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Sandimmune

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Sandimmune

Sandimmune

WARNINGS

Kidney, Liver and Heart Transplant

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

Nephrotoxicity

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

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

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

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

Parameter Nephr Nephrotoxicity otoxicity vs. Rejection Rejection
History Donor > 50 years old or hypotensive Prolonged kidney preservation Prolonged anastomosis time Concomitant nephrotoxic drugs Antidonor immune response Retransplant patient
Clinical Often > 6 weeks postopb Prolonged initial nonfunction (acute tubular necrosis) Often < 4 weeks postopb Fever > 37.5°C
Weight gain > 0.5 kg Graft swelling and tenderness Decrease in daily urine volume > 500 mL (or 50%)
Laboratory CyA serum trough level > 200 ng/mL Gradual rise in Cr ( < 0.15 mg/dl/day)a Cr plateau < 25% above baseline BUN/Cr ≥ 20 CyA serum trough level < 150 ng/mL Rapid rise in Cr ( > 0.3 mg/dl/day)a Cr > 25% above baseline BUN/Cr < 20
Biopsy Arteriolopathy (medial hypertrophya, hyalinosis, nodular deposits, intimal thickening, endothelial vacuolization, progressive scarring) T ubular atrophy, isometric vacuolization, isolated calcifications Minimal edema Mild focal infiltratesc Diffuse interstitial fibrosis, often striped form Endovasculitisc (proliferationa, intimal arteritisb, necrosis, sclerosis)
Tubulitis with RBCb and WBCb casts, some irregular vacuolization Interstitial edemac and hemorrhageb Diffuse moderate to severe mononuclear infiltratesd Glomerulitis (mononuclear cells)c
Aspiration Cytology CyA deposits in tubular and endothelial cells
Fine isometric vacuolization of tubular cells
Inflammatory infiltrate with mononuclear phagocytes, macrophages, lymphoblastoid cells, and activated T-cells
These strongly express HLA-DR antigens
Urine Cytology Tubular cells with vacuolization and granularization Degenerative tubular cells, plasma cells, and lymphocyturia > 20% of sediment
Manometry Ultrasonography Intracapsular pressure < 40 mm Hgb Unchanged graft cross-sectional area Intracapsular pressure > 40 mm Hgb Increase in graft cross-sectional area AP diameter ≥ Transverse diameter
Magnetic Resonance Imagery Normal appearance Loss of distinct corticomedullary junction, swelling, image intensity of parachyma approaching that of psoas, loss of hilar fat
Radionuclide Scan Normal or generally decreased perfusion Decrease in tubular function (131 I-hippuran) > decrease in perfusion (99m Tc DTPA) Patchy arterial flow Decrease in perfusion > decrease in tubular function Increased uptake of Indium 111 labeled platelets or Tc-99m in colloid
Therapy Responds to decreased Sandimmune® (cyclosporine) Responds to increased steroids or antilymphocyte globulin
ap < 0.05,
bp < 0.01,
cp < 0.001,
dp < 0.0001

A form of chronic progressive cyclosporine-associated nephrotoxicity is characterized by serial deterioration in renal function and morphologic changes in the kidneys. From 5%-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 Sandimmune® (cyclosporine) 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 co-administering Sandimmune 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 Sandimmune® (cyclosporine) and 1) administration of streptokinase and heparin or 2) plasmapheresis, this appears to depend upon early detection with Indium 111 labeled platelet scans. (See ADVERSE REACTIONS.)

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 comorbidities, 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 Sandimmune® (cyclosporine) were used. The chemistry elevations usually decreased with a reduction in dosage.

Malignancies

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

Anaphylactic Reactions

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

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

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

Alcohol (ethanol)

The alcohol content (See DESCRIPTION) of Sandimmune should be taken into account when given to patients in whom alcohol intake should be avoided or minimized, e.g. pregnant or breast feeding 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 which is approximately 6% of the amount of alcohol contained in a standard drink. The daily intravenous dose would deliver approximately 15% of the amount of alcohol contained in a standard drink.

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

Conversion from Neoral to Sandimmune

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

PRECAUTIONS

General

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

Hypertension

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

Vaccination

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

Laboratory Tests

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

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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

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

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

Cyclosporine has not been found mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A recent study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave indication of a positive effect (i.e., induction of SCE), at high concentrations in this system. In two published research studies, rabbits exposed to cyclosporine in utero (10 mg/kg/day subcutaneously) demonstrated reduced numbers of nephrons, renal hypertrophy, systemic hypertension and progressive renal insufficiency up to 35 weeks of age. Pregnant rats which received 12 mg/kg/day of cyclosporine intravenously (twice the recommended human intravenous dose) had fetuses with an increased incidence of ventricular septal defect. These findings have not been demonstrated in other species and their relevance for humans is unknown.

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

Pregnancy

Pregnancy Category C

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

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

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

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

The alcohol content of the Sandimmune formulations should also be taken into account in pregnant women. (See WARNINGS, Special Excipients)

Nursing Mothers

Cyclosporine is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from Sandimmune, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Sandimmune contains ethanol. Ethanol will be present in human milk at levels similar to that found in maternal serum and if present in breast milk will be orally absorbed by a nursing infant. (See WARNINGS)

Pediatric Use

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

Geriatric Use

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

Last reviewed on RxList: 5/17/2013
This monograph has been modified to include the generic and brand name in many instances.

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