Pill Identifier App

Cyclosporine (Systemic)



INN:

Ciclosporin

VA CLASSIFICATION
Primary: IM403
Secondary: DE801; MS109

Commonly used brand name(s): Neoral; Sandimmune; SangCya.

Another commonly used name is
cyclosporin A .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Immunosuppressant—

antipsoriatic—

antirheumatic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Transplant rejection, organ (prophylaxis)—Cyclosporine is indicated, usually in combination with corticosteroids, for prevention of rejection of renal, hepatic, and cardiac transplants (allografts) {01} {02} {03} {31} {37} {43}. [Cyclosporine is also indicated for prevention of rejection of heart-lung{07}{10} and pancreatic{10} transplants.]

Transplant rejection, organ (treatment)—Cyclosporine is indicated for treatment of chronic rejection in patients previously treated with other immunosuppressants.

Arthritis, rheumatoid (treatment)—Cyclosporine is indicated for severe, active, rheumatoid arthritis failing to respond adequately to therapy with methotrexate alone {01} {02} {03}.

Psoriasis, severe (treatment)—Cyclosporine is indicated for severe, recalcitrant, plaque-type psoriasis failing to respond to at least one systemic therapy or in patients unable to tolerate other systemic therapy {01} {02} {03} {14} {40}.

[Graft-versus-host disease (prophylaxis)]or
[Graft-versus-host disease (treatment)]—Cyclosporine is indicated for prophylaxis and treatment of graft-versus-host disease after bone marrow transplantation {02}.

[Nephrotic syndrome (treatment)]—Cyclosporine is indicated to induce and maintain remissions for steroid-dependent and steroid-resistant nephrotic syndrome due to glomerular diseases {02}.

Acceptance not established
Data are insufficient to prove that cyclosporine is effective for treatment of generalized pustular or erythrodermic psoriasis {47}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    1202.64 {11}

Mechanism of action/Effect:

The exact mechanism of action is unknown but seems to be related to the inhibition of production and release of interleukin-2, which is a proliferative factor necessary for the induction of cytotoxic T lymphocytes in response to alloantigenic challenge, and which plays a major role in both cellular and humoral immune responses. Cyclosporine does not affect the nonspecific defense system of the host and does not cause significant myelosuppression {01}.

Absorption:

Variable and incomplete from gastrointestinal tract; bioavailability of Sandimmune® is about 30% but may increase with increasing dosage and duration of treatment {03}. Absorption may be decreased after liver transplantation or in patients with liver disease or gastrointestinal function impairment (e.g., diarrhea, vomiting, ileus) {10}.

Cyclosporine modified capsules and oral solution (i.e., Neoral®) have increased bioavailability compared to the standard oral formulations of cyclosporine (i.e., Sandimmune®) {01} {53}. However, the absorption is still variable and incomplete from the gastrointestinal tract; bioavailability may be less than 10% in some liver transplant patients, but may be as high as 89% in some kidney transplant patients {01}. In studies in kidney transplant, liver transplant, psoriasis, and rheumatoid arthritis patients, the mean area under the serum concentration-versus-time curve (AUC) was 20 to 50% greater following administration of Neoral® compared to the AUC following administration of Sandimmune® {01}.

Protein binding:

Very high (90%), primarily to lipoproteins {01} {02} {03}.

Biotransformation:

Hepatic, extensive, primarily by cytochrome P450 3A enzymes {01}. Cyclosporine is metabolized to a lesser extent in the gastrointestinal system and in the kidneys {02}.

Half-life:


Biphasic {01}, variable:


Terminal—

Children—Approximately 7 hours (range, 7 to 19 hours) {03}.

Adults—Approximately 19 hours (range, 10 to 27 hours) {03}.



Time to peak concentration:


Cyclosporine capsules and oral solution ( Sandimmune®):

Plasma or blood: 3.5 hours {03}.



Cyclosporine modified capsules and oral solution ( Neoral®):

Blood: 1.5 to 2 hours {01}.


Peak serum concentration:

Plasma or blood—Whole blood concentrations may be 2 to 9 times higher than plasma concentrations {10}.

Elimination:
    Biliary/fecal; renal, 6% (0.1% unchanged) {01}.
    In dialysis—Not dialyzable {01} {02} {03}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to polyoxyethylated castor oil may be sensitive to the injectable dosage form also, since the injection contains a polyoxyethylated castor oil vehicle {01}.

Carcinogenicity/Tumorigenicity

A 78-week study in mice at doses of 1, 4, and 16 mg per kg of body weight (mg/kg) a day found a statistically significant trend for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value {01}. A 24-month study in rats at doses of 0.5, 2, and 8 mg/kg a day found that incidence of pancreatic islet cell adenomas significantly exceeded the control rate in the low dose level {01}. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose-related {01}.

Lymphomas and skin malignancies have developed in humans treated with cyclosporine {01}. The risk of these malignancies is related to the intensity and duration of immunosuppression {01}. The incidence of malignancies is similar to that in patients receiving other (e.g., tacrolimus-based) regimens {01}.

Psoriasis patients receiving cyclosporine are at increased risk of developing skin malignancies if they were treated previously with psoralen plus ultraviolet light A (PUVA), methotrexate, ultraviolet light B (UVB), coal tar, or radiation therapy {01}. The risk of skin cancer is greatest with previous PUVA treatment {01}.

Mutagenicity

No evidence of mutagenicity/genotoxicity was found 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 {01}. However, one 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 {01}.

Pregnancy/Reproduction
Fertility—
Studies in male and female rats found no evidence of impairment of fertility {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.

Cyclosporine crosses the placenta {01} {02} {03}.

In a retrospective study of 116 pregnancies of women who received cyclosporine during (and usually throughout) pregnancy, the only consistent patterns of abnormality were premature birth (gestational period of 28 to 36 weeks) and low birth weight for gestational age {01}. Preterm delivery occurred in 47% {01}. Seven malformations were reported in 5 viable infants and in 2 cases of fetal loss {01}. Neonatal complications occurred in 27% {01}. The exact relationship of cyclosporine to these effects has not been established {01}.

Studies in rats and rabbits have shown that cyclosporine is embryotoxic and fetotoxic at doses 2 to 5 times the human dose. At toxic doses (30 mg/kg a day in rats and 100 mg/kg a day in rabbits), cyclosporine was embryotoxic and fetotoxic, as indicated by increased prenatal and postnatal mortality and reduced fetal weight together with related skeletal retardations {01}. No embryolethal or teratogenic effects occurred at normal doses (up to 17 mg/kg a day in rats and up to 30 mg/kg a day in rabbits) {01}.

FDA Pregnancy Category C {01} {03}.

Breast-feeding

Cyclosporine is distributed into breast milk {01} {02} {03}. Mothers taking cyclosporine should not breast-feed their babies, because of the potential risk of serious adverse effects (e.g., hypertension, nephrotoxicity, malignancy) in the infant.

Pediatrics

Appropriate studies performed to date in pediatric patients receiving cyclosporine for organ transplantation have not demonstrated pediatrics-specific problems that would limit the usefulness of cyclosporine in children. Cyclosporine has been used in pediatric patients 1 year of age and older receiving organ transplantations. Pediatric patients have increased clearance of cyclosporine as compared with adult patients {52}. The safety and efficacy of cyclosporine to treat psoriasis and rheumatoid arthritis in pediatric patients have not been established {01}.


Geriatrics


Geriatric patients were included in the clinical trials of cyclosporine to treat rheumatoid arthritis. Geriatric patients were more likely to experience hypertension and increases in serum creatinine concentrations than were younger adult patients {01}.


Dental

Gingival hyperplasia, a common complication of cyclosporine therapy, usually starts as gingivitis or gum inflammation in the first month of treatment {04}. The incidence is higher in children under 15 years of age than in adults {07}. Gingival tissue changes are similar to those produced by phenytoin, although with less-mature collagen {04}. Tissue overgrowth may be greater anteriorly than posteriorly {07}, creating aesthetic and psychological problems for the young patient. A strict program of teeth cleaning by a professional combined with plaque control by the patient, if begun within 10 days of initiation of cyclosporine therapy, will minimize the growth rate and the severity of gingival enlargement. Periodontal surgery may be indicated and should be followed by careful plaque control to inhibit recurrence of gum enlargement.

The immunosuppressant effects of cyclosporine may result in an increased incidence of microbial infection and delayed healing. Dental work, whenever possible, should be completed prior to initiation of therapy with cyclosporine. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Allopurinol{01} or
» Androgens{18}{19} or
» Bromocriptine{01} or
» Cimetidine{01}{04}{10} or
» Clarithromycin{01} or
» Danazol{19} or
» Diltiazem{27}{28}{29} or
» Erythromycin{05}{17}{32}{33}{34} or
» Estrogens{30} or
» Fluconazole{01} or
» Human immunodeficiency virus (HIV) protease inhibitors{01} or
» Itraconazole{01} or
» Ketoconazole{01} or
Metoclopramide{01} or
Miconazole or
» Nefazodone{45} or
» Nicardipine{01} or
» Verapamil{01}    (may increase blood concentrations of cyclosporine by inhibiting cytochrome P450 3A enzymes, and may increase the risk of hepatotoxicity and nephrotoxicity; because of its similarity to ketoconazole, miconazole may be expected to have the same effect; although concurrent use of HIV protease inhibitors and cyclosporine have not been studied, HIV protease inhibitors are known to inhibit cytochrome P450 3A enzymes; frequent monitoring of blood cyclosporine concentrations and hepatic and renal function may be needed if these drugs are used concurrently with cyclosporine)


Anti-inflammatory drugs, nonsteroidal (NSAIDs){01}{02}{03}    (concurrent use of NSAIDs, especially indomethacin, with cyclosporine may increase the risk of renal failure; concurrent administration with cyclosporine may also result in hyperkalemia; additive decreases in renal function have been reported with concurrent use of diclofenac or naproxen with cyclosporine {01})


» Coal tar or
» Methoxsalen or
» Radiation therapy or
» Trioxsalen    (patients with psoriasis receiving cyclosporine are at increased risk of developing skin malignancies if they were previously treated with a psoralen [e.g., methoxsalen or trioxsalen] plus ultraviolet light A [PUVA] or coal tar, or if they received previous radiation therapy)


» Grapefruit or
» Grapefruit juice{01}{02}{03}    (decreased metabolism of cyclosporine, resulting in increased blood concentrations of cyclosporine, may occur; there is an increased risk of toxicity with concurrent use)


Hepatic enzyme inducers (see Appendix II )    (may enhance metabolism of cyclosporine by induction of cytochrome P450 3A enzymes {01}; dosage adjustment may be required)


Hyperkalemia-causing medications{01}{02}{03} , such as:
Angiotensin-converting enzyme (ACE) inhibitors
Beta-adrenergic blocking agents
Digitalis glycosides, with acute overdose
» Diuretics, potassium-sparing
Heparin
Penicillins, potassium-containing, with high doses
Phosphates, potassium-containing
Potassium citrate–containing medications
Potassium iodide
Potassium supplements
Succinylcholine chloride    (concurrent administration with cyclosporine may result in hyperkalemia)


» Immunosuppressants, other{01}{02}{03} , such as:
Azathioprine
Chlorambucil
Corticosteroids, glucocorticoid
Cyclophosphamide
Mercaptopurine
Muromonab-CD3    (concurrent use with cyclosporine may increase the risk of infection and development of lymphoproliferative disorders)


» Lovastatin or
» Simvastatin    (increased risk of rhabdomyolysis and acute renal failure {01} {54} {58})


Methotrexate    (in one study, concurrent administration of cyclosporine and methotrexate to patients to treat rheumatoid arthritis resulted in higher blood concentrations of methotrexate and lower blood concentrations of the primary metabolite of methotrexate than in patients receiving methotrexate alone; the clinical significance of this interaction is not known {01}; patients with psoriasis receiving cyclosporine are at increased risk of developing skin malignancies if they were previously treated with methotrexate)


Methylprednisolone    (seizures have been observed in patients receiving cyclosporine and high doses of methylprednisolone {01})


Nephrotoxic medications (see Appendix II )    (concurrent use with cyclosporine may result in enhanced nephrotoxicity; dosage reduction or withdrawal of both medications may be necessary if renal impairment occurs)


Nifedipine{01}    (increased risk of gingival hyperplasia)


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by cyclosporine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)

{01}
» Vaccines, live virus{01}{02}{03}    (because normal defense mechanisms may be suppressed by cyclosporine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only after review of the patient's hematologic status and only with the knowledge and consent of the physician managing the cyclosporine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Oral poliovirus vaccine should not be used in persons in close contact with the patient, especially family members)

{01}

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) values, serum and
Alkaline phosphatase values, serum and
Amylase values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin concentrations, serum    (may be increased in association with hepatotoxicity {01} {02} {03})


Blood urea nitrogen (BUN) and
Creatinine, serum    (concentrations are commonly increased during first few days of cyclosporine therapy; does not necessarily indicate rejection in renal transplant patients {01} {02} {03})


Magnesium    (serum concentrations may be decreased {06} {08} {13} {15}; may be related to nephrotoxicity {06} {13})


Potassium and
Uric acid{10}{16}    (serum concentrations may be increased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Malignancy, current or
» Premalignant skin lesions    (cyclosporine is associated with an increased susceptibility to malignancies {01} {02} {03})


Risk-benefit should be considered when the following medical problems exist
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


» Hepatic function impairment    (reduced biotransformation; reduced absorption; dosage reduction may be necessary)


Hyperkalemia
Hypertension    (cyclosporine may exacerbate hypertension {01})


» Infection
Malabsorption    (achieving therapeutic plasma concentrations of cyclosporine may be difficult)


» Renal function impairment    (dose reduction may be necessary; cyclosporine should not be used to treat psoriasis in patients with renal function impairment {01})


» Sensitivity to cyclosporine{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Alanine aminotransferase (ALT [SGPT]) values, serum and
Alkaline phosphatase values, serum and
Amylase values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin concentrations, serum    (determinations recommended at periodic intervals to monitor hepatic function)


Blood pressure measurements    (recommended at periodic intervals to detect hypertension)

    (blood pressure should be measured every 2 weeks for the first 2 months following the conversion from Sandimmune® to Neoral® {01})


» Blood urea nitrogen (BUN) concentrations and
» Creatinine concentrations, serum and
» Uric acid concentrations, serum    (determinations recommended at regular intervals to monitor renal function)

    (serum creatinine concentrations should be measured every 2 weeks for the first 2 months following the conversion from Sandimmune® to Neoral® {01})


Cholesterol, serum    (values may be increased {01})


» Cyclosporine concentrations, plasma or blood, trough, by radioimmunoassay (RIA) or high pressure liquid chromatography (HPLC)    (recommended for all patients, especially those receiving oral cyclosporine, because of erratic absorption, or for transplant patients to ensure that the patient is receiving an adequate but not toxic dose; because of extreme variability in results achieved depending on whether plasma or whole blood concentrations are measured, timing of samples, handling of samples, and choice of RIA or HPLC, determinations must be standardized within each individual medical center {04} {20}; trough blood concentrations usually are used to monitor therapy {44})

    (when converting a transplant patient from cyclosporine capsules or cyclosporine oral solution [ Sandimmune®] to cyclosporine modified capsules or cyclosporine modified oral solution [ Neoral®], the trough blood concentration should be measured every 4 to 7 days during the conversion {01}; if a patient is suspected of having poor absorption of Sandimmune®, the cyclosporine trough blood concentration should be monitored very frequently during the conversion because higher-than-expected trough blood concentrations are possible {01}; the manufacturer recommends measuring the trough blood concentration daily until steady-state is reached for patients who required Sandimmune® doses exceeding 10 mg per kg of body weight a day {01})


» Dental examinations    (recommended at 3-month intervals for teeth cleaning and reinforcement of patient's careful plaque control for inhibition of gingival hyperplasia)


Magnesium concentrations, serum and
Potassium concentrations, serum    (determinations recommended at periodic intervals)


Note: Neoral® product labeling gives specific guidance for monitoring patients receiving Neoral® for treatment of psoriasis and rheumatoid arthritis. Patients receiving Neoral® for treatment of psoriasis should have two baseline serum creatinine measurements {01}. Blood pressure, BUN, cholesterol, complete blood count (CBC), serum magnesium, serum potassium, and uric acid should be measured prior to beginning therapy with Neoral® {01}. During the initial 3 months of therapy these parameters should be measured once every 2 weeks {01}. After the first 3 months of therapy, these parameters should be measured once every month in stable patients {01}. Patient condition or changes in dose may necessitate more frequent measurements {01}.
Patients receiving Neoral® for treatment of rheumatoid arthritis should have two baseline blood pressure measurements and two baseline serum creatinine measurements {01}. During the initial 3 months of therapy these parameters should be measured once every 2 weeks {01}. After the first 3 months of therapy, these parameters should be measured once every month in stable patients {01}. Addition of increased doses of nonsteroidal anti-inflammatory drug therapy to the regimen may necessitate additional monitoring of blood pressure and serum creatinine {01}. Patients receiving methotrexate in addition to Neoral® should have CBC and liver function tests (LFT) monitored each month {01}.
In patients receiving Neoral® for treatment of nephrotic syndrome, changes in renal function related to nephrotic syndrome may be difficult to distinguish from cyclosporine-induced renal dysfunction {02}. Renal biopsy should be considered for patients with steroid-dependent minimal change nephropathy maintained on Neoral® for more than 1 year {02}.




Side/Adverse Effects

Note: Post-transplant lymphoproliferative disorders (PTLDs), including lymphomas and skin malignancies, have been reported in patients receiving cyclosporine; some have regressed when the medication was discontinued {01} {02} {03}. PTLD results from the degree of immunosuppression, not specifically from the use of cyclosporine. Similarly, infection may occur in patients receiving cyclosporine. The occurrence of infections results from the degree of immunosuppression, not specifically from the use of cyclosporine.
Gingival hyperplasia, hypertension, hirsutism, nephrotoxicity, and tremor are the most significant adverse effects in transplant patients resulting from the use of cyclosporine {01} {02} {03}.
Gastrointestinal disturbances, including abdominal discomfort, dyspepsia, and nausea, headache, hirsutism, hypertension, and nephrotoxicity are the most significant adverse effects resulting from the use of cyclosporine in patients with rheumatoid arthritis {01} {02}.
Gastrointestinal disturbances, headache, hirsutism, hypertension, lethargy, muscle or joint pain, nephrotoxicity, and paresthesias are the most significant adverse effects resulting from the use of cyclosporine in patients with psoriasis {01} {02}.
Gastrointestinal disturbances, gingival hyperplasia, hirsutism, hypertension, nephrotoxicity, paresthesia, and tremor are the most significant adverse effects resulting from the use of cyclosporine in patients with nephrotic syndrome {02}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Gingival hyperplasia{04}{07} (bleeding, tender, or enlarged gums)
    
hypertension{01}{26} —usually asymptomatic
    
nephrotoxicity{01}{26} —usually asymptomatic

Note: Gingival hyperplasia is usually reversible within 6 months after withdrawal of cyclosporine {07}.
Hypertension occurs commonly and may be acute, severe, and dose-related (usually associated with doses of 25 to 50 mg per kg of body weight [mg/kg] a day) or chronic and mild to moderate (usually associated with reduced renal function) {35}.
Nephrotoxicity has been reported in 25%, 37%, and 38% of kidney, liver, and heart transplantation patients receiving cyclosporine, respectively {02}. Mild nephrotoxicity (presenting as an arrest in the fall of pre-operative elevations of blood urea nitrogen [BUN] and creatinine at a range of 35 to 45 mg per deciliter and 2 to 2.5 mg per deciliter, respectively) usually occurs 2 to 3 months after renal, cardiac, or hepatic transplantation and usually responds to dosage reduction {01}. More overt toxicity, with rapidly rising BUN and creatinine concentrations, occurs early after transplantation {01} and must be differentiated from rejection episodes; toxicity usually responds to dosage reduction {01}. Up to 20% of renal transplant patients may have simultaneous nephrotoxicity and rejection {01}.
A form of chronic progressive nephrotoxicity {35} {36}, characterized by serial deterioration in renal function and morphologic changes in the kidneys (interstitial fibrosis with tubular atrophy), may occur; reduction in a rising serum creatinine will fail to occur despite reduction in dose or withdrawal of cyclosporine in 5 to 15% of patients {01}; in addition, toxic tubulopathy, peritubular capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tubular atrophy may be present {01}. Development of chronic nephrotoxicity may be related to high cumulative doses or persistently high circulating trough concentrations of cyclosporine {01}. Effects may be irreversible {35} {36}.
Nephrotoxicity (interstitial fibrosis with tubular atrophy) has been reported in 21% of psoriasis patients receiving cyclosporine for an average period of 23 months, and in 10% of rheumatoid arthritis patients receiving cyclosporine for an average period of 19 months {01}. Nephrotoxicity in these patients was established by biopsy {01}. Most patients with nephrotoxicity were receiving daily doses in excess of 4 mg per kg of body weight {01}.


Incidence less frequent
    
Hepatotoxicity —usually asymptomatic; usually seen as elevations of hepatic enzymes and bilirubin{01}
    
hypomagnesemia —usually asymptomatic
    
infection (fever or chills; frequent urge to urinate)
    
seizures
    
vomiting

Note: Seizures may be related to nephrotoxicity and hypomagnesemia {06} {13} {15} {21} {22} {23} {24} {25}.
Hepatotoxicity usually responds to dosage reduction {01}.


Incidence rare
    
Anaphylaxis (flushing of face and neck; wheezing or shortness of breath)—with parenteral use
    
hemolytic-uremic syndrome{01}
    
hyperkalemia{09}{10} (confusion; irregular heartbeat; numbness or tingling in hands, feet, or lips; shortness of breath or difficult breathing; unexplained nervousness; unusual tiredness or weakness; weakness or heaviness of legs)
    
pancreatitis (severe stomach pain with nausea and vomiting)
    
paresthesia (tingling)
    
PTLD (fever; general feeling of discomfort and illness; weight loss)
    
renal toxicity (blood in urine)

Note: Anaphylaxis occurs only with intravenous use and may be related to the vehicle {04} {10}. The reaction includes facial flushing, acute respiratory distress, blood pressure changes, and tachycardia {01}. A fatality has been reported {01}. Subsequent oral administration of cyclosporine in patients who have experienced an anaphylactic reaction to intravenous cyclosporine has not produced a reaction {01}.
The hemolytic-uremic syndrome can occur in the absence of rejection {01} but may result in graft failure {01}. It is accompanied by avid platelet consumption within the graft {01}. It usually responds, if detected early, to dosage reduction or withdrawal of cyclosporine {01}.
Irregular heartbeat is usually the earliest clinical indication of hyperkalemia and is readily detected by electrocardiogram (ECG). Hyperkalemia sometimes may be associated with hyperchloremic metabolic acidosis {01}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Hirsutism (increase in hair growth)
    
tremor (trembling and shaking of hands)—dose-related

Incidence less frequent
    
Acne or oily skin
    
gastrointestinal disturbances including abdominal discomfort, dyspepsia, and nausea
    
headache
    
leg cramps
    
lethargy





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Flushing of face{02}
gum soreness and bleeding
    
headache{02}
    
hepatotoxicity{02} (flu-like symptoms)
    
hyperesthesia{02} (tingling in the hands and feet)
    
nephrotoxicity{02} —usually asymptomatic


Treatment of overdose
In general, treatment is symptomatic and supportive {01} {02} {03}.

To decrease absorption—Forced emesis may be useful for up to 2 hours after oral ingestion of toxic doses of cyclosporine {01} {02} {03}.

To enhance elimination—Cyclosporine is not removable by hemodialysis or charcoal hemoperfusion {01} {02} {03}.

Specific treatment—Transient hepatotoxicity and nephrotoxicity usually respond to withdrawal of cyclosporine {01} {02} {03}.

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Cyclosporine (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to cyclosporine

Pregnancy—Crosses the placenta; causes birth defects or fetal death in animals





Breast-feeding—Distributed into breast milk; breast-feeding not recommended because of risk of serious side effects





Dental—Dental work should be completed prior to initiation of therapy whenever possible
Other medications, especially allopurinol, androgens, bromocriptine, cimetidine, clarithromycin, coal tar, danazol, diltiazem, erythromycin, estrogens, fluconazole, human immunodeficiency virus (HIV) protease inhibitors, itraconazole, other immunosuppressants, ketoconazole, lovastatin, methoxsalen, nefazodone, nicardipine, potassium-sparing diuretics, radiation therapy, simvastatin, trioxsalen or verapamil
Other medical problems, especially chickenpox, current malignancy, hepatic function impairment, herpes zoster, infection, premalignant skin lesions, or renal function impairment

Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed

Getting into the habit of taking at the same time each day and in a consistent relation to the type and timing of the intake of food to help increase compliance and maintain steady blood concentrations; if cyclosporine causes stomach upset, checking with physician before changing relation between cyclosporine intake and type and timing of food intake

Not drinking grapefruit juice or eating grapefruit

Taking solution orally; special dropper to be used for accurate measuring

Mixing oral solution ( Sandimmune®) with milk, chocolate milk, or orange juice and mixing modified oral solution ( Neoral®) with apple juice or orange juice (preferably at room temperature) in a glass (not wax-lined or plastic disposable) container to improve palatability; stirring well and drinking immediately, then rinsing the glass with a small amount of additional liquid and drinking that also to make sure all medication is taken; wiping dropper dry but not rinsing with water (to prevent cloudiness) {01} {03}

» Checking with physician before discontinuing medication; possible need for lifelong therapy

» Proper dosing
Missed dose: Taking as soon as possible if remembered within 12 hours; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Importance of close monitoring by physician

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

» Maintaining good dental hygiene and seeing dentist frequently for teeth cleaning to prevent tenderness, bleeding, and gum enlargement


Side/adverse effects
Importance of discussing possible effects, including cancer, with physician

Signs of potential side effects, especially gingival hyperplasia, hypertension, nephrotoxicity, hepatotoxicity, hypomagnesemia, infection, seizures, vomiting, anaphylaxis, hemolytic-uremic syndrome, hyperkalemia, pancreatitis, paresthesia, post-transplant lymphoproliferative disorders (PTLD), and renal toxicity


General Dosing Information
Patients receiving cyclosporine should be under the supervision of a physician experienced in immunosuppressive therapy.

If an infection develops, it must be treated promptly; reduction of dosage or withdrawal of cyclosporine may be necessary.

For parenteral dosage form
Because of the risk of anaphylaxis, it is recommended that the parenteral dosage form be used only in patients unable to take cyclosporine orally for prophylaxis and treatment of transplant rejection {01}.

Cyclosporine usually should be administered by slow intravenous infusion over a period of 2 to 6 hours; however, it may be given over a period of up to 24 hours. Rapid intravenous administration may cause acute nephrotoxicity, as well as less serious side effects such as flushing and nausea {10}.

It is recommended that patients receiving intravenous cyclosporine be under continuous observation for at least the first 30 minutes of the infusion and at frequent intervals after that {01}. Equipment and medications (including epinephrine and oxygen) necessary for treatment of a possible anaphylactic reaction should be immediately available during each administration of cyclosporine {01}.

For use in prophylaxis and treatment of transplant rejection
The dose of cyclosporine should be adjusted based on the clinical response of the patient, trough blood concentrations of the medicine {10}, and the appearance or severity of toxicity.

If signs of allograft rejection occur, a larger dose may be necessary; other therapy should be considered if they persist.

Cyclosporine usually is used in conjunction with other immunosuppressants (e.g., corticosteroids and azathioprine) {01}.

Antiviral prophylaxis, i.e., with acyclovir, ganciclovir, and immune globulins, may be advisable for some patients receiving cyclosporine, especially cytomegalovirus (CMV) prophylaxis in patients who have not been exposed to CMV prior to transplantation and who receive a CMV-positive graft {46}.

Vaccination schedules should be continued, except for live vaccines. Vaccinations against hepatitis A and B are recommended. Inactivated poliovirus vaccine should be used instead of oral poliovirus vaccine both for the patient and for people living in the same household as the patient. Vaccines given to immunosuppressed patients may not result in a protective antibody response {50}. Protective antibody concentrations should be checked after the vaccine has been administered {50}.

If a patient is exposed to measles, mumps, rubella, or varicella for the first time while receiving cyclosporine, the patient should receive prophylactic therapy with immune globulin, i.e., pooled human immune globulin or varicella immune globulin {46}.

Newly transplanted patients usually receive adjunctive treatment with corticosteroids {01}. The corticosteroids are tapered to target doses within a few months of transplantation. A typical dosage schedule may start with the equivalent of prednisone 2 mg/kg a day and taper to 0.15 mg/kg a day by 2 months following transplantation {01}.

For use in treatment of rheumatoid arthritis
Salicylates, nonsteroidal anti-inflammatory drugs, and corticosteroids may be continued with cyclosporine {01}.

There is little long-term data on the use of cyclosporine in the treatment of rheumatoid arthritis. Recurrence of disease activity is usually seen within 4 weeks after stopping cyclosporine {01}.

For use in treatment of psoriasis
When cyclosporine is used to treat psoriasis, any skin lesions not typical for psoriatic plaque should be biopsied and assessed for malignant or premalignant status before beginning therapy with cyclosporine {01}. Psoriasis patients receiving psoralen and ultraviolet light A (PUVA), ultraviolet light B (UVB), other radiation therapy, or other immunosuppressants should not receive cyclosporine because of the risk of excessive immunosuppression and malignancies {01}.

Patients usually experience some improvement within 2 weeks of beginning cyclosporine, but satisfactory control may require 12 to 16 weeks of therapy with cyclosporine. After satisfactory control of psoriasis is achieved, the dose of cyclosporine should be decreased to the lowest dose needed to control the disease {01}.

There is little experience with long-term treatment of psoriasis with cyclosporine, and continuous treatment longer than one year is not recommended. Relapse of psoriasis occurs in up to 75% of patients within 16 weeks of stopping treatment with cyclosporine {01}.

Diet/Nutrition
The rate of absorption of oral cyclosporine is decreased in the presence of food, but the extent of absorption may or may not be affected, depending on the type of food ingested. Cyclosporine should be given consistently in relation to food {01} {02}.

Bioavailability of cyclosporine may be increased by ingestion of grapefruit or grapefruit juice, resulting in toxic blood concentrations of cyclosporine {01}.

Cyclosporine oral solution ( Sandimmune®) should be mixed with milk, chocolate milk, or orange juice to improve taste {01}. Cyclosporine modified oral solution ( Neoral®) should be mixed with apple juice or orange juice to improve taste {01}. Neoral® should not be mixed with milk because the mixture may be unpalatable {01}. Patients should avoid switching diluents frequently because the absorption may change with different diluents {01}.

Bioequivalence information
Cyclosporine modified capsules and cyclosporine modified oral solution ( Neoral®) are not bioequivalent to cyclosporine capsules and cyclosporine oral solution ( Sandimmune®) {01}. For a given trough concentration, the mean area under the serum concentration-versus-time curve (AUC) is larger with Neoral® than it is with Sandimmune® {01}. When converting from one product to another, frequent monitoring of cyclosporine blood concentrations and patient status are needed to monitor for organ rejection and/or cyclosporine toxicity {01}.

When converting a transplant patient from cyclosporine capsules or cyclosporine oral solution ( Sandimmune®) to cyclosporine modified capsules or cyclosporine modified oral solution ( Neoral®), the same daily dose (i.e., a 1-to-1 dose conversion) of Neoral® should be started and adjusted based on trough blood concentration {01} {56}. The same target trough concentration should be used. The trough blood concentration should be measured once every 4 to 7 days during the conversion {01}. If a patient is suspected of having poor absorption of Sandimmune®, the cyclosporine trough blood concentration should be monitored very frequently during the conversion because higher-than-expected trough blood concentrations are possible {01}. The manufacturer recommends measuring the trough blood concentration daily until steady-state is reached for patients who required Sandimmune® doses exceeding 10 mg per kg of body weight a day {01}. Blood pressure and serum creatinine should also be measured frequently (i.e., every 2 weeks) for the first 2 months following the conversion to Neoral® {01}.

When converting a rheumatoid arthritis, psoriasis, or nephrotic syndrome patient from oral Sandimmune® to Neoral®, the initial dose of Neoral® should be 70% of the Sandimmune® dose (i.e., a 1-to-0.7 dose conversion) {02}. The dose should be adjusted based on the trough blood concentration and the clinical condition of the patient {02}.

For treatment of adverse effects
Recommended treatment consists of the following:
Transplant patients

   • Many adverse effects (e.g., gastrointestinal toxicity, hyperkalemia, hypomagnesemia, nephrotoxicity) may respond to a reduction in dose. If adverse effects do not respond to a reduction in dose, it may be advisable to convert the patient to a tacrolimus-based immunosuppressant regimen {55}.
Nephrotic syndrome and rheumatoid arthritis patients

   • The dose of cyclosporine should be decreased by 25 to 50% if a patient experiences hypertension, elevations in serum creatinine that are ³ 30% above baseline, or other laboratory abnormalities {01}. If this does not control the adverse effect, or if the adverse effect is severe, cyclosporine should be discontinued {01}.
Psoriasis patients

   • The dose of cyclosporine should be decreased by 25 to 50% if a patient experiences hypertension, elevations in serum creatinine that are ³ 25% above baseline, or other laboratory abnormalities {01}. If this does not control the adverse effect, or if the adverse effect is severe, cyclosporine should be discontinued {01}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CYCLOSPORINE CAPSULES USP

Usual adult and adolescent dose
Transplant rejection (prophylaxis) or
Transplant rejection (treatment)
Initial: Oral, 12 to 15 mg per kg of body weight a day beginning four to twelve hours before surgery and continuing for one to two weeks postoperatively, then reduced, usually by 5% a week, to the maintenance dose {03}.

Maintenance: Oral, 5 to 10 mg per kg of body weight a day {03}.


Usual pediatric dose
See Usual adult and adolescent dose . Pediatric patients may require higher or more frequent dosing because of accelerated clearance {35}.

Strength(s) usually available
U.S.—


25 mg (Rx) [Sandimmune{03}]


50 mg (Rx) [Sandimmune{03}]


100 mg (Rx) [Sandimmune{03}]

Canada—


25 mg (Rx) [Sandimmune{02}]


100 mg (Rx) [Sandimmune{02}]

Packaging and storage:
Store below 25 °C (77 °F), in a tight container, unless otherwise specified by manufacturer.


CYCLOSPORINE ORAL SOLUTION USP

Usual adult and adolescent dose
See Cyclosporine Capsules USP .

Usual pediatric dose
See Cyclosporine Capsules USP .

Strength(s) usually available
U.S.—


100 mg per mL (Rx) [Sandimmune{03} (ethanol 100 mg per mL)]

Canada—


100 mg per mL (Rx) [Sandimmune{02} (ethanol 100 mg per mL)]

Packaging and storage:
Store below 30 °C (86 °F), unless otherwise specified by manufacturer. Store in a tight container. Do not refrigerate {03}.

Stability:
Contents of opened container must be used within 2 months.

Note: When dispensing, include a calibrated liquid measuring device provided by the manufacturer.



CYCLOSPORINE MODIFIED CAPSULES

Usual adult and adolescent dose
Transplant rejection (prophylaxis) or
Transplant rejection (treatment)
See Cyclosporine Capsules USP .

Rheumatoid arthritis (treatment)
Oral, 2.5 mg per kg of body weight a day, in two divided doses {01}. If insufficient clinical benefit has been observed after eight weeks, the dose may be increased by 0.5 to 0.75 mg per kg of body weight a day {01} {02}. The dose may be increased again after four additional weeks of therapy to a maximum dose of 4 mg per kg of body weight a day {01} {02}. If no clinical benefit is evident after sixteen weeks of therapy, treatment with cyclosporine should be discontinued {01} {02}.

Psoriasis (treatment)
Oral, 2.5 mg per kg of body weight a day, in two divided doses {01} {02}. If insufficient clinical benefit has been observed after four weeks the dose may be increased by 0.5 mg per kg of body weight a day {01} {02}. The dose may be increased again at two-week intervals to a maximum dose of 4 mg per kg of body weight a day {01} {02}. If no clinical benefit is evident after six weeks of treatment with 4 mg per kg of body weight a day, cyclosporine should be discontinued {01} {02}. After satisfactory control of psoriasis is achieved, the dose of cyclosporine should be decreased to the lowest dose needed to control the disease {01} {02}.

[Graft-versus-host disease (prophylaxis)]
Oral, 12.5 mg per kg of body weight a day, in two divided doses {02}. After three to six months of treatment, the cyclosporine dose should be tapered gradually to zero after one year following transplantation {02}.

[Graft-versus-host disease (treatment)]
Mild graft-versus-host disease occurring after discontinuation of cyclosporine may be treated by the re-introduction of low-dose Neoral® {02}.

[Nephrotic syndrome (treatment)]
Initial: Oral, 3.5 mg per kg of body weight a day, in two divided doses {02}. If no clinical benefit is evident after three months of treatment, cyclosporine should be discontinued {02}.

Maintenance: The dose should be adjusted based on efficacy, as measured by proteinuria, and side effects but should not exceed 5 mg per kg of body weight a day {02}.


Usual pediatric dose
Transplant rejection (prophylaxis)
See Cyclosporine Capsules USP .

[Nephrotic syndrome (treatment)]
Initial: Oral, 4.2 mg per kg of body weight a day, in two divided doses {02}. If no clinical benefit is evident after three months of treatment, cyclosporine should be discontinued {02}.

Maintenance: The dose should be adjusted based on efficacy, as measured by proteinuria, and side effects but should not exceed 6 mg per kg of body weight a day {02}.


Strength(s) usually available
U.S.—


25 mg (Rx) [Neoral{01} (ethanol 95 mg per mL)]


100 mg (Rx) [Neoral{01} (ethanol 95 mg per mL)]

Canada—


10 mg (Rx) [Neoral{02}]


25 mg (Rx) [Neoral{02}]


50 mg (Rx) [Neoral{02}]


100 mg (Rx) [Neoral{02}]

Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F) {01}. Store in a tight container. Do not refrigerate {01}.


CYCLOSPORINE MODIFIED ORAL SOLUTION

Usual adult and adolescent dose
See Cyclosporine Modified Capsules .

Usual pediatric dose
See Cyclosporine Modified Capsules .

Strength(s) usually available
U.S.—


100 mg per mL (Rx) [Neoral{01} (ethanol 95 mg per mL)]


100 mg per mL (Rx) [SangCya{59} (ethanol 84 mg per mL)]

Canada—


100 mg per mL (Rx) [Neoral{02} (ethanol 95 mg per mL)]

Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F) {01}. Store in a tight container. Do not refrigerate {01}.

Stability:
Contents of opened container must be used within 2 months {01}.

Note: When dispensing, include the calibrated liquid measuring device provided by the manufacturer {01}.




Parenteral Dosage Forms

CYCLOSPORINE CONCENTRATE FOR INJECTION USP

Usual adult and adolescent dose
Transplant rejection (prophylaxis)
Initial: Intravenous infusion, 2 to 6 mg per kg of body weight a day beginning four to twelve hours prior to surgery and continuing postoperatively until the patient can tolerate the oral solution.


Usual pediatric dose
See Usual adult and adolescent dose . Pediatric patients may require higher or more frequent dosing because of accelerated clearance {35}.

Strength(s) usually available
U.S.—


50 mg per mL (Rx) [Sandimmune{03} (polyoxyethylated castor oil 650 mg per mL) (ethanol 278 mg per mL)]

Canada—


50 mg per mL (Rx) [Sandimmune{02} (polyoxyethylated castor oil 650 mg per mL) (ethanol 278 mg per mL)]

Packaging and storage:
Store below 30 °C (86 °F) {01}, unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
Cyclosporine Concentrate for Injection USP is prepared for intravenous administration by diluting each mL in 20 to 100 mL of 0.9% sodium chloride injection or 5% dextrose injection. Use of glass containers is recommended because of possible leaching of diethylhexylphthalate (DEHP) from polyvinyl chloride (PVC) bags into cyclosporine solutions {35} {38}.

Stability:
Reconstituted solutions are stable for up to 24 hours in 5% dextrose injection and for 6 hours (in PVC containers) to 12 hours (in glass containers) in 0.9% sodium chloride injection {57}. Significant amounts of cyclosporine are lost when it is administered through PVC tubing {57}.



Revised: 02/26/1999



References
  1. Neoral package insert (Novartis—US), Rev 6/97, Rec 9/97.
  1. Neoral and Sandimmune package insert (Novartis—Canada), Rev 7/97, Rec 2/98.
  1. Sandimmune package insert (Novartis—US), Rev 11/96, Rec 3/98.
  1. Page E, Wexler D, Guenther L. Cyclosporin A. J Am Acad Dermatol 1986; 14(5 Pt 1): 785-91.
  1. Kohan D. Possible interaction between cyclosporine and erythromycin [letter]. N Engl J Med 1986; 314: 448.
  1. Allen R, Hunnisett A, Morris P. Cyclosporin and magnesium [letter]. Lancet 1985; 1(8440): 1283-4.
  1. Daley T, Wysocki G. Cyclosporine therapy. Its significance to the periodontist. J Periodontol 1984; 55: 708-12.
  1. Hypomagnesaemia and cyclosporin toxicity [letter]. Lancet 1985; 12; 1(8420): 103-5.
  1. Petersen K, Silberman H, Berne T. Hyperkalaemia after cyclosporin therapy [letter]. Lancet 1984; 1(8392): 1470.
  1. Ptachcinski RJ, Burckart GJ, Venkataramanan R. Cyclosporine. Drug Intell Clin Pharm 1985; 19: 90-100.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1997. p. 203.
  1. Ptachcinski R, Venkataramanan R, Rosenthal J, et al. The effect of food on cyclosporine absorption. Transplantation 1985; 40: 174-6.
  1. June C, Thompson C, Kennedy M, et al. Profound hypomagnesemia and renal magnesium wasting associated with the use of cyclosporine for marrow transplantation. Transplantation 1985; 39: 620-4.
  1. Shupack J, Abel E, Bauer E, et al. Cyclosporine as maintenance therapy in patients with severe psoriasis. J Am Acad Dermatol 1997; 36: 423-32.
  1. Thompson C, June C, Sullivan K, et al. Association between cyclosporin neurotoxicity and hypomagnesaemia. Lancet 1984; 2(8412): 1116-20.
  1. Tiller D, Hall B, Horvarth J, et al. Gout and hyperuricaemia in patients on cyclosporin and diuretics [letter]. Lancet 1985; 1(8426): 453.
  1. Ptachcinski R, Carpenter B, Burckart G, et al. Effect of erythromycin on cyclosporine levels [letter]. N Engl J Med 1985; 313: 1416-7.
  1. Moller B, Ekelund B. Toxicity of cyclosporine during treatment with androgens [letter]. N Engl J Med 1985; 313: 1416.
  1. Ross W, Roberts D, Griffin P, et al. Cyclosporin interaction with danazol and norethisterone [letter]. Lancet 1986; 1(8476): 330.
  1. Burckart G, Canafax D, Yee G. Cyclosporine monitoring. Drug Intell Clin Pharm 1986; 20: 649-52.
  1. Beaman M, Parvin S, Veitch P, et al. Convulsions associated with cyclosporin A in renal transplant recipients. Br Med J (Clin Res Ed) 1985; 290: 139-40.
  1. Velu T, Debusscher L, Stryckmans P. Cyclosporin-associated fatal convulsions [letter]. Lancet 1985; 1(8422): 219.
  1. Berden J, Hoitsma A, Merx J, et al. Severe central-nervous-system toxicity associated with cyclosporin [letter]. Lancet 1985; 1(8422): 219-20.
  1. Gross M, Pearson R, Sweny P, et al. Convulsions associated with cyclosporin A in renal transplant recipients [letter]. Br Med J (Clin Res Ed) 1985; 290: 555.
  1. Polson R, Powell-Jackson P, Williams R. Convulsions associated with cyclosporin A in transplant recipients [letter]. Br Med J (Clin Res Ed) 1985; 290: 1003.
  1. Hansen J, Fogh-Anderson N, Christensen N, et al. Cyclosporine-induced hypertension and decline in renal function in healthy volunteers. J Hypertens 1997; 15: 319-26.
  1. Pochet J, Pirson Y. Cyclosporin-diltiazem interaction [letter]. Lancet 1986; 1(8487): 979.
  1. Grino J, Sabate I, Castelao A, et al. Influence of diltiazem on cyclosporin clearance [letter]. Lancet 1986; 1(8494): 1387.
  1. Neumayer H, Wagner K. Diltiazem and economic use of cyclosporin [letter]. Lancet 1986; 2(8505): 523.
  1. Deray G, le Hoang P, Cacoub P, et al. Oral contraceptive interaction with cyclosporin [letter]. Lancet 1987; 1(8525): 158-9.
  1. Hemming A, Greig P, Cattral M, et al. A microemulsion of cyclosporine without intravenous cyclosporine in liver transplantation. Transplantation 1996; 62: 1798-802.
  1. Ptachcinski R, Carpenter B, Burckart G. et al. Effect of erythromycin on cyclosporine levels [letter]. N Engl J Med 1985; 313: 1416-7.
  1. Martell R, Heinrichs D, Stiller C, et al. The effects of erythromycin in patients treated with cyclosporine. Ann Intern Med 1986; 104: 660-1.
  1. Grino J, Sabate J, Castelao A, et al. Erythromycin and cyclosporine [letter]. Ann Intern Med 1986; 105: 467-8.
  1. Panel comments, 1989.
  1. Myers B, Sibley R, Newton L, et al. The long-term course of cyclosporine-associated chronic nephropathy. Kidney Int 1988; 33: 590-600.
  1. Keown P, Landsberg D, Halloran P, et al. A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Transplantation 1996; 62: 1744-52.
  1. Venkataramanan R, Burckart G, Ptachcinski R, et al. Leaching of diethylhexyl phthalate from polyvinyl chloride bags into intravenous cyclosporine solution. Am J Hosp Pharm 1986; 43: 2800-2.
  1. Dermatology Advisory Panel Meeting, 5/20/89.
  1. Lowe N, Wieder J, Rosenbach A, et al. Long-term low-dose cyclosporine therapy for severe psoriasis: effects on renal function and structure. J Am Acad Dermatol 1996; 35: 710-9.
  1. Noble S, Markham A. Cyclosporin: a review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (Neoral®). Drugs 1995; 50: 924-41.
  1. Dermatology Advisory Panel Meeting, 10/91.
  1. Pescovitz M, Barone G, Choc M, et al. Safety and tolerability of cyclosporine microemulsion versus cyclosporine: two-year data in primary renal allograft recipients. Transplantation 1997; 63: 778-80.
  1. Oellerich M, Armstrong V, Kahan B, et al. Lake Louise Consensus Conference on cyclosporine monitoring in organ transplantation: report of the consensus panel. Ther Drug Monit 1995; 17: 642-54.
  1. Helms-Smith K, Curtis S. Apparent interaction between nefazodone and cyclosporine. Ann Intern Med 1996; 125: 424.
  1. Panel comment, 2/97.
  1. Responses to Dermatology Advisory Panel Memorandum No. 5, 4/93.
  1. Fahey JL, Sarna G, Gale RP, et al. UCLA Conference. Immune interventions in disease. Ann Intern Med 1987; 106: 257-74.
  1. Scott JP, Higenbottam TW. Adverse reactions and interactions of cyclosporine. Med Toxicol Adverse Drug Exp 1988; 3: 107-27.
  1. CDC: Recommendations of the Advisory Committee on Immunization Practices: Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR Morb Mortal Wkly Rep 1993; 42(RR-4): 1-18.
  1. Busuttil R, Klintmalm G, Lake J, et al. General guidelines for the use of tacrolimus in adult liver transplant patients. Transplantation 1996; 61: 845-7.
  1. Cooney G, Habucky K, Hoppu K. Cyclosporin pharmacokinetics in paediatric transplant recipients. Clin Pharmacokinet 1997; 32: 481-95.
  1. Dunn S, Cooney G, Sommerauer J, et al. Pharmacokinetics of an oral solution of the microemulsion formulation of cyclosporine in maintenance pediatric liver transplant recipients. Transplantation 1997; 63: 1762-7.
  1. Olbricht C, Wanner C, Eisenhauer T, et al. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. Clin Pharmacol Ther 1997; 62: 311-21.
  1. Pratschke J, Neuhaus R, Tullius S, et al. Treatment of cyclosporine-related adverse effects by conversion to tacrolimus after liver transplantation. Transplantation 1997; 64: 938-40.
  1. Laine J, Hoppu K, Jalanko H, et al. Kidney function after 1:1 conversion to the cyclosporine microemulsion formulation in children with liver allografts. Transplantation 1997; 63: 1768-72.
  1. Ptachcinski R, Logue L, Burckart G, et al. Stability and availability of cyclosporine in 5% dextrose injection or 0.9% sodium chloride injection. Am J Hosp Pharm 1986; 43: 94-7.
  1. Akhlaghi F, McLachlan A, Keogh A, et al. Effect of simvastatin on cyclosporine unbound fraction and apparent blood clearance in heart transplant recipients. Br J Clin Pharmacol 1997; 44: 537-42.
  1. SangCya package insert (Sangstat—US), Rev 11/98, Rec 12/98.
Hide
(web4)