Gengraf Capsules

Gengraf Capsules

SIDE EFFECTS

Kidney, Liver, and Heart Transplantation

The principal adverse reactions of 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 resembled 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 post-transplantation.

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.

In controlled studies, the nature, severity and incidence of the adverse events that were observed in 493 transplanted patients treated with cyclosporine (MODIFIED) were comparable with those observed in 208 transplanted patients who received Sandimmune® (cyclosporine capsules) 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.

Body System Adverse Reactions Randomized Kidney Patients Cyclosporine Patients (Sandimmune®)
Sandimmune®
(N=227) %
Azathioprine
(N=228) %
Kidney
(N=705) %
Heart
(N=112) %
Liver
(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

Among 705 kidney transplant patients treated with cyclosporine oral solution 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 Sandimmune®-treated 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.

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

Complication Cyclosporine Treatment (N=227)
% of Complications
Azathioprine with Steroids* (N=228)
% 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.

Rheumatoid Arthritis

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:

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

  Studies 651 + 652 + 2008 Study 302 Study 654 Study 654 Study 302 Studies 651 + 652 + 2008
Body System Preferred Term Sandimmune®
(N=269)
Sandimmune®
(N=155)
Methotrexate & Sandimmune®
(N=74)
Methotrexate & Placebo
(N=73)
Cyclosporine (MODIFIED)
(N=143)
Placebo
(N=201)
Autonomic Nervous System Disorders
   Flushing 2% 2% 3% 0% 5% 2%
Body As A Whole - General Disorders
  Accidental Trauma 0% 1% 10% 4% 4% 0%
Edema NOS* 5% 14% 12% 4% 10% < 1%
Fatigue 6% 3% 8% 12% 3% 7%
Fever 2% 3% 0% 0% 2% 4%
Influenza-like symptoms < 1% 6% 1% 0% 3% 2%
Pain 6% 9% 10% 15% 13% 4%
Rigors 1% 1% 4% 0% 3% 1%
Cardiovascular Disorders
  Arrhythmia 2% 5% 5% 6% 2% 1%
Chest Pain 4% 5% 1% 1% 6% 1%
Hypertension 8% 26% 16% 12% 25% 2%
Central and Peripheral Nervous System Disorders
  Dizziness 8% 6% 7% 3% 8% 3%
Headache 17% 23% 22% 11% 25% 9%
Migraine 2% 3% 0% 0% 3% 1%
Paresthesia 8% 7% 8% 4% 11% 1%
Tremor 8% 7% 7% 3% 13% 4%
Gastrointestinal System Disorders
  Abdominal Pain 15% 15% 15% 7% 15% 10%
Anorexia 3% 3% 1% 0% 3% 3%
Diarrhea 12% 12% 18% 15% 13% 8%
Dyspepsia 12% 12% 10% 8% 8% 4%
Flatulence 5% 5% 5% 4% 4% 1%
Gastrointestinal Disorder NOS* 0% 2% 1% 4% 4% 0%
Gingivitis 4% 3% 0% 0% 0% 1%
Gum Hyperplasia 2% 4% 1% 3% 4% 1%
Nausea 23% 14% 24% 15% 18% 14%
Rectal Hemorrhage 0% 3% 0% 0% 1% 1%
Stomatitis 7% 5% 16% 12% 6% 8%
Vomiting 9% 8% 14% 7% 6% 5%
Hearing and Vestibular Disorders
  Ear Disorders NOS* 0% 5% 0% 0% 1% 0%
Metabolic and Nutritional Disorders
  Hypomagnesemia 0% 4% 0% 0% 6% 0%
Musculoskeletal System Disorders
  Arthropathy 0% 5% 0% 1% 4% 0%
Leg Cramps/Involuntary Muscle Contractions 2% 11% 11% 3% 12% 1%
Psychiatric Disorders
  Depression 3% 6% 3% 1% 1% 2%
Insomnia 4% 1% 1% 0% 3% 2%
Renal
  Creatinine elevations ≥ 30% 43% 39% 55% 19% 48% 13%
Creatinine elevations ≥ 50% 24% 18% 26% 8% 18% 3%
Reproductive Disorders, Female
  Leukorrhea 1% 0% 4% 0% 1% 0%
Menstrual Disorder 3% 2% 1% 0% 1% 1%
Respiratory System Disorders
  Bronchitis 1% 3% 1% 0% 1% 3%
Coughing 5% 3% 5% 7% 4% 4%
Dyspnea 5% 1% 3% 3% 1% 2%
Infection NOS* 9% 5% 0% 7% 3% 10%
Pharyngitis 3% 5% 5% 6% 4% 4%
Pneumonia 1% 0% 4% 0% 1% 1%
Rhinitis 0% 3% 11% 10% 1% 0%
Sinusitis 4% 4% 8% 4% 3% 3%
Upper Respiratory Tract 0% 14% 23% 15% 13% 0%
Skin and Appendages Disorders
  Alopecia 3% 0% 1% 1% 4% 4%
Bullous Eruption 1% 0% 4% 1% 1% 1%
Hypertrichosis 19% 17% 12% 0% 15% 3%
Rash 7% 12% 10% 7% 8% 10%
Skin Ulceration 1% 1% 3% 4% 0% 2%
Urinary System Disorders
  Dysuria 0% 0% 11% 3% 1% 2%
Micturition Frequency 2% 4% 3% 1% 2% 2%
NPN, Increased 0% 19% 12% 0% 18% 0%
Urinary Tract Infection 0% 3% 5% 4% 3% 0%
Vascular (Extracardiac) Disorders
  Purpura 3% 4% 1% 1% 2% 0%
Includes patients in 2.5 mg/kg/day dose group only. *NOS = Not Otherwise Specified.

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 U.S. 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.

Adverse Events Occurring in 3% or More of Psoriasis Patients in Controlled Clinical Trials

Body System* Preferred Term Cyclosporine (MODIFIED)
(N=182)
Sandimmune®
(N=185)
Infection or Potential Infection 24.7% 24.3%
  Influenza-like Symptoms 9.9% 8.1%
Upper Respiratory Tract Infections 7.7% 11.3%
Cardiovascular System 28.0% 25.4%
  Hypertension** 27.5% 25.4%
Urinary System 24.2% 16.2%
  Increased Creatinine 19.8% 15.7%
Central and Peripheral Nervous System 26.4% 20.5%
  Headache 15.9% 14.0%
Paresthesia 7.1% 4.8%
Musculoskeletal System 13.2% 8.7%
  Arthralgia 6.0% 1.1%
Body As a Whole - General 29.1% 22.2%
  Pain 4.4% 3.2%
Metabolic and Nutritional 9.3% 9.7%
Reproductive, Female 8.5%
(4 of 47 females)
11.5%
(6 of 52 females)
Resistance Mechanism 18.7% 21.1%
Skin and Appendages 17.6% 15.1%
  Hypertrichosis 6.6% 5.4%
Respiratory System Bronchospasm, Coughing, 5.0% 6.5%
  Dyspnea, Rhinitis 5.0% 4.9%
Psychiatric 5.0% 3.8%
Gastrointestinal System 19.8% 28.7%
  Abdominal Pain 2.7% 6.0%
Diarrhea 5.0% 5.9%
Dyspepsia 2.2% 3.2%
Gum Hyperplasia 3.8% 6.0%
Nausea 5.5% 5.9%
White cell and RES 4.4% 2.7%
* Total percentage of events within the system.
** Newly occurring hypertension = SBP ≥ 160 mm Hg and/or DBP ≥ 90 mm Hg.

The following events occurred in 1% to less than 3% of psoriasis patients treated with cyclosporine:

Body as a Whole: fever, flushes, hot flushes; Cardiovascular: chest pain; Central and Peripheral Nervous System: appetite increased, insomnia, dizziness, nervousness, vertigo; Gastrointestinal: abdominal distention, constipation, gingival bleeding; Liver and Biliary System: hyperbilirubinemia; Neoplasms: skin malignancies [squamous cell (0.9%) and basal cell (0.4%) carcinomas]; Reticuloendothelial: platelet, bleeding, and clotting disorders, red blood cell disorder; Respiratory: infection, viral and other infection; Skin and Appendages: acne, folliculitis, keratosis, pruritus, rash, dry skin; Urinary System: micturition frequency; Vision: abnormal vision.

Mild hypomagnesemia and hyperkalemia may occur but are asymptomatic. Increases in uric acid may occur and attacks of gout have been rarely reported. A minor and dose related hyperbilirubinemia has been observed in the absence of hepatocellular damage. Cyclosporine therapy may be associated with a modest increase of serum triglycerides or cholesterol. Elevations of triglycerides ( > 750 mg/dL) occur in about 15% of psoriasis patients; elevations of cholesterol ( > 300 mg/dL) are observed in less than 3% of psoriasis patients. Generally these laboratory abnormalities are reversible upon dose reduction or discontinuation of cyclosporine.

Read the Gengraf Capsules (cyclosporine capsules) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

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

Antibiotics Antineoplastics Anti-inflammatory Drugs Gastrointestinal Agents
ciprofloxacin melphalan azapropazon cimetidine
gentamicin Antifungals colchicine ranitidine
tobramycin amphotericin B diclofenac Immunosuppressives
vancomycin ketoconazole naproxen tacrolimus
trimethoprim with sulfamethoxazole   sulindac Other Drugs
      fibric acid derivatives (e.g., bezafibrate, fenofibrate)

Drugs That Alter Cyclosporine Concentrations: Compounds that decrease cyclosporine absorption such as orlistat should be avoided. Cyclosporine is extensively metabolized by cytochrome P-450 III-A. Substances that inhibit this enzyme could decrease metabolism and increase cyclosporine concentrations. Substances that are inducers of cytochrome P-450 activity could increase metabolism and decrease cyclosporine concentrations. Monitoring of circulating cyclosporine concentrations and appropriate Gengraf® (cyclosporine capsules, USP [MODIFIED]) dosage adjustment are essential when these drugs are used concomitantly (see DOSAGE AND ADMINISTRATION - Blood Concentration Monitoring).

Drugs That Increase Cyclosporine Concentrations

Calcium Channel Blockers Antibiotics Other Drugs
diltiazem azithromycin allopurinol
nicardipine clarithromycin bromocriptine
verapamil erythromycin danazol
Antifungals quinupristin/dalfopristin metoclopramide
fluconazole   colchicine
itraconazole Glucocorticoids amiodarone
ketoconazole methylprednisolone imatinib
oral contraceptives

The HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 III-A 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 and grapefruit juice affect metabolism, increasing blood concentrations of cyclosporine, thus should be avoided.

Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations

Antibiotics Anticonvulsants Other Drugs
nafcillin carbamazepine octreotide
rifampin phenobarbital ticlopidine
  phenytoin orlistat
    sulfinpyrazone
    terbinafine 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 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.

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 99mTc-diethylenetriaminepentaacetic acid (DTPA) and (p-aminohippuric acid) PAH clearances. Although concomitant administration of diclofenac does not affect blood levels of cyclosporine, it has been associated with approximate doubling of diclofenac blood levels 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 coadministered 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).

Other Drug Interactions: Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, and HMG-CoA reductase inhibitors (statins). Severe digitalis toxicity has been seen within days of starting cyclosporine in several patients taking digoxin. There are also reports on the potential of cyclosporine to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction. If digoxin or colchicine are used concurrently with cyclosporine, close clinical observation is required in order to enable early detection of toxic manifestations of digoxin or colchicine, followed by reduction of dosage or its withdrawal.

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.

Cyclosporine should not be used with potassium sparing diuretics because hyperkalemia can occur. Caution is also required when cyclosporine is coadministered 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.

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 levels of sirolimus. To minimize increases in sirolimus blood concentrations, it is recommended that sirolimus be given 4 hours after cyclosporine administration.

During treatment with cyclosporine, vaccination may be less effective. The use of live vaccines should be avoided. Frequent gingival hyperplasia with nifedipine, and convulsions with high dose methylprednisolone have been reported.

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.

For additional information on Cyclosporine Drug Interactions please contact Abbott Laboratories Medical Information Department at 1-800-633-9110.

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

Last reviewed on RxList: 5/11/2009
This monograph has been modified to include the generic and brand name in many instances.

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