Gengraf Side Effects
Generic Name: Cyclosporine
Please note - some side effects for Gengraf may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).
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For the consumer For the professional
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Side Effects of Gengraf - for the consumer
Gengraf
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 Gengraf:
Seek medical attention right away if any of these SEVERE side effects occur when using Gengraf:Acne; burning sensation; coughing; dizziness; flushing; increased hair growth; headache; nausea; runny nose; sleeplessness; stomach discomfort; vomiting.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stool; blood in the urine; chest pain; chills; confusion; dark urine; diarrhea; fast or irregular heartbeat; fever; gum disease or overgrowth; increased or decreased urination; infection; 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; sore throat; tremors; unusual bleeding or bruising; unusual lumps; unusual thickening or lesion of the skin; unusual tiredness or weakness; vision changes; wheezing; yellowing of the skin or eyes.
Gengraf 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 Gengraf Solution:
Seek medical attention right away if any of these SEVERE side effects occur when using Gengraf Solution:Acne; burning sensation; coughing; dizziness; flushing; increased hair growth; headache; nausea; runny nose; sleeplessness; stomach discomfort; vomiting.
TopSevere allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stool; blood in the urine; chest pain; chills; confusion; dark urine; diarrhea; fast or irregular heartbeat; fever; gum disease or overgrowth; increased or decreased urination; infection; 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; sore throat; tremors; unusual bleeding or bruising; unusual lumps; unusual thickening or lesion of the skin; unusual tiredness or weakness; vision changes; wheezing; yellowing of the skin or eyes.
For the professional
Gengraf
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® 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.
| Randomized Kidney Patients | Cyclosporine
Patients Sandimmune® |
|||||
| Body System | Adverse Reactions | |||||
| 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.
| Complication | Cyclosporine Treatment (N = 227) % of Complications |
Azathioprine with
Steroids* (N = 228) % of Complications |
* Some patients also received ALG. | ||
| 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 |
Rheumatoid Arthritis
The principal adverse reactions associated with the use of cyclosporine in rheumatoid arthritis are renal dysfunction, hypertension, 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
| 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) |
|
|
† Includes patients in 2.5 mg/kg/day dose group only. * NOS = Not Otherwise Specified. | ||||||||
| 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% | ||
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 Systemdry mouth, increased sweating
Body as a Wholeallergy, asthenia, hot flushes, malaise, overdose, procedure NOS*, tumor NOS*, weight decrease, weight increase
Cardiovascularabnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemia
Central and Peripheral Nervous Systemhypoesthesia, neuropathy, vertigo
Endocrinegoiter
Gastrointestinalconstipation, dysphagia, enanthema, eructation,esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland enlargement, tongue disorder, tooth disorder
Infectionabscess, bacterial infection, cellulitis, folliculitis, fungal infection, herpes simplex, herpes zoster, renal abscess, moniliasis, tonsillitis, viral infection
Hematologicanemia, epistaxis, leukopenia, lymphadenopathy
Liver and Biliary Systembilirubinemia
Metabolic and Nutritionaldiabetes mellitus, hyperkalemia, hyperuricemia, hypoglycemia
Musculoskeletal Systemarthralgia, bone fracture, bursitis, joint dislocation, myalgia, stiffness, synovial cyst, tendon disorder
Neoplasmsbreast fibroadenosis, carcinoma
Psychiatricanxiety, confusion, decreased libido, emotional lability, impaired concentration, increased libido, nervousness, paroniria, somnolence
Reproductive (Female)breast pain, uterine hemorrhage
Respiratory Systemabnormal chest sounds, bronchospasm
Skin and Appendagesabnormal pigmentation, angioedema, dermatitis, dry skin, eczema, nail disorder, pruritus, skin disorder, urticaria
Special Sensesabnormal vision, cataract, conjunctivitis, deafness, eye pain, taste perversion, tinnitus, vestibular disorder
Urinary Systemabnormal 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.
| Body System* Preferred Term |
Cyclosporine (MODIFIED) (N = 182) |
Cyclosporine (N = 185) |
|
* Total percentage of events within the system. ** Newly occurring hypertension = SBP≥ 160 mm Hg and/or DBP ≥ 90 mm Hg. | ||
| 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 | 5.0% | 6.5% |
| Bronchospasm, Coughing, 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% |
The following events occurred in 1% to less than 3% of psoriasis patients treated with cyclosporine:
Body as a Wholefever, flushes, hot flushes
Cardiovascularchest pain
Central and Peripheral Nervous Systemappetite increased, insomnia, dizziness, nervousness, vertigo
Gastrointestinalabdominal distention, constipation, gingival bleeding; Liver and Biliary System: hyperbilirubinemia
Neoplasmsskin malignancies [squamous cell (0.9%) and basal cell (0.4%) carcinomas]
Reticuloendothelialplatelet, bleeding, and clotting disorders, red blood cell disorder
Respiratoryinfection, viral and other infection
Skin and Appendagesacne, folliculitis, keratosis, pruritus, rash, dry skin
Urinary Systemmicturition frequency
Visionabnormal 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.
TopGengraf Capsules
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.
| Randomized Kidney Patients |
Cyclosporine
Patients (Sandimmune® ) |
|||||
| Body System | Adverse Reactions | |||||
| 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.
| Complication | Cyclosporine Treatment (N = 227) % of Complications |
Azathioprine with
Steroids* (N = 228) % of Complications |
* Some patients also received ALG. | ||
| 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 |
Rheumatoid Arthritis
The principal adverse reactions associated with the use of cyclosporine in rheumatoid arthritis are renal dysfunction, hypertension, 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
| 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) |
|
† Includes patients in 2.5 mg/kg/day dose group only. * NOS = Not Otherwise Specified. | |||||||
| 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% | |
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 Systemdry mouth, increased sweating
Body as a Wholeallergy, asthenia, hot flushes, malaise, overdose, procedure NOS*, tumor NOS*, weight decrease, weight increase
Cardiovascularabnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemia
Central and Peripheral Nervous Systemhypoesthesia, neuropathy, vertigo
Endocrinegoiter
Gastrointestinalconstipation, dysphagia, enanthema, eructation, esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland enlargement, tongue disorder, tooth disorder
Infectionabscess, bacterial infection, cellulitis, folliculitis, fungal infection, herpes simplex, herpes zoster, renal abscess, moniliasis, tonsillitis, viral infection
Hematologicanemia, epistaxis, leukopenia, lymphadenopathy
Liver and Biliary Systembilirubinemia
Metabolic and Nutritionaldiabetes mellitus, hyperkalemia, hyperuricemia, hypoglycemia
Musculoskeletal Systemarthralgia, bone fracture, bursitis, joint dislocation, myalgia, stiffness, synovial cyst, tendon disorder
Neoplasmsbreast fibroadenosis, carcinoma
Psychiatricanxiety, confusion, decreased libido, emotional lability, impaired concentration, increased libido, nervousness, paroniria, somnolence
Reproductive (Female)breast pain, uterine hemorrhage
Respiratory Systemabnormal chest sounds, bronchospasm
Skin and Appendagesabnormal pigmentation, angioedema, dermatitis, dry skin, eczema, nail disorder, pruritus, skin disorder, urticaria
Special Sensesabnormal vision, cataract, conjunctivitis, deafness, eye pain, taste perversion, tinnitus, vestibular disorder
Urinary Systemabnormal 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.
| Body System* Preferred Term |
Cyclosporine (MODIFIED) (N = 182) |
Sandimmune® (N = 185) |
|
* Total percentage of events within the system. ** Newly occurring hypertension = SBP≥160 mm Hg and/or DBP ≥90 mm Hg. | ||
| 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 | 5.0% | 6.5% |
| Bronchospasm, Coughing, 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% |
The following events occurred in 1% to less than 3% of psoriasis patients treated with cyclosporine:
Body as a Wholefever, flushes, hot flushes
Cardiovascularchest pain
Central and Peripheral Nervous Systemappetite increased, insomnia, dizziness, nervousness, vertigo
Gastrointestinalabdominal distention, constipation, gingival bleeding; Liver and Biliary System: hyperbilirubinemia
Neoplasmsskin malignancies [squamous cell (0.9%) and basal cell (0.4%) carcinomas]
Reticuloendothelialplatelet, bleeding, and clotting disorders, red blood cell disorder
Respiratoryinfection, viral and other infection
Skin and Appendagesacne, folliculitis, keratosis, pruritus, rash, dry skin
Urinary Systemmicturition frequency
Visionabnormal 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.
TopMore resources:
Cyclosporine - Includes detailed dosage instructions.
Neoral - Includes detailed dosage instructions.
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