Rx Drugs Info

cyclosporine (Cyclosporinecapsule, liquid filled 
[Apotex Corp.]

WARNING

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Cyclosporine Capsules USP NON-MODIFIED. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Cyclosporine Capsules USP NON-MODIFIED should be administered with adrenal corticosteroids but not with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.

Cyclosporine Soft Gelatin Capsules USP (NON-MODIFIED) have decreased bioavailability in comparison to Neoral®* (cyclosporine capsules, USP) MODIFIED.

Cyclosporine Capsules USP (NON-MODIFIED) and Neoral® (cyclosporine capsules, USP) MODIFIED are not bioequivalent and cannot be used interchangeably without physician supervision.

The absorption of cyclosporine during chronic administration Cyclosporine Capsules USP NON-MODIFIED was found to be erratic.  It is recommended that patients taking Cyclosporine Capsules USP NON-MODIFIED over a period of time be monitored at repeated intervals for cyclosporine blood levels and subsequent dose adjustments be made in order to avoid toxity due to high levels and possible organ rejection due to low absorption of cyclosporine.  This is of special importance in liver transplants.  Numerous assays are being developed to measure blood levels of cyclosporine.  Comparison of levels in published literature to patient levels using current assays must be done with detailed knowledge of the assay methods employed.  (See Blood Level Monitoring under DOSAGE AND ADMINISTRATION)

DESCRIPTION

Cyclosporine, the active principle in Cyclosporine Capsules USP is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Tolypocladium inflatum Gams.

Chemically, cyclosporine is designated as [R-[R*,R*-(E)]]-cyclic(L-alanyl-D-alanyl-N-methyl-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-L-leucyl).

Cyclosporine Capsules USP are available in 25 mg and 100 mg strengths.

Each 25 mg capsule contains:
cyclosporine, USP……………………………………………………………………...25 mg

Each 100 mg capsule contains:
cyclosporine, USP……………………………………………………..……………...100 mg

Each capsules contains the following inactive ingredients: methanol, purified water, sodium lauryl sulfate and talc.  The 25 mg and the 100 mg capsule shell contains gelatin, red iron oxide and titanium dioxide.

The 25 mg and 100 mg capsule black imprinting ink contains the following inactive ingredients: n-butyl alcohol, D&C yellow #10 aluminum lake, FD&C blue #1 aluminum lake, FD&C blue #2 aluminum lake, FD&C red #40 aluminum lake, pharmaceutical glaze, propylene glycol, SDA-3A alcohol and synthetic black iron oxide.

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

Image from Drug Label Content

CLINICAL PHARMACOLOGY

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. 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 cyclosporine. The exact mechanism of action of 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. 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. 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 to 1.4 ng/mL/mg of dose for blood (for low to high doses).

Cyclosporine is distributed largely outside the blood volume. In blood, the distribution is concentration dependent. Approximately 33% to 47% is in plasma, 4% to 9% in lymphocytes, 5% to 12% in granulocytes, and 41% to 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 to 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 N-demethylation 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.

INDICATIONS AND USAGE

Cyclosporine Capsules USP are 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.   

CONTRAINDICATIONS

Cyclosporine capsules are contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation.

WARNINGS

(See boxed WARNINGS): Cyclosporine Capsules USP NON-MODIFIED, when used in high doses, can cause hepatotoxicity and nephrotoxicity.

It is not unusual for serum creatinine and BUN levels to be elevated during 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 to 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 to 45 mg/dl and 2.0 to 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 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.

Nephrotoxicityvs. Rejection
Parameter Nephrotoxicity Rejection
History Donor > 50 years old or hypotensive Antidonor immune response
Prolonged kidney preservation Retransplant patient
Prolonged anastomosis time
Concomitant nephrotoxic drugs
Clinical Often > 6 weeks postopb Often < 4 weeks postopb
Prolonged initial nonfunction  Fever > 37.5°C
(acute tubular necrosis) Weight gain > 0.5 kg
Graft swelling and tenderness
Decrease in daily urine volume > 500 mL 
(or 50%)
Laboratory CyA serum trough level > 200 ng/mL CyA serum trough level < 150 ng/mL
Gradual rise in Cr (< 0.15 mg/dl/day)a Rapid rise in Cr (> 0.3 mg/dl/day)a
Cr plateau < 25% above baseline Cr > 25% above baseline
BUN/Cr ≥ 20 BUN/Cr < 20
Biopsy Arteriolopathy (medial hypertrophya, Endovasculitisc (proliferationa,
hyalinosis, nodular deposits, intimal  intimal arteritisb, necrosis, sclerosis)
thickening, endothelial vacuolization,
progressive scarring)
Tubular atrophy, isometric vacuolization, Tubulitis with RBCb and WBCb casts,
isolated calcifications some irregular vacuolization
Minimal edema Interstitial edemac and hemorrhageb
Mild focal infiltratesc Diffuse moderate to severe mononuclear
infiltratesd
Diffuse interstitial fibrosis, Glomerulitis (mononuclear cells)c
often striped form
Aspiration Cytology CyA deposits in tubular and Inflammatory infiltrate with mononuclear phagocytes,
endothelial cells macrophages, lymphoblastoid cells, and
activated T-cells
Fine isometric vacuolization of
tubular cells
These strongly express HLA-DR antigens
Urine Cytology Tubular cells with vacuolization and Degenerative tubular cells, plasma cells, and
granularization lymphocyturia > 20% of sediment
Manometry Intracapsular pressure < 40 mm Hgb Intracapsular pressure > 40 mm Hgb
Ultrasonography Unchanged graft cross-sectional area Increase in graft cross-sectional area
AP diameter ≥ Transverse diameter
Magnetic Resonance Normal appearance Loss of distinct corticomedullary junction, swelling,
Imagery image intensity of parachyma approaching that
of psoas, loss of hilar fat
Radionuclide Scan Normal or generally decreased perfusion Patchy arterial flow
Decrease in tubular function Decrease in perfusion > decrease in tubular function
(131 I-hippuran) > decrease in perfusion Increased uptake of Indium 111 labeled platelets or
(99m Tc DTPA) Tc-99m in colloid
Therapy Responds to decreased Sandimmune®  Responds to increased steroids or
(cyclosporine) antilymphocyte globulin

ap < 0.05, bp < 0.01, cp < 0.001, dp < 0.0001

A form of chronic progressive cyclosporine-associated nephrotoxicity is characterized by serial deterioration in renal function and morphologic changes in the kidneys. From 5% to 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 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 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 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 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, 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.

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.

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

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

PRECAUTIONS

General

Patients with malabsorption may have difficulty in achieving therapeutic levels with cyclosporine.

Hypertension is a common side effect of 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 Cyclosporine Capsules USP NON-MODIFIED, vaccination may be less effective and the use of live attenuated vaccines should be avoided.

Information for Patients

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.

Laboratory Tests

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


Drug Interactions

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

Antibiotics Antineoplastic Antifungals Anti-
Inflammatory

Drugs
Gastrointestinal
Agents
Immunosuppressives Other Drugs
ciprofloxacin melphalan amphotericin B azapropazon cimetidine tacrolimus fibric acid
derivatives
gentamicin ketoconazole colchicine ranitidine (e.g., bezafibrate,
fenofibrate)
tobramycin diclofenac
trimethoprim 
with sulfamethoxazole
naproxen
vancomycin sulindac

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 cyclosporine dosage adjustment are essential when these drugs are used concomitantly. (See Blood Concentration Monitoring.)

Drugs That Increase Cyclosporine Concentrations

Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem fluconazole azithromycin methylprednisolone allopurinol
nicardipine itraconazole clarithromycin amiodarone
verapamil ketoconazole erythromycin bromocriptine
quinupristin/ dalfopristin colchicine
danazol
imatinib
metoclopramide
oral contraceptives

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

Antibiotics Anticonvulsants Other Drugs /Dietary Supplements
nafcillin carbamazepine octreotide  St. John’s Wort
rifampin phenobarbital orlistat
phenytoin sulfinpyrazone
terbinafine
ticlopidine

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 subtherapeuticlevels, 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, 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).

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.

     

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 V79-HGPRT 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). 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), 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), 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, 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 cyclosporine during pregnancy, 90% of whom were transplant patients, and most of whom received 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 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.

A limited number of observations in children exposed to cyclosporine in utero is 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 Cyclosporine Capsules USP 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 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.

ADVERSE REACTIONS

The principal adverse reactions of 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:

Randomized
Kidney Patients
All Cyclosporine
Patients
Cyclosporine Azathioprine Kidney Heart Liver
Body System/ (N=227) (N=228) (N=705) (N=112) (N=75)
      Adverse Reactions % % % % %
Genitourinary
      Renal Dysfunction 32 6 25 38 37
Cardiovascular
      Hypertension 26 18 13 53 27
      Cramps 4 < 1 2 < 1 0
Skin
      Hirsutism 21 < 1 21 28 45
      Acne 6 8 2 2 1
Central Nervous System
      Tremor 12 0 21 31 55
      Convulsions 3 1 1 4 5
      Headache 2 < 1 2 15 4
Gastrointestinal
      Gum Hyperplasia 4 0 9 5 16
      Diarrhea 3 < 1 3 4 8
      Nausea/Vomiting 2 < 1 4 10 4
      Hepatotoxicity < 1 < 1 4 7 4
      Abdominal Discomfort < 1 0 < 1 7 0
Autonomic Nervous System
      Paresthesia 3 0 1 2 1
      Flushing < 1 0 4 0 4
Hematopoietic
      Leukopenia 2 19 < 1 6 0
      Lymphoma < 1 0 1 6 1
Respiratory
      Sinusitis < 1 0 4 3 7
Miscellaneous
      Gynecomastia < 1 0 < 1 4 3

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
Randomized
Patients
All Cyclosporine
Patients
Cyclosporine Azathioprine
(N=227) (N=228) (N=705)
Reason for Discontinuation % % %
Renal Toxicity 5.7 0 5.4
Infection 0 0.4 0.9
Lack of Efficacy 2.6 0.9 1.4
Acute Tubular Necrosis 2.6 0 1.0
Lymphoma/Lymphoproliferative Disease 0.4 0 0.3
Hypertension 0 0 0.3
Hematological Abnormalities 0 0.4 0
Other 0 0 0.7
Cyclosporine was discontinued on a temporary basis and then restarted in 18 additional patients.

Infectious Complications in the Randomized Renal Transplant Patients
 Cyclosporine Treatment Standard Treatment*
(N=227) (N=228)
Complication % of Complications % of Complications
Septicemia 5.3 4.8
Abscesses 4.4 5.3
Systemic Fungal Infection 2.2 3.9
Local Fungal Infection 7.5 9.6
Cytomegalovirus 4.8 12.3
Other Viral Infections 15.9 18.4
Urinary Tract Infections 21.1 20.2
Wound and Skin Infections 7.0 10.1
Pneumonia 6.2 9.2

*Some patients also received ALG.

    

OVERDOSAGE

There is a minimal experience with overdosage. Because of the slow absorption of Cyclosporine Capsules USP NON-MODIFIED, 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. 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.

DOSAGE AND ADMINISTRATION

Cyclosporine Capsules USP NON-MODIFIED 

Cyclosporine Capsules USP (NON-MODIFIED) have decreased bioavailability in comparison to Neoral®* (cyclosporine capsules, USP) MODIFIED. Cyclosporine Capsules USP (NON-MODIFIED) and Neoral®* (cyclosporine capsules, USP) MODIFIED are not bioequivalent and cannot be used interchangeably without physician supervision.

The initial oral dose of Cyclosporine Capsules USP NON-MODIFIED should be given 4 to 12 hours prior to transplantation as a single dose of 15 mg/kg. Although a daily single dose of 14 to 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 to 14 mg/kg/day. The initial single daily dose is continued postoperatively for 1 to 2 weeks and then tapered by 5% per week to a maintenance dose of 5 to 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.

Cyclosporine Capsules USP NON-MODIFIED should be administered on a consistent schedule with regard to time of day and relation to meals.

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 to 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 to 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.

HOW SUPPLIED

Cyclosporine Capsules USP NON-MODIFIED

25 mg

Hard gelatin capsules with a pale reddish brown opaque body and a pale reddish brown opaque cap.  "APO" over "133" and "25" are imprinted on each capsule in black ink; supplied in bottles of 30 (NDC 60505-0133-0), in bottles of 500 (NDC 60505-0133-2), and in bottles of 1000 (NDC 60505-0133-1).

100 mg

Hard gelatin capsules with a reddish brown opaque body and a reddish brown opaque cap.  "APO" over "134" and "100" are imprinted on each capsule in black ink; supplied in bottles of 30 (NDC 60505-0134-0), in bottles of 500 (NDC 60505-0134-2), and in bottles of 1000 (NDC 60505-0134-1).

Store and Dispense

Store at 20° to 25°C (66° to 77°F); excursions permited to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Dispense in a tight, light-resistant container [see USP].

APOTEX INC.
CYCLOSPORINE CAPSULES USP
25 mg and 100 mg

Manufactured by:                  Manufactured for:
Apotex Inc.                             Apotex Corp.
Toronto, Ontario                      Weston, Florida
Canada M9L 1T9                     33326

Rev: April 2006
Rev. 5

*Neoral® (cyclosporine capsules, USP) MODIFIED manufactured by Novartis.


Cyclosporine (Cyclosporine)
PRODUCT INFO
Product Code 60505-0133 Dosage Form CAPSULE, LIQUID FILLED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
cyclosporine (cyclosporine) Active 25 MILLIGRAM  In 1 CAPSULE
methanol Inactive  
water Inactive  
sodium lauryl sulfate Inactive  
talc Inactive  
gelatin Inactive  
red iron oxide Inactive  
titanium dioxide Inactive  
n-butyl alcohol Inactive  
D&C yellow #10 aluminum lake Inactive  
FD&C blue #1 aluminum lake Inactive  
FD&C blue #2 aluminum lake Inactive  
FD&C red #40 aluminum lake Inactive  
pharmaceutical glaze Inactive  
propylene glycol Inactive  
SDA-3A alcohol Inactive  
synthetic black iron oxide Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color BROWN Score 1
Shape CAPSULE Symbol false
Imprint Code APO;133;25 Coating false
Size 14mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 60505-0133-0 30 CAPSULE In 1 BOTTLE None
2 60505-0133-2 500 CAPSULE In 1 BOTTLE None
3 60505-0133-1 1000 CAPSULE In 1 BOTTLE None

Cyclosporine (Cyclosporine)
PRODUCT INFO
Product Code 60505-0134 Dosage Form CAPSULE, LIQUID FILLED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
cyclosporine (cyclosporine) Active 100 MILLIGRAM  In 1 CAPSULE
methanol Inactive  
water Inactive  
sodium lauryl sulfate Inactive  
talc Inactive  
gelatin Inactive  
red iron oxide Inactive  
titanium dioxide Inactive  
n-butyl alcohol Inactive  
D&C yellow #10 aluminum lake Inactive  
FD&C blue #1 aluminum lake Inactive  
FD&C blue #2 aluminum lake Inactive  
FD&C red #40 aluminum lake Inactive  
pharmaceutical glaze Inactive  
propylene glycol Inactive  
SDA-3A alcohol Inactive  
synthetic black iron oxide Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color BROWN Score 1
Shape CAPSULE Symbol false
Imprint Code APO;134;100 Coating false
Size 16mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 60505-0134-0 30 CAPSULE In 1 BOTTLE None
2 60505-0134-2 500 CAPSULE In 1 BOTTLE None
3 60505-0134-1 1000 CAPSULE In 1 BOTTLE None

Revised: 02/2007Apotex Corp.

Data are from FDA and U.S. National Library of Medicine.