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Neoral (Cyclosporine) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

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 included 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 Neoral® 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 ® )
Sandimmune ® Azathioprine Kidney Heart Liver
Body System Adverse Reactions (N=227)% (N=228)% (N=705)% (N=112)% (N=75)%
GenitourinaryRenal Dysfunction326253837
CardiovascularHypertension2618135327
Cramps4<12<10
SkinHirsutism21<1212845
Acne68221
Central Nervous System Tremor120213155
Convulsions31145
Headache2<12154
GastrointestinalGum Hyperplasia409516
Diarrhea3<1348
Nausea/Vomiting2<14104
Hepatotoxicity<1<1474
Abdominal Discomfort<10<170
Autonomic Nervous SystemParesthesia30121
Flushing <10404
HematopoieticLeukopenia219<160
 Lymphoma<10161
RespiratorySinusitis<10437
MiscellaneousGynecomastia<10<143

Among 705 kidney transplant patients treated with cyclosporine oral solution (Sandimmune®) 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®
Cyclosporine Treatment Azathioprine with Steroids*
(N=227) (N=228)
Complication % of Complications % of Complications
Septicemia5.34.8
Abscesses4.45.3
Systemic Fungal Infection2.23.9
Local Fungal Infection7.59.6
Cytomegalovirus4.812.3
Other Viral Infections15.918.4
Urinary Tract Infections21.120.2
Wound and Skin Infections7.010.1
Pneumonia6.29.2

      *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:

Neoral ® /Sandimmune ® Rheumatoid Arthritis
Percentage of Patients with Adverse Events 3% in any Cyclosporine Treated Group
Studies Study Study Study Study Studies
651+652+2008 302 654 654 302 651+652+2008
Body Preferred Sandimmune ® Sandimmune ®   Methotrexate &
Sandimmune
®
Methotrexate
& Placebo
Neoral ® Placebo
System Term (N=269) (N=155) (N=74) (N=73) (N=143) (N=201)
Autonomic Nervous System Disorders
Flushing 2%2%3%0%5%2%
Body As A Whole–General Disorders
Accidental Trauma0%1%10%4%4%0%
Edema NOS*5%14%12%4%10%<1%
Fatigue6%3%8%12%3%7%
Fever2%3%0%0%2%4%
Influenza-like symptoms<1%6%1%0%3%2%
Pain6%9%10%15%13%4%
Rigors1%1%4%0%3%1%
Cardiovascular Disorders
Arrhythmia2%5%5%6%2%1%
Chest Pain4%5%1%1%6%1%
Hypertension8%26%16%12%25%2%
Central and Peripheral Nervous System Disorders
Dizziness8%6%7%3%8%3%
Headache17%23%22%11%25%9%
Migraine2%3%0%0%3%1%
Paresthesia8%7%8%4%11%1%
Tremor8%7%7%3%13%4%
Gastrointestinal System Disorders
Abdominal Pain15%15%15%7%15%10%
Anorexia3%3%1%0%3%3%
Diarrhea12%12%18%15%13%8%
Dyspepsia12%12%10%8%8%4%
Flatulence5%5%5%4%4%1%
Gastrointestinal Disorder NOS*0%2%1%4%4%0%
Gingivitis4%3%0%0%0%1%
Gum Hyperplasia2%4%1%3%4%1%
Nausea23%14%24%15%18%14%
Rectal Hemorrhage0%3%0%0%1%1%
Stomatitis7%5%16%12%6%8%
Vomiting9%8%14%7%6%5%
Hearing and Vestibular Disorders
Ear Disorder NOS*0%5%0%0%1%0%
Metabolic and Nutritional Disorders
Hypomagnesemia0%4%0%0%6%0%
Musculoskeletal System Disorders
Arthropathy0%5%0%1%4%0%
Leg Cramps / Involuntary Muscle Contractions2%11%11%3%12%1%
Psychiatric Disorders
Depression3%6%3%1%1%2%
Insomnia4%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
Leukorrhea1%0%4%0%1%0%
Menstrual Disorder3%2%1%0%1%1%
Respiratory System Disorders
Bronchitis1%3%1%0%1%3%
Coughing5%3%5%7%4%4%
Dyspnea5%1%3%3%1%2%
Infection NOS*9%5%0%7%3%10%
Pharyngitis3%5%5%6%4%4%
Pneumonia1%0%4%0%1%1%
Rhinitis0%3%11%10%1%0%
Sinusitis4%4%8%4%3%3%
Upper Respiratory Tract0%14%23%15%13%0%
Skin and Appendages Disorders
Alopecia3%0%1%1%4%4%
Bullous Eruption1%0%4%1%1%1%
Hypertrichosis19%17%12%0%15%3%
Rash7%12%10%7%8%10%
Skin Ulceration1%1%3%4%0%2%
Urinary System Disorders
Dysuria0%0%11%3%1%2%
Micturition Frequency2%4%3%1%2%2%
NPN, Increased0%19%12%0%18%0%
Urinary Tract Infection0%3%5%4%3%0%
Vascular (Extracardiac) Disorders
Purpura3%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 US 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 Neoral ® (N=182) Sandimmune ® (N=185)
Infection or Potential Infection24.7%24.3%
Influenza-Like Symptoms9.9%8.1%
Upper Respiratory Tract Infections7.7%11.3%
Cardiovascular System28.0%25.4%
Hypertension**27.5%25.4%
Urinary System24.2%16.2%
Increased Creatinine19.8%15.7%
Central and Peripheral Nervous System26.4%20.5%
Headache15.9%14.0%
Paresthesia7.1%4.8%
Musculoskeletal System13.2%8.7%
Arthralgia6.0%1.1%
Body As a Whole–General29.1%22.2%
Pain4.4%3.2%
Metabolic and Nutritional9.3%9.7%
Reproductive, Female8.5% (4 of 47 females)11.5% (6 of 52 females)
Resistance Mechanism18.7%21.1%
Skin and Appendages17.6%15.1%
Hypertrichosis6.6%5.4%
Respiratory System5.0%6.5%
Bronchospasm, Coughing, Dyspnea, Rhinitis5.0%4.9%
Psychiatric5.0%3.8%
Gastrointestinal System19.8%28.7%
Abdominal Pain2.7%6.0%
Diarrhea5.0%5.9%
Dyspepsia2.2%3.2%
Gum Hyperplasia3.8%6.0%
Nausea5.5%5.9%
White cell and RES4.4%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.



REPORTS OF SUSPECTED NEORAL SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Neoral. The information is not vetted and should not be considered as verified clinical evidence.

Possible Neoral side effects / adverse reactions in 65 year old male

Reported by a health professional (non-physician/pharmacist) from Japan on 2011-10-04

Patient: 65 year old male

Reactions: Complications of Transplanted Kidney, Liver Disorder

Adverse event resulted in: hospitalization

Suspect drug(s):
Neoral



Possible Neoral side effects / adverse reactions in 3 year old male

Reported by a health professional (non-physician/pharmacist) from Japan on 2011-10-04

Patient: 3 year old male

Reactions: Anal Fistula, Hypercholesterolaemia, Lymphadenopathy, Pneumonia, Epstein-Barr Virus Associated Lymphoproliferative Disorder, Oral Herpes

Adverse event resulted in: hospitalization

Suspect drug(s):
Certican
    Dosage: 0.5 mg
    Administration route: Oral
    Start date: 2005-12-08
    End date: 2007-08-08

Neoral
    Dosage: 60 mg,
    Administration route: Oral
    Start date: 2003-11-01

Certican
    Administration route: Oral
    Indication: Heart Transplant
    Start date: 2005-12-08

Certican
    Dosage: 0.75 mg, unk
    Administration route: Oral
    Start date: 2007-08-09
    End date: 2008-01-04

Polygam S/D

Other drugs received by patient: Cyclosporine; Sirolimus; Valganciclovir; Zovirax; Sulfamethoxazole; Mycophenolate Mofetil (Cellcept)



Possible Neoral side effects / adverse reactions in 48 year old male

Reported by a health professional (non-physician/pharmacist) from Japan on 2011-10-05

Patient: 48 year old male

Reactions: Angina Pectoris, Myocardial Ischaemia, Chest Pain, Coronary Artery Restenosis, Coronary Artery Stenosis, Nephropathy Toxic, Renal Tubular Necrosis

Adverse event resulted in: hospitalization

Suspect drug(s):
Neoral
    Dosage: unk ukn, unk
    Administration route: Oral
    Start date: 2010-01-01

Neoral
    Dosage: unk ukn, unk
    Administration route: Oral
    Indication: Renal Transplant

Other drugs received by patient: Methylprednisolone; Steroids NOS; Nafamostat Mesilate; Aspirin; Mycophenolate Mofetil; Basiliximab



See index of all Neoral side effect reports >>

Drug label data at the top of this Page last updated: 2006-10-10

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