Sandimmune Side Effects

Generic Name: cyclosporine

Please note - some side effects for Sandimmune may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Sandimmune - for the Consumer

Sandimmune

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Sandimmune:

Acne; dizziness; headache; increased hair growth; nausea; runny nose; sleeplessness; stomach discomfort; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Sandimmune:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; blood in the urine; change in the appearance of a mole; chest pain; confusion; dark urine; diarrhea; fast or irregular heartbeat; flushing of the face, chest, back, or abdomen; gum disease or overgrowth; increased or decreased urination; loss of coordination; mental or mood changes; muscle cramps; numbness or tingling of the skin; seizures; severe or persistent headache or dizziness; shortness of breath; symptoms of infection (eg, chills, cough, fever, painful urination, sore throat); tremors; unusual bleeding or bruising; unusual lumps; unusual thickening or growth on the skin; unusual tiredness or weakness; vision changes; wheezing; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Sandimmune Soft Gelatin Capsules

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Sandimmune Soft Gelatin Capsules:

Acne; dizziness; flushing; headache; increased hair growth; nausea; runny nose; sleeplessness; stomach discomfort; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Sandimmune Soft Gelatin Capsules:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; blood in the urine; change in the appearance of a mole; chest pain; confusion; dark urine; diarrhea; fast or irregular heartbeat; gum disease or overgrowth; increased or decreased urination; loss of coordination; mental or mood changes; muscle cramps; numbness or tingling of the skin; seizures; severe or persistent headache or dizziness; shortness of breath; symptoms of infection (eg, chills, cough, fever, painful urination, sore throat); tremors; unusual bleeding or bruising; unusual lumps; unusual thickening or growth on the skin; unusual tiredness or weakness; vision changes; wheezing; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Sandimmune Solution

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Sandimmune Solution:

Acne; dizziness; flushing; headache; increased hair growth; nausea; runny nose; sleeplessness; stomach discomfort; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Sandimmune Solution:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; blood in the urine; change in the appearance of a mole; chest pain; confusion; dark urine; diarrhea; fast or irregular heartbeat; gum disease or overgrowth; increased or decreased urination; loss of coordination; mental or mood changes; muscle cramps; numbness or tingling of the skin; seizures; severe or persistent headache or dizziness; shortness of breath; symptoms of infection (eg, chills, cough, fever, painful urination, sore throat); tremors; unusual bleeding or bruising; unusual lumps; unusual thickening or growth on the skin; unusual tiredness or weakness; vision changes; wheezing; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Sandimmune Side Effects - for the Professional

Sandimmune

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:

	Randomized Kidney Patients		All Sandimmune® (cyclosporine) Patients
	Sandimmune®	Azathioprine	Kidney	Heart	Liver
Body System/	(N=227)	(N=228)	(N=705)	(N=112)	(N=75)
Adverse Reactions	%	%	%	%	%
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
	Randomized Patients		All Sandimmune® Patients
	Sandimmune®	Azathioprine
	(N=227)	(N=228)	(N=705)
Reason for Discontinuation	%	%	%
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.

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.

Infectious Complications in the Randomized Renal Transplant Patients
	Sandimmune® Treatment	Standard Treatment*
	(N=227)	(N=228)
Complication	% 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 lipoproteins. These effects are reversible upon discontinuation of treatment but are usually not a reason to stop treatment.

Postmarketing Experience

BK virus associated nephropathy has been observed in patients receiving immunosuppressants, including Sandimmune.  This infection is associated with serious outcomes, including deteriorating renal function and renal graft loss  .

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Side Effects by Body System - for Healthcare Professionals

Renal

BK virus associated nephropathy has been associated with serious outcomes, including deteriorating renal function and renal graft loss.

Elevations in serum creatinine and BUN are common during cyclosporine therapy and do not necessarily indicate allograft rejection.

In addition, cyclosporine-induced hyperuricemia may predispose the patient to renal calculi.

Renal insufficiency is dose-related. It is often accompanied by hypertension. Cyclosporine causes a reversible reduction in renal blood flow and glomerular filtration rate. The mechanism of cyclosporine-induced nephrotoxicity is now considered to be vasoconstriction of the afferent arterioles. ET1 is also considered to be a key substance of cyclosporine-induced nephrotoxicity. Mild nephrotoxicity generally responds to reductions in cyclosporine doses. A chronic, progressive nephrotoxicity may also occur in which discontinuation of cyclosporine fails to alleviate the renal insufficiency. Renal biopsies from these patients may demonstrate interstitial fibrosis, tubular atrophy, global or segmental glomerulosclerosis, or smooth vascular muscle damage. It has been suggested that higher cumulative doses or high cyclosporine trough levels may be associated with the development of interstitial fibrosis.

Renal function should be closely monitored. Differentiation between cyclosporine-induced nephrotoxicity, allograft rejection, and other causes of impaired renal function should be made before considering cyclosporine dosage adjustments.

The use of nonsteroidal anti-inflammatory agents in combination with cyclosporine may increase the risk of renal toxicity, especially in rheumatoid arthritis patients. Intact renal prostaglandins are necessary for maintaining adequate renal blood flow in patients treated with cyclosporine. Renal deterioration may occur independent of changes in cyclosporine levels.

Renal side effects including renal insufficiency (up to 38%) and BK virus associated nephropathy have been reported. A chronic, progressive, irreversible nephrotoxicity has also been reported. Elevations in serum creatinine and BUN are common during cyclosporine therapy and do not necessarily indicate allograft rejection. A case of hemolytic uremic syndrome (HUS) associated with cyclosporine therapy has been reported. A fatal case of acute tubular necrosis has been reported. In addition, cyclosporine-induced hyperuricemia may predispose the patient to renal calculi.

Nervous system

Seizures in patients on cyclosporine therapy may be associated with hypomagnesemia or concomitant high-dose corticosteroids. In addition, hypercholesterolemia and hypertension may contribute to cyclosporine neurotoxicity. Hypomagnesemia and hypercholesterolemia allow easier diffusion of cyclosporine across the blood-brain barrier potentiating neurotoxicity.

A review of cyclosporine-induced neurotoxicity revealed a 10% incidence after liver transplantation. Intravenous administration of cyclosporine was associated with more severe reactions such as psychosis, however severe reactions occurred rarely. MRI abnormalities were seldom found. Only 61% of patients that experienced neurotoxicity (n=46) had cyclosporine trough levels suggestive of toxicity. Temporary discontinuation and lowering the dose of cyclosporine resolved the neurotoxicity. Three patients were successfully switched to tacrolimus therapy without return of neurotoxicity. No patient exhibited abnormal magnesium levels.

The speech disorder leading to mutism which has been associated with cyclosporine therapy was reversible. Symptoms resolved within 1 to 2 weeks after withdrawal of the cyclosporine.

The permanent blindness which was reported in one patient was suspected to be due to neurotoxicity associated with elevated cyclosporine levels. Dechallenge with cyclosporine did not reverse the blindness . The blindness occurred over a 36 hour period 3 weeks following a kidney-pancreas transplant. The cyclosporine trough level was at its highest on the day of complete blindness (495 ng/mL). The mechanism by which cyclosporine induces neurologic blindness is unknown.

Nervous system side effects of cyclosporine have included tremors (12% to 55%) and headache (2% to 15%). Depression, somnolence, decreased visual acuity, confusion, paresthesias, seizures, and a reversible speech disorder leading to mutism have also been associated with cyclosporine therapy. Three cases of leukoencephalopathy have also been reported.

Dermatologic

Dermatologic side effects of cyclosporine have included hypertrichosis (30%), acne (1% to 8%), and pruritus. Cyclosporine has been associated with pilosebaceous lesions, including hypertrichosis, epidermal cysts, keratosis pilaris, acne, folliculitis, sebaceous gland hyperplasia, and cutaneous malignancies. A case of erythroderma resembling Sezary syndrome with lymphocytic infiltrates of the skin has been reported. Cases of folliculodystrophy and pseudoporphyria have also been reported.

Hepatic

Hepatic side effects have been common, occurring in up to 50% of patients, generally mild and self-limited, and manifest as elevated bilirubin, serum transaminases, and alkaline phosphatase values. In addition, cholestatic jaundice has been reported.

Hematologic

A syndrome characterized by thrombocytopenia and microangiopathic anemia is reported in some patients and may result in allograft rejection.

Hematologic side effects have included leukopenia (less than 1% to 6%), anemia, and thrombocytopenia.

Metabolic

Metabolic side effects of cyclosporine have included significant hyperkalemia, which is sometimes associated with hyperchloremic metabolic acidosis.

Gastrointestinal

Gastrointestinal side effects have included gum hyperplasia (4% to 16%), diarrhea (3% to 8%), nausea and vomiting (2% to 10%), anorexia, abdominal discomfort, and rare reports of upper gastrointestinal bleeding. Pancreatitis has also been reported rarely.

The incidence of gum hyperplasia is lower with the microemulsion form of cyclosporine. A 14 day course of metronidazole 750 mg three times a day has been effective in remitting gum hyperplasia in patients with rheumatoid arthritis. No increase in serum cyclosporine levels and creatinine levels were observed during metronidazole therapy. The effect of metronidazole on gum hyperplasia may be due to its antibacterial activity, although data is lacking.

Cardiovascular

One study has reported that reduced basal and stimulated nitrous oxide production in cyclosporine-treated renal transplant recipients. The authors stated that this suggests endothelial dysfunction, and may explain the increased risk of premature atherosclerosis and cardiovascular death. They felt this might also provide, at least in part, a potential mechanism to explain cyclosporine-induced hypertension.

Cardiovascular side effects have included hypertension (50%) induced by cyclosporine. Myocardial infarction has also been reported rarely.

Endocrine

Endocrine side effects of cyclosporine have included hypertriglyceridemia, increases in serum prolactin, decreases in serum testosterone, gynecomastia, hyperglycemia, and hypertrichosis. Cremophor EL (polyoxyethylated castor oil), the vehicle for the intravenous form of cyclosporine, may cause hyperlipidemia and electrophoretic abnormalities of lipoproteins. These effects are reversible upon cessation of therapy, but usually do not necessitate drug withdrawal.

Other

Other side effects including a significant risk of acute rejection and death and/or graft loss have been reported in one study of 108 living related renal transplant recipients when cyclosporine was withdrawn after an average of twelve and a half months after transplantation because of economic constraints. One case of trichomegaly has been reported. A case of calcineurin inhibitor induced pain syndrome (CIPS) has also been reported.

Hypersensitivity

Hypersensitivity side effects to cyclosporine have occurred in less than 2% of patients.

Anaphylaxis, manifest as acute dyspnea, tachypnea, pruritus, rash, and chest discomfort has been reported in rare cases after intravenous administration of cyclosporine. The vehicle, Cremophor EL, is suspected of inducing anaphylaxis as some patients who experienced anaphylaxis following IV administration were subsequently safely treated with oral dosage forms. Intravenous cyclosporine should be reserved for those patients who are unable to tolerate oral medications. If this route is necessary, continuous observation for at least the first 30 minutes of the infusion is recommended.

Ocular

A rare manifestation of neurotoxicity induced by cyclosporine (which has occurred in transplant patients more frequently than in other indications) is optic disc edema including papilledema, with possible visual impairment, secondary to benign intracranial hypertension.

Ocular side effects have included reports of pseudotumor cerebri, which resolved rapidly upon discontinuation of cyclosporine, and optic disk edema. Permanent blindness has been reported in one patient. A case of cyclosporine-induced retinal toxic blindness has also been reported.

Oncologic

Oncologic side effects including one fatal case of metastatic angiosarcoma during cyclosporine and prednisone immunosuppression (after kidney transplantation) have been reported.

The development of neoplasms, particularly lymphomas and skin malignancies, is more likely in immunosuppressed patients.

Whether neoplasms are more likely due to underlying disease, the immunosuppressed state, or to cyclosporine itself is somewhat speculative. In a large study, an increased incidence of lymphoma and Kaposi's sarcoma was found in patients treated with cyclosporine relative to those treated with a combination of azathioprine and prednisone. In some reported cases of B-cell lymphoma, the Epstein-Barr virus genome was found in the malignant cells, suggesting opportunistic infection during a cyclosporine-induced immunosuppressed state.

Immunologic

Immunologic side effects have included an increased patient susceptibility to opportunistic infections due to cyclosporine-induced immunosuppression.

Accelerated hepatitis B and C infections, sometimes resulting in hepatic necrosis, Pneumocystis pneumoniae infections, as well as other viral, fungal, and bacterial infections have been reported in patients treated with cyclosporine. An in vitro study demonstrated enhanced intracellular cytomegalovirus production and virus spread, indicating an increased risk of CMV infection in cyclosporine-treated patients.

Local

Local side effects including a case of recurrent infusion phlebitis have been reported.

Respiratory

The death was part caused by an anaphylactic reaction which may have actually been a reaction to the Cremophor EL (polyoxyethylated castor oil) used as the vehicle for the intravenous formulation.

Respiratory side effects have included respiratory arrest and aspiration pneumonia in one patient that lead to the death of that patient.

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