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CycloSPORINE (Systemic)

Pronunciation

Pronunciation

(SYE kloe spor een)

Index Terms

  • Ciclosporin
  • CsA
  • CyA
  • Cyclosporin A

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Gengraf: 25 mg [contains cremophor el, fd&c blue #2 (indigotine)]

Gengraf: 50 mg [contains alcohol, usp, fd&c blue #2 aluminum lake]

Gengraf: 100 mg [contains cremophor el, fd&c blue #2 (indigotine)]

Neoral: 25 mg, 100 mg [contains alcohol, usp]

SandIMMUNE: 25 mg, 100 mg

Generic: 25 mg, 50 mg, 100 mg

Solution, Intravenous:

SandIMMUNE: 50 mg/mL (5 mL) [contains alcohol, usp, cremophor el]

Generic: 50 mg/mL (5 mL)

Solution, Oral:

Gengraf: 100 mg/mL (50 mL) [contains propylene glycol]

Neoral: 100 mg/mL (50 mL) [contains alcohol, usp]

SandIMMUNE: 100 mg/mL (50 mL) [contains alcohol, usp]

Generic: 100 mg/mL (50 mL)

Brand Names: U.S.

  • Gengraf
  • Neoral
  • SandIMMUNE

Pharmacologic Category

  • Calcineurin Inhibitor
  • Immunosuppressant Agent

Pharmacology

Inhibition of production and release of interleukin II and inhibits interleukin II-induced activation of resting T-lymphocytes.

Absorption

Oral:

Cyclosporine (non-modified): Erratic and incomplete; dependent on presence of food, bile acids, and GI motility; larger oral doses are needed in pediatrics due to shorter bowel length and limited intestinal absorption

Cyclosporine (modified): Erratic and incomplete; increased absorption, up to 30% when compared to cyclosporine (non-modified); less dependent on food, bile acids, or GI motility when compared to cyclosporine (non-modified)

Distribution

Widely distributed in tissues and body fluids including the liver, pancreas, and lungs

Vdss: 4-6 L/kg in renal, liver, and marrow transplant recipients (slightly lower values in cardiac transplant patients; children <10 years of age have higher values); ESRD: 3.49 L/kg

Metabolism

Extensively hepatic via CYP3A4; forms at least 25 metabolites; extensive first-pass effect following oral administration

Excretion

Primarily feces; urine (6%, 0.1% as unchanged drug and metabolites); clearance is more rapid in pediatric patients than in adults

Time to Peak

Serum: Oral:

Cyclosporine (non-modified): 2-6 hours; some patients have a second peak at 5-6 hours

Cyclosporine (modified): Renal transplant: 1.5-2 hours

Half-Life Elimination

Oral: May be prolonged with hepatic impairment and shorter in pediatric patients due to the higher metabolism rate

Cyclosporine (non-modified): Biphasic: Alpha: 1.4 hours; Terminal: 19 hours (range: 10-27 hours)

Cyclosporine (modified): Biphasic: Terminal: 8.4 hours (range: 5-18 hours)

Protein Binding

90% to 98% to lipoproteins

Special Populations: Renal Function Impairment

In a limited number of patients with end-stage renal disease (ESRD) (creatinine clearance <5 mL/minute), cyclosporine 3.5 mg/kg IV over 4 hours administered at the end of a hemodialysis session resulted in a mean volume of distribution of 3.49 L/kg and systemic clearance of 0.369 L/h/kg. This systemic clearance was approximately two-thirds the mean systemic clearance (0.56 L/h/kg) of cyclosporine in controls with normal renal function. In a small number of liver transplant patients, the mean clearance on and off hemodialysis was 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose was recovered in the dialysate.

Special Populations: Hepatic Function Impairment

Severe hepatic impairment may result in significantly reduced clearance and increased cyclosporine exposures.

Use: Labeled Indications

Cyclosporine modified:

Transplant rejection prophylaxis: Prophylaxis of organ rejection in kidney, liver, and heart transplants (has been used with azathioprine and/or corticosteroids)

Rheumatoid arthritis: Treatment of severe, active rheumatoid arthritis (RA) not responsive to methotrexate alone

Psoriasis: Treatment of severe, recalcitrant plaque psoriasis in nonimmunocompromised adults unresponsive to or unable to tolerate other systemic therapy

Cyclosporine non-modified: Transplant rejection (prophylaxis/treatment): Prophylaxis of organ rejection in kidney, liver, and heart transplants (has been used with azathioprine and/or corticosteroids; treatment of chronic organ rejection)

Canadian labeling: Additional uses (not in US labeling):

Cyclosporine modified: Nephrotic syndrome: Induction and maintenance of remission in steroid dependent/resistant nephrotic syndrome due to glomerular disease (eg, minimal change nephropathy, membranous glomerulonephritis, focal and segmental glomerulosclerosis); maintenance of steroid induced remission allowing for steroid dose reduction or withdrawal.

Cyclosporine modified/non-modified: Bone marrow transplantation: Prophylaxis of graft rejection following bone marrow transplantation; prophylaxis or treatment of graft-versus-host disease (GVHD)

Use: Unlabeled

Prevention and treatment of acute graft-versus-host disease (GVHD) in allogeneic stem cell transplantation; treatment of chronic GVHD in allogeneic stem cell transplant; treatment of lupus nephritis; treatment of focal segmental glomerulosclerosis; treatment of severe refractory ulcerative colitis

Contraindications

Hypersensitivity to cyclosporine or any component of the formulation. IV cyclosporine is contraindicated in hypersensitivity to polyoxyethylated castor oil (Cremophor EL).

Rheumatoid arthritis and psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies. Concomitant treatment with PUVA or UVB therapy, methotrexate, other immunosuppressive agents, coal tar, or radiation therapy are also contraindications for use in patients with psoriasis.

Canadian labeling: Additional contraindications (not in US labeling): Concurrent use with bosentan; rheumatoid arthritis and psoriasis patients with primary or secondary immunodeficiency excluding autoimmune disease, uncontrolled infection, or malignancy (excluding non-melanoma skin cancer).

Dosing: Adult

Neoral/Gengraf and Sandimmune are not bioequivalent and cannot be used interchangeably.

Psoriasis: Oral: Cyclosporine (modified): Initial dose: 2.5 mg/kg daily, divided twice daily

Titration:

US labeling: Increase by 0.5 mg/kg daily if insufficient response is seen after 4 weeks of treatment. Additional dosage increases may be made every 2 weeks if needed (maximum dose: 4 mg/kg daily)

Canadian labeling: Increase by 0.5 to 1 mg/kg daily if insufficient response is seen after 4 weeks of treatment. Additional dosage increases may be made every 4 weeks if needed (maximum dose: 5 mg/kg daily)

Discontinue if no benefit is seen by 6 weeks of therapy at the maximum dose. Once patients are adequately controlled, the dose should be decreased to the lowest effective dose. Doses lower than 2.5 mg/kg daily may be effective. The Canadian labeling recommends attempting to wean patients off therapy if no relapse occurs within 6 months of achieving remission. Treatment longer than 1 year is not recommended.

Note: Increase the frequency of blood pressure monitoring after each alteration in dosage of cyclosporine. Cyclosporine dosage should be decreased by 25% to 50% in patients with no history of hypertension who develop sustained hypertension during therapy and, if hypertension persists, treatment with cyclosporine should be discontinued.

Rheumatoid arthritis: Oral: Cyclosporine (modified): Initial dose: 2.5 mg/kg daily, divided twice daily; salicylates, NSAIDs, and oral glucocorticoids may be continued (refer to Drug Interactions)

Titration:

US labeling: Dose may be increased by 0.5 to 0.75 mg/kg daily if insufficient response is seen after 8 weeks of treatment; additional dosage increases may be made again at 12 weeks (maximum dose: 4 mg/kg daily). Discontinue if no benefit is seen by 16 weeks of therapy.

Canadian labeling: If insufficient response to initial dose after 6 weeks, may increase dose gradually as tolerated (maximum dose: 5 mg/kg daily); maintenance therapy should be individualized to the lowest effective and tolerable dose; may take up to 12 weeks before full effect is achieved.

Note: Increase the frequency of blood pressure monitoring after each alteration in dosage of cyclosporine. Cyclosporine dosage should be decreased by 25% to 50% in patients with no history of hypertension who develop sustained hypertension during therapy and, if hypertension persists, treatment with cyclosporine should be discontinued.

Solid organ transplant (newly transplanted patients): Adjunct therapy with corticosteroids is recommended. Initial dose should be given 4 to 12 hours prior to transplant or may be given postoperatively; adjust initial dose to achieve desired plasma concentration.

Oral: Dose is dependent upon type of transplant and formulation:

Cyclosporine (modified):

Renal: 9 ± 3 mg/kg daily, in 2 divided doses

Liver: 8 ± 4 mg/kg daily, in 2 divided doses

Heart: 7 ± 3 mg/kg daily, in 2 divided doses

Cyclosporine (non-modified): Initial doses of 10 to 14 mg/kg daily have been used for renal transplants (the manufacturer’s labeling includes dosing from initial clinical trials of 15 mg/kg daily [range: 14 to 18 mg/kg daily]; however, this higher dosing level is rarely used any longer). Continue initial dose daily for 1 to 2 weeks; taper by 5% per week to a maintenance dose of 5 to 10 mg/kg daily; some renal transplant patients may be dosed as low as 3 mg/kg daily

Note: When using the non-modified formulation, cyclosporine levels may increase in liver transplant patients when the T-tube is closed; dose may need decreased

IV: Cyclosporine (non-modified): Manufacturer's labeling: Initial dose: 5 to 6 mg/kg daily or one-third of the oral dose as a single dose, infused over 2 to 6 hours; use should be limited to patients unable to take capsules or oral solution; patients should be switched to an oral dosage form as soon as possible.

Note: Many transplant centers administer cyclosporine as "divided dose" infusions (in 2 to 3 doses daily) or as a continuous (24-hour) infusion; dosages range from 3 to 7.5 mg/kg daily. Specific institutional protocols should be consulted.

Note: Conversion to cyclosporine (modified) from cyclosporine (non-modified): Start with daily dose previously used and adjust to obtain preconversion cyclosporine trough concentration. Plasma concentrations should be monitored every 4 to 7 days and dose adjusted as necessary, until desired trough level is obtained. When transferring patients with previously poor absorption of cyclosporine (non-modified), monitor trough levels at least twice weekly (especially if initial dose exceeds 10 mg/kg daily); high plasma levels are likely to occur.

Acute graft versus host disease (GVHD), prevention (off-label use in the US): IV followed by oral:

Initial: IV: 3 mg/kg daily 1 day prior to transplant; may convert to oral therapy when tolerated; titrate dose to appropriate cyclosporine trough concentration (in combination with methotrexate); taper per protocol (refer to specific references for tapering and target trough details); discontinue 6 months post-transplant in the absence of acute GVHD (Ratanatharathorn 1998; Ruutu 2013; Storb 1986a; Storb 1986b)

or

Initial: IV: 5 mg/kg (continuous infusion over 20 hours) each day for 6 days (loading dose) starting 2 days prior to transplant, then 3 mg/kg over 20 hours each day for 11 days starting on post-transplant day 4, then 3.75 mg/kg over 20 hours each day for 21 days starting on day 15, then oral (in 2 divided daily doses): 10 mg/kg daily days 36 to 83, then 8 mg/kg daily days 84 to 97, then 6 mg/kg daily days 98 to 119, then 4 mg/kg daily days 120 to 180, then discontinue (in combination with methotrexate +/- corticosteroid) (Chao 1993; Chao 2000)

Bone marrow transplantation (Canadian labeling): Note: IV administration is preferred for initial therapy.

Oral: Cyclosporine (modified): Initial: 12.5 to 15 mg/kg daily in 2 divided doses beginning 1 day prior to transplant; Maintenance: ~12.5 mg/kg daily in 2 divided doses every 12 hours for at least 3 to 6 months (higher doses may be required in patients with gastrointestinal conditions which may decrease absorption); decrease dose gradually to zero by 1 year following transplant. Patients who develop GVHD after discontinuation of cyclosporine may be reinitiated on therapy with a loading dose of 10 to 12.5 mg/kg followed by the previously established maintenance dose. Patients with mild, chronic GVHD should be treated with lowest effective dose.

IV: Cyclosporine (non-modified): Initial: 3 to 5 mg/kg daily or one-third of the oral dose as a single dose (infused over 2 to 6 hours) beginning 1 day prior to transplant; Maintenance: May continue initial dose for up to 2 weeks; however, patients should be switched to an oral dosage form as soon as possible.

Focal segmental glomerulosclerosis (off-label use in the US): Oral: Initial: 3.5 to 5 mg/kg daily divided every 12 hours (in combination with oral prednisone) (Braun 2008; Cattran 1999)

Interstitial cystitis (bladder pain syndrome) (off-label use): Oral: Initial: 2 to 3 mg/kg/day in 2 divided doses (maximum of 300 mg daily). Once symptom relief is established, the dose can be tapered as tolerated (to as low as 1 mg/kg as a single daily dose) and in some cases can be stopped with continued benefit. Treatment duration was at least 6 months to more than 1 year in some patients (Forrest 2012; Sairanen 2004; Sairanen 2005; Sairanen 2008).

Nephrotic syndrome (Canadian labeling): Oral: Cyclosporine (modified):

Initial: 3.5 mg/kg daily in 2 divided doses every 12 hours; titrate for induction of remission and renal function. Adjunct therapy with low-dose oral corticosteroids is recommended for patients with an inadequate response to cyclosporine (particularly if steroid-resistant).

Maintenance: Dose is individualized based on proteinuria, serum creatinine, and tolerability but should be maintained at lowest effective dose; maximum dose: 5 mg/kg daily. Discontinue if no improvement is observed after 3 months.

Lupus nephritis (off-label use): Oral: Cyclosporine (modified): Initial: 4 mg/kg daily for 1 month (reduce dose if trough concentrations >200 ng/mL); reduce dose by 0.5 mg/kg every 2 weeks to a maintenance dose of 2.5 to 3 mg/kg daily (Moroni 2006)

Ulcerative colitis, severe (steroid-refractory) (off-label use):

IV: Cyclosporine (non-modified): 2 to 4 mg/kg daily, infused continuously over 24 hours. (Lichtiger 1994; Van Assche 2003). Note: Some studies suggest no therapeutic difference between low-dose (2 mg/kg) and high-dose (4 mg/kg) cyclosporine regimens (Van Assche 2003).

Oral: Cyclosporine (modified): 2.3 to 3 mg/kg every 12 hours (De Saussure 2005; Weber 2006)

Note: Patients responsive to IV therapy should be switched to oral therapy when possible.

Dosing: Geriatric

Refer to adult dosing. Sandimmune and Neoral/Gengraf are not bioequivalent and cannot be used interchangeably.

Dosing: Pediatric

Bone marrow transplantation (Canadian labeling): Note: IV administration is preferred for initial therapy.

Oral: Cyclosporine (modified): Initial: 12.5 to 15 mg/kg daily in 2 divided doses beginning 1 day prior to transplant; Maintenance: ~12.5 mg/kg daily in 2 divided doses every 12 hours for at least 3 to 6 months (higher doses may be required in patients with gastrointestinal conditions which may decrease absorption); decrease dose gradually to zero by 1 year following transplant. Patients who develop graft versus host disease (GVHD) after discontinuation of cyclosporine may be reinitiated on therapy with a loading dose of 10 to 12.5 mg/kg followed by the previously established maintenance dose. Patients with mild, chronic GVHD should be treated with lowest effective dose.

IV: Cyclosporine (non-modified): Initial: 3 to 5 mg/kg daily or one-third of the oral dose as a single dose (infused over 2 to 6 hours) beginning 1 day prior to transplant; Maintenance: may continue initial dose for up to 2 weeks; however, patients should be switched to an oral dosage form as soon as possible.

Nephrotic syndrome (Canadian labeling): Oral: Cyclosporine (modified):

Initial: 4.2 mg/kg daily in 2 divided doses every 12 hours; titrate for induction of remission and renal function. Adjunct therapy with low-dose oral corticosteroids is recommended for patients with an inadequate response to cyclosporine (particularly if steroid-resistant).

Maintenance: Dose is individualized based on proteinuria, serum creatinine, and tolerability but should be maintained at lowest effective dose; maximum dose: 6 mg/kg daily. Discontinue if no improvement is observed after 3 months.

Solid organ transplant: Refer to adult dosing. Children may require, and are able to tolerate, larger doses than adults.

Dosing: Renal Impairment

Nephrotic syndrome: Canadian labeling: Initial: 2.5 mg/kg daily

Serum creatinine levels >30% above pretreatment levels: Take another sample within 2 weeks; if the level remains >30% above pretreatment levels, decrease dosage of cyclosporine (modified) by 25% to 50%.

Psoriasis (severe):

Abnormal renal function prior to treatment: Use is contraindicated.

Abnormal renal function during treatment:

US labeling:

Serum creatinine levels ≥25% above pretreatment levels: Take another sample within 2 weeks; if the level remains ≥25% above pretreatment levels, decrease dosage of cyclosporine (modified) by 25% to 50%. If two dosage adjustments do not reverse the increase in serum creatinine levels, treatment should be discontinued.

Serum creatinine levels ≥50% above pretreatment levels: Decrease cyclosporine dosage by 25% to 50%. If two dosage adjustments do not reverse the increase in serum creatinine levels, treatment should be discontinued.

Canadian labeling: Serum creatinine levels >30% above pretreatment levels: Decrease dosage of cyclosporine (modified) by 25% to 50%. If dosage adjustment does not reverse the increase in serum creatinine levels within 30 days, discontinue treatment.

Rheumatoid arthritis:

Abnormal renal function prior to treatment: Use is contraindicated.

Abnormal renal function during treatment: Canadian labeling:

Serum creatinine levels >30% above pretreatment levels: Take another sample within 2 weeks; if the level remains ≥30% above pretreatment levels, manufacturer labeling recommends reducing dose but does not provide specific dosing recommendation. If dosage adjustment does not reverse the increase in serum creatinine levels within 30 days, discontinue treatment.

Serum creatinine levels >50% above pretreatment levels: Reduce dose by 50%; if dosage adjustment does not reverse the increase in serum creatinine levels within 30 days, discontinue treatment.

Hemodialysis: Supplemental dose is not necessary.

Peritoneal dialysis: Supplemental dose is not necessary.

Dosing: Hepatic Impairment

Mild-to-moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; monitor blood concentrations.

Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling; however, metabolism is extensively hepatic (exposure is increased). Monitor blood concentrations; may require dose reduction.

Reconstitution

Hazardous agent - use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Injection: To minimize leaching of DEHP, non-PVC containers and sets should be used for preparation and administration.

Sandimmune injection: Injection should be further diluted (1 mL [50 mg] of concentrate in 20-100 mL of D5W or NS) for administration by intravenous infusion.

Oral solution: Should be mixed in glass containers (not in plastic).

Administration

Oral solution: Do not administer liquid from plastic or styrofoam cup. May dilute Neoral oral solution with orange juice or apple juice. May dilute Sandimmune oral solution with milk, chocolate milk, or orange juice. Avoid changing diluents frequently. Mix thoroughly and drink at once. Use syringe provided to measure dose. Mix in a glass container and rinse container with more diluent to ensure total dose is taken. Do not rinse syringe before or after use (may cause dose variation).

Administer this medication consistently with relation to time of day and meals.

Combination therapy with renal transplantation:

Everolimus: Administer cyclosporine at the same time as everolimus

Sirolimus: Administer cyclosporine 4 hours prior to sirolimus

IV: The manufacturer recommends that following dilution, intravenous admixture be administered over 2-6 hours. However, many transplant centers administer as divided doses (2-3 doses/day) or as a 24-hour continuous infusion. Discard solution after 24 hours. Anaphylaxis has been reported with IV use; reserve for patients who cannot take oral form. Patients should be under continuous observation for at least the first 30 minutes of the infusion, and should be monitored frequently thereafter. Maintain patent airway; other supportive measures and agents for treating anaphylaxis should be present when IV drug is given. To minimize leaching of DEHP, non-PVC sets should be used for administration.

Hazardous agent - use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Dietary Considerations

Avoid grapefruit juice with oral cyclosporine use.

Compatibility

Stable in D5W, fat emulsion 10%, fat emulsion 20%, NS.

Y-site administration: Incompatible with acyclovir, amphotericin B cholesteryl sulfate complex, drotrecogin alfa, mycophenolate, pantoprazole.

Storage

Capsules (modified): Store in the original unit-dose container at 20°C to 25°C (68°F to 77°F).

Capsules (non-modified): Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). An odor may be detected upon opening the unit-dose container, which will dissipate shortly thereafter. This odor does not affect the quality of the product.

Injection: Store below 30°C (86°F) or at controlled room temperature (product dependent). Protect from light. The manufacturer recommends discarding diluted infusion solutions in D5W or NS after 24 hours.

Oral solution (modified): Store in the original container at 20°C to 25°C (68°F to 77°F). Do not store in the refrigerator. Once opened, use within 2 months. At temperatures below 20°C (68°F), the solution may gel; light flocculation or the formation of a light sediment also may occur. There is no impact on product performance or dosing using the syringe provided. Allow to warm to room temperature (25°C [77°F]) to reverse these changes.

Oral solution (non-modified): Store in the original container at temperatures below 30°C (86°F). Do not store in the refrigerator. Protect from freezing. Once opened, use within 2 months.

Drug Interactions

AcetaZOLAMIDE: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Adalimumab: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Aliskiren: CycloSPORINE (Systemic) may increase the serum concentration of Aliskiren. Avoid combination

Ambrisentan: CycloSPORINE (Systemic) may increase the serum concentration of Ambrisentan. Management: Limit ambrisentan dose to 5 mg/day and monitor for ambrisentan adverse reactions in patients receiving systemic cyclosporine. Consider therapy modification

Aminoglycosides: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Amiodarone: May decrease the metabolism of CycloSPORINE (Systemic). Consider therapy modification

Amphotericin B: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Androgens: May enhance the hepatotoxic effect of CycloSPORINE (Systemic). Androgens may increase the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

Angiotensin II Receptor Blockers: May enhance the hyperkalemic effect of CycloSPORINE (Systemic). Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of CycloSPORINE (Systemic). Fluconazole and isavuconazonium considerations are addressed in separate monographs. Exceptions: Fluconazole; Isavuconazonium Sulfate. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Armodafinil: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Ascorbic Acid: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Asunaprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: CycloSPORINE (Systemic) may increase the serum concentration of AtorvaSTATin. Avoid combination

Barbiturates: May increase the metabolism of CycloSPORINE (Systemic). Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Boceprevir: CycloSPORINE (Systemic) may increase the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of CycloSPORINE (Systemic). Management: Cyclosporine dose adjustments will likely be necessary when used together with boceprevir. Monitor serum cyclosporine concentrations closely, and monitor patients for evidence of cyclosporine toxicity. Consider therapy modification

Bosentan: CycloSPORINE (Systemic) may increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of CycloSPORINE (Systemic). Avoid combination

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Bromocriptine: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Calcium Channel Blockers (Dihydropyridine): May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Exceptions: Clevidipine. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Consider therapy modification

CarBAMazepine: May decrease the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

Carvedilol: May increase the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

Caspofungin: CycloSPORINE (Systemic) may enhance the adverse/toxic effect of Caspofungin. CycloSPORINE (Systemic) may increase the serum concentration of Caspofungin. Management: Weigh potential benefits of caspofungin against a possible elevated risk of hepatotoxicity. Monitor liver function and re-evaluate treatment in patients with abnormal values. Mild transaminase elevations may occur relatively commonly. Consider therapy modification

Chloramphenicol: May increase the serum concentration of CycloSPORINE (Systemic). Management: Cyclosporine dose reductions will likely be required with initiation of concurrent chloramphenicol. Monitor cyclosporine concentrations and response closely following initiation and/or discontinuation of chloramphenicol. Consider therapy modification

Cholic Acid: BSEP/ABCB11 Inhibitors (Clinically Relevant) may decrease the excretion of Cholic Acid. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Colesevelam: May decrease the serum concentration of CycloSPORINE (Systemic). Management: Administer cyclosporine at least 4 hours prior to colesevelam. Monitor for decreased cyclosporine concentrations during concomitant colesevelam therapy. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Crizotinib: May increase the serum concentration of CycloSPORINE (Systemic). Avoid combination

Cyclophosphamide: May enhance the immunosuppressive effect of CycloSPORINE (Systemic). Cyclophosphamide may decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dexamethasone (Systemic): May decrease the serum concentration of CycloSPORINE (Systemic). Dexamethasone (Systemic) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Dexamethasone (Systemic). Monitor therapy

Digoxin: CycloSPORINE (Systemic) may increase the serum concentration of Digoxin. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

DOXOrubicin (Conventional): CycloSPORINE (Systemic) may increase the serum concentration of DOXOrubicin (Conventional). Management: Consider a doxorubicin dose reduction, as clinically appropriate, when used with cyclosporine. Use this combination with caution; increase monitoring for toxic effects of doxorubicin. Consider therapy modification

Dronabinol: May increase the serum concentration of CycloSPORINE (Systemic). Specifically, dronabinol may displace cyclosporine from its protein-binding sites, leading to an increased concentration of active, unbound drug. Monitor therapy

Dronedarone: CycloSPORINE (Systemic) may increase the serum concentration of Dronedarone. Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Efavirenz: May decrease the serum concentration of CycloSPORINE (Systemic). Management: Increase monitoring of cyclosporine concentrations when starting, stopping, or adjusting doses of concurrent efavirenz, particularly within the first 2 weeks. Cyclosporine dose adjustment may be required. Consider therapy modification

Eltrombopag: CycloSPORINE (Systemic) may decrease the serum concentration of Eltrombopag. Monitor therapy

Eluxadoline: CycloSPORINE (Systemic) may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with cyclosporine and monitor patients for increased eluxadoline effects/toxicities. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CycloSPORINE (Systemic). Avoid combination

Eplerenone: May enhance the hyperkalemic effect of CycloSPORINE (Systemic). Avoid combination

Etoposide: CycloSPORINE (Systemic) may decrease the metabolism of Etoposide. Management: Consider reducing the dose of etoposide by 50% if the patient is receiving, or has recently received, cyclosporine. Monitor for increased toxic effects of etoposide if cyclosporine is initiated, the dose is increased, or it has been recently discontinued. Consider therapy modification

Etoposide Phosphate: CycloSPORINE (Systemic) may increase the serum concentration of Etoposide Phosphate. CycloSPORINE may decrease the metabolism, via CYP isoenzymes, and decrease the p-glycoprotein-mediated elimination of Etoposide Phosphate. Consider therapy modification

Everolimus: CycloSPORINE (Systemic) may increase the serum concentration of Everolimus. Management: When using everolimus for renal cell carcinoma, avoid concurrent cyclosporine. When using everolimus as post-transplant immunosuppression, concurrent cyclosporine should be used at lower doses and with lower target serum cyclosporine concentrations. Consider therapy modification

Ezetimibe: May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Ezetimibe. Monitor therapy

Fibric Acid Derivatives: CycloSPORINE (Systemic) may enhance the nephrotoxic effect of Fibric Acid Derivatives. Fibric Acid Derivatives may decrease the serum concentration of CycloSPORINE (Systemic). Management: Careful consideration of the risks and benefits should be undertaken prior to use of this combination; extra monitoring of renal function and cyclosporine concentrations will likely be required. Adjustment of cyclosporine dose may be necessary. Consider therapy modification

Fimasartan: CycloSPORINE (Systemic) may increase the serum concentration of Fimasartan. Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fluconazole: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Fluvastatin: CycloSPORINE (Systemic) may increase the serum concentration of Fluvastatin. Management: Limit fluvastatin to 20 mg twice daily in patients who are also receiving cyclosporine. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Foscarnet: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Avoid combination

Fosphenytoin: May decrease the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

GlyBURIDE: CycloSPORINE (Systemic) may diminish the therapeutic effect of GlyBURIDE. GlyBURIDE may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Grapefruit Juice: May decrease the metabolism of CycloSPORINE (Systemic). Management: Monitor for altered cyclosporine concentrations/effects if grapefruit intake is increased/decreased. Advise patients to not alter their pattern of grapefruit/grapefruit juice intake without consulting their healthcare provider. Consider therapy modification

Grazoprevir: CycloSPORINE (Systemic) may increase the serum concentration of Grazoprevir. Avoid combination

Griseofulvin: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Imatinib: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Imipenem: CycloSPORINE (Systemic) may enhance the neurotoxic effect of Imipenem. Imipenem may decrease the serum concentration of CycloSPORINE (Systemic). Imipenem may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lercanidipine: May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Lercanidipine. Avoid combination

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Loop Diuretics: CycloSPORINE (Systemic) may enhance the adverse/toxic effect of Loop Diuretics. Monitor therapy

Lovastatin: CycloSPORINE (Systemic) may increase the serum concentration of Lovastatin. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of CycloSPORINE (Systemic). Exceptions: Fidaxomicin; Roxithromycin; Spiramycin. Monitor therapy

Melphalan: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Methotrexate: CycloSPORINE (Systemic) may increase the serum concentration of Methotrexate. This may result in nausea, vomiting, oral ulcers, hepatotoxicity and/or nephrotoxicity. Methotrexate may increase the serum concentration of CycloSPORINE (Systemic). This may result in nephrotoxicity. Consider therapy modification

MethylPREDNISolone: CycloSPORINE (Systemic) may increase the serum concentration of MethylPREDNISolone. MethylPREDNISolone may increase the serum concentration of CycloSPORINE (Systemic). MethylPREDNISolone may decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Metoclopramide: May increase the absorption of CycloSPORINE (Systemic). Monitor therapy

Metreleptin: May decrease the serum concentration of CycloSPORINE (Systemic). Metreleptin may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

MiFEPRIStone: May increase the serum concentration of CycloSPORINE (Systemic). Management: Avoid cyclosporine during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Minoxidil (Systemic): CycloSPORINE (Systemic) may enhance the adverse/toxic effect of Minoxidil (Systemic). Severe hypertrichosis has been reported. Monitor therapy

Minoxidil (Topical): CycloSPORINE (Systemic) may enhance the adverse/toxic effect of Minoxidil (Topical). Specifically, hypertrichosis risk may be increased. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

MitoXANTRONE: CycloSPORINE (Systemic) may increase the serum concentration of MitoXANTRONE. Management: Consider mitoxantrone dose reduction, as clinically appropriate, when used with cyclosporine. Use this combination with caution and monitor closely for toxic effects of mitoxantrone. Consider therapy modification

Modafinil: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Multivitamins/Fluoride (with ADE): May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Mycophenolate: CycloSPORINE (Systemic) may decrease the serum concentration of Mycophenolate. Specifically, cyclosporine may decrease concentrations of the active metabolite mycophenolic acid. Management: Mycophenolate requirements may be greater in patients receiving cyclosporine. Monitor mycophenolate dosing and response to therapy particularly closely when adjusting concurrent cyclosporine (starting, stopping, or changing dose). Consider therapy modification

Nafcillin: May increase the metabolism of CycloSPORINE (Systemic). Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Neuromuscular-Blocking Agents: CycloSPORINE (Systemic) may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Specifically, elevated diclofenac concentrations have been reported. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (e.g., hypertension) during concomitant therapy with NSAIDs. Consider therapy modification

Norfloxacin: May decrease the metabolism of CycloSPORINE (Systemic). Monitor therapy

Ombitasvir, Paritaprevir, and Ritonavir: May increase the serum concentration of CycloSPORINE (Systemic). Management: Reduce cyclosporine dose by 80% when initiating therapy with ombitasvir/paritaprevir/ritonavir and monitor cyclosporine blood levels closely. Consider therapy modification

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of CycloSPORINE (Systemic). Management: Reduce cyclosporine dose 80% when initiating therapy with ombitasvir/paritaprevir/ritonavir/dasabuvir and monitor cyclosporine blood levels closely. Consider therapy modification

Omeprazole: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Orlistat: May decrease the serum concentration of CycloSPORINE (Systemic). Management: Administer orlistat at least 3 hours before or after oral cyclosporine. Monitor for decreased serum concentrations of oral cyclosporine, even with the recommended dose separation. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Phenytoin: May increase the metabolism of CycloSPORINE (Systemic). Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Pitavastatin: CycloSPORINE (Systemic) may increase the serum concentration of Pitavastatin. Avoid combination

Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of CycloSPORINE (Systemic). Avoid combination

Pravastatin: CycloSPORINE (Systemic) may increase the serum concentration of Pravastatin. Pravastatin may increase the serum concentration of CycloSPORINE (Systemic). Management: Limit pravastatin to 20 mg/day in patients who are also receiving cyclosporine. Consider therapy modification

PrednisoLONE (Systemic): May decrease the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of PrednisoLONE (Systemic). PrednisoLONE (Systemic) may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

PredniSONE: CycloSPORINE (Systemic) may increase serum concentrations of the active metabolite(s) of PredniSONE. PredniSONE may decrease the serum concentration of CycloSPORINE (Systemic). PredniSONE may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Protease Inhibitors: May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Protease Inhibitors. Consider therapy modification

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Pyrazinamide: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Quinupristin: May increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Repaglinide: CycloSPORINE (Systemic) may increase the serum concentration of Repaglinide. Monitor therapy

Rifamycin Derivatives: May increase the metabolism of CycloSPORINE (Systemic). Consider therapy modification

RifAXIMin: CycloSPORINE (Systemic) may increase the serum concentration of RifAXIMin. Monitor therapy

Ritonavir: May increase the serum concentration of CycloSPORINE (Systemic). Management: Consider empiric cyclosporine dose reductions and monitor cyclosporine serum concentrations closely if ritonavir is initiated. Consider therapy modification

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Rosuvastatin: CycloSPORINE (Systemic) may increase the serum concentration of Rosuvastatin. Management: Limit rosuvastatin to 5 mg/day in patients who are also receiving cyclosporine. Canadian labeling contraindicates concomitant use of rosuvastatin with cyclosporine. Consider therapy modification

Sevelamer: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Simeprevir. Avoid combination

Simvastatin: CycloSPORINE (Systemic) may increase the serum concentration of Simvastatin. Avoid combination

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Sirolimus: May enhance the adverse/toxic effect of CycloSPORINE (Systemic). An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described. CycloSPORINE (Systemic) may increase the serum concentration of Sirolimus. This is of specific concern with cyclosporine [MODIFIED]. Management: Administer oral doses of sirolimus 4 hours after doses of cyclosporine. Monitor for toxic effects of sirolimus if used with cyclosporine. Consider therapy modification

Somatostatin Analogs: May decrease the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

St John's Wort: May decrease the serum concentration of CycloSPORINE (Systemic). Management: Consider alternatives to St. John's wort (SJW). If the combination cannot be avoided, monitor for decreased cyclosporine concentrations/effects. Monitor for increased cyclosporine concentrations/effects following SJW discontinuation. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Sulfinpyrazone: May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Sulfonamide Derivatives: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Sulfonamide Derivatives may decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Tacrolimus (Systemic): May enhance the nephrotoxic effect of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may enhance the nephrotoxic effect of Tacrolimus (Systemic). Tacrolimus (Systemic) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Tacrolimus (Systemic). Avoid combination

Tacrolimus (Topical): May enhance the nephrotoxic effect of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may enhance the nephrotoxic effect of Tacrolimus (Topical). Tacrolimus (Topical) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Tacrolimus (Topical). Avoid combination

Telaprevir: May increase the serum concentration of CycloSPORINE (Systemic). Management: Significant cyclosporine dose reductions are likely to be required if used with telaprevir. Concurrent use should be performed with great caution and close monitoring of both cyclosporine concentrations and clinical response. Consider therapy modification

Temsirolimus: May enhance the adverse/toxic effect of CycloSPORINE (Systemic). An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described with concomitant sirolimus use. Consider therapy modification

Ticagrelor: CycloSPORINE (Systemic) may increase the serum concentration of Ticagrelor. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vitamin E (Systemic): May decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Test Interactions

Specific whole blood assay for cyclosporine may be falsely elevated if sample is drawn from the same central venous line through which dose was administered (even if flush has been administered and/or dose was given hours before); cyclosporine metabolites cross-react with radioimmunoassay and fluorescence polarization immunoassay

Adverse Reactions

Adverse reactions reported with systemic use, including rheumatoid arthritis, psoriasis, and transplantation (kidney, liver, and heart). Percentages noted include the highest frequency regardless of indication/dosage. Frequencies may vary for specific conditions or formulation.

>10%:

Cardiovascular: Hypertension (8% to 53%), edema (5% to 14%)

Central nervous system: Headache (2% to 25%), paresthesia (1% to 11%)

Dermatologic: Hypertrichosis (5% to 19%)

Endocrine & metabolic: Hirsutism (21% to 45%), increased serum triglycerides (15%), female genital tract disease (9% to 11%)

Gastrointestinal: Nausea (2% to 23%), diarrhea (3% to 13%), gingival hyperplasia (2% to 16%), abdominal distress (<1% to 15%), dyspepsia (2% to 12%)

Genitourinary: Urinary tract infection (kidney transplant: 21%)

Infection: Increased susceptibility to infection (3% to 25%), viral infection (kidney transplant: 16%)

Neuromuscular & skeletal: Tremor (7% to 55%), leg cramps (2% to 12%)

Renal: Increased serum creatinine (16% to ≥50%), renal insufficiency (10% to 38%)

Respiratory: Upper respiratory tract infection (1% to 14%)

Kidney, liver, and heart transplant only (≤2% unless otherwise noted):

Cardiovascular: Chest pain (≤4%), flushing (<1% to 4%), glomerular capillary thrombosis, myocardial infarction

Central nervous system: Convulsions (1% to 5%), anxiety, confusion, lethargy, tingling sensation

Dermatologic: Skin infection (7%), acne vulgaris (1% to 6%), nail disease (brittle fingernails), hair breakage, night sweats, pruritus

Endocrine & metabolic: Gynecomastia (<1% to 4%), hyperglycemia, hypomagnesemia, weight loss

Gastrointestinal: Vomiting (2% to 10%), anorexia, aphthous stomatitis, constipation, dysphagia, gastritis, hiccups, pancreatitis

Genitourinary: Hematuria

Hematologic & oncologic: Leukopenia (<1% to 6%), lymphoma (<1% to 6%), anemia, thrombocytopenia, upper gastrointestinal hemorrhage

Hepatic: Hepatotoxicity (<1% to 7%)

Infection: Localized fungal infection (8%), cytomegalovirus disease (5%), septicemia (5%), abscess (4%), fungal infection (systemic: 2%)

Neuromuscular & skeletal: Arthralgia, myalgia, weakness

Ophthalmic: Conjunctivitis, visual disturbance

Otic: Hearing loss, tinnitus

Respiratory: Sinusitis (<1% to 7%), pneumonia (6%)

Miscellaneous: Fever

Rheumatoid arthritis only (1% to <3% unless otherwise noted):

Cardiovascular: Chest pain (4%), cardiac arrhythmia (2%), abnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemia

Central nervous system: Dizziness (8%), pain (6%), insomnia (4%), depression (3%), migraine (2% to 3%), anxiety, drowsiness, emotional lability, hypoesthesia, lack of concentration, malaise, neuropathy, nervousness, paranoia, vertigo

Dermatologic: Cellulitis, dermatological reaction, dermatitis, diaphoresis, dyschromia, eczema, enanthema, folliculitis, nail disease, pruritus, urticaria, xeroderma

Endocrine & metabolic: Menstrual disease (3%), decreased libido, diabetes mellitus, goiter, hot flash, hyperkalemia, hyperuricemia, hypoglycemia, increased libido, weight gain, weight loss

Gastrointestinal: Vomiting (9%), flatulence (5%), gingivitis (4%), constipation, dysgeusia, dysphagia, enlargement of salivary glands, eructation, esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival hemorrhage, glossitis, peptic ulcer, tongue disease, xerostomia

Genitourinary: Leukorrhea (1%), breast fibroadenosis, hematuria, mastalgia, nocturia, urine abnormality, urinary incontinence, urinary urgency, uterine hemorrhage

Hematologic & oncologic: Purpura (3% to 4%), anemia, carcinoma, leukopenia, lymphadenopathy

Hepatic: Hyperbilirubinemia

Infection: Abscess (including renal), bacterial infection, candidiasis, fungal infection, herpes simplex infection, herpes zoster, viral infection

Neuromuscular & skeletal: Arthralgia, bone fracture, dislocation, myalgia, stiffness, synovial cyst, tendon disease, weakness

Ophthalmic: Cataract, conjunctivitis, eye pain, visual disturbance

Otic: Tinnitus, deafness, vestibular disturbance

Renal: Abscess (renal), increased blood urea nitrogen, polyuria, pyelonephritis

Respiratory: Cough (5%), dyspnea (5%), sinusitis (4%), abnormal breath sounds, bronchospasm, epistaxis, tonsillitis

Psoriasis only (1% to <3% unless otherwise noted):

Cardiovascular: Chest pain, flushing

Central nervous system: Psychiatric disturbance (4% to 5%), pain (3% to 4%), dizziness, insomnia, nervousness, vertigo

Dermatologic: Acne vulgaris, folliculitis, hyperkeratosis, pruritus, skin rash, xeroderma

Endocrine & metabolic: Hot flash

Gastrointestinal: Abdominal distention, constipation, gingival hemorrhage, increased appetite

Genitourinary: Urinary frequency

Hematologic & oncologic: Abnormal erythrocytes, altered platelet function, blood coagulation disorder, carcinoma, hemorrhagic diathesis

Hepatic: Hyperbilirubinemia

Neuromuscular & skeletal: Arthralgia (1% to 6%)

Ophthalmic: Visual disturbance

Respiratory: Flu-like symptoms (8% to 10%), bronchospasm (5%), cough (5%), dyspnea (5%), rhinitis (5%), respiratory tract infection

Miscellaneous: Fever

Postmarketing and/or case reports (Limited to important or life-threatening; any indication): Anaphylaxis/anaphylactoid reaction (possibly associated with Cremophor EL vehicle in injection formulation), brain disease, central nervous system toxicity, cholestasis, cholesterol increased, exacerbation of psoriasis (transformation to erythrodermic or pustular psoriasis), gout, haemolytic uremic syndrome, hepatic insufficiency, hepatitis, hyperbilirubinemia, hyperkalemia, hyperlipidemia, hypertrichosis, hyperuricemia, hypomagnesemia, impaired consciousness, increased susceptibility to infection (including JC virus and BK virus), jaundice, leg pain (possibly a manifestation of Calcineurin-Inhibitor Induced Pain Syndrome), malignant lymphoma, migraine, myalgia, myopathy, myositis, papilledema, progressive multifocal leukoencephalopathy, pseudotumor cerebri, pulmonary edema (noncardiogenic), renal disease (polyoma virus-associated), reversible posterior leukoencephalopathy syndrome, rhabdomyolysis, thrombotic microangiopathy

ALERT: U.S. Boxed Warning

Experienced physician:

Only health care providers experienced in immunosuppressive therapy and management of organ transplant patients should prescribe cyclosporine. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The health care provider responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Immunosuppression:

Administer Sandimmune and cyclosporine injection with adrenal corticosteroids but not with other immunosuppressive agents. Increased susceptibility to infection and other possible development of lymphoma may result from immunosuppression.

Neoral and Gengraf may increase the susceptibility to infection and the development of neoplasia. In kidney, liver, and heart transplant patients, Gengraf and Neoral may be administered with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma and other neoplasms may result from the increase in the degree of immunosuppression in transplant patients.

Bioavailability:

The absorption of Sandimmune during long-term administration was found to be erratic. It is recommended that patients taking Sandimmune over a period of time be monitored at repeated intervals for cyclosporine blood levels and that subsequent dose adjustments be made to avoid toxicity from high levels and possible organ rejection from low absorption of cyclosporine. This is of special importance in liver transplants. Numerous assays are being developed to measure blood levels of cyclosporine.

Sandimmune capsules and oral solution have decreased bioavailability in comparison with Gengraf and Neoral capsules and Gengraf and Neoral oral solution. Gengraf and Neoral are not bioequivalent to Sandimmune and cannot be used interchangeably without the supervision of a health care provider. For given trough concentrations, cyclosporine exposure will be greater with Neoral and Gengraf than with Sandimmune. If a patient receiving exceptionally high doses of Sandimmune is converted to Neoral or Gengraf, exercise particular caution. Monitor cyclosporine blood concentrations in transplant and rheumatoid arthritis (RA) patients taking Gengraf and Neoral to avoid toxicity due to high concentrations. Make dose adjustments in transplant patients to minimize possible organ rejection due to low concentrations. Comparison of blood concentrations in the published literature with blood concentrations obtained using current assays must be done with detailed knowledge of the assay methods employed.

Psoriasis (Neoral, Gengraf):

Psoriasis patients previously treated with psoralens plus ultraviolet A (PUVA) and, to a lesser extent, methotrexate or other immunosuppressive agents, ultraviolet B (UVB), coal tar, or radiation therapy, are at an increased risk of developing skin malignancies when taking cyclosporine.

Cyclosporine, in recommended doses, can cause systemic hypertension and nephrotoxicity. The risk increases with increasing dose and duration of cyclosporine therapy. Renal dysfunction, including structural kidney damage, is a potential consequence of cyclosporine and, therefore, renal function must be monitored during therapy.

Warnings/Precautions

Concerns related to adverse effects:

• Gingival hyperplasia: Gingival hyperplasia may occur; avoid concomitant nifedipine in patients who develop gingival hyperplasia (may increase frequency of hyperplasia).

• Hepatotoxicity: Hepatotoxicity (transaminase and bilirubin elevations) and liver injury (including cholestasis, jaundice, hepatitis, and liver failure) have been reported. These events were mainly in patients with confounding factors including infections, coadministration with other potentially hepatotoxic medications, underlying conditions, and significant comorbidities. Fatalities have also been reported rarely, primarily in transplant patients. Increased hepatic enzymes and bilirubin have occurred, usually in the first month and when used at high doses; improvement is usually seen with dosage reduction.

• Hyperkalemia: Significant hyperkalemia, with or without hyperchloremic metabolic acidosis, has been reported.

• Hypertension: [US Boxed Warning]: May cause hypertension; risk is increased with increasing doses/duration.

• Hyperuricemia: Significant hyperuricemia has been reported.

• Infections: [US Boxed Warning]: Increased risk of infection with use; fatal infections have been reported. Bacterial, viral, fungal, and protozoal infections (including opportunistic infections) have occurred. Polyoma virus infections, such as the JC virus and BK virus, may result in serious and sometimes fatal outcomes. The JC virus is associated with progressive multifocal leukoencephalopathy (PML), and PML has been reported in patients receiving cyclosporine. PML may be fatal and presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia; consider neurologic consultation as indicated. The BK virus is associated with nephropathy, and polyoma virus-associated nephropathy (PVAN) has been reported in patients receiving cyclosporine. PVAN is associated with serious adverse effects including renal dysfunction and renal graft loss. If PML or PVAN occur in transplant patients, consider reducing immunosuppression therapy as well as the risk that reduced immunosuppression poses to grafts.

• Malignancy: [US Boxed Warning]: Increased risk of lymphomas and other malignancies (including fatal outcomes), particularly skin cancers; risk is related to intensity/duration of therapy and the use of more than one immunosuppressive agent; all patients should avoid excessive sun/UV light exposure.

• Nephrotoxicity: [US Boxed Warning]: Renal impairment, including structural kidney damage has occurred (when used at high doses); risk is increased with increasing doses/duration; monitor renal function closely. Use caution with other potentially nephrotoxic drugs (eg, acyclovir, aminoglycoside antibiotics, amphotericin B, ciprofloxacin); monitor renal function closely with concomitant use. If significant renal impairment occurs, reduce the dose of the coadministered medication or consider alternative treatment. Elevations in serum creatinine and BUN associated with nephrotoxicity generally respond to dosage reductions. In renal transplant patients with rapidly rising BUN and creatinine, carefully evaluate to differentiate between cyclosporine-associated nephrotoxicity and renal rejection episodes. In cases of severe rejection that fail to respond to pulse steroids and monoclonal antibodies, switching to an alternative immunosuppressant agent may be preferred to increasing cyclosporine to excessive blood concentrations.

• Neurotoxicity: May cause seizures, particularly if used with high-dose corticosteroids. Encephalopathy (including posterior reversible encephalopathy syndrome [PRES]) has also been reported; predisposing factors include hypertension, hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine serum concentration, and graft-versus-host disease (GVHD). Encephalopathy may be more common in patients with liver transplant compared to kidney transplant. Other neurotoxic events, such as optic disc edema (including papilloedema and potential visual impairment), have been rarely reported primarily in transplant patients.

• Skin cancer: [US Boxed Warning]: Risk of skin cancer may be increased in psoriasis patients with a history of PUVA and possibly methotrexate or other immunosuppressants, UVB, coal tar, or radiation; increased risk of skin cancer has also been established in transplant patients; risk is related to intensity/duration of therapy and the use of more than one immunosuppressive agent; all patients should avoid excessive sun/UV light exposure.

• Thrombotic microangiopathy: In transplant patients, syndromes of microangiopathic hemolytic anemia and thrombocytopenia have occurred and may result in graft failure; it is accompanied by platelet consumption within the graft. Syndrome may occur without graft rejection. Although management of the syndrome is unclear, discontinuation or reduction of cyclosporine, in addition to streptokinase and heparin administration or plasmapheresis, has been associated with syndrome resolution. However, resolution seems to be dependent upon early detection of the syndrome via indium 111 labeled platelet scans.

Disease-related concerns:

• Hepatic impairment: Cyclosporine has extensive hepatic metabolism and exposure is increased in patients with severe hepatic impairment. May require dose reduction.

• Psoriasis: Appropriate use: If receiving other immunosuppressive agents, radiation or UV therapy, concurrent use of cyclosporine is not recommended.

Concurrent drug therapy issues:

• Cyclosporine combination therapy in renal transplant: Due to the increased risk for nephrotoxicity in renal transplantation, avoid using standard doses of cyclosporine in combination with everolimus; reduced cyclosporine doses are recommended; monitor cyclosporine concentrations closely. Cyclosporine and everolimus combination therapy may increase the risk for proteinuria. Cyclosporine combined with either everolimus or sirolimus may increase the risk for thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TMA/TTP/HUS).

• Drug-drug/drug-food interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Transplant patients: To be used initially with corticosteroids. Make dose adjustments based on cyclosporine blood concentrations. Anaphylaxis has been reported with IV use; reserve for patients who cannot take oral form.

Dosage form specific issues:

• Corn oil: Product may contain corn oil.

• Ethanol: Products may contain ethanol. The alcohol content should be considered in certain patient populations, including pregnant or breast-feeding women, patients with liver disease, seizure disorders, alcohol dependency, or pediatric patients.

• Non-interchangeability of modified/non-modified forms: [US Boxed Warning]: The modified/non-modified formulations are not bioequivalent; cyclosporine (modified) has increased bioavailability as compared to cyclosporine (non-modified) and the products cannot be used interchangeably without close monitoring. Cyclosporine (modified) refers to the oral solution and capsule dosage formulations of cyclosporine in an aqueous dispersion (previously referred to as “microemulsion”).

• Polyoxyethylated castor oil: Cyclosporine for injection contains the vehicle polyoxyethylated castor oil (Cremophor EL), which is associated with hypersensitivity (anaphylactic) reactions. Due to the risk for anaphylaxis, IV cyclosporine should be reserved for use in patients unable to take an oral formulation.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007).

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Other warnings/precautions:

• Experienced physician: [US Boxed Warning]: Prescribing and dosage adjustment should only be under the direct supervision of an experienced physician. Adequate laboratory/medical resources and follow-up are necessary.

• Monitoring of concentrations: Monitor cyclosporine concentrations closely following the addition, modification, or deletion of other medications. [US Boxed Warning]: Cyclosporine non-modified absorption is erratic; monitor blood concentrations closely.

• Vaccines: Live, attenuated vaccines may be less effective; vaccination should be avoided.

Monitoring Parameters

Monitor plasma concentrations periodically and following the addition, modification, or deletion of other medications. Monitor renal function (serum creatinine and BUN) after any cyclosporine dosage changes or addition, modification, or deletion of other medications. Monitor blood pressure after any cyclosporine dosage changes or addition, modification, or deletion of other medications. Monitor for hypersensitivity reactions (IV cyclosporine). Monitor for signs/symptoms of hepatotoxicity, secondary malignancy, infection.

Nephrotic syndrome (Canadian labeling): Baseline blood pressure (2 readings within 2 weeks), fasting serum creatinine (at least 3 levels within 2 weeks), creatinine clearance, urinalysis, CBC, liver function, serum uric acid, serum potassium, and malignancy screening (eg, skin, mouth, lymph nodes). Biweekly monitoring of blood pressure for initial 3 months and then monthly thereafter, frequent monitoring of renal function and periodic cyclosporine trough levels are recommended during therapy. Consider renal biopsy in patients with steroid-dependent minimal change neuropathy who have been maintained on therapy >1 year.

Transplant patients: Cyclosporine trough levels, serum electrolytes, renal function, hepatic function, blood pressure, lipid profile

Psoriasis therapy: Baseline blood pressure, serum creatinine (2 levels each), BUN, CBC, serum magnesium, potassium, uric acid, lipid profile. Biweekly monitoring of blood pressure, complete blood count, serum creatinine, and levels of BUN, uric acid, potassium, lipids, and magnesium during the first 3 months of treatment for psoriasis. Monthly monitoring is recommended after this initial period. (Note: The Canadian labeling recommends bimonthly monitoring of serum creatinine after the initial period if serum creatinine remains stable and cyclosporine dose is ≤2.5 mg/kg daily, and monthly monitoring for higher doses). Also evaluate any atypical skin lesions prior to therapy. Increase the frequency of blood pressure monitoring after each alteration in dosage of cyclosporine.

Rheumatoid arthritis: Baseline blood pressure, and serum creatinine (2 levels each); serum creatinine every 2 weeks for first 3 months, then monthly if patient is stable. Increase the frequency of blood pressure monitoring after each alteration in dosage of cyclosporine. Additional Canadian labeling recommendations include CBC, hepatic function, urinalysis, serum potassium and uric acid (baseline and periodic thereafter).

Pregnancy Risk Factor

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Pregnancy Considerations

Adverse events were not observed following the use of oral cyclosporine in animal reproduction studies (using doses that were not maternally toxic). In humans, cyclosporine crosses the placenta; maternal concentrations do not correlate with those found in the umbilical cord. Cyclosporine may be detected in the serum of newborns for several days after birth (Claris 1993). Based on clinical use, premature births and low birth weight were consistently observed in pregnant transplant patients (additional pregnancy complications also present). Formulations may contain alcohol; the alcohol content should be taken into consideration in pregnant women.

The pharmacokinetics of cyclosporine may be influenced by pregnancy (Grimer 2007). Cyclosporine may be used in pregnant renal, liver, or heart transplant patients (Cowan 2012; EBPG Expert Group on Renal Transplantation 2002; McGuire 2009; Parhar 2012). If therapy is needed for psoriasis, other agents are preferred; however, cyclosporine may be used as an alternative agent along with close clinical monitoring; use should be avoided during the first trimester if possible (Bae 2012). If treatment is needed for lupus nephritis, other agents are recommended to be used in pregnant women (Hahn 2012).

Following transplant, normal menstruation and fertility may be restored within months; however, appropriate contraception is recommended to prevent pregnancy until 1-2 years following the transplant to improve pregnancy outcomes (Cowan 2012; EBPG Expert Group on Renal Transplantation 2002; McGuire 2009; Parhar 2012).

A pregnancy registry has been established for pregnant women taking immunosuppressants following any solid organ transplant (National Transplantation Pregnancy Registry, Temple University, 877-955-6877).

A pregnancy registry has also been established for pregnant women taking Neoral for psoriasis or rheumatoid arthritis (Neoral Pregnancy Registry for Psoriasis and Rheumatoid Arthritis, Thomas Jefferson University, 888-522-5581).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, diarrhea, hair growth, acne, vomiting, or nausea. Have patient report immediately to prescriber signs of infection, signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), gum changes, burning or numbness feeling, angina, tachycardia, arrhythmia, muscle pain, hearing impairment, shortness of breath, tremors, edema, blindness, signs of posterior reversible encephalopathy syndrome (illogical thinking, not alert, vision changes, seizures, or severe headache), or signs of progressive multifocal leukoencephalopathy (confusion, depression, trouble with memory, behavioral changes, change in strength on one side, trouble speaking, change in balance, vision changes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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