Cyclosporine, USP, the active principle in cyclosporine capsules, USP (NON-MODIFIED) 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 (NON-MODIFIED) 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 capsule contains the following inactive ingredients: methanol, 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:

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 G 0- or G 1-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 (C max) in blood and plasma are achieved at about 3.5 hours. C max 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, C max is approximately 1 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.

Specific Populations
Renal Impairment
In a study performed in 4 subjects with end-stage renal disease (creatinine clearance <5 mL/min), an intravenous infusion of 3.5 mg/kg of cyclosporine over 4 hours administered at the end of a hemodialysis session resulted in a mean volume of distribution (Vdss) of 3.49 L/kg and systemic clearance (CL) of 0.369 L/hr/kg. This systemic CL (0.369 L/hr/kg) was approximately two thirds of the mean systemic CL (0.56 L/hr/kg) of cyclosporine in historical control subjects with normal renal function. In 5 liver transplant patients, the mean clearance of cyclosporine on and off hemodialysis was 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose of cyclosporine was recovered in the dialysate.

Hepatic Impairment
Cyclosporine is extensively metabolized by the liver. Since severe hepatic impairment may result in significantly increased cyclosporine exposures, the dosage of cyclosporine may need to be reduced in these patients.

Cyclosporine capsules, (NON-MODIFIED) 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.

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

Kidney, Liver, and Heart Transplant
Cyclosporine capsules, (NON-MODIFIED), when used in high doses, can cause hepatotoxicity and nephrotoxicity (see Boxed Warning.)

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 capsules 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% 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 concentrations 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 capsules dosage to a very high level in an attempt to reverse the rejection.

Due to the potential for additive or synergistic impairment of renal function, caution should be exercised when coadministering cyclosporine capsules with other drugs that may impair renal function (see PRECAUTIONS, Drug Interactions).

Thrombotic Microangiopathy
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 capsules 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).

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

Hepatotoxicity
Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis, and liver failure have been reported in patients treated with cyclosporine. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see ADVERSE REACTIONS, Postmarketing Experience).

Hepatotoxicity, usually manifested by elevations in hepatic enzymes and bilirubin, was reported in patients treated with cyclosporine in clinical trials: 4% in renal transplantation, 7% in cardiac transplantation, and 4% in liver transplantation. This was usually noted during the first month of therapy when high doses of cyclosporine capsules were used. The chemistry elevations usually decreased with a reduction in dosage.

Malignancies
As in patients receiving other immunosuppressants, those patients receiving cyclosporine capsules 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 capsules 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. Some malignancies may be fatal. Transplant patients receiving cyclosporine are at increased risk for serious infection with fatal outcome.

Serious Infections
Patients receiving immunosuppressants, including cyclosporine capsules are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes (see BOXED WARNING, and ADVERSE REACTIONS).

Polyoma Virus Infections
Patients receiving immunosuppressants, including cyclosporine capsules, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes, fatal outcomes. These include cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), and polyoma virus-associated nephropathy (PVAN), especially due to BK virus infection, which have been observed in patients receiving cyclosporine.

PVAN is associated with serious outcomes, including deteriorating renal function and renal graft loss, (see ADVERSE REACTIONS, Postmarketing Experience). Patient monitoring may help detect patients at risk for PVAN.

Cases of PML have been reported in patients treated with cyclosporine capsules. PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.

Consideration should be given to reducing the total immunosuppression in transplant patients who develop PML or PVAN. However, reduced immunosuppression may place the graft at risk.

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

Encephalopathy, including Posterior Reversible Encephalopathy Syndrome (PRES), 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.

Specific Excipients
Alcohol (methanol)
The alcohol content (see DESCRIPTION) of cyclosporine capsules should be taken into account when given to patients in whom alcohol intake should be avoided or minimized, e.g. pregnant or breastfeeding women, in patients presenting with liver disease or epilepsy, in alcoholic patients, or pediatric patients. For an adult weighing 70 kg, the maximum daily oral dose would deliver about 1 gram of alcohol. (See DESCRIPTIONfor alcohol content of each formulation).

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

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

The principal adverse reactions of cyclosporine capsules therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.

Hypertension
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
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 post transplantation.

Hypomagnesemia
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.

Clinical Studies
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.

Cyclosporine capsules was discontinued on a temporary basis and then restarted in 18 additional patients.

Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine-containing regimens, are at increased risk of infections (viral, bacterial, fungal, and parasitic). Both generalized and localized infections can occur. Preexisting infections may also be aggravated. Fatal outcomes have been reported (see WARNINGS).

There is a minimal experience with overdosage. Because of the slow absorption of cyclosporine capsules, forced emesis and gastric lavage would be of value up to 2 hours after administration. Transient hepatotoxicity and nephrotoxicity may occur which should resolve following drug withdrawal. Oral doses of cyclosporine up to 10 g (about 150 mg/kg) have been tolerated with relatively minor clinical consequences, such as vomiting, drowsiness, headache, tachycardia, and in a few patients, moderately severe, reversible impairment of renal function. However, serious symptoms of intoxication have been reported following accidental parenteral overdosage with cyclosporine in premature neonates. General supportive measures and symptomatic treatment should be followed in all cases of overdosage. Cyclosporine capsules is not dialyzable to any great extent, nor is it cleared well by charcoal hemoperfusion. The oral LD 50 is 2,329 mg/kg in mice, 1,480 mg/kg in rats, and >1,000 mg/kg in rabbits. The intravenous (IV) LD 50 is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.

Cyclosporine capsules, USP (NON-MODIFIED)

25 mg
Pale reddish brown opaque body, pale reddish brown opaque cap, hard gelatin capsule, imprinted "APO" over "133" and "25" in black ink; supplied in unit dose packages of 30 (5 × 6) NDC 68084-879-25.

100 mg
Reddish brown opaque body, reddish brown opaque cap, hard gelatin capsule, imprinted "APO" over "134" and "100" in black ink; supplied in unit dose packages of 30 (5 x 6) NDC 68084-921-25.

Store and Dispense
Store at 20°C to 25°C (66°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

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

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Apotex Corp. as follows:
(25 mg / 30 UD) NDC 68084-879-25 packaged from NDC 60505-0133
(100 mg / 30 UD) NDC 68084-921-25 packaged from NDC 60505-0134

Distributed by:
American Health Packaging
Columbus, OH 43217

8287925/0424F

NDC 68084- 879-25

CycloSPORINE
Capsules, USP

25 mg

30 Capsules (5 x 6)             Rx Only

WARNING: Cyclosporine Capsules, USP
(NON-MODIFIED) is NOT BIOEQUIVALENT to
Neoral ®* (cyclosporine capsules, USP)
MODIFIED. Do NOT use interchangeably
without a physician’s supervision.

Each Capsule Contains:
Cyclosporine, USP.................................................. 25 mg

Usual Dosage: See full prescribing information.

Store at 20° to 25°C (68° to 77°F); excursions permitted
between 15° to 30°C (59° to 86°F) [see USP Controlled
Room Temperature].

FOR YOUR PROTECTION: Do not use if blister is torn
or broken.

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

The drug product contained in this package is from
NDC # 60505-0133, Apotex Corp.

Distributed by: American Health Packaging, Columbus,
Ohio 43217

087925
0287925/0424

CycloSPORINE
Capsule, USP
(NON-MODIFIED)

25 mg

NDC 68084- 921-25

CycloSPORINE
Capsules, USP

100 mg

30 Capsules (5 x 6)              Rx Only

WARNING: Cyclosporine Capsules, USP
(NON-MODIFIED) is NOT BIOEQUIVALENT to
Neoral ®* (cyclosporine capsules, USP)
MODIFIED. Do NOT use interchangeably
without a physician’s supervision.

Each Capsule Contains:
Cyclosporine, USP..................................................100 mg

Usual Dosage: See full prescribing information.

Store at 20° to 25°C (68° to 77°F); excursions permitted
between 15° to 30°C (59° to 86°F) [see USP Controlled
Room Temperature].

FOR YOUR PROTECTION: Do not use if blister is torn
or broken.

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

The drug product contained in this package is from
NDC # 60505-0134, Apotex Corp.

Distributed by: American Health Packaging, Columbus,
Ohio 43217

092125
0292125/0424

CycloSPORINE
Capsule, USP
(NON-MODIFIED)

100 mg