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U.S. Department of Health and Human Services

Safety

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Neoral (Cyclosporine) Soft Gelatin Capsule and Neoral (Cyclosporine) Oral Solution

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

 

May 2013

Summary View

WARNINGS 

Kidney, Liver, and Heart Transplant/Nephrotoxicity 
  • When considering the development of cyclosporine-associated nephropathy, it is noteworthy that several authors have reported an association between the appearance of interstitial fibrosis and higher cumulative doses or persistently high circulating trough concentrations of cyclosporine. This is particularly true during the first 6 post-transplant months when the dosage tends to be highest and when, in kidney recipients, the organ appears to be most vulnerable to the toxic effects of cyclosporine. Among other contributing factors to the development of interstitial fibrosis in these patients are prolonged perfusion time, warm ischemia time, as well as episodes of acute toxicity, and acute and chronic rejection. The reversibility of interstitial fibrosis and its correlation to renal function have not yet been determined. Reversibility of arteriolopathy has been reported after stopping cyclosporine or lowering the dosage.
  • In the event of severe and unremitting rejection, when rescue therapy with pulse steroids and monoclonal antibodies fail to reverse the rejection episode, it may be preferable to switch to alternative immunosuppressive therapy rather than increase the Neoral® dose to excessive blood concentrations.
  • Due to the potential for additive or synergistic impairment of renal function, caution should be exercised when co-administering Neoral with other drugs that may impair renal function. (See PRECAUTIONS, Drug Interactions)
Kidney, Liver, and Heart Transplant/Neurotoxicity 
  • Encephalopathy, including Posterior Reversible Encephalopathy Syndrome (PRES), has been described both in post-marketing reports and in the literature. Manifestations include …..
Special Excipients 

Alcohol (ethanol) 

  • The alcohol content (See DESCRIPTION) of Neoral should be taken into account when given to patients in whom alcohol intake should be avoided or minimized, e.g. pregnant or breast feeding women, in patients presenting with liver disease or epilepsy, in alcoholic patients, or pediatric patients. For an adult weighing 70 kg, the maximum daily oral dose would deliver about 1 gram of alcohol which is approximately 6% of the amount of alcohol contained in a standard drink.

PRECAUTIONS

Drug Interactions

Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety

  • All of the individual drugs cited below (see table) are well substantiated to interact with cyclosporine. In addition, concomitant use of nonsteroidal anti-inflammatory drugs with cyclosporine, particularly in the setting of dehydration, may potentiate renal dysfunction. Caution should be exercised when using other drugs which are known to impair renal function. (See WARNINGS, Nephrotoxicity)

Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations 

three new subsections has been added after the table as follows:

Bosentan /Boceprevir/Telaprevir 

  • Co-administration of bosentan (250 - 1000 mg every 12 hours based on tolerability) and cyclosporine (300 mg every 12 hours for 2 days then dosing to achieve a Cmin of 200-250 ng/mL) for 7 days in ……

Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents 

subsection is revised and four new subsections added as follows:

Ambrisentan

  • Co-administration of ambrisentan (5 mg daily) and cyclosporine (100-150 mg twice daily initially, then dosing to achieve Cmin 150-200 ng/mL) for 8 days in healthy subjects resulted in mean increases in ambrisentan AUC and Cmax of approximately 2-fold and 1.5-fold, respectively, compared to ambrisentan alone

Anthracycline antibiotics

  • High doses of cyclosporine (e.g., at starting intravenous dose of 16 mg/kg/day) may increase the exposure to anthracycline antibiotics (e.g., doxorubicin, mitoxantrone, daunorubicin) in cancer patients.

Bosentan

  • In healthy subjects, co-administration of bosentan and cyclosporine resulted in mean increases in dose-normalized bosentan trough concentrations on day 1 and day 8 of approximately 21-fold and 2-fold, respectively, compared to when bosentan was given alone as a single dose on day 1 (See also Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety).

Nifedipine

  • Frequent gingival hyperplasia when nifedipine is given concurrently with cyclosporine has been reported. The concomitant use of nifedipine should be avoided in patients in whom gingival hyperplasia develops as a side effect of cyclosporine.

Pregnancy Pregnancy Category C 

  • The alcohol content of the Neoral formulations should also be taken into account in pregnant women. (See WARNINGS, Special Excipients)

Nursing Mothers 

  • Cyclosporine is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from Neoral, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Neoral contains ethanol. Ethanol will be present in human milk at levels similar to that found in maternal serum and if present in breast milk will be orally absorbed by a nursing infant. (See WARNINGS)

ADVERSE REACTIONS 

Postmarketing Experience, Psoriasis
  • Cases of transformation to erythrodermic psoriasis or generalized pustular psoriasis upon either withdrawal or reduction of cyclosporine in patients with chronic plaque psoriasis have been reported.

 

August 2012

Summary View

 

WARNINGS

Kidney, Liver, and Heart Transplant
  • Nephrotoxicity
  • Thrombotic Microangiopathy…
  • Hepatotoxicity-Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure have been reported in patients treated with cyclosporine…
  • Serious Infections-Patients receiving immunosuppressants, including Neoral, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections
  • Polyoma Virus Infections-Patients receiving immunosuppressants including Neoral are at increased risk for opportunistic infections, including polyoma virus infections…
  • Neurotoxicity…
 

PRECAUTIONS

Drug Interactions
A. Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety…
1. Drugs That Increase Cyclosporine Concentrations
  • HIV protease inhibitors…
  • Grapefruit…
 

2. Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations

  • St. John’s Word…
  • Rifabutin…
 
  • B. Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents
  • and, Aliskiren, Repaglinide, NSAIDs, Sirolimus, Etoposide, and other drugs. See the full prescribing information of the other drug for further information and specific recommendations...
  • Digoxin-If digoxin is used concurrently with cyclosporine, serum digoxin concentrations should be monitored.
  • Colchicine- Concomitant administration of cyclosporine and Colchicine results in significant increases in Colchicine plasma concentrations…a reduction in the dosage of Colchicine is recommended.
 
  • HMG-CoA reductase inhibitors (statins)…
  • Repaglinide…
 
  • Aliskiren- Cyclosporine alters the pharmacokinetics of aliskiren, a substrate of P-glycoprotein and CYP3A4…
  • Potassium-Sparing Diuretics…
  • Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)-Clinical status and serum creatinine should be closely monitored when cyclosporine is used with nonsteroidal anti-inflammatory agents in rheumatoid arthritis patients…
  • Methotrexate InteractionPreliminary data indicate that when methotrexate and cyclosporine were co-administered to rheumatoid arthritis patients (N=20), methotrexate concentrations (AUCs) were increased approximately 30% and the concentrations (AUCs) of its metabolite, 7-hydroxy methotrexate, were decreased by approximately 80%. The clinical significance of this interaction is not known. Cyclosporine concentrations do not appear to have been altered (N=6).
 
  • Sirolimus…
  • Nifedipine… is given concurrently with cyclosporine have been reported.
  • Methypredinisolone… is given concomitantly with cyclosporine…
  • Other Immunosuppressive Drugs and Agents…
  • Effect of Cyclosporine on the Efficacy of Live Vaccines-During treatment with cyclosporine, vaccination may be less effective. The use of live vaccines should be avoided.
 

ADVERSE REACTIONS

Kidney, Liver, and Heart Transplantation
  • Hypertension…
  • Glomerular Capillary Thrombosis…
  • Hypomagnesemia…
  • Clinical Studies…migraine…
 
Postmarketing Experience
Kidney, Liver and Heart Transplantation
  • Hepatotoxicity-Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure; serious and/or fatal outcomes have been reported.
  • Increased Risk of Infections-Cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), sometimes fatal; and polyoma virus-associated nephropathy (PVAN), especially due to BK virus, resulting in graft loss, have been reported.
  • Headache, including Migraine-Cases of migraine have been reported. In some cases, patients have been unable to continue cyclosporine, however the final decision on treatment discontinuation should be made by the treating physician following the careful assessment of benefits versus risks.