Usual Adult Dose for Organ Transplant - Rejection Prophylaxis

ORAL FORMULATION (MODIFIED):

• Note: The dose is dependent upon type of transplant and formulation; refer to local protocol for specific dosing.
• Initial dose: Give 4 to 12 hours prior to transplantation or postoperatively; the initial dose varies depending on the organ and concomitant immunosuppressives.

NEWLY TRANSPLANTED PATIENTS:

• Renal: 9 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses
• Liver: 8 mg/kg/day (plus or minus 4 mg/kg/day) orally in 2 divided doses
• Heart: 7 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses

COMMENTS:

• The initial dose of this drug varies depending on the transplanted organ and the other immunosuppressive agents included in the protocol.
• In newly transplanted patients, the initial oral dose is the same as the initial oral dose of the non-modified formulation.
• Titrate the dose based on rejection and tolerability.
• Lower doses of the modified formulation may be sufficient as maintenance therapy.
• Adjunct therapy with adrenal corticosteroids is recommended initially. Consult local protocol and/or manufacturer product information.

ORAL FORMULATION (NON-MODIFIED):
NOTE: The dosing presented here is to be used as a guideline only. Local protocol should be consulted for specific dosing. Dosing in clinical practice may be very different than the manufacturer labeling. Non-modified formulations have decreased bioavailability in comparison to modified formulations. Modified and non-modified formulations are not bioequivalent and cannot be used interchangeably without physician supervision.
Manufacturer recommendation:

• Initial dose: 15 mg/kg orally 4 to 12 hours prior to transplantation; although a single dose of 14 to 18 mg/kg was used in most clinical trials, most clinicians favor the lower end of the scale; lower initial doses are usually used for renal transplantation in the ranges of 10 to 14 mg/kg/day
• Maintenance dose: 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 clinicians prefer to reduce the maintenance dose to 3 mg/kg/day in some renal transplant patients without an apparent rise in rejection rate

PARENTERAL FORMULATION:

• Note: Local protocol should be consulted for dosing recommendations.

Manufacturer suggested dosing:

• Initial dose: 5 to 6 mg/kg/day IV (or one-third of the oral dose) as a single dose infused over 2 to 6 hours given 4 to 12 hours prior to transplantation
• Maintenance dose: 5 to 6 mg/kg/day IV continued postoperatively until the patient can tolerate capsules or oral solution

COMMENTS:

• Due to the risk of anaphylaxis, the IV formulation should be reserved for patients who are unable to take the oral formulation.
• Adjunct steroid therapy should be used with this drug.

Uses: For the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants concomitantly with adrenal corticosteroids and in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents

Usual Adult Dose for Rheumatoid Arthritis

ORAL FORMULATION (MODIFIED):

• Initial dose: 1.25 mg/kg orally 2 times a day; onset of action usually occurs between 4 and 8 weeks
• Titration: If insufficient benefit is seen and tolerability is good at the initial dose (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
• Maximum dose: 4 mg/kg/day orally in 2 divided doses; if no benefit is seen by 16 weeks, therapy should be discontinued

COMMENTS:

• Salicylates, nonsteroidal anti-inflammatory agents, and oral corticosteroids may be continued concomitantly with this drug.
• 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 pretreatment level), or significant laboratory abnormalities.
• Most patients can be treated with the modified formulation at doses of 3 mg/kg/day or below when combined with methotrexate doses of up to 15 mg/week.

Use: For severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate; this drug can be used in combination with methotrexate in rheumatoid arthritis patients who do not respond adequately to methotrexate alone

Usual Adult Dose for Psoriasis

ORAL FORMULATION (MODIFIED):

• Initial dose: 1.25 mg/kg orally 2 times a day for at least 4 weeks
• Titration: If insufficient benefit is seen at 4 weeks and tolerability is good at the initial dose, the dose may be increased by 0.5 mg/kg/day at 2-week intervals based on patient response.
• Maximum dose: 4 mg/kg/day in 2 divided doses
• Note: Doses below 2.5 mg/kg/day may also be effective.

COMMENTS:

• Dose decreases by 25% to 50% should be made at any time for adverse events (e.g., hypertension, elevations in serum creatinine greater than or equal to 25% above pretreatment level), or significant laboratory abnormalities. Discontinue therapy if dose reduction is not effective.
• Improvement is usually seen in 2 weeks; stabilization may take 12 to 16 weeks.
• Discontinue therapy if a satisfactory response cannot be achieved after 6 weeks at 4 mg/kg/day or the maximum tolerated dose.
• When a patient appears stable the dose should be lowered, and the patient treated with the lowest dose that maintains an adequate response (not necessarily a complete response).
• Doses at the lower end of the recommended range are effective in maintaining a satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day may also be effective.
• Most patients will experience relapse of their psoriasis upon cessation of therapy.
• Long term experience in psoriasis patients is limited; therefore, therapy beyond one year is not recommended. Alternating with other forms of therapy should be considered in the long-term management of psoriasis.

Use: For nonimmunocompromised patients with severe (i.e., extensive and/or disabling), recalcitrant, plaque psoriasis who have failed to respond to at least one systemic therapy (e.g., PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated

Usual Pediatric Dose for Organ Transplant - Rejection Prophylaxis

The same dose and dosing regimen may be used in children as in adults although in several studies, children have required and tolerated higher doses than adults. Consult the manufacturer product information/and or local protocol.

ORAL FORMULATION (MODIFIED):
1 year and older:

• Note: The dose is dependent upon type of transplant and formulation; refer to local protocol for specific dosing.
• Initial dose: Give 4 to 12 hours prior to transplantation or postoperatively; the initial dose varies depending on the organ and concomitant immunosuppressives.

NEWLY TRANSPLANTED PATIENTS:

• Renal: 9 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses
• Liver: 8 mg/kg/day (plus or minus 4 mg/kg/day) orally in 2 divided doses
• Heart: 7 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses

COMMENTS:

• The initial dose of this drug varies depending on the transplanted organ and the other immunosuppressive agents included in the protocol.
• In newly transplanted patients, the initial oral dose is the same as the initial oral dose of the non-modified formulation.
• Titrate the dose based on rejection and tolerability.
• Lower doses of the modified formulation may be sufficient as maintenance therapy.
• Adjunct therapy with adrenal corticosteroids is recommended initially. Consult local protocol and/or manufacturer product information.

ORAL FORMULATION (NON-MODIFIED):
6 months and older:
NOTE: The dosing presented here is to be used as a guideline only. Local protocol should be consulted for specific dosing. Dosing in clinical practice may be very different than the manufacturer labeling. Non-modified formulations have decreased bioavailability in comparison to modified formulations. Modified and non-modified formulations are not bioequivalent and cannot be used interchangeably without physician supervision.
Manufacturer recommendation:

• Initial dose: 15 mg/kg orally 4 to 12 hours prior to transplantation; although a single dose of 14 to 18 mg/kg was used in most clinical trials, most clinicians favor the lower end of the scale; lower initial doses are usually used for renal transplantation in the ranges of 10 to 14 mg/kg/day
• Maintenance dose: 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 clinicians prefer to reduce the maintenance dose to 3 mg/kg/day in some renal transplant patients without an apparent rise in rejection rate

PARENTERAL FORMULATION:
6 months and older:

• Note: Local protocol should be consulted for dosing recommendations.

Manufacturer suggested dosing:

• Initial dose: 5 to 6 mg/kg/day IV (or one-third of the oral dose) as a single dose infused over 2 to 6 hours given 4 to 12 hours prior to transplantation
• Maintenance dose: 5 to 6 mg/kg/day IV continued postoperatively until the patient can tolerate capsules or oral solution

COMMENTS:

• Due to the risk of anaphylaxis, the IV formulation should be reserved for patients who are unable to take the oral formulation.
• Adjunct steroid therapy should be used with this drug.

Uses: For the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants concomitantly with adrenal corticosteroids and in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents

Renal Dose Adjustments

• Rheumatoid arthritis or psoriasis patients with abnormal renal function: Contraindicated
• Careful monitoring of blood or plasma concentrations of this drug is necessary to avoid exacerbation of renal impairment.

Liver Dose Adjustments

• Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range
• Due to decreased plasma clearance of this drug in patients with liver disease, plasma or blood concentrations should be monitored closely and dose adjustments made as necessary.

Dose Adjustments

CONVERSION FROM THE NON-MODIFIED FORMULATION TO THE MODIFIED FORMULATION IN TRANSPLANT PATIENTS:

• Start the modified formulation with the same daily dose as the non-modified formulation. Adjust the dose of the modified formulation to attain the pre-conversion cyclosporine blood trough concentration. Patients who absorb the non-modified formulation poorly require different dosing strategies
• The blood trough concentration should be monitored every 5 to 7 days until the it attains the pre-conversion value.
• Parameters such as serum creatinine and blood pressure should be monitored every 2 weeks during the first 2 months after conversion.
• If blood trough concentrations are outside the desired range and/or if the safety parameters worsen, adjust the dose of the modified formulation accordingly.

TRANSPLANT PATIENTS WHO ABSORB THE NON-MODIFIED FORMULATION POORLY:

• Patients with lower than expected blood trough concentrations in relation to the oral dose of the non-modified formulation may have poor or inconsistent absorption.
• After conversion to the modified formulation, patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability following conversion to the modified formulation, the cyclosporine blood trough concentration may exceed the target range. Caution should be exercised when converting patients to the modified formulation at doses greater than 10 mg/kg/day; the dose should be titrated individually based on trough concentrations, tolerability, and clinical response. In this population, the blood trough concentration should be measured more frequently, at least 2 times a week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes.

See Black Box Warning in Precaution Section: NON-MODIFIED/MODIFIED FORMULATION

Precautions

US BOXED WARNINGS:

• Only physicians experienced in management of systemic immunosuppressive therapy should prescribe this drug.
• Patients should be managed in facilities with laboratory and supportive medical resources.
• The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.
• Immunosuppressants may increase the susceptibility to infection and the development of neoplasia; the increased degree of immunosuppression in transplant patients may put this population at a greater risk.
• Psoriasis patients previously treated with PUVA and to a lesser extent, methotrexate or other immunosuppressive agents, UVB, coal tar, or radiation therapy, are at an increased risk of developing skin malignancies when taking this drug.
• This drug can cause systemic hypertension and nephrotoxicity. The risk increases with increasing dose and duration of therapy. Renal dysfunction, including structural kidney damage, is a potential consequence of cyclosporine, and therefore, renal function must be monitored during therapy.

NON-MODIFIED/MODIFIED FORMULATION:

• The non-modified formulation should be administered with adrenal corticosteroids but not with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.
• The non-modified formulation has decreased bioavailability in comparison to the modified formulation.
• The absorption of cyclosporine during chronic administration of the non-modified formulation is erratic. Patients taking this formulation over a prolonged time should be monitored at intervals for cyclosporine blood concentrations and dose adjustments should be made to avoid toxicity due to high concentrations and possible organ rejection due to low absorption of the drug. This is especially important in liver transplants.
• The non-modified formulation and the modified formulation are not bioequivalent and cannot be used interchangeably without physician supervision.
• The modified formulation has increased bioavailability in comparison to the non-modified formulation. For a given trough concentration, cyclosporine exposure will be greater with the modified formulation than with the non-modified formulation. If a patient who is receiving exceptionally high doses of the non-modified formulation is converted to the modified formulation, caution should be exercised. Cyclosporine blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking the modified formulation to avoid toxicity due to high concentrations. Dose adjustments should be made in transplant patients to minimize possible organ rejection due to low concentrations.

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.

• Safety and efficacy of the modified formulation have not been established in patients younger than 1 year for transplant.
• Safety and efficacy of the non-modified formulation have not been established in patients younger than 6 months for transplant.
• Safety and efficacy have not been established in patients younger than 18 years for juvenile rheumatoid arthritis or psoriasis.

Consult WARNINGS section for additional precautions.

Dialysis

Neither dialysis nor renal failure alters the clearance of this drug significantly.

Other Comments

Administration advice:

• The oral formulation should be administered in 2 divided doses, with a mouthful of water, and swallowed whole.
• The oral solution should be diluted and stirred with water, orange juice, squash, or apple juice immediately prior to administration. The measuring device should not come into contact with the diluent and it should not be rinsed with water, alcohol, or any other liquid. The outside of the measuring device may be wiped with a dry tissue. Grapefruit and grapefruit juice should not be used as a diluent for the oral solution or ingested for one hour prior to administration because it increases the bioavailability of this drug.

General:

• The polyoxyethylated castor oil contained in the IV formulation can cause phthalate stripping from PVC.
• Active Herpes simplex infections should be permitted to clear prior to initiating therapy.
• The IV dose is approximately one-third of the recommended oral dose.
• Transferring or switching between different oral formulations of this drug is not recommended; however, if substitution is necessary, appropriate monitoring of drug blood levels, serum creatinine levels, and blood pressure is recommended.
• Modified formulations and non-modified formulations are not bioequivalent and cannot be used interchangeably.

Patient advice:

• Patients should be advised that any change of formulation should be made cautiously and only under physician supervision because it may result in the need for a change in dose.
• Patients should be informed of the necessity of repeated laboratory tests while they are receiving this drug.
• Patients should be given careful dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia.
• Patients using the oral solution with its accompanying syringe for dosage measurement should be cautioned not to rinse the syringe either before or after use. Introduction of water into the product by any means will cause variation in dose.

Frequently asked questions

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