A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
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P1,
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Q-R,
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U-V,
W-Z
Sandimmune Warnings, Precautions, Pregnancy, Nursing, Abuse - Cyclosporine
Sandimmune Warnings, Precautions, Pregnancy, Nursing, Abuse - Cyclosporine
WARNINGS
See DESCRIPTION
: BOXED WARNINGS
.
Sandimmune® (cyclosporine), when used in high doses, can cause hepatotoxicity
and 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.
|
Nephrotoxicity vs Rejection
|
| Parameter
|
Nephrotoxicity
|
Rejection
|
| History |
Donor >50 years old or hypotensive |
Antidonor immune response |
| Prolonged kidney preservation |
Retransplant patient |
| Prolonged anastomosis time |
|
| Concomitant nephrotoxic drugs |
|
| Clinical |
Often > 6 weeks post op & arteritis |
Often < weeks post op & arteritis |
| Prolonged initial nonfunction |
Fever > 37.5° C |
| (acute tubular necrosis) |
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 |
CyA serum trough level < 150 ng/mL |
| Gradual rise in Cr (< 0.15 mg/dl/day)a |
Rapid rise in Cr ( > 0.3 mg/ dl/day)a
|
| Cr plateau < 25% above baseline
|
Cr > 25% above baseline
|
| BUN/ Cr 20
|
BUN/ Cr < 20
|
| Biopsy
|
Arteriolopathy (medial hypertrophya, hyalinosis,
nodular deposits, intimal thickening, endothelial vacuolization, progressive
scarring)
|
Endovasculitisc (proliferationa, intimal arteritisb,
necrosis, sclerosis)
|
| Tubular atrophy, isometric vacuolization, isolated
calcifications
|
Tubulitis with RBCb and WBCb casts, some irregular
vacuolization
|
| Minimal edema
|
Interstitial edemac and hemorrhageb
|
| Mild focal infiltratesc
|
Diffuse moderate to severe mononuclear infiltratesd
|
| Diffuse interstitial fibrosis, often striped form
|
Glomerulitis (mononuclear cells) c |
| Aspiration Cytology
|
CyA deposits in tubular and endothelial cells
Fine isomeric vacuolization of tubular cells |
Inflammatory infiltrate with mononuclear phagocytes,
macrophages, lymphoblastoid cells, and activated 1- 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
|
Intracapsular pressure < 40 mm Hgb
|
Intracapsular pressure > 40 mm Hgb
|
| Ultra- sonography
|
Unchanged graft cross sectional area
|
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 |
Normal or generally decreased perfusion |
Patchy arterial wflow |
| Scan |
Decrease in tubular function (131
I-hippuran) > decrease in perfusion (99m Tc DTPA) |
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 |
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 wshow 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 levels 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.
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)
Significant hyperkalemia (sometimes associated with hyperchloremic metabolic
acidosis) and hyperuricemia have been seen occasionally in individual
patients.
Hepatotoxicity has been noted in 4% of cases of renal transplantation,
7% of cases of cardiac transplantation, and 4% of cases of liver transplantation.
This was usually noted during the first month of therapy when high doses
of Sandimmune® (cyclosporine) were used and consisted of elevations of
hepatic enzymes and bilirubin. The chemistry elevations usually decreased
with a reduction in dosage.
As in patients receiving other immunosuppressants, those patients receiving
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.
There have been reports of convulsions in adult and pediatric patients
receiving cyclosporine, particularly in combination with high dose methylprednisolone.
Rarely (approximately 1 in 1000), patients receiving Sandimmune® injection
(cyclosporine concentrate for 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 have consisted
of flushing of the face and upper thorax, acute respiratory distress with
dyspnea and 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 concentrate for
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.
Care should be taken in using Sandimmune® (cyclosporine) with nephrotoxic
drugs. (See PRECAUTIONS
)
Because Sandimmune® is not bioequivalent to Neoral®, conversion from
Neoral® to Sandimmune® using a 1:1 ratio (mg/kg/day) may result in a lower
cyclosporine blood concentration. Conversion from Neoral® to Sandimmune®
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
levels with Sandimmune® soft gelatin capsules or oral solution.
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 anti-hypertensive 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)
During treatment with Sandimmune® (cyclosporine), vaccination may be
less effective; and the use of live attenuated vaccines should be avoided.
Information for Patients
See PATIENT INFORMATION section.
Laboratory Tests
Renal and liver functions should be assessed repeatedly by measurement
of BUN, serum creatinine, serum bilirubin, and liver enzymes.
Drug Interactions
See DRUG INTERACTIONS section.
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 below)
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.
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. Sandimmune® oral solution (cyclosporine
oral solution, USP) has been shown to be embryoand 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.
Sandimmune® (cyclosporine) should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
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, pre-eclampsia, 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 Sandoz Pharmaceuticals
Corporation.
Nursing Mothers
Since Sandimmune® (cyclosporine) is excreted in human milk, nursing should
be avoided.
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.
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