DESCRIPCION

La ciclosporina es un polipéptido cíclico consistente en 11 aminoácidos con propiedades inmuosupresoras. Es producido como metabolito del hongo Beauveria nivea. La ciclosporina está indicada para la prevención del rechazo de órganos en los trasplantes de riñón, higado y corazón. Se utiliza siempre conjuntamente con corticosteroides

Mecanismo de acción: la ciclosporina es una potente fármaco inmunosupresor que prolonga la supervivencia de los alotrasplantes, de piel, corazón, riñón, páncreas, médula ósea, intestino y pulmón. La ciclosporina suprime cierta inmunidad humoral y en mayor medida, las reacciones mediadas por células como el rechazo del aloinjerto, la hipersen-sibilidad retardada, la encefalomielitis alérgica experimental, artritis adyuvante de Freund, etc en muchas especies animales y para una variedad de órganos.

No se conoce el mecanismo exacto de acción de la ciclosporina. La evidencia experimental sugiere que la eficacia de la ciclosporina es debido a la inhibición específica y reversible de los linfocitos inmunocompetentes en la fase G0 o G1 del del ciclo celular. Los linfocitos T son inhibidor preferentemente. La célula T-helper es el objetivo principal, aunque también puede suprimirse la célula T-supresor. La ciclosporina también inhibe la producción y la liberación de linfocinas, incluyendo interleucina-2 o factor de crecimiento de células T (TCGF)..

No se han detectado efectos funcionales sobre los fagocitos (secreciones de enzimas, migración quimiotáctica de los granulocitos, migración de macrófago) o las células tumorales (tasa de crecimient , metástasis) en los animales. La ciclosporina no causa la supresión de la médula ósea en los modelos animales o el hombre .

Farmacocinética: la absorción de la ciclosporina en el tracto gastrointestinal es incompleta y variable. Se alcanzan las concentra-ciones máximas (Cmax) en plasma y sangre en unas 3.5 horas. La Cmax y el área bajo la curva de concentración/tiempo (AUC) en plasma o sangre aumentan con la dosis administrada; en la sangre sangre, la relación es curvilínea (parabólica) entre 0 y 1400 mg . La Cmax es aproximadamente 1,0 ng/mL/mg de la dosis en el plasma y 2.7- 1.4 ng/mL/mg de la dosis en la sangre. Comparada con una infusión intravenosa, la biodisponibilidad absoluta de la solución oral es aproximadamente del 30%. La biodisponibilidad de las cápsulas blandas de gelatina de ciclosporina rd equivalente a la solución oral de ciclosporina.

La ciclosporina se distribuye en gran parte fuera de la sangre. En la sangre, la distribución es dependiente de la concentración. Aproximadamente el 33% - 47% se encuentra en el plasma, 4-9% en los linfocitos, 5% - 12% en los granulocitos y 41% - 58% en los eritrocitos A altas concentraciones, la absorción de leucocitos y eritrocitos se satura . En el plasma , aproximadamente el 90% está enlazado a proteínas, principalmente de las lipoproteínas .

La disposición de la ciclosporina de sangre es bifásica con una semi-vida terminal de aproximadamente 19 horas (rango: 10-27 horas). La eliminación es principalmente biliar con sólo el 6% de la dosis excretada en la orina.

La ciclosporina se metaboliza extensamenre, pero no hay ninguna ruta metabólica preferente. Sólo el 0,1% de la dosis se excreta en la orina como fármaco inalterado. De los 15 metabolitos aislados en la orina humana. 9 han sido identificados . Las vías metabólica principales consisten en la hidroxilación del carbono de 2 de los residuos de leucina , y y la formación del éter cíclico (con oxidación del doble enlace) en la cadena lateral del aminoácido ácido 3-hidroxil-N-4-dimetil-L-2-amino-6-octenoico y la N-desmetilación de residuos de leucinal. La hidrólisis de la cadena cíclica de péptido o la conjugación de los metabolitos mencionados no parecen ser vías importantes de biotransformación.

En un estudio realizado en 4 pacientes con insuficiencia renal (aclaramiento de creatinina < 5 mL/min), una infusión intravenosa de 3.5 mg/kg de ciclosporina durante 4 horas administrados el final de una sesión de hemodiálisis dio lugar a un volumen medio de distribución (Vdss) de 3,49 L/kg con un aclaramiento sistémico (CL) de 0,369 L/hr/kg . Este CL sistémico (0,369 L/hr/kg) fue de aproximadamente dos tercios del aclaramiento medio sistémico (0,56 L/hr/kg) de la ciclosporina en los pacientes con función renal normal . En 5 pacientes con trasplante de hígado, el aclaramiento de la ciclosporina al terminar la hemodiálisis fue de 398 mL/min. . Menos del 1% de la dosis de ciclosporina fue recuperado en el dializado.

La ciclosporina es metabolizada extensamente por el hígado. Debido a que la insuficiencia hepática severa puede resultar en exposiciones de ciclosporina mas elevadas, la dosis de ciclosporina puede necesitar ser reducida en estos pacientes.

Toxicidad: se han llevado a cabo estudios de carcinogénesis ratas y ratones de ambos sexos. Las dosis utilizadas en los estudios del ratón y la rata eran 0.01 a 0.16 veces la dosis clínica de mantenimiento (6 mg/kg).

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 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.

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 WARNINGS ) 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.

INDICACIONES Y POSOLOGIA

Trasplantes de órganos:

Adminstración oral

The initial oral dose of Sandimmune® (cyclosporine) should be given 4-12 hours prior to transplantation as a single dose of 15 mg/kg. Although a daily single dose of 14-18 mg/kg was used in most clinical trials, few centers continue to use the highest dose, most favoring the lower end of the scale. There is a trend towards use of even lower initial doses for renal transplantation in the ranges of 10-14 mg/kg/day. The initial single daily dose is continued postoperatively for 1-2 weeks and then tapered by 5% per week to a maintenance dose of 5-10 mg/kg/day. Some centers have successfully tapered the maintenance dose to as low as 3 mg/kg/day in selected renal transplant patients without an apparent rise in rejection rate.

La dosis pediátrica recomendada es la misma que la de los adultos, aunque en la profilaxis de rechazo de trasplante de órganos, la do sis requerida eventualmente puede exceder la dosis habitual en adultos.La dosificación descrita a continuación sirve únicamente a título de recomendación , ya que para establecer la dosificación más adecuada, es preciso monitorizar rutinariamente los niveles de ciclosporina en sangre. ?

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Trasplante de órganos En caso de que no sea posible la vía oral, en el transplante se puede administrar por vía intravenosa. La dosis recomendada es de aproximadamente un tercio de la dosis oral,por el efecto de primer paso hepático. Debido al riesgo de anafilaxis asociado a la forma intravenosa, junto con la mayor comodidad de la vía oral y menor riesgo de infección se recomienda pasar a la vía oral tan pronto como sea posible. La dosis inicial varía en función del órgano transplantado y de la dosis de otros agentes inmunosupresores incluidos en el protocolo. En general, se administrarán 10-15mg/Kg/día en dos dosis durante las 12 h anteriores al trasplante (5 - 6 mg/Kg/día i.v si imposibilidad de vía oral); se mantiene durante 1-2 semanas y posteriormente se ajustan las dosis en función de las concentraciones plasmáticas deseadas . En función del tipo de trasplante pueden utilizarse como dosis iniciales: - Renal: 9 ± 3 mg/kg/día , repartidos cada 12 h - Hepático: 8 ± 4 mg/kg/dí a , repartidos cada 12 h - Cardiaco: 7 ± 3 mg/kg/d ía , repartidos cada 12 h Dosis de m antenimiento: 2 - 6 mg/kg/día repartidos en dos dosis . ? Trasplante de médula ósea En transplante de médula ósea en pacientes ped iátricos, se administrará ciclosporina intraven osa (1,5 mg/Kg) cada 12 horas, hasta que sea posible la administración por vía oral. La dosis oral es de 6,25 mg/12 horas durante 3 - 6 meses y después disminuir gradualmente hasta suspender al año del trasplante.

Síndrome nefrótico Inicial: Función r enal normal: 6 mg/K g/día ( dosis máxima en niños) dividido en 2 dosis, cada 12 horas. Función renal alterada: ? 2,5 mg/K g/día 3 de 9 Suspender a los 3 meses si no se observa mejoría Mantenimiento : a justar individualmente al nivel mínimo efectivo

Dermatitis atópica I nicial : 2,5 mg/G g/día dividido en 2 dosis, cada 12 horas. Si después de 2 semanas de tratamiento la respuesta no es satisfactoria, puede aumentarse gradualmente hasta una dosis máxima de 5 mg/K g/día. Suspender si no se observa respuesta después de 1 mes de tratamiento a la dosis máxima. ? Uveitis Inicial: 5 mg/K g/día dividido en 2 dosis, cada 12 horas . En casos refractarios y durante un periodo de tiempo limita do podrá aumentarse hasta 7 mg/K g/día. En caso de respuesta insuficiente, podrán añadirse corticoid es a dosis de 0,2 - 0,6 mg/kg/día de prednisona o equivalente. Mantenimiento: r educir lentamente a la dosis mínima eficaz, sin exceder los 5mg/kg/día.

Otras indicaciones en pacientes pediátricos (off - label): Ciclosporina se utiliza sola o en combinación co n otros agentes (normalmente corticosteroides), lo que permite un efecto ahorrador de esteroides, reduciendo la toxicidad asociada a altas dosis y uso prolongado de los mismos. ?

H epatitis autoinmune 4 a 6 mg/Kg/día ? D istrofia muscular de Duchenne, 5 mg/Kg/d ía durante 8 semanas ? C olitis ulcerosa severa : En la CU severa refractaria a corticoesteroides puede evitar o retrasar la colectomía de urgencia . L a ter apia debe iniciarse con 2 - 4 mg/K g/día por vía intravenosa ( con dosis elevadas de corticoides), continuan do al menos 7 - 10 días y modificando las dosis hasta alcanzar concentraciones plasmáticas deseadas. Posteriormente, se puede cambiar a terapia oral a dosis de 8 mg/kg/día en 2 dosis, 1 - 3 meses . ? Histiocitosis de las c élulas de Langerhans: 12 - 15 mg/K g/día, en combinación con otros fármacos, como vinblastina y prednisona . ? D ermatomiositis juvenil : dosis inicial de 2 , 5 mg/Kg/día que puede modificarse en función de la respuesta clínica y las concentracion es plasmáticas. Mantenimiento 2, 5 a 7, 5 mg/Kg/día. La adm inistración de ciclosporina ha demostrado la reducción de dosis de corticosteroides e incluso su retirada. ? A plasia pura de c élulas rojas: t erapia inicial de 4 - 5 mg/Kg/día , para mantener concentraciones valle entre 120 y 300 (ng/mL). Mantenimiento durante 6 meses. ? G lomeru lonefritis de Henoch - Schonlein: d osis de 4 - 8mg/Kg/día, para mantener concentraciones séricas de 150 a 200 mcg/L en los primeros 6 meses del tratamiento. Durante la fase de mantenimiento , dosis de 1 - 5 4 de 9 mg/Kg/día para alcanzar niveles de 80 - 100 mcg/L. El tiempo medio de respuesta al tratamiento fue de 1,4 meses. ? S equedad ocular e n la queratoconjuntivitis seca en adolescentes >16 años: e mulsión oftálmica de ciclosporina al 0,05%: 1 gota en cada ojo/12 horas.

Insuficiencia renal y hepática : no hay recomendaciones específicas en población pediátrica.

Insuficiencia renal: en el tratamiento de las enfermedades autoinmunes en pacientes adultos, se recomienda reducir la dosis en un 25 - 50% cuando la creatinina sérica permanezca incrementada por encima del 30% de los niveles basales en más de una determinación, incluso si los valores del creatinina están dentro del intervalo normal. (Considerar que los cambios en la función renal pueden ser debidos a la propia patología y no al fármaco)

Hemodiálisis: elimina menos del 1% de la dosis de ciclosporina.

Insuficiencia hepática: se recomienda precaución.

Niños con fibrosis quística: Los pacientes con fibrosis quística receptores de transplante pulmonar requieren dosis mayores de ciclosporina, que pueden llegar a ser el doble que en otros pacientes transplantados. Esta población de pacientes muestra una gran variabilidad en las dosis, lo que hace aún más necesario una monitorización intensiva de los niveles plasmáticos.

CONTRAINDICACIONES Y PRECAUCIONES

Cyclosporine, the active ingredient of Neoral®, can cause nephrotoxicity and hepatotoxicity. The risk increases with increasing doses of cyclosporine. Renal dysfunction including structural kidney damage is a potential consequence of Neoral® and therefore renal function must be monitored during therapy. Care should be taken in using cyclosporine with nephrotoxic drugs . (See PRECAUTIONS )

Patients receiving Neoral® require frequent monitoring of serum creatinine. (See Special Monitoring under DOSAGE AND ADMINISTRATION ) 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 Neoral® 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.

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

Kidney, Liver, and Heart Transplant

Nephrotoxicity

Cyclosporine, the active ingredient of Neoral®, 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® 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 2-3 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 35-45 mg/dl and 2.0-2.5 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%-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 Neoral® dose to excessive levels.

Thrombotic Microangiopathy

Occasionally patients have developed a syndrome of thrombocytopenia and microangiopathic hemolytic anemia which may result in graft failure. The vasculopathy can occur in the absence of rejection and is accompanied by avid platelet consumption within the graft as demonstrated by Indium 111 labeled platelet studies. Neither the pathogenesis nor the management of this syndrome is clear. Though resolution has occurred after reduction or discontinuation of cyclosporine 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, Kidney, Liver and Heart Transplantation ).

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

Malignancies

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.

Serious Infections

Patients receiving immunosuppressants, including Neoral, 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 ].

Polyomavirus Infections

Patients receiving immunosuppressants, including Neoral, are at increased risk for opportunistic infections, including polyomavirus 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, Kidney, Liver and Heart Transplantation ). Patient monitoring may help detect patients at risk for PVAN.

Cases of PML have been reported in patients treated with Neoral. 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 has been described both in post-marketing 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 PRECAUTIONS )

Rheumatoid Arthritis

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 Neoral® treatment for the development of malignancies. Moreover, use of Neoral® therapy with other immunosuppressive agents may induce an excessive immunosuppression which is known to increase the risk of malignancy.

Psoriasis

(See also BOXED WARNINGS for Psoriasis )

Since cyclosporine is a potent immunosuppressive agent with a number of potentially serious side effects, the risks and benefits of using Neoral® should be considered before treatment of patients with psoriasis . Cyclosporine, the active ingredient in Neoral®, can cause nephrotoxicity and hypertension (see PRECAUTIONS ) 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 Neoral®.

Renal dysfunction is a potential consequence of Neoral® therefore renal function must be monitored during therapy.

Patients receiving Neoral® require frequent monitoring of serum creatinine. (See Special Monitoring under DOSAGE AND ADMINISTRATION ) 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 Neoral® 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 1.2-7.6 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 ≥ 5.0 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.

Patients should not be treated concurrently with cyclosporine and PUVA or UVB, other radiation therapy, or other immunosuppressive agents, because of the possibility of excessive immunosuppression and the subsequent risk of malignancies. (See CONTRAINDICATIONS ) Patients should also be warned to protect themselves appropriately when in the sun, and to avoid excessive sun exposure. Patients should be thoroughly evaluated before and during treatment for the presence of malignancies remembering that malignant lesions may be hidden by psoriatic plaques. Skin lesions not typical of psoriasis should be biopsied before starting treatment. Patients should be treated with Neoral® only after complete resolution of suspicious lesions, and only if there are no other treatment options. (See Special Monitoring for Psoriasis Patients )

Hypertension

Cyclosporine is the active ingredient of Neoral®. Hypertension is a common side effect of cyclosporine therapy which may persist. (See ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION for monitoring recommendations ) Mild or moderate hypertension is encountered more frequently than severe hypertension and the incidence decreases over time. In recipients of kidney, liver, and heart allografts treated with cyclosporine, antihypertensive therapy may be required. (See Special Monitoring of Rheumatoid Arthritis and Psoriasis Patients ) 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, they can interfere with cyclosporine metabolism . (See DRUG INTERACTIONS )

Vaccination

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

Special Monitoring of Rheumatoid Arthritis Patients

Before initiating treatment, a careful physical examination, including blood pressure measurements (on at least two occasions) and two creatinine levels to estimate baseline should be performed. Blood pressure and serum creatinine should be evaluated every 2 weeks during the initial 3 months and then monthly if the patient is stable. It is advisable to monitor serum creatinine and blood pressure always after an increase of the dose of nonsteroidal anti-inflammatory drugs and after initiation of new nonsteroidal anti-inflammatory drug therapy during Neoral® treatment. If co-administered with methotrexate, CBC and liver function tests are recommended to be monitored monthly. (See also PRECAUTIONS , General , Hypertension )

In patients who are receiving cyclosporine, the dose of Neoral® should be decreased by 25%-50% if hypertension occurs. If hypertension persists, the dose of Neoral® should be further reduced or blood pressure should be controlled with antihypertensive agents. In most cases, blood pressure has returned to baseline when cyclosporine was discontinued.

In placebo-controlled trials of rheumatoid arthritis patients, systolic hypertension (defined as an occurrence of two systolic blood pressure readings > 140 mmHg) and diastolic hypertension (defined as two diastolic blood pressure readings > 90 mmHg) occurred in 33% and 19% of patients treated with cyclosporine, respectively. The corresponding placebo rates were 22% and 8%.

Special Monitoring for Psoriasis Patients

Before initiating treatment, a careful dermatological and physical examination, including blood pressure measurements (on at least two occasions) should be performed. Since Neoral® is an immunosuppressive agent, patients should be evaluated for the presence of occult infection on their first physical examination and for the presence of tumors initially, and throughout treatment with Neoral®. Skin lesions not typical for psoriasis should be biopsied before starting Neoral®. Patients with malignant or premalignant changes of the skin should be treated with Neoral® only after appropriate treatment of such lesions and if no other treatment option exists.

Baseline laboratories should include serum creatinine (on two occasions), BUN, CBC, serum magnesium, potassium, uric acid , and lipids .

The risk of cyclosporine nephropathy is reduced when the starting dose is low (2.5 mg/kg/day), the maximum dose does not exceed 4.0 mg/kg/day, serum creatinine is monitored regularly while cyclosporine is administered, and the dose of Neoral® is decreased when the rise in creatinine is greater than or equal to 25% above the patient's pretreatment level. The increase in creatinine is generally reversible upon timely decrease of the dose of Neoral® or its discontinuation.

Serum creatinine and BUN should be evaluated every 2 weeks during the initial 3 months of therapy and then monthly if the patient is stable. If the serum creatinine is greater than or equal to 25% above the patient's pretreatment level, serum creatinine should be repeated within two weeks. If the change in serum creatinine remains greater than or equal to 25% above baseline, Neoral® should be reduced by 25%-50%. If at any time the serum creatinine increases by greater than or equal to 50% above pretreatment level, Neoral® should be reduced by 25%-50%. Neoral® should be discontinued if reversibility (within 25% of baseline) of serum creatinine is not achievable after two dosage modifications. It is advisable to monitor serum creatinine after an increase of the dose of nonsteroidal anti-inflammatory drug and after initiation of new nonsteroidal anti-inflammatory therapy during Neoral® treatment.

Blood pressure should be evaluated every 2 weeks during the initial 3 months of therapy and then monthly if the patient is stable, or more frequently when dosage adjustments are made. Patients without a history of previous hypertension before initiation of treatment with Neoral®, should have the drug reduced by 25%-50% if found to have sustained hypertension. If the patient continues to be hypertensive despite multiple reductions of Neoral®, then Neoral® should be discontinued. For patients with treated hypertension, before the initiation of Neoral® therapy, their medication should be adjusted to control hypertension while on Neoral®. Neoral® should be discontinued if a change in hypertension management is not effective or tolerable.

CBC, uric acid, potassium, lipids, and magnesium should also be monitored every 2 weeks for the first 3 months of therapy, and then monthly if the patient is stable or more frequently when dosage adjustments are made. Neoral® dosage should be reduced by 25%-50% for any abnormality of clinical concern.

In controlled trials of cyclosporine in psoriasis patients, cyclosporine blood concentrations did not correlate well with either improvement or with side effects such as renal dysfunction.

Laboratory Tests

In all patients treated with cyclosporine, renal and liver functions should be assessed repeatedly by measurement of serum creatinine, BUN, serum bilirubin, and liver enzymes. Serum lipids, magnesium, and potassium should also be monitored. Cyclosporine blood concentrations should be routinely monitored in transplant patients (see DOSAGE AND ADMINISTRATION , Blood Concentration Monitoring in Transplant Patients ), and periodically monitored in rheumatoid arthritis patients.

INTERACCIONES

Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety

All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition, concomitant non-steroidal anti-inflammatory drugs, particularly in the setting of dehydration, may potentiate renal dysfunction.

Drugs That May Potentiate Renal Dysfunction

Cyclosporine is extensively metabolized by CYP 3A isoenzymes, in particular CYP3A4, and is a substrate of the multidrug efflux transporter P-glycoprotein. Various agents are known to either increase or decrease plasma or whole blood of cyclosporine levels usually by inhibition or induction of CYP3A4 or P-glycoprotein transporter or both. Compounds that decrease cyclosporine absorption such as orlistat should be avoided. Monitoring of circulating cyclosporine concentrations and appropriate Neoral® dosage adjustment are essential when these drugs are used concomitantly. (See Blood Concentration Monitoring )

Drugs That Increase Cyclosporine Concentrations

HIV Protease inhibitors

The HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 3A and thus could potentially increase the concentrations of cyclosporine, however no formal studies of the interaction are available. Care should be exercised when these drugs are administered concomitantly.

Grapefruit juice

Grapefruit and grapefruit juice affect metabolism , increasing blood concentrations of cyclosporine, thus should be avoided.

Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations

St. John's Wort

There have been reports of a serious drug interaction between cyclosporine and the herbal dietary supplement, St. John's Wort. This interaction has been reported to produce a marked reduction in the blood concentrations of cyclosporine, resulting in subtherapeutic levels, rejection of transplanted organs, and graft loss.

Rifabutin

Rifabutin is known to increase the metabolism of other drugs metabolized by the cytochrome P-450 system. The interaction between rifabutin and cyclosporine has not been studied. Care should be exercised when these two drugs are administered concomitantly.

Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents

Cyclosporine is an inhibitor of CYP3A4 and of the multidrug efflux transporter P-glycoprotein and may increase plasma concentrations of comedications that are substrates of CYP3A4 or Pglycoprotein or both.

Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors ( statins ), and, aliskiren, repaglinide, NSAIDs, sirolimus , etoposide, and other drugs. See the full prescribing information of the other drug for further information and specific recommendations. The decision on co-administration of cyclosporine with other drugs or agents should be made by the physician following the careful assessment of benefits and risks.

Digoxin

Severe digitalis toxicity has been seen within days of starting cyclosporine in several patients taking digoxin. If digoxin is used concurrently with cyclosporine, serum digoxin concentrations should be monitored.

Colchicine

There are reports on the potential of cyclosporine to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction. Concomitant administration of cyclosporine and colchicine results in significant increases in colchicine plasma concentrations. If colchicine is used concurrently with cyclosporine, a reduction in the dosage of colchicine is recommended.

HMG-CoA reductase inhibitors (statins)

Literature and postmarketing cases of myotoxicity, including muscle pain and weakness, myositis , and rhabdomyolysis , have been reported with concomitant administration of cyclosporine with lovastatin, simvastatin, atorvastatin , pravastatin, and, rarely fluvastatin. When concurrently administered with cyclosporine, the dosage of these statins should be reduced according to label recommendations. Statin therapy needs to be temporarily withheld or discontinued in patients with signs and symptoms of myopathy or those with risk factors predisposing to severe renal injury, including renal failure, secondary to rhabdomyolysis.

Repaglinide

Cyclosporine may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycemia. In 12 healthy male subjects who received two doses of 100mg cyclosporine capsule orally 12 hours apart with a single dose of 0.25mg repaglinide tablet (one half of a 0.5mg tablet) orally 13 hours after the cyclosporine initial dose, the repaglinide mean Cmax and AUC were increased 1.8 fold (range: 0.6 - 3.7 fold) and 2.4 fold (range 1.2 - 5.3 fold), respectively. Close monitoring of blood glucose level is advisable for a patient taking cyclosporine and repaglinide concomitantly.

Aliskiren

Cyclosporine alters the pharmacokinetics of aliskiren, a substrate of P-glycoprotein and CYP3A4. In 14 healthy subjects who received concomitantly single doses of cyclosporine (200 mg) and reduced dose aliskiren (75 mg), the mean Cmax of aliskiren was increased by approximately 2.5 fold (90% CI: 1.96 - 3.17) and the mean AUC by approximately 4.3 fold (90% CI: 3.52 - 5.21), compared to when these subjects received aliskiren alone. The concomitant administration of aliskiren with cyclosporine prolonged the median aliskiren elimination half-life (26 hours versus 43 to 45 hours) and the Tmax (0.5 hours versus 1.5 to 2.0 hours). The mean AUC and Cmax of cyclosporine were comparable to reported literature values. Co-administration of cyclosporine and aliskiren in these subjects also resulted in an increase in the number and/or intensity of adverse events, mainly headache, hot flush, nausea, vomiting, and somnolence. The co-administration of cyclosporine with aliskiren is not recommended.

Potassium-Sparing Diuretics

Cyclosporine should not be used with potassium -sparing diuretics because hyperkalemia can occur. Caution is also required when cyclosporine is co-administered with potassium sparing drugs (e.g. angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists), potassium containing drugs as well as in patients on a potassium rich diet. Control of potassium levels in these situations is advisable.

Nonsteroidal Anti-inflammatory Drug (NSAID) Interactions

Clinical status and serum creatinine should be closely monitored when cyclosporine is used with nonsteroidal anti-inflammatory agents in rheumatoid arthritis patients. (See WARNINGS )

Pharmacodynamic interactions have been reported to occur between cyclosporine and both naproxen and sulindac, in that concomitant use is associated with additive decreases in renal function, as determined by 99m Tc-diethylenetriaminepentaacetic acid (DTPA) and (p-aminohippuric acid) PAH clearances. Although concomitant administration of diclofenac does not affect blood concentrations of cyclosporine, it has been associated with approximate doubling of diclofenac blood concentrations and occasional reports of reversible decreases in renal function. Consequently, the dose of diclofenac should be in the lower end of the therapeutic range.

Methotrexate Interaction

Preliminary data indicate that when methotrexate and cyclosporine were co-administered to rheumatoid arthritis patients (N=20), methotrexate concentrations (AUCs) were increased approximately 30% and the concentrations (AUCs) of its metabolite, 7-hydroxy methotrexate, were decreased by approximately 80%. The clinical significance of this interaction is not known. Cyclosporine concentrations do not appear to have been altered (N=6).

Sirolimus

Elevations in serum creatinine were observed in studies using sirolimus in combination with full-dose cyclosporine. This effect is often reversible with cyclosporine dose reduction. Simultaneous coadministration of cyclosporine significantly increases blood concentrations of sirolimus. To minimize increases in sirolimus concentrations, it is recommended that sirolimus be given 4 hours after cyclosporine administration.

Nifedipine

Frequent gingival hyperplasia when nifedipine is given concurrently with cyclosporine have been reported.

Methylprednisolone

Convulsions when high dose methylprednisolone is given concurrently with cyclosporine have been reported.

Other Immunosuppressive Drugs and Agents

Psoriasis patients receiving other immunosuppressive agents or radiation therapy (including PUVA and UVB) should not receive concurrent cyclosporine because of the possibility of excessive immunosuppression .

Effect of Cyclosporine on the Efficacy of Live Vaccines

During treatment with cyclosporine, vaccination may be less effective. The use of live vaccines should be avoided.

For additional information on Cyclosporine Drug Interactions please contact Novartis Medical Affairs Department at 888-NOW-NOVA [888-669-6682].

Read the Neoral Drug Interactions Center for a complete guide to possible interactions

REACCIONES ADVERSAS

Kidney, Liver, and Heart Transplantation

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

Hypertension

Hypertension, which is usually mild to moderate, may occur in approximately 50% of patients following renal transplantation and in most cardiac transplant patients.

Glomerular Capillary Thrombosis

Glomerular capillary thrombosis has been found in patients treated with cyclosporine and may progress to graft failure. The pathologic changes 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

Hypomagnesemia has been reported in some, but not all, patients exhibiting convulsions while on cyclosporine therapy. Although magnesium-depletion studies in normal subjects suggest that hypomagnesemia is associated with neurologic disorders, multiple factors, including hypertension, high dose methylprednisolone, hypocholesterolemia, and nephrotoxicity associated with high plasma concentrations of cyclosporine appear to be related to the neurological manifestations of cyclosporine toxicity.

Clinical Studies

In controlled studies, the nature, severity, and incidence of the adverse events that were observed in 493 transplanted patients treated with Neoral® were comparable with those observed in 208 transplanted patients who received Sandimmune® 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®, 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 cyclosporine oral solution (Sandimmune®) 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 1.0%, 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 cyclosporine-treated patients: allergic reactions, anemia , anorexia , confusion, conjunctivitis , edema, fever, brittle fingernails, gastritis , hearing loss, hiccups , hyperglycemia , migraine (Neoral®) 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. Pre-existing infections may also be aggravated. Fatal outcomes have been reported. (see WARNINGS )

Infectious Complications in Historical Randomized Studies in Renal Transplant Patients Using Sandimmune®

Postmarketing Experience, Kidney, Liver and Heart Transplantation

Hepatotoxicity

Cases of hepatotoxicity and liver injury including cholestasis, jaundice , hepatitis and liver failure; serious and/or fatal outcomes have been reported. [See WARNINGS / Hepatotoxicity ]

Increased Risk of Infections

Cases of JC virus -associated progressive multifocal leukoencephalopathy (PML), sometimes fatal; and polyoma virus-associated nephropathy (PVAN), especially BK virus resulting in graft loss have been reported. [See WARNINGS / Polyoma Virus Infection ]

Headache, including Migraine

Cases of migraine have been reported. In some cases, patients have been unable to continue cyclosporine, however, the final decision on treatment discontinuation should be made by the treating physician following the careful assessment of benefits versus risks.

The principal adverse reactions associated with the use of cyclosporine in rheumatoid arthritis are renal dysfunction (see WARNINGS ), hypertension (see PRECAUTIONS ), 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:

Neoral®/Sandimmune® Rheumatoid Arthritis Percentage of Patients with Adverse Events ≥ 3% in any Cyclosporine Treated Group

In addition, the following adverse events have been reported in 1% to < 3% of the rheumatoid arthritis patients in the cyclosporine treatment group in controlled clinical trials.

Autonomic Nervous System: dry mouth , increased sweating;

Body as a Whole: allergy , asthenia , hot flushes, malaise , overdose, procedure NOS*, tumor NOS*, weight decrease, weight increase;

Cardiovascular: abnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemia;

Central and Peripheral Nervous System: hypoesthesia, neuropathy , vertigo ;

Endocrine: goiter ;

Gastrointestinal: constipation, dysphagia , enanthema, eructation , esophagitis , gastric ulcer , gastritis, gastroenteritis , gingival bleeding, glossitis , peptic ulcer, salivary gland enlargement, tongue disorder, tooth disorder;

Infection: abscess , bacterial infection, cellulitis , folliculitis , fungal infection, herpes simplex, herpes zoster , renal abscess, moniliasis, tonsillitis , viral infection ;

Hematologic: anemia, epistaxis , leukopenia , lymphadenopathy ;

Liver and Biliary System: bilirubinemia;

Metabolic and Nutritional: diabetes mellitus , hyperkalemia , hyperuricemia , hypoglycemia ;

Musculoskeletal System: arthralgia , bone fracture, bursitis , joint dislocation, myalgia , stiffness, synovial cyst, tendon disorder;

Neoplasms: breast fibroadenosis, carcinoma ;

Psychiatric: anxiety, confusion, decreased libido, emotional lability, impaired concentration, increased libido, nervousness, paroniria, somnolence ;

Reproductive (Female): breast pain , uterine hemorrhage;

Respiratory System: abnormal chest sounds, bronchospasm;

Skin and Appendages: abnormal pigmentation, angioedema , dermatitis , dry skin, eczema, nail disorder, pruritus, skin disorder, urticaria ;

Special Senses: abnormal vision, cataract , conjunctivitis, deafness, eye pain, taste perversion, tinnitus, vestibular disorder;

Urinary System: abnormal urine, hematuria, increased BUN , micturition urgency, nocturia , polyuria , pyelonephritis , urinary incontinence .

*NOS = Not Otherwise Specified.

Psoriasis

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 1.0% 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

PRESENTACION

Sandimmune, caps 50 y 100 mg

REFERENCIAS