Cyclosporine Information
Cyclosporine ()
Cyclosporine () Description
Cyclosporine () Oral Solution USP MODIFIED is an oral formulation of Cyclosporine () that immediately forms an emulsion in an aqueous environment.
Cyclosporine () , the active principle in Cyclosporine () Oral Solution USP MODIFIED, is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Mycelium sterilae.
Chemically, Cyclosporine () is designated as [-[*,*-(E)]]-cyclic-(L-alanyl-D-alanyl--methyl-L-leucyl--methyl-L-leucyl--methyl-L-valyl-3-hydroxy-,4-dimethyl-L-2-amino-6-octenoyl-L-α-amino-butyryl--methylglycyl--methyl-L-leucyl-L-valyl--methyl-L-leucyl) and has the following structural formula:
Each mL of Cyclosporine () Oral Solution USP MODIFIED contains 100 mg/mL Cyclosporine () and 15.3% v/v (12.18% wt/vol) dehydrated alcohol and has the following inactive ingredients: polyoxyl 40 hydrogenated castor oil, polyglycerol (3) oleate and polyglycerol (10) oleate.
Cyclosporine () Clinical Pharmacology
Cyclosporine () is a potent immunosuppressive agent that in animals prolongs survival of allogeneic transplants involving skin, kidney, liver, heart, pancreas, bone marrow, small intestine, and lung. Cyclosporine () has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated immune 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.
The effectiveness of Cyclosporine () results from specific and reversible inhibition of immunocompetent lymphocytes in the G- and G-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.
No effects on phagocytic function (changes in enzyme secretions, chemotactic migration of granulocytes, macrophage migration, carbon clearance ) have been detected in animals. Cyclosporine () does not cause bone marrow suppression in animal models or man.
Cyclosporine () Indications And Usage
Cyclosporine () Oral Solution USP MODIFIED is indicated for the treatment of patients with severe (i.e., extensive and/or disabling), recalcitrant, plaque psoriasis who have failed to respond to at least one systemic therapy (e.g., PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated.
While rebound rarely occurs, most patients will experience relapse with Cyclosporine () Oral Solution USP MODIFIED as with other therapies upon cessation of treatment.
Cyclosporine () Warnings
(See also )
Cyclosporine () , the active ingredient of Cyclosporine () Oral Solution USP MODIFIED, can cause nephrotoxicity and hepatotoxicity. The risk increases with increasing doses of Cyclosporine () . Renal dysfunction including structural kidney damage is a potential consequence of Cyclosporine () Oral Solution USP MODIFIED and therefore renal function must be monitored during therapy. see
Patients receiving Cyclosporine () Oral Solution USP MODIFIED require frequent monitoring of serum creatinine (see ). Elderly patients should be monitored with particular care, since decreases in renal function also occur with age. If patients are not properly monitored and doses are not properly adjusted, Cyclosporine () therapy can be associated with the occurrence of structural kidney damage and persistent renal dysfunction.
An increase in serum creatinine and BUN may occur during Cyclosporine () Oral Solution USP MODIFIED therapy and reflect a reduction in the glomerular filtration rate. Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated. The frequency and severity of serum creatinine elevations increase with dose and duration of Cyclosporine () therapy. These elevations are likely to become more pronounced without dose reduction or discontinuation.
Cyclosporine () , the active ingredient of Cyclosporine () Oral Solution USP MODIFIED, can cause nephrotoxicity and hepatotoxicity when used in high doses. 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.
Based on the historical Sandimmune (Cyclosporine () Oral Solution USP) experience with oral solution, nephrotoxicity associated with Cyclosporine () had 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 renal transplant and consisted of an arrest in the fall of the pre-operative elevations of BUN and creatinine at a range of 35 to 45 mg/dL and 2 to 2.5 mg/dL respectively. These elevations were often responsive to Cyclosporine () 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 renal 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 with one or the other. It should be noted however, that up to 20% of patients may have simultaneous nephrotoxicity and rejection.
A form of a Cyclosporine () -associated nephropathy is characterized by serial deterioration in renal function and morphologic changes in the kidneys. From 5% to 15% of transplant recipients who have received Cyclosporine () will fail to show a reduction in rising serum creatinine despite a decrease or discontinuation of Cyclosporine () therapy. Renal biopsies from these patients will demonstrate one or several of the following alterations: tubular vacuolization, tubular microcalcifications, peritubular capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tubular atrophy. Though none of these morphologic changes is entirely specific, a diagnosis of Cyclosporine () -associated structural nephrotoxicity requires evidence of these findings.
When considering the development of Cyclosporine () -associated nephropathy, it is noteworthy that several authors have reported an association between the appearance of interstitial fibrosis and higher cumulative doses or persistently high circulating trough levels of Cyclosporine () . This is particularly true during the first 6 post-transplant months when the dosage tends to be highest and when, in kidney recipients, the organ appears to be most vulnerable to the toxic effects of Cyclosporine () . Among other contributing factors to the development of interstitial fibrosis in these patients are prolonged perfusion time, warm ischemia time, as well as episodes of acute toxicity, and acute and chronic rejection. The reversibility of interstitial fibrosis and its correlation to renal function have not yet been determined. Reversibility of arteriolopathy has been reported after stopping Cyclosporine () or lowering the dosage.
Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated.
In the event of severe and unremitting rejection, when rescue therapy with pulse steroids and monoclonal antibodies fail to reverse the rejection episode, it may be preferable to switch to alternative immunosuppressive therapy rather than increase the Cyclosporine () Oral Solution USP MODIFIED dose to excessive levels.
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 ).
Significant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and hyperuricemia have been seen occasionally in individual patients.
Hepatotoxicity associated with Cyclosporine () use had 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. Patients taking Cyclosporine () should be warned to avoid excess ultraviolet light exposure. 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 resulting in increased risk of infection or malignancy, a treatment regimen containing multiple immunosuppressants should be used with caution. Some malignancies may be fatal. Transplant patients receiving Cyclosporine () are at increased risk for serious infection with fatal outcome.
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 Cyclosporine () Oral Solution USP MODIFIED. 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, occurring in transplant patients more frequently than in other indications, 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 ).
Cyclosporine () nephropathy was detected in renal biopsies of 6 out of 60 (10%) rheumatoid arthritis patients after the average treatment duration of 19 months. Only one patient, out of these 6 patients, was treated with a dose ≤ 4 mg/kg/day. Serum creatinine improved in all but one patient after discontinuation of Cyclosporine () . The “maximal creatinine increase” appears to be a factor in predicting Cyclosporine () nephropathy.
There is a potential, as with other immunosuppressive agents, for an increase in the occurrence of malignant lymphomas with Cyclosporine () . It is not clear whether the risk with Cyclosporine () is greater than that in rheumatoid arthritis patients or in rheumatoid arthritis patients on cytotoxic treatment for this indication. Five cases of lymphoma were detected: four in a survey of approximately 2,300 patients treated with Cyclosporine () for rheumatoid arthritis, and another case of lymphoma was reported in a clinical trial. Although other tumors (12 skin cancers, 24 solid tumors of diverse types, and 1 multiple myeloma) were also reported in this survey, epidemiologic analyses did not support a relationship to Cyclosporine () other than for malignant lymphomas.
Patients should be thoroughly evaluated before and during Cyclosporine () Oral Solution USP MODIFIED treatment for the development of malignancies. Moreover, use of Cyclosporine () Oral Solution USP MODIFIED therapy with other immunosuppressive agents may induce an excessive immunosuppression which is known to increase the risk of malignancy.
(See also for )
Since Cyclosporine () is a potent immunosuppressive agent with a number of potentially serious side effects, the risks and benefits of using Cyclosporine () Oral Solution USP MODIFIED should be considered before treatment of patients with psoriasis. Cyclosporine () , the active ingredient in Cyclosporine () Oral Solution USP MODIFIED, can cause nephrotoxicity and hypertension (see ) and the risk increases with increasing dose and duration of therapy. Patients who may be at increased risk such as those with abnormal renal function, uncontrolled hypertension or malignancies, should not receive Cyclosporine () Oral Solution USP MODIFIED.
Renal dysfunction is a potential consequence of Cyclosporine () Oral Solution USP MODIFIED therefore renal function must be monitored during therapy.
Patients receiving Cyclosporine () Oral Solution USP MODIFIED require frequent monitoring of serum creatinine (see ). Elderly patients should be monitored with particular care, since decreases in renal function also occur with age. If patients are not properly monitored and doses are not properly adjusted, Cyclosporine () therapy can cause structural kidney damage and persistent renal dysfunction.
An increase in serum creatinine and BUN may occur during Cyclosporine () Oral Solution USP MODIFIED therapy and reflects a reduction in the glomerular filtration rate.
Kidney biopsies from 86 psoriasis patients treated for a mean duration of 23 months with 1.2 to 7.6 mg/kg/day of Cyclosporine () showed evidence of Cyclosporine () nephropathy in 18/86 (21%) of the patients. The pathology consisted of renal tubular atrophy and interstitial fibrosis. On repeat biopsy of 13 of these patients maintained on various dosages of Cyclosporine () for a mean of 2 additional years, the number with Cyclosporine () induced nephropathy rose to 26/86 (30%). The majority of patients (19/26) were on a dose of ≥5 mg/kg/day (the highest recommended dose is 4 mg/kg/day). The patients were also on Cyclosporine () for greater than 15 months (18/26) and/or had a clinically significant increase in serum creatinine for greater than 1 month (21/26). Creatinine levels returned to normal range in 7 of 11 patients in whom Cyclosporine () therapy was discontinued.
There is an increased risk for the development of skin and lymphoproliferative malignancies in Cyclosporine () -treated psoriasis patients. The relative risk of malignancies is comparable to that observed in psoriasis patients treated with other immunosuppressive agents.
Tumors were reported in 32 (2.2%) of 1439 psoriasis patients treated with Cyclosporine () worldwide from clinical trials. Additional tumors have been reported in 7 patients in Cyclosporine () postmarketing experience. Skin malignancies were reported in 16 (1.1%) of these patients; all but 2 of them had previously received PUVA therapy. Methotrexate was received by 7 patients. UVB and coal tar had been used by 2 and 3 patients, respectively. Seven patients had either a history of previous skin cancer or a potentially predisposing lesion was present prior to Cyclosporine () exposure. Of the 16 patients with skin cancer, 11 patients had 18 squamous cell carcinomas and 7 patients had 10 basal cell carcinomas.
There were two lymphoproliferative malignancies; one case of non-Hodgkin’s lymphoma which required chemotherapy, and one case of mycosis fungoides which regressed spontaneously upon discontinuation of Cyclosporine () . There were four cases of benign lymphocytic infiltration: 3 regressed spontaneously upon discontinuation of Cyclosporine () , while the fourth regressed despite continuation of the drug. The remainder of the malignancies, 13 cases (0.9%), involved various organs.
Cyclosporine () Precautions
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 Cyclosporine () . Patients should be advised of the potential risks during pregnancy and informed of the increased risk of neoplasia. Patients should also be informed of the risk of hypertension and renal dysfunction.
Patients should be advised that during treatment with Cyclosporine () , vaccination may be less effective and the use of live attenuated vaccines should be avoided.
Patients should be given careful dosage instructions. Cyclosporine () Oral Solution USP MODIFIED should be diluted, preferably with orange or apple juice that is at room temperature. This solution, when mixed with juice, may appear cloudy. The combination of Cyclosporine () Oral Solution USP MODIFIED with milk can be unpalatable.
Patients should be advised to take Cyclosporine () Oral Solution USP MODIFIED on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of Cyclosporine () , thus should be avoided.
Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, 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, pancreatic islet cell adenomas significantly exceeded the control rate in the low dose level. Doses used in the mouse and rat studies were 0.01 to 0.16 times the clinical maintenance dose (6 mg/kg). The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related. Published reports indicate that co-treatment of hairless mice with UV irradiation and Cyclosporine () or other immunosuppressive agents shorten the time to skin tumor formation compared to UV irradiation alone.
Cyclosporine () was not mutagenic in appropriate test systems. Cyclosporine () has not been found to be 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 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 () (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.
No impairment in fertility was demonstrated in studies in male and female rats.
Widely distributed papillomatosis of the skin was observed after chronic treatment of dogs with Cyclosporine () at 9 times the human initial psoriasis treatment dose of 2.5 mg/kg, where doses are expressed on a body surface area basis. This papillomatosis showed a spontaneous regression upon discontinuation of Cyclosporine () .
An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants and patients with rheumatoid arthritis and psoriasis. 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. Reduction or discontinuance of immunosuppression may cause the lesions to regress.
In psoriasis patients on Cyclosporine () , development of malignancies, especially those of the skin has been reported (see ). Skin lesions not typical for psoriasis should be biopsied before starting Cyclosporine () treatment. Patients with malignant or premalignant changes of the skin should be treated with Cyclosporine () only after appropriate treatment of such lesions and if no other treatment option exists.
In rheumatoid arthritis clinical trials with Cyclosporine () , 17.5% of patients were age 65 or older. These patients were more likely to develop systolic hypertension on therapy, and more likely to show serum creatinine rises ≥50% above the baseline after 3 to 4 months of therapy.
Clinical studies of Cyclosporine () Oral Solution USP MODIFIED in transplant and psoriasis patients did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experiences have not identified differences in response 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.
Cyclosporine () 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 resembled those seen in the hemolytic-uremic syndrome and included 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 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.
In controlled studies, the nature, severity and incidence of the adverse events that were observed in 493 transplanted patients treated with Cyclosporine () Oral Solution USP MODIFIED were comparable with those observed in 208 transplanted patients who received Sandimmune (Cyclosporine () Oral Solution USP) in these same studies when the dosage of the two drugs was adjusted to achieve the same Cyclosporine () blood trough concentrations.
Based on the historical experience with Sandimmune (Cyclosporine () Oral Solution USP), the following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants.
Among 705 kidney transplant patients treated with Sandimmune (Cyclosporine () Oral Solution USP) in clinical trials, the reason for treatment discontinuation was renal toxicity in 5.4%, infection in 0.9%, lack of efficacy in 1.4%, acute tubular necrosis in 1%, lymphoproliferative disorders in 0.3%, hypertension in 0.3%, and other reasons in 0.7% of the patients.
The following reactions occurred in 2% or less of Sandimmune (Cyclosporine () Oral Solution USP) treated 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.
Patients receiving immunosuppressive therapies, including Cyclosporine () and Cyclosporine () -containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic). Both generalized and localized infections can occur. Preexisting infections may also be aggravated. Fatal outcomes have been reported (see ).
The principal adverse reactions associated with the use of Cyclosporine () in rheumatoid arthritis are renal dysfunction (see ), hypertension (see ), headache, gastrointestinal disturbances, and hirsutism/hypertrichosis.
In rheumatoid arthritis patients treated in clinical trials within the recommended dose range, Cyclosporine () therapy was discontinued in 5.3% of the patients because of hypertension and in 7% of the patients because of increased creatinine. These changes are usually reversible with timely dose decrease or drug discontinuation. The frequency and severity of serum creatinine elevations increase with dose and duration of Cyclosporine () therapy. These elevations are likely to become more pronounced without dose reduction or discontinuation.
The following adverse events occurred in controlled clinical trials:
In addition, the following adverse events have been reported in 1% to
The principal adverse reactions associated with the use of Cyclosporine () in patients with psoriasis are renal dysfunction, headache, hypertension, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia or hyperesthesia, influenza-like symptoms, nausea/vomiting, diarrhea, abdominal discomfort, lethargy, and musculoskeletal or joint pain.
In psoriasis patients treated in US controlled clinical studies within the recommended dose range, Cyclosporine () therapy was discontinued in 1% of the patients because of hypertension and in 5.4% of the patients because of increased creatinine. In the majority of cases, these changes were reversible after dose reduction or discontinuation of Cyclosporine () .
There has been one reported death associated with the use of Cyclosporine () in psoriasis. A 27 year-old male developed renal deterioration and was continued on Cyclosporine () . He had progressive renal failure leading to death.
Frequency and severity of serum creatinine increases with dose and duration of Cyclosporine () therapy. These elevations are likely to become more pronounced and may result in irreversible renal damage without dose reduction or discontinuation.
The following events occurred in 1% to less than 3% of psoriasis patients treated with Cyclosporine () .
Cyclosporine () Overdosage
There is a minimal experience with Cyclosporine () overdosage. Forced emesis and gastric lavage can be of value up to 2 hours after administration of Cyclosporine () Oral Solution USP MODIFIED. 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 () is not dialyzable to any great extent, nor is it cleared well by charcoal hemoperfusion. The oral dosage at which half of experimental animals are estimated to die is 31 times, 39 times and >54 times the human maintenance dose for transplant patients (6 mg/kg; corrections based on body surface area) in mice, rats, and rabbits.
Cyclosporine () Dosage And Administration
The daily dose of Cyclosporine () Oral Solution USP MODIFIED should always be given in two divided doses (BID). It is recommended that Cyclosporine () Oral Solution USP MODIFIED be administered on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of Cyclosporine () , thus should be avoided.
Cyclosporine () How Supplied
Cyclosporine () Oral Solution USP MODIFIED is available as a yellowish to yellow-brown oily liquid containing 100 mg/mL Cyclosporine () in a 50 mL bottle.
PHARMACIST: Store and dispense in the original container at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Do not store in the refrigerator. Once opened, the contents must be used within two months. At temperatures below 20°C (68°F) the solution may gel; light flocculation or the formation of a light sediment may also occur. This solution, when mixed with juice, may appear cloudy. There is no impact on product performance or dosing using the syringe provided. Allow to warm to room temperature 25°C (77°F) to reverse these changes.
Sandimmune is a registered trademark of Novartis.
Rev. C 4/2010
Manufactured In Czech Republic By
TEVA CZECH INDUSTRIES s.r.o.
Opava-Komarov, Czech Republic
Manufactured For:
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Cyclosporine () Principal Display Panel
NDC 0172-7313-20
Cyclosporine () ORAL
SOLUTION USP MODIFIED
100 mg/mL
Each mL Contains:
Cyclosporine () , USP 100 mg
dehydrated alcohol, USP 15.3% v/v (12.2% wt/vol)
WARNING: Cyclosporine () Oral Solution USP
MODIFIED is NOT BIOEQUIVALENT to
Sandimmune (Cyclosporine () Oral Solution USP).
DO NOT use interchangeably without a physician's
supervision.
Rx only
50 mL size
TEVA
