CycloSPORINE (Systemic)

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)

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.

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

Acute graft-versus-host disease (prophylaxis) (adults)

Based on the Prophylaxis and Treatment of GVHD: EBMT-ELN Working Group Recommendations for a Standardized Practice, cyclosporine as combination therapy given to prevent acute graft-versus-host disease (aGVHD) is effective and recommended in the management of this condition [Ruutu 2014].

Data from a randomized study support the use of cyclosporine (in combination with methotrexate and prednisone) to prevent aGVHD following allogeneic hematopoietic stem cell transplantation [Chao 1993]. This combination was more effective than using cyclosporine and prednisone alone. Subsequently, data from a follow-up, prospective, randomized study demonstrated that the addition of prednisone did not have an impact on the incidence of acute or chronic GVHD; however, the addition of prednisone was associated with a somewhat lower incidence of early post-transplant complications [Chao 2000]. Further data suggest that the combination of cyclosporine and prednisone with or without methotrexate results in comparable chronic GVHD-free survival [Ross 1999]. A number of other trials support the use of cyclosporine (in combination with methotrexate) for this condition [Ratanatharathorn 1998], [Storb 1986a], [Storb 1986b].

Acute graft-versus-host disease (prophylaxis) (pediatrics)

Data from several studies support the use of cyclosporine as a component of aGVHD prophylaxis following hematopoietic stem cell or marrow transplantation in pediatric patients with primarily hematologic malignancies [Lanino 2009], [Martin 2003], [Nash 2000], [Storb 1986a]. Additional data may be necessary to further define the role of cyclosporine in this condition.

Chronic graft-versus-host disease (treatment)

Based on the American Society for Blood and Marrow Transplant (ASBMT) Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease, the use of calcineurin inhibitors (eg, cyclosporine) is effective and recommended for the treatment of patients with refractory chronic GVHD [Wolff 2011].

Focal segmental glomerulosclerosis

Data from a randomized controlled trial in patients with steroid-resistant focal segmental glomerulosclerosis (FSGS) treated with cyclosporine (in combination with low-dose prednisone) support the use of cyclosporine for this condition [Cattran 1999]. A meta-analysis of trials evaluating the use of various treatment strategies for adult patients with FSGS, demonstrated that treatment with cyclosporine (with or without prednisone) was more likely to achieve partial remission of nephrotic syndrome compared with symptomatic treatment or prednisone alone [Braun 2008]. Additional trials may be necessary to further define the role of cyclosporine for the treatment FSGS.

Immune thrombocytopenia, refractory (adults)

Cyclosporine in the management of refractory or relapsed immune thrombocytopenia (ITP) has primarily been evaluated in non-controlled settings and demonstrated beneficial results in at least half of the patients treated. In consensus guidelines, cyclosporine is recommended as second-line treatment for the management of ITP.

Interstitial cystitis (bladder pain syndrome)

Oral cyclosporine in the management of interstitial cystitis/bladder pain syndrome has been studied in controlled and noncontrolled trials demonstrating high efficacy rates. American Urological Association guidelines recommend oral cyclosporine as a fifth-line treatment option to be considered after other treatment modalities have failed. The guidelines also note that while sustained efficacy has been demonstrated, use of cyclosporine is limited by a high rate of adverse events and the potential for serious events (eg, immunosuppression, hypertension, nephrotoxicity).

Lung transplant (prevention of acute rejection)

Data from a small, prospective, randomized controlled trial support the use of cyclosporine (in combination with other transplant immunosuppressants) for the prevention of acute rejection in lung transplant recipients [Zuckermann 2003]. However, based on a systematic review, tacrolimus may be preferred over cyclosporine for lung transplant immunosuppression [Penninga 2013]. Additional trials may be necessary to further define the role of cyclosporine in the treatment of this condition.

Lupus nephritis

Data from a multicenter, prospective, randomized, open-label, blinded-end point, controlled trial in patients with diffuse proliferative lupus nephritis treated with cyclosporine or azathioprine support the use of cyclosporine (in combination with corticosteroids) in the treatment of this condition [Moroni 2006].

Although a consensus regarding the use of calcineurin inhibitors in the treatment of lupus nephritis was not reached by the American College of Rheumatology, evidence exists for use as an induction agent and during refractory disease [Moroni 2006], [Ogawa 2007].

Nephrotic syndrome (pediatrics)

Data from a randomized, multicenter, open label study support the use of cyclosporine in the treatment of frequently relapsing nephrotic syndrome in pediatric patients [Gellermann 2013].

Based on the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis, cyclosporine is recommended as a corticosteroid-sparing agent for children with frequently relapsing steroid dependent nephrotic syndrome, as well as in patients with steroid resistant nephrotic syndrome [KDIGO 2012].

Psoriasis (pediatrics)

American Academy of Dermatology guidelines state that the evidence for use in pediatric psoriasis was limited. A review of its use in children with several different rheumatologic and dermatologic conditions suggested that the adverse effect profile was similar in adults and children. It was concluded that cyclosporine may be considered for children with severe psoriasis.

Ulcerative colitis, severe refractory

Data from a single center, randomized, double-blind, controlled trial and in patients with severe ulcerative colitis [Van Assche 2003] and in patients with severe ulcerative colitis refractory to intravenous corticosteroid therapy [Lichitiger 1994] support the use of intravenous cyclosporine for the treatment of this condition. Additional trials using oral cyclosporine in patients with severe, refractory ulcerative colitis supports the use of oral cyclosporine in the treatment of this condition [De Saussure 2005], [Weber 2006].

Based on the American College of Gastroenterology Ulcerative Colitis Guidelines in Adults, intravenous cyclosporine is effective and recommended for use when patients with severe ulcerative colitis fail to show significant improvement within 3 to 5 days with intravenous corticosteroid therapy.

Uveitis (adults)

Results from controlled and noncontrolled studies demonstrate that cyclosporine is generally effective in treating noninfectious uveitis. However, limited prospective controlled clinical trials have been performed. Further data are needed to establish the efficacy, safety, optimal dosage, and length of cyclosporine therapy in the treatment of uveitis in adults. An expert review panel recommends cyclosporine as second-line treatment for noninfectious uveitis.

Additional Off-Label Uses

Juvenile idiopathic arthritis (refractory)

Neoral/Gengraf (cyclosporine modified) and Sandimmune (cyclosporine non-modified) are not bioequivalent and cannot be used interchangeably. Use caution when selecting, dispensing, and administrating cyclosporine products; in general, cyclosporine (modified) is more commonly used clinically.

Acute graft versus host disease (aGVHD), prevention (off-label use): Infants, Children, and Adolescents: IV followed by oral: Initial: 3 to 5 mg/kg/day in 2 divided doses (every 12 hours) administered over 2 hours or as a single daily dose administered over 8 hours (Lanino 2009; Martin 2003; Storb 1986a) or 3 mg/kg/day as a continuous infusion (Nash 2000) beginning one day prior to transplant; may be given with or without methotrexate. May convert to oral therapy when tolerating oral intake; titrate dose to appropriate cyclosporine trough concentration (reported doses ranged from 6 to 12.5 mg/kg/day in divided doses every 12 hours); taper per protocol (refer to specific references for tapering and target trough details). Discontinue 6 months post-transplant in the absence of acute GVHD; refer to specific references for discontinuation details (Lanino 2009; Martin 2003; Storb 1986a).

Nephrotic syndrome (off-label use): Children and Adolescents: Oral: Initial: 4 to 5 mg/kg/day in 2 divided doses for at least 12 months or 150 mg/m2/day in 2 divided doses; adjust doses based on trough levels (Gellermann 2013; KDIGO 2012).

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

Psoriasis (severe):

Abnormal renal function prior to treatment: Use is contraindicated.

Abnormal renal function during treatment:

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.

Rheumatoid arthritis:

Abnormal renal function prior to treatment: Use is contraindicated.

Abnormal renal function during treatment: Serum creatinine levels >30% above pretreatment levels: Decrease cyclosporine dosage by 25% to 50%; discontinue if dose reduction is ineffective in controlling serum creatinine elevation or if serum creatinine is severe.

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%.

Hemodialysis: Adults: Supplemental dose is not necessary (Aronoff 2007). Dialysis does not significantly alter cyclosporine clearance.

Peritoneal dialysis: Adults: Supplemental dose is not necessary (Aronoff 2007).

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.

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

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

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

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

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

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

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

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

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

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

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 increase the serum concentration of CycloSPORINE (Systemic). 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

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

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

Ganciclovir-Valganciclovir: May enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Glecaprevir and Pibrentasvir: CycloSPORINE (Systemic) may increase the serum concentration of Glecaprevir and Pibrentasvir. 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

Ibrutinib: CycloSPORINE (Systemic) may increase the serum concentration of Ibrutinib. Management: When treating B-cell malignancies, consider decreasing ibrutinib to 140 mg daily. When treating graft versus host disease, monitor patients closely and reduce the ibrutinib dose as needed based on adverse reactions. Consider therapy modification

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

Isavuconazonium Sulfate: May increase the serum concentration of CycloSPORINE (Systemic). 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

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

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. 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

Neratinib: CycloSPORINE (Systemic) may increase the serum concentration of Neratinib. Management: Avoid concomitant use of neratinib and cyclosporine if possible. If combined, monitor for increased neratinib effects/toxicities. Consider therapy modification

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. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (eg, hypertension) during concomitant therapy with NSAIDs. Consider therapy modification

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

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. 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 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

Probucol: May decrease 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

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

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

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

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

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

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. Consider therapy modification

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

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