, retransplants, multi-organ transplants, and patients with a high panel of reactive antibodies. The duration of cyclosporine and sirolimus coadministration should not exceed 3 months, after which immunosuppressant treatment should be initiated.

Storage requirements:

• The oral solution should be stored at 2 to 8 degrees C (36 to 46 degrees F). Unused contents should be discarded one month after opening. A dose drawn up in a dosing syringe may be kept at room temperature up to 25 degrees C (77 degrees F) or refrigerated at 2 to 8 degrees C (36 to 46 degrees F) in the dosing syringe for up to 24 hours. However, it should be used immediately after dilution.
• Antimicrobial prophylaxis against cytomegalovirus (CMV) should be administered for 3 months, and Pneumocystis jiroveci infections for 1 year post-transplant.

Monitoring:

• Monitoring of triglycerides and cholesterol should be included as part of routine post-transplant patient management.
• Blood sirolimus levels should be monitored in pediatric patients, patients with hepatic impairment, and/or if cyclosporine dosing is markedly reduced or discontinued.