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U.S. Department of Health and Human Services

Safety

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Sandimmune (Cyclosporine, USP) Injection, Oral solution and Gelatin Capsules

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
  • Due to the potential for additive or synergistic impairment of renal function, caution should be exercised when co-administering Sandimmune 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 postmarketing reports and in the literature. Manifestations include impaired consciousness, convulsions, visual .....
Specific Excipients

Anaphylactic Reactions

  • The alcohol content (See DESCRIPTION) of Sandimmune 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. The daily intravenous dose would deliver approximately 15% of the amount of alcohol contained in a standard drink.

PRECAUTIONS

Drug Interactions

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

All of the individual drugs cited below 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) .....During the concomitant use of a drug that may exhibit additive or synergistic renal impairment potential with cyclosporine, close .....

2. Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations

Bosentan

  • 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 healthy subjects resulted in decreases in the cyclosporine mean dosenormalized AUC, Cmax, and trough concentration of approximately 50%, 30% and 60%, respectively, compared to when cyclosporine was given alone. (See also Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents)

Boceprevir

  • Co-administration of boceprevir (800 mg three times daily for 7 days) and cyclosporine (100 mg single dose) in healthy subjects resulted in increases in the mean AUC and Cmax of cyclosporine approximately 2.7-fold and 2-fold, respectively, compared to when cyclosporine was given alone.

Telaprevir

  • Co-administration of telaprevir (750 mg every 8 hours for 11 days) with cyclosporine (10 mg on day 8) in healthy subjects resulted in increases in the mean dose-normalized AUC and Cmax of cyclosporine approximately 4.5-fold and 1.3-fold, respectively, compared to when cyclosporine (100 mg single dose) was given alone.

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

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 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 have 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 Sandimmune formulations should also be taken into account in pregnant women. (See WARNINGS, Special Excipients)

Nursing Mothers

  • Cyclosporine is present in passes into breast milk. Because of the potential for serious adverse drug reactions in nursing infants from Sandimmune, 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. Sandimmune 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)

 

 

August 2012

Summary View

WARNINGS

  • Kidney, Liver and Heart Transplant…
  • Nephrotoxicity…
  • Thrombotic Microangiopathy…
  • Hyperkalemia…
 
  • Hepatotixicity-Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis, and liver failure have been reported in patients treated with cyclosporine…
 
  • Malignancies…
 
  • Serious Infections-Patients receiving immunosuppressants, including Sandimmune, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes.
 
  • Polyoma Virus Infections-Patients receiving immunosuppressants, including Sandimmune are at increased risk for opportunistic infections, including polyoma virus infections…
 
  • Neurotoxicity…
  • Anaphylactic reactions…
  • Conversion from Neoral to Sandimmune…
 

PRECAUTIONS

  • Hypertension…
  • Vaccination…
 
Drug Interactions
  • A.Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety
Other Drugs
  • Methotrexate
 
Drugs that Increase Cyclosporine Concentrations
  • HIV protease inhibitors…
  • Grapefruit Juice…
 
Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations
  • St. John’s Wort…
  • Rifabutin…
  • B. Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents
  • … Aliskiren, Repaglinide, NSAIDs, Sirolimus, Etoposide, and other drugs…
 
  • Digoxin-If digoxin are 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-Cyclosporine should not be used with potassium-sparing diuretics because hyperkalemia can occur…
  • 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 Interaction-Preliminary data indicate that when Methotrexate and Cyclosporine were coadministered 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 -Frequent gingival hyperplasia when with nifedipine is given concurrently with cyclosporine have been reported.
  • Methypredisolone - Convulsions when high dose methylprednisolone is given concomitantly with cyclosporine have been reported.
  • Other Immunosuppressive Drugs and Agents -Psoriasis patients receiving other immunosuppressive agents or radiation therapy (including PUVA and UVB) should not receive concurrent cyclosporine because of the possibility of excessive immunosuppression.
 
  • C. Effect of Cyclosporine on the Efficacy of Live Vaccines
 

ADVERSE REACTIONS

  • Hypertension…
  • Glomerular Capillary Thrombosis…
  • Hypomagnesemia…
  • Clinical Studies…
 
Postmarketing Experience
  • 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.