A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Sandimmune Side Effects, and Drug Interactions - Cyclosporine
Sandimmune Side Effects, and Drug Interactions - Cyclosporine
SIDE EFFECTS
The principal adverse reactions of Sandimmune® (cyclosporine) therapy
are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.
Hypertension, which is usually mild to moderate, may occur in approximately
50% of patients following renal transplantation and in most cardiac transplant
patients.
Glomerular capillary thrombosis has been found in patients treated with
cyclosporine and may progress to graft failure. The pathologic changes
resemble those seen in the hemolytic-uremic syndrome and include 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 posttransplantation.
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.
The following reactions occurred in 3% or greater of 892 patients involved
in clinical trials of kidney, heart, and liver transplants:
| Body System/ Adverse REACTIONS |
Randomized Kidney Patients |
All Sandimmune® (cyclosporine)
Patients |
|
Sandimmune®
|
Azathioprine |
Kidney |
Heart |
Liver |
| (N=227) |
(N=228) |
(N=705) |
(N=112) |
(N=75) |
| % |
% |
% |
% |
% |
| Genitourinary |
| Renal Dysfunction |
32 |
6 |
25 |
38 |
37 |
| Cardiovascular |
| Hypertension |
26 |
18 |
13 |
53 |
27 |
| Cramps |
4 |
<1 |
2 |
<1 |
0 |
| Skin |
| Hirsutism |
21 |
<1 |
21 |
28 |
45 |
| Acne |
6 |
8 |
2 |
2 |
1 |
| Central Nervous System |
| Tremor |
12 |
0 |
21 |
31 |
55 |
| Convulsions |
3 |
1 |
1 |
4 |
5 |
| Headache |
2 |
<1 |
2 |
15 |
4 |
| Gastrointestinal |
| Gum Hyperplasia |
4 |
0 |
9 |
5 |
16 |
| Diarrhea |
3 |
<1 |
3 |
4 |
8 |
| Nausea/ Vomiting |
2 |
<1 |
4 |
10 |
4 |
| Hepatotoxicity |
<1 |
<1 |
4 |
7 |
4 |
| Abdominal Discomfort |
<1 |
0 |
<1 |
7 |
0 |
| Autonomic Nervous System |
| Paresthesia |
3 |
0 |
1 |
2 |
1 |
| Flushing |
<1 |
0 |
4 |
0 |
4 |
| Hematopoietic |
| Leukopenia |
2 |
19 |
<1 |
6 |
0 |
| Lymphoma |
<1 |
0 |
1 |
6 |
1 |
| Respiratory |
| Sinusitis |
<1 |
0 |
4 |
3 |
7 |
| Miscellaneous |
| Gynecomastia |
<1 |
0 |
<1 |
4 |
3 |
The following reactions occurred in 2% or less of patients: allergic
reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever,
brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia,
muscle pain, peptic ulcer, thrombocytopenia, tinnitus.
The following reactions occurred rarely: anxiety, chest pain, constipation,
depression, hair breaking, hematuria, joint pain, lethargy, mouth sores,
myocardial infarction, night sweats, pancreatitis, pruritus, swallowing
difficulty, tingling, upper GI bleeding, visual disturbance, weakness,
weight loss.
| Renal
Transplant Patients in Whom Therapy Was Discontinued |
| Reason for Discontinuation |
Randomized
Patients |
All Sandimmune® Patients |
| Sandimmune® |
Azathioprine |
| (N=227) |
(N=228) |
(N=705) |
| % |
% |
% |
| Renal Toxicity |
5.7 |
0 |
5.4 |
| Infection |
0 |
0.4 |
0.9 |
| Lack of Efficacy |
2.6 |
0.9 |
1.4 |
| Acute Tubular Necrosis |
2.6 |
0 |
1.0 |
| Lymphoma/Lymphoproliferative Disease |
0.4 |
0 |
0.3 |
| Hypertension |
0 |
0 |
0.3 |
| Hematological Abnormalities |
0 |
0.4 |
0 |
| Other |
0 |
0 |
0.7 |
Sandimmune® (cyclosporine) was discontinued on a temporary basis and
then restarted in 18 additional patients.
| Infectious Complications
in the Randomized Renal Transplant Patients |
|
Complication
|
Sandimmune® Treatment |
Standard Treatment* |
| (N=227) |
(N=228) |
| % of Complications |
% of Complications |
| Septicemia |
5.3 |
4.8 |
| Abscesses |
4.4 |
5.3 |
| Systemic Fungal Infection |
2.2 |
3.9 |
| Local Fungal Infection |
7.5 |
9.6 |
| Cytomegalovirus |
4.8 |
12.3 |
| Other Viral Infections |
15.9 |
18.4 |
| Urinary Tract infections |
21.1 |
20.2 |
| Wound and Skin Infections |
7.0 |
10.1 |
| Pneumonia |
6.2 |
9.2 |
*Some patients also received ALG.
Cremophor® EL (polyoxyethylated castor oil) is known to cause hyperlipemia
and electrophoretic abnormalities of lipo-proteins. These effects are
reversible upon discontinuation of treatment but are usually not a reason
to stop treatment.
DRUG INTERACTIONS
All Of the individual drugs cited below are well substantiated to interact
with Sandimmune® (cyclosporine).
Drugs That Exhibit Nephrotoxic Synergy
| gentamicin |
|
amphotericin B |
|
cimetidine |
|
trimethoprim |
| tobramycin |
|
ketoconazole |
|
ranitidine |
|
with sulfamethoxazole |
| vancomycin |
|
melphalan |
|
diclofenac |
|
azapropazon |
Careful monitoring of renal function should be practiced when Sandimmune®
(cyclosporine) is used with nephrotoxic drugs.
Drugs That Alter Cyclosporine Levels
Cyclosporine is extensively metabolized by the liver. Therefore, circulating
cyclosporine levels may be influenced by drugs that affect hepatic microsomal
enzymes, particularly the cytochrome P-450 system. Substances known to
inhibit these enzymes will decrease hepatic metabolism and increase cyclosporine
levels. Substances that are inducers of cytochrome P-450 activity will
increase hepatic metabolism and decrease cyclosporine levels. Monitoring
of circulating cyclosporine levels and appropriate Sandimmune® (cyclosporine)
dosage adjustment are essential when these drugs are used concomitantly.
(See Blood Level Monitoring)
Drugs That Increase Cyclosporine Levels
| diltiazem |
|
ketoconazole |
|
danazol |
|
eryth romycin |
| nicardipine |
|
fluconazole |
|
bromocriptine |
|
methylprednisolone |
| verapamil |
|
itraconazole |
|
metoclopramide |
|
|
Drugs That Decrease Cyclosporine Levels
| rifampin |
|
phenytoin |
|
phenobarbital |
|
carbamazepine |
Other Drug Interactions
Reduced clearance of prednisolone, digoxin, and lovastatin has been observed
when these drugs are administered with Sandimmune® (cyclosporine). In
addition, a decrease in the apparent volume of distribution of digoxin
has been reported after Sandimmune® (cyclosporine) administration. Severe
digitalis toxicity has been seen within days of starting cyclosporine
in several patients taking digoxin. Sandimmune® (cyclosporine) should
not be used with potassium-sparing diuretics because hyperkalemia can
occur. During treatment with Sandimmune® (cyclosporine), vaccination may
be less effective; and the use of live vaccines should be avoided. Myositis
has occurred with concomitant lovastatin, frequent gingival hyperplasia
with nifedipine, and convulsions with high dose methylprednisolone. Further
information on drugs that have been reported to interact with Sandimmune
(cyclosporine) is available from Sandoz Pharmaceuticals Corporation.
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