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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.

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

Body System Preferred Term Studies
651+652+2008
Study 302 Study 654 Study 654 Study 302 Studies
651+652+2008
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, gastroenteritus, 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, influenzalike 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)
Cyclosporine
(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 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%
* 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.