Gengraf Side Effects

Generic name: cyclosporine

Note: This document contains side effect information about cyclosporine. Some of the dosage forms listed on this page may not apply to the brand name Gengraf.

Some side effects of Gengraf may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

For the Consumer

Applies to cyclosporine: oral capsule, oral liquid, oral solution

Get emergency medical help if you have any of these signs of an allergic reaction while taking cyclosporine (the active ingredient contained in Gengraf) hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

• fever, sweating, chills, body aches, flu symptoms, sores in your mouth and throat, weight loss;

• change in your mental state, problems with speech or walking, decreased vision (may start gradually and get worse quickly);

• easy bruising or bleeding, pale skin, confusion or weakness;

• feeling light-headed or short of breath, rapid heart rate, trouble concentrating;

• pain in the lower back or side, blood in your urine, pain or burning when you urinate;

• urinating less than usual or not at all, rapid weight gain;

• swelling, warmth, redness, or oozing of the skin;

• vomiting and bloody diarrhea;

• seizure (convulsions);

• high potassium (slow heart rate, weak pulse, muscle weakness, tingly feeling);

• nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

• dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, chest pain, shortness of breath, uneven heartbeats).

Less serious side effects of cyclosporine may include:

• swollen or painful gums;

• mild headache;

• stomach pain, constipation, mild diarrhea; or

• tremors or shaking, muscle spasm, numbness or tingly feeling.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

For Healthcare Professionals

Applies to cyclosporine: compounding powder, injectable solution, oral capsule, oral liquid, oral solution

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 (the active ingredient contained in Gengraf) 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 (the active ingredient contained in Gengraf) 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. Postmarketing reports of migraine headache have been reported.

Dermatologic

Dermatologic side effects of cyclosporine (the active ingredient contained in Gengraf) 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, and are generally mild and self-limited, and manifest as elevated bilirubin, serum transaminases, and alkaline phosphatase values. In addition, cholestatic jaundice has been reported. Postmarketing reports of cholestasis, jaundice, hepatitis and liver failure with serious and/or fatal outcomes have 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 (the active ingredient contained in Gengraf) 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 (the active ingredient contained in Gengraf) 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 (the active ingredient contained in Gengraf) 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 (the active ingredient contained in Gengraf) 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 (the active ingredient contained in Gengraf) (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 (the active ingredient contained in Gengraf) 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. Postmarketing reports of progressive multifocal leukoencephalopathy (PML), sometimes fatal; and polyoma virus associated nephropathy (PVAN), especially BK virus resulting in graft loss have been reported.

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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