Cyclosporine, the active principle in Sandimmune® (cyclosporine) is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea.

Chemically, cyclosporine is designated as [R-[R*,R*-(E )]]-cyclic(L-alanyl-D-alanyl-Nmethyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-α-amino-butyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-Lleucyl).

Sandimmune® Soft Gelatin Capsules (cyclosporine capsules, USP) are available in 25 mg and 100 mg strengths.

Each 25 mg capsule contains:

cyclosporine, USP……………………………..………….25 mg
alcohol, USP dehydrated……………………………..…...max 12.7% by volume

Each 100 mg capsule contains:

cyclosporine, USP……………………………..………….100 mg
alcohol, USP dehydrated……………………………..…...max 12.7% by volume

Inactive Ingredients: corn oil, gelatin, iron oxide red, linoleoyl macrogolglycerides, sorbitol, and titanium dioxide. May also contain glycerol. 100 mg capsules may contain iron oxide yellow.

Sandimmune® Oral Solution (cyclosporine oral solution, USP) is available in 50 mL bottles.

Each mL contains:

cyclosporine, US……………………………..………….100 mg
alcohol, Ph. Helv……………………………..…...12.5% by volume

dissolved in an olive oil, Ph. Helv./Labrafil M 1944 CS (polyoxyethylated oleic glycerides) vehicle which must be further diluted with milk, chocolate milk, or orange juice before oral administration.

Sandimmune® Injection (cyclosporine injection, USP) is available in a 5 mL sterile ampul for I.V. administration.

Each mL contains:

cyclosporine, USP……………………………..………….50 mg
*Cremophor® EL (polyoxyethylated castor oil)…………………650 mg
alcohol, Ph. Helv……………………………..…...32.9% by volume
nitrogen……………………………..…...qs

which must be diluted further with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use.

The chemical structure of cyclosporine (also known as cyclosporin A) is

Last updated on RxList: 10/27/2009

Sandimmune® (cyclosporine) is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. It is always to be used with adrenal corticosteroids. The drug may also be used in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents.

Because of the risk of anaphylaxis, Sandimmune® Injection (cyclosporine injection, USP) should be reserved for patients who are unable to take the soft gelatin capsules or oral solution.

Sandimmune® Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune® Oral Solution (cyclosporine oral solution, USP)

Sandimmune® Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune® Oral Solution (cyclosporine oral solution, USP) have decreased bioavailability in comparison to Neoral® Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral® Oral Solution (cyclosporine oral solution, USP) MODIFIED. Sandimmune® and Neoral® are not bioequivalent and cannot be used interchangeably without physician supervision.

The initial oral dose of Sandimmune® (cyclosporine) should be given 4-12 hours prior to transplantation as a single dose of 15 mg/kg. Although a daily single dose of 14-18 mg/kg was used in most clinical trials, few centers continue to use the highest dose, most favoring the lower end of the scale. There is a trend towards use of even lower initial doses for renal transplantation in the ranges of 10-14 mg/kg/day. The initial single daily dose is continued postoperatively for 1-2 weeks and then tapered by 5% per week to a maintenance dose of 5-10 mg/kg/day. Some centers have successfully tapered the maintenance dose to as low as 3 mg/kg/day in selected renal transplant patients without an apparent rise in rejection rate.

(See Blood Level Monitoring below.)

In pediatric usage, the same dose and dosing regimen may be used as in adults although in several studies, children have required and tolerated higher doses than those used in adults.

Adjunct therapy with adrenal corticosteroids is recommended. Different tapering dosage schedules of prednisone appear to achieve similar results. A dosage schedule based on the patient's weight started with 2.0 mg/kg/day for the first 4 days tapered to 1.0 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Another center started with an initial dose of 200 mg tapered by 40 mg/day until reaching 20 mg/day. After 2 months at this dose, a further reduction to 10 mg/day was made. Adjustments in dosage of prednisone must be made according to the clinical situation.

To make Sandimmune® Oral Solution (cyclosporine oral solution, USP) more palatable, the oral solution may be diluted with milk, chocolate milk, or orange juice preferably at room temperature. Patients should avoid switching diluents frequently. Sandimmune® Soft Gelatin Capsules and Oral Solution should be administered on a consistent schedule with regard to time of day and relation to meals.

Take the prescribed amount of Sandimmune® (cyclosporine) from the container using the dosage syringe supplied after removal of the protective cover, and transfer the solution to a glass of milk, chocolate milk, or orange juice. Stir well and drink at once. Do not allow to stand before drinking. It is best to use a glass container and rinse it with more diluent to ensure that the total dose is taken. After use, replace the dosage syringe in the protective cover. Do not rinse the dosage syringe with water or other cleaning agents either before or after use. If the dosage syringe requires cleaning, it must be completely dry before resuming use. Introduction of water into the product by any means will cause variation in dose.

Sandimmune® Injection (cyclosporine injection, USP)

FOR INFUSION ONLY

Note: Anaphylactic reactions have occurred with Sandimmune® Injection (cyclosporine injection, USP). (See WARNINGS.)

Patients unable to take Sandimmune® Soft Gelatin Capsules or Oral Solution pre-or postoperatively may be treated with the I.V. concentrate. Sandimmune® Injection (cyclosporine injection, USP) is administered at 1/3 the oral dose. The initial dose of Sandimmune® Injection (cyclosporine injection, USP) should be given 4-12 hours prior to transplantation as a single I.V. dose of 5-6 mg/kg/day. This daily single dose is continued postoperatively until the patient can tolerate the soft gelatin capsules or oral solution. Patients should be switched to Sandimmune® Soft Gelatin Capsules or Oral Solution as soon as possible after surgery. In pediatric usage, the same dose and dosing regimen may be used, although higher doses may be required.

Adjunct steroid therapy is to be used. (See aforementioned.)

Immediately before use, the I.V. concentrate should be diluted 1 mL Sandimmune® Injection (cyclosporine injection, USP) in 20 mL-100 mL 0.9% Sodium Chloride Injection or 5% Dextrose Injection and given in a slow intravenous infusion over approximately 2-6 hours.

Diluted infusion solutions should be discarded after 24 hours.

The Cremophor® EL (polyoxyethylated castor oil) contained in the concentrate for intravenous infusion can cause phthalate stripping from PVC.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Blood Level Monitoring

Several study centers have found blood level monitoring of cyclosporine useful in patient management. While no fixed relationships have yet been established, in one series of 375 consecutive cadaveric renal transplant recipients, dosage was adjusted to achieve specific whole blood 24-hour trough levels of 100-200 ng/mL as determined by high-pressure liquid chromatography (HPLC).

Of major importance to blood level analysis is the type of assay used. The above levels are specific to the parent cyclosporine molecule and correlate directly to the new monoclonal specific radioimmunoassays (mRIA-sp). Nonspecific assays are also available which detect the parent compound molecule and various of its metabolites. Older studies often cited levels using a nonspecific assay which were roughly twice those of specific assays. Assay results are not interchangeable and their use should be guided by their approved labeling. If plasma specimens are employed, levels will vary with the temperature at the time of separation from whole blood. Plasma levels may range from 1/2-1/5 of whole blood levels. Refer to individual assay labeling for complete instructions. In addition, Transplantation Proceedings (June 1990) contains position papers and a broad consensus generated at the Cyclosporine-Therapeutic Drug Monitoring conference that year. Blood level monitoring is not a replacement for renal function monitoring or tissue biopsies.

Sandimmune® Soft Gelatin Capsules (cyclosporine capsules, USP)

25 mg: Oblong, pink, branded “78/240”. Unit dose packages of 30 capsules,

3 blister cards of 10 capsules……………..NDC 0078-0240-15

100 mg: Oblong, dusty rose, branded “78/241”. Unit dose packages of 30 capsules,

3 blister cards of 10 capsules……………..NDC 0078-0241-15

Store and Dispense: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

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.

Sandimmune® Oral Solution (cyclosporine oral solution, USP)

Supplied in 50 mL bottles containing 100 mg of cyclosporine per mL

NDC 0078-0110-22

A dosage syringe is provided for dispensing.

Store and Dispense: In the original container at temperatures below 30°C (86°F). Do not store in the refrigerator. Protect from freezing. Once opened, the contents must be used within 2 months.

Sandimmune® Injection (cyclosporine injection, USP)

FOR INTRAVENOUS INFUSION

Supplied as a 5 mL sterile ampul containing 50 mg of cyclosporine per mL, in boxes of 10 ampuls……………..NDC 0078-0109-01

Store and Dispense: At temperatures below 30°C (86°F). Protect from light.

Sandimmune® Soft Gelatin Capsules (cyclosporine capsules, USP)
Manufactured by: Catalent Pharma Solutions, LLC St. Petersburg, Florida 33716 or R.P. Scherer GmbH Eberbach/Baden, Germany. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936. Sandimmune® Oral Solution (cyclosporine oral solution, USP), Manufactured by: Novartis Pharma S.A.S. Huningue, France. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936

Sandimmune® Injection (cyclosporine injection, USP) FOR INFUSION ONLY
Manufactured by: Novartis Pharma Stein AG Stein, Switzerland. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936. Rev: October 2009.

Last updated on RxList: 10/26/2009

The principal adverse reactions of Sandimmune® (cyclosporine) therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.

Hypertension, which is usually mild to moderate, may occur in approximately 50% of patients following renal transplantation and in most cardiac transplant patients.

Glomerular capillary thrombosis has been found in patients treated with cyclosporine and may progress to graft failure. The pathologic changes resemble those seen in the hemolytic-uremic syndrome and include thrombosis of the renal microvasculature, with platelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, and decreased renal function. Similar findings have been observed when other immunosuppressives have been employed posttransplantation.

Hypomagnesemia has been reported in some, but not all, patients exhibiting convulsions while on cyclosporine therapy. Although magnesium-depletion studies in normal subjects suggest that hypomagnesemia is associated with neurologic disorders, multiple factors, including hypertension, high-dose methylprednisolone, hypocholesterolemia, and nephrotoxicity associated with high plasma concentrations of cyclosporine appear to be related to the neurological manifestations of cyclosporine toxicity.

The following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants:

The following reactions occurred in 2% or less of patients: allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, muscle pain, peptic ulcer, thrombocytopenia, tinnitus.

The following reactions occurred rarely: anxiety, chest pain, constipation, depression, hair breaking, hematuria, joint pain, lethargy, mouth sores, myocardial infarction, night sweats, pancreatitis, pruritus, swallowing difficulty, tingling, upper GI bleeding, visual disturbance, weakness, weight loss.

Renal Transplant Patients in Whom Therapy Was Discontinued

Infectious Complications in the Randomized Renal Transplant Patients

Cremophor® EL (polyoxyethylated castor oil) is known to cause hyperlipemia and electrophoretic abnormalities of lipoproteins. These effects are reversible upon discontinuation of treatment but are usually not a reason to stop treatment.

Postmarketing Experience

BK virus associated nephropathy has been observed in patients receiving immunosuppressants, including Sandimmune. This infection is associated with serious outcomes, including deteriorating renal function and renal graft loss (see WARNINGS).

All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition, concomitant nonsteroidal anti-inflammatory drugs, particularly in the setting of dehydration, may potentiate renal dysfunction.

Drugs That May Potentiate Renal Dysfunction

Drugs That Alter Cyclosporine Concentrations

Compounds that decrease cyclosporine absorption such as orlistat should be avoided. Cyclosporine is extensively metabolized by cytochrome P-450 3A. Substances that inhibit this enzyme could decrease metabolism and increase cyclosporine concentrations. Substances that are inducers of cytochrome P-450 activity could increase metabolism and decrease cyclosporine concentrations. Monitoring of circulating cyclosporine concentrations and appropriate Sandimmune® (cyclosporine) dosage adjustment are essential when these drugs are used concomitantly. (See Blood Level Monitoring.)

DRUGS THAT INCREASE CYCLOSPORINE CONCENTRATIONS

The HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 3A and thus could potentially increase the concentrations of cyclosporine, however no formal studies of the interaction are available. Care should be exercised when these drugs are administered concomitantly.

Grapefruit and grapefruit juice affect metabolism, increasing blood concentrations of cyclosporine, thus should be avoided.

DRUGS/DIETARY SUPPLEMENTS THAT DECREASE CYCLOSPORINE CONCENTRATIONS

There have been reports of a serious drug interaction between cyclosporine and the herbal dietary supplement, St. John's Wort. This interaction has been reported to produce a marked reduction in the blood concentrations of cyclosporine, resulting in subtherapeutic levels, rejection of transplanted organs, and graft loss.

Rifabutin is known to increase the metabolism of other drugs metabolized by the cytochrome P-450 system. The interaction between rifabutin and cyclosporine has not been studied. Care should be exercised when these two drugs are administered concomitantly.

Nonsteroidal Anti-inflammatory Drug (NSAID) Interactions

Clinical status and serum creatinine should be closely monitored when cyclosporine is used with nonsteroidal anti-inflammatory agents in rheumatoid arthritis patients. (See WARNINGS.)

Pharmacodynamic interactions have been reported to occur between cyclosporine and both naproxen and sulindac, in that concomitant use is associated with additive decreases in renal function, as determined by ^99mTc-diethylenetriaminepentaacetic acid (DTPA) and (p-aminohippuric acid) PAH clearances. Although concomitant administration of diclofenac does not affect blood levels of cyclosporine, it has been associated with approximate doubling of diclofenac blood levels and occasional reports of reversible decreases in renal function. Consequently, the dose of diclofenac should be in the lower end of the therapeutic range.

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, 7hydroxy 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).

Other Drug Interactions

Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone and HMG-CoA reductase inhibitors (statins). Severe digitalis toxicity has been seen within days of starting cyclosporine in several patients taking digoxin. There are also reports on the potential of cyclosporine to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction. If digoxin or colchicine are used concurrently with cyclosporine, close clinical observation is required in order to enable early detection of toxic manifestations of digoxin or colchicine, followed by reduction of dosage and its withdrawal.

Literature and postmarketing cases of myotoxicity, including muscle pain and weakness, myositis, and rhabdomyolysis, have been reported with concomitant administration of cyclosporine with lovastatin, simvastatin, atorvastatin, pravastatin, and rarely, fluvastatin. When concurrently administered with cyclosporine, the dosage of these statins should be reduced according to label recommendations. Statin therapy needs to be temporarily withheld or discontinued in patients with signs and symptoms of myopathy or those with risk factors predisposing to severe renal injury, including renal failure, secondary to rhabdomyolysis. Cyclosporine should not be used with potassium-sparing diuretics because hyperkalemia can occur. Caution is also required when cyclosporine is coadministered with potassium-sparing drugs (e.g., angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists), potassium-containing drugs as well as in patients on a potassium-rich diet. Control of potassium levels in these situations is advisable.

Elevations in serum creatinine were observed in studies using sirolimus in combination with full-dose cyclosporine. This effect is often reversible with cyclosporine dose reduction. Simultaneous coadministration of cyclosporine significantly increases blood levels of sirolimus. To minimize increases in sirolimus blood concentrations, it is recommended that sirolimus be given 4 hours after cyclosporine administration.

During treatment with cyclosporine, vaccination may be less effective. The use of live vaccines should be avoided. Frequent gingival hyperplasia with nifedipine, and convulsions with high-dose methylprednisolone have been reported.

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.

For additional information on Cyclosporine Drug Interactions please contact Novartis Medical Affairs Department at 888-NOW-NOVA (888-669-6682).

Last updated on RxList: 10/27/2009

(See Boxed Warnings): Sandimmune® (cyclosporine), when used in high doses, can cause hepatotoxicity and nephrotoxicity.

It is not unusual for serum creatinine and BUN levels to be elevated during Sandimmune® (cyclosporine) therapy. These elevations in renal transplant patients do not necessarily indicate rejection, and each patient must be fully evaluated before dosage adjustment is initiated.

Nephrotoxicity has been noted in 25% of cases of renal transplantation, 38% of cases of cardiac transplantation, and 37% of cases of liver transplantation. Mild nephrotoxicity was generally noted 2-3 months after transplant and consisted of an arrest in the fall of the preoperative elevations of BUN and creatinine at a range of 35-45 mg/dl and 2.0-2.5 mg/dl, respectively. These elevations were often responsive to dosage reduction.

More overt nephrotoxicity was seen early after transplantation and was characterized by a rapidly rising BUN and creatinine. Since these events are similar to rejection episodes, care must be taken to differentiate between them. This form of nephrotoxicity is usually responsive to Sandimmune® (cyclosporine) dosage reduction.

Although specific diagnostic criteria which reliably differentiate renal graft rejection from drug toxicity have not been found, a number of parameters have been significantly associated to one or the other. It should be noted however, that up to 20% of patients may have simultaneous nephrotoxicity and rejection.

A form of chronic progressive cyclosporine-associated nephrotoxicity is characterized by serial deterioration in renal function and morphologic changes in the kidneys. From 5%-15% of transplant recipients will fail to show a reduction in a rising serum creatinine despite a decrease or discontinuation of cyclosporine therapy. Renal biopsies from these patients will demonstrate an interstitial fibrosis with tubular atrophy. In addition, toxic tubulopathy, peritubular capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tubular atrophy may be present. Though none of these morphologic changes is entirely specific, a histologic diagnosis of chronic progressive cyclosporine-associated nephrotoxicity requires evidence of these.

When considering the development of chronic nephrotoxicity 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 levels of cyclosporine. This is particularly true during the first 6 posttransplant 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 must be included, 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.

Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated. In patients with persistent high elevations of BUN and creatinine who are unresponsive to dosage adjustments, consideration should be given to switching to other immunosuppressive therapy. In the event of severe and unremitting rejection, it is preferable to allow the kidney transplant to be rejected and removed rather than increase the Sandimmune® (cyclosporine) dosage to a very high level in an attempt to reverse the rejection.

Occasionally patients have developed a syndrome of thrombocytopenia and microangiopathic hemolytic anemia which may result in graft failure. The vasculopathy can occur in the absence of rejection and is accompanied by avid platelet consumption within the graft as demonstrated by Indium 111 labeled platelet studies. Neither the pathogenesis nor the management of this syndrome is clear. Though resolution has occurred after reduction or discontinuation of Sandimmune® (cyclosporine) and 1) administration of streptokinase and heparin or 2) plasmapheresis, this appears to depend upon early detection with Indium 111 labeled platelet scans. (See ADVERSE REACTIONS.)

Significant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and hyperuricemia have been seen occasionally in individual patients.

Hepatotoxicity has been noted in 4% of cases of renal transplantation, 7% of cases of cardiac transplantation, and 4% of cases of liver transplantation. This was usually noted during the first month of therapy when high doses of Sandimmune® (cyclosporine) were used and consisted of elevations of hepatic enzymes and bilirubin. The chemistry elevations usually decreased with a reduction in dosage.

As in patients receiving other immunosuppressants, those patients receiving Sandimmune® (cyclosporine) are at increased risk for development of lymphomas and other malignancies, particularly those of the skin. The increased risk appears related to the intensity and duration of immunosuppression rather than to the use of specific agents. Because of the danger of oversuppression of the immune system, which can also increase susceptibility to infection, Sandimmune® (cyclosporine) should not be administered with other immunosuppressive agents except adrenal corticosteroids. The efficacy and safety of cyclosporine in combination with other immunosuppressive agents have not been determined.

Latent Viral Infections

Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections. These include BK virus-associated nephropathy which has been observed in patients receiving immunosuppressants, including Sandimmune. This infection is associated with serious outcomes, including deteriorating renal function and renal graft loss. Patient monitoring may help detect patients at risk for BK virus-associated nephropathy. Reduction in immunosuppression should be considered for patients who develop evidence of BK virus-associated nephropathy.

There have been reports of convulsions in adult and pediatric patients receiving cyclosporine, particularly in combination with high-dose methylprednisolone.

Encephalopathy has been described both in postmarketing reports and in the literature. Manifestations include impaired consciousness, convulsions, visual disturbances (including blindness), loss of motor function, movement disorders and psychiatric disturbances. In many cases, changes in the white matter have been detected using imaging techniques and pathologic specimens. Predisposing factors such as hypertension, hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine blood concentrations, and graft-versus-host disease have been noted in many but not all of the reported cases. The changes in most cases have been reversible upon discontinuation of cyclosporine, and in some cases, improvement was noted after reduction of dose. It appears that patients receiving liver transplant are more susceptible to encephalopathy than those receiving kidney transplant. Another rare manifestation of cyclosporine-induced neurotoxicity is optic disc edema including papilloedema, with possible visual impairment, secondary to benign intracranial hypertension.

Rarely (approximately 1 in 1000), patients receiving Sandimmune® Injection (cyclosporine injection, USP) have experienced anaphylactic reactions. Although the exact cause of these reactions is unknown, it is believed to be due to the Cremophor® EL (polyoxyethylated castor oil) used as the vehicle for the I.V. formulation. These reactions can consist of flushing of the face and upper thorax, and noncardiogenic pulmonary edema, with acute respiratory distress, dyspnea, wheezing, blood pressure changes, and tachycardia. One patient died after respiratory arrest and aspiration pneumonia. In some cases, the reaction subsided after the infusion was stopped.

Patients receiving Sandimmune® Injection (cyclosporine injection, USP) should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If anaphylaxis occurs, the infusion should be stopped. An aqueous solution of epinephrine 1:1000 should be available at the bedside as well as a source of oxygen.

Anaphylactic reactions have not been reported with the soft gelatin capsules or oral solution which lack Cremophor® EL (polyoxyethylated castor oil). In fact, patients experiencing anaphylactic reactions have been treated subsequently with the soft gelatin capsules or oral solution without incident.

Care should be taken in using Sandimmune® (cyclosporine) with nephrotoxic drugs. (See PRECAUTIONS.)

Because Sandimmune® (cyclosporine) is not bioequivalent to Neoral®, conversion from Neoral® to Sandimmune® (cyclosporine) using a 1:1 ratio (mg/kg/day) may result in a lower cyclosporine blood concentration. Conversion from Neoral® to Sandimmune® (cyclosporine) should be made with increased blood concentration monitoring to avoid the potential of underdosing.

General

Patients with malabsorption may have difficulty in achieving therapeutic levels with Sandimmune® Soft Gelatin Capsules or Oral Solution.

Hypertension is a common side effect of Sandimmune® (cyclosporine) therapy. (See ADVERSE REACTIONS.) Mild or moderate hypertension is more frequently encountered than severe hypertension and the incidence decreases over time. Antihypertensive therapy may be required. Control of blood pressure can be accomplished with any of the common antihypertensive agents. However, since cyclosporine may cause hyperkalemia, potassium-sparing diuretics should not be used. While calcium antagonists can be effective agents in treating cyclosporine-associated hypertension, care should be taken since interference with cyclosporine metabolism may require a dosage adjustment. (See DRUG INTERACTIONS.)

During treatment with Sandimmune® (cyclosporine), vaccination may be less effective and the use of live attenuated vaccines should be avoided.

Laboratory Tests

Renal and liver functions should be assessed repeatedly by measurement of BUN, serum creatinine, serum bilirubin, and liver enzymes.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Cyclosporine gave no evidence of mutagenic or teratogenic effects in appropriate test systems. Only at dose levels toxic to dams, were adverse effects seen in reproduction studies in rats. (See Pregnancy.)

Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the 24-month rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomas significantly exceeded the control rate in the low-dose level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related.

No impairment in fertility was demonstrated in studies in male and female rats.

Cyclosporine has not been found mutagenic/genotoxic in the Ames Test, the V79HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A recent study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave indication of a positive effect (i.e., induction of SCE), at high concentrations in this system. In two published research studies, rabbits exposed to cyclosporine in utero (10 mg/kg/day subcutaneously) demonstrated reduced numbers of nephrons, renal hypertrophy, systemic hypertension and progressive renal insufficiency up to 35 weeks of age. Pregnant rats which received 12 mg/kg/day of cyclosporine intravenously (twice the recommended human intravenous dose) had fetuses with an increased incidence of ventricular septal defect. These findings have not been demonstrated in other species and their relevance for humans is unknown.

An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin's lymphoma and carcinomas of the skin. The risk of malignancies in cyclosporine recipients is higher than in the normal, healthy population, but similar to that in patients receiving other immunosuppressive therapies. It has been reported that reduction or discontinuance of immunosuppression may cause the lesions to regress.

Pregnancy

Pregnancy Category C

Animal studies have shown reproductive toxicity in rats and rabbits. Cyclosporine gave no evidence of mutagenic or teratogenic effects in the standard test systems with oral application (rats up to 17 mg/kg and rabbits up to 30 mg/kg per day orally). Sandimmune® Oral Solution (cyclosporine oral solution, USP) has been shown to be embryo- and fetotoxic in rats and rabbits when given in doses 2-5 times the human dose. At toxic doses (rats at 30 mg/kg/day and rabbits at 100 mg/kg/day), Sandimmune® Oral Solution (cyclosporine oral solution, USP) was embryo-and fetotoxic as indicated by increased pre- and postnatal mortality and reduced fetal weight together with related skeletal retardations. In the well-tolerated dose range (rats at up to 17 mg/kg/day and rabbits at up to 30 mg/kg/day), Sandimmune® Oral Solution (cyclosporine oral solution, USP) proved to be without any embryolethal or teratogenic effects.

There are no adequate and well-controlled studies in pregnant women and therefore, Sandimmune® (cyclosporine) should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus.

In pregnant transplant recipients who are being treated with immunosuppressants, the risk of premature birth is increased. The following data represent the reported outcomes of 116 pregnancies in women receiving Sandimmune® (cyclosporine) during pregnancy, 90% of whom were transplant patients, and most of whom received Sandimmune® (cyclosporine) throughout the entire gestational period. Since most of the patients were not prospectively identified, the results are likely to be biased toward negative outcomes. The only consistent patterns of abnormality were premature birth (gestational period of 28 to 36 weeks) and low birth weight for gestational age. It is not possible to separate the effects of Sandimmune® (cyclosporine) on these pregnancies from the effects of the other immunosuppressants, the underlying maternal disorders, or other aspects of the transplantation milieu. Sixteen fetal losses occurred. Most of the pregnancies (85 of 100) were complicated by disorders; including, preeclampsia, eclampsia, premature labor, abruptio placentae, oligohydramnios, Rh incompatibility and fetoplacental dysfunction. Preterm delivery occurred in 47%. Seven malformations were reported in 5 viable infants and in 2 cases of fetal loss. Twenty-eight percent of the infants were small for gestational age. Neonatal complications occurred in 27%. In a report of 23 children followed up to 4 years, postnatal development was said to be normal. More information on cyclosporine use in pregnancy is available from Novartis Pharmaceuticals Corporation.

A limited number of observations in children exposed to cyclosporine in utero are available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal.

Nursing Mothers

Cyclosporine passes into breast milk. Mothers receiving treatment with Sandimmune® (cyclosporine) should not breast-feed.

Pediatric Use

Although no adequate and well-controlled studies have been conducted in children, patients as young as 6 months of age have received the drug with no unusual adverse effects.

Geriatric Use

Clinical studies of Sandimmune® (cyclosporine) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Last updated on RxList: 10/27/2009

There is a minimal experience with overdosage. Because of the slow absorption of Sandimmune® Soft Gelatin Capsules or Oral Solution, forced emesis would be of value up to 2 hours after administration. Transient hepatotoxicity and nephrotoxicity may occur which should resolve following drug withdrawal. General supportive measures and symptomatic treatment should be followed in all cases of overdosage. Sandimmune® (cyclosporine) is not dialyzable to any great extent, nor is it cleared well by charcoal hemoperfusion. The oral LD₅₀ is 2329 mg/kg in mice, 1480 mg/kg in rats, and > 1000 mg/kg in rabbits. The I.V. LD₅₀ is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.

Sandimmune® Injection (cyclosporine injection, USP) is contraindicated in patients with a hypersensitivity to Sandimmune® (cyclosporine) and/or Cremophor® EL (polyoxyethylated castor oil).

Last updated on RxList: 10/26/2009

Sandimmune® (cyclosporine) is a potent immunosuppressive agent which in animals prolongs survival of allogeneic transplants involving skin, heart, kidney, pancreas, bone marrow, small intestine, and lung. Sandimmune® (cyclosporine) has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, and graft vs. host disease in many animal species for a variety of organs.

Successful kidney, liver, and heart allogeneic transplants have been performed in man using Sandimmune® (cyclosporine).

The exact mechanism of action of Sandimmune® (cyclosporine) is not known. Experimental evidence suggests that the effectiveness of cyclosporine is due to specific and reversible inhibition of immunocompetent lymphocytes in the G₀- or G₁-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although the T-suppressor cell may also be suppressed. Sandimmune® (cyclosporine) also inhibits lymphokine production and release including interleukin-2 or T-cell growth factor (TCGF).

No functional effects on phagocytic (changes in enzyme secretions not altered, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo) or tumor cells (growth rate, metastasis) can be detected in animals. Sandimmune® (cyclosporine) does not cause bone marrow suppression in animal models or man.

The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable. Peak concentrations (Cmax) in blood and plasma are achieved at about 3.5 hours. Cmax and area under the plasma or blood concentration/time curve (AUC) increase with the administered dose; for blood, the relationship is curvilinear (parabolic) between 0 and 1400 mg. As determined by a specific assay, Cmax is approximately 1.0 ng/mL/mg of dose for plasma and 2.7-1.4 ng/mL/mg of dose for blood (for low to high doses). Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients. The bioavailability of Sandimmune® Soft Gelatin Capsules (cyclosporine capsules, USP) is equivalent to Sandimmune® Oral Solution, (cyclosporine oral solution, USP).

Cyclosporine is distributed largely outside the blood volume. In blood, the distribution is concentration dependent. Approximately 33%-47% is in plasma, 4%-9% in lymphocytes, 5%-12% in granulocytes, and 41%-58% in erythrocytes. At high concentrations, the uptake by leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins.

The disposition of cyclosporine from blood is biphasic with a terminal half-life of approximately 19 hours (range: 10-27 hours). Elimination is primarily biliary with only 6% of the dose excreted in the urine.

Cyclosporine is extensively metabolized but there is no major metabolic pathway. Only 0.1% of the dose is excreted in the urine as unchanged drug. Of 15 metabolites characterized in human urine, 9 have been assigned structures. The major pathways consist of hydroxylation of the Cγ-carbon of 2 of the leucine residues, Cη-carbon hydroxylation, and cyclic ether formation (with oxidation of the double bond) in the side chain of the amino acid 3-hydroxyl-N,4-dimethyl-L-2-amino-6-octenoic acid and Ndemethylation of N-methyl leucine residues. Hydrolysis of the cyclic peptide chain or conjugation of the aforementioned metabolites do not appear to be important biotransformation pathways.

Last updated on RxList: 10/26/2009

Patients should be advised that any change of cyclosporine formulation should be made cautiously and only under physician supervision because it may result in the need for a change in dosage.

Patients should be informed of the necessity of repeated laboratory tests while they are receiving the drug. They should be given careful dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia.

Patients using cyclosporine oral solution with its accompanying syringe for dosage measurement should be cautioned not to rinse the syringe either before or after use. Introduction of water into the product by any means will cause variation in dose.

Last updated on RxList: 10/26/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

CYCLOSPORINE SOLUTION - ORAL

(sye-klo-SPORE-een)

COMMON BRAND NAME(S): Sandimmune

WARNING: Cyclosporine is a drug that reduces the body's ability to fight illness/disease (an immunosuppressant), leaving patients vulnerable to infection or other problems (including cancers such as lymphoma). Using other drugs that treat organ transplant rejection along with this drug may increase these tendencies.

Cyclosporine can also cause high blood pressure and kidney problems. The risk of both problems increases with higher doses and longer treatment with this drug. Psoriasis patients who have had certain previous treatments (e.g., PUVA, UVB, coal tar, radiation therapy, methotrexate) are at increased risk to develop skin cancer. Therefore, cyclosporine must be given only under close medical supervision.

Because different brands deliver different amounts of medication, do not switch brands of cyclosporine without your doctor's permission and directions.

Laboratory tests (e.g., kidney function tests, blood tests) may be performed to monitor your progress.

USES: This medication is used to prevent organ rejection in people who have received a liver, kidney, or heart transplant. It is usually taken along with other medications to allow your new organ to function normally. Cyclosporine is also used to treat severe rheumatoid arthritis and a certain skin condition (severe psoriasis). Cyclosporine belongs to a class of drugs known as immunosuppressants. It works by slowing down your body's defense system (immune system) to prevent your body from rejecting a transplanted organ, further damaging your joints (in rheumatoid arthritis patients), or further damaging your skin (in psoriasis patients). For the treatment of psoriasis or arthritis, it is generally used to treat people who cannot take other medications or have not found relief from other treatments.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used to prevent rejection in other types of organ transplants (e.g., cornea, pancreas) or bone marrow transplant. It may also be used to treat other conditions that may be helped by affecting the immune system (e.g., Crohn's disease).

HOW TO USE: Take this medication by mouth, usually twice daily at the same times each day, or take as directed by your doctor. You may take it with or without food, but it is important to choose one way and take every dose that way. Dosage is based on your medical condition, cyclosporine blood level, kidney function, and response to therapy. Follow the dosing schedule for this medication carefully.

To improve the taste of this liquid medication, mix it with milk, chocolate milk, or orange juice. Using the dosing syringe, measure your dose into a cup of milk or orange juice, stir well, and drink as soon as possible. It is best to use a glass cup whenever possible, but a hard plastic cup may also be used. Do not use plastic foam cups. To make sure that all the medication is taken, add more juice to the cup, stir, and drink, then repeat. Dry the outside of the dropper. Do not rinse it in water.

Avoid eating grapefruit or drinking grapefruit juice while being treated with this medication unless your doctor instructs you otherwise. Grapefruit products can increase the amount of this medication in your bloodstream. Consult your doctor or pharmacist for more details.

Use this medication regularly in order to get the most benefit from it. Remember to use it at the same times each day.

This medication works best when the amount of medicine in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals.

If you are taking this drug to treat arthritis, it may take 4-8 weeks to notice improvement, and up to 4 months for the full benefit.

If you are taking this drug to treat psoriasis, it may take 2-4 weeks to notice improvement, and up to 4 months for the full benefit. Your dose will slowly be increased during your therapy with this drug. Inform your doctor if your condition does not improve after 6 weeks of taking the highest recommended dose. If you are taking this medication to treat psoriasis, do not take it continuously for longer than one year unless directed to do so by your doctor.

Headache, nausea, vomiting, diarrhea, stomach upset, acne, cramps, increased hair growth on the face/body, shaking fingers/hands (tremor), swollen/red/painful gums, dizziness, flushing, and high blood pressure may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Your risk of infection may be higher while you are taking this medication. Tell your doctor immediately if any of these symptoms of infection occur: fever, sore throat, flu-like symptoms, painful urination.

Tell your doctor immediately if any of these unlikely but serious side effects occur: severe muscle spasms, fast/irregular heartbeat, muscle weakness, confusion, change in the amount/color of urine, unusual weight gain/loss, tingling of the hands/feet, hearing problems, easy bruising/bleeding, unusual tiredness.

Tell your doctor immediately if any of these rare but very serious side effects occur: dark urine, persistent nausea/vomiting, severe stomach/abdominal pain, yellowing of the skin/eyes, vomit that looks like coffee grounds, change in the appearance or size of skin moles/lesions, changes in skin color, loss of consciousness, mental/mood changes, vision changes, swollen glands, unusual lumps, night sweats.

Seek immediate medical attention if any of these rare but very serious side effects occur: chest pain, seizures.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking cyclosporine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: history of chickenpox/shingles, uncontrolled high blood pressure, cancer, skin lesions of unknown cause, current use of radiation therapy (including phototherapy with PUVA or UVB), kidney problems (for arthritis or psoriasis patients only).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, any recent/current infections, seizures, untreated mineral imbalance (e.g., low magnesium or high potassium), blood disorders, diabetes, a certain gut problem (malabsorption), high blood fats (cholesterol or triglycerides).

This drug may make you dizzy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

This drug may reduce the magnesium levels in your blood. Ask your doctor about adding magnesium to your diet. Your doctor may prescribe a magnesium supplement.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or nasal flu vaccine.

Avoid contact with people who have the flu or other contagious illness.

This drug may increase your risk for developing skin cancer. Avoid prolonged sun exposure, tanning booths and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

This medication may cause swelling and growth of the gums (gingival hyperplasia). Brush your teeth and floss daily to minimize this problem. See your dentist regularly.

The elderly may be at greater risk for the effects on blood pressure and kidneys while using this drug.

This medication should be used only when clearly needed during pregnancy. Cyclosporine used during pregnancy has resulted in newborns with problems such as low birth weight and being born too early (premature). Other more serious problems have also been reported, including death of the unborn baby. Discuss the risks and benefits with your doctor.

This medication passes into breast milk. Therefore, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: aliskiren, bosentan, coal tar, live vaccines, rosuvastatin, tacrolimus.

If you are currently using any of these medications, tell your doctor or pharmacist before starting cyclosporine.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: birth control pills, carvedilol, caspofungin, digoxin, etoposide, ezetimibe, other immunosuppressants (e.g., azathioprine, methotrexate, sirolimus), drugs that worsen kidney problems (e.g., acyclovir, aminoglycoside antibiotics including tobramycin; amphotericin B; colchicine; fibrates including fenofibrate; melphalan; NSAIDs including diclofenac and sulindac; ranitidine; sulfa drugs including sulfamethoxazole; vancomycin), drugs affecting liver enzymes that remove cyclosporine from your system (such as allopurinol; amiodarone; azole antifungals including fluconazole and ketoconazole; barbiturates including phenobarbital; bromocriptine; calcium channel blockers including diltiazem, nicardipine, and verapamil; cimetidine; HIV protease inhibitors including indinavir; imatinib; macrolide antibiotics including erythromycin; certain man-made male hormones such as danazol and methyltestosterone; methylprednisolone; metoclopramide; metronidazole; nafcillin; nefazodone; octreotide; quinupristin/dalfopristin; rifamycins including rifampin; certain anti-seizure drugs including carbamazepine and phenytoin; St. Johns wort; ticlopidine), nifedipine, orlistat, certain quinolones (ciprofloxacin, norfloxacin), other statins (atorvastatin), sulfinpyrazone, temsirolimus, terbinafine, tolterodine, drugs that may increase potassium levels (e.g., ACE inhibitors including lisinopril, ARBs including losartan, potassium supplements, "water pill" including amiloride, spironolactone).

Do not use potassium-containing salt substitutes while taking this medication. Consult your doctor or pharmacist for more information.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Keep all laboratory and medical appointments. Laboratory and/or medical tests (e.g., liver and kidney function, blood pressure, blood mineral levels, uric acid, cyclosporine blood levels) should be performed from time to time to monitor your progress or check for side effects. Consult your doctor for more details.

Have your blood pressure checked regularly while taking this medication. Discuss with your doctor how to monitor your own blood pressure. Inform your doctor of your blood pressure readings.

If you have had an organ transplant, it is recommended that you attend a transplant education class or support group. Learn the symptoms of organ rejection such as a feeling of being ill, fever, pain around the transplanted organ, and signs of a failing transplanted organ (a decrease in the amount of urine with kidney transplant, yellowing of the skin/eyes with liver transplant, shortness of breath/inability to exercise with heart transplant). Seek immediate medical attention if these symptoms of rejection occur.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store in the original container at room temperature below 86 degrees F (30 degrees C). Do not refrigerate or freeze. Once the bottle is opened, use the solution within 2 months. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.