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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

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

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

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.

Clinical Studies

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)%
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 (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 cyclosporine-treated patients: allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, migraine (Neoral®), 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.

Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine -containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic). Both generalized and localized infections can occur. Pre-existing infections may also be aggravated. Fatal outcomes have been reported. (See WARNINGS)

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
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.

Postmarketing Experience, Kidney, Liver and Heart Transplantation

Hepatotoxicity

Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure; serious and/or fatal outcomes have been reported. (See WARNINGS, Hepatotoxicity)

Increased Risk of Infections

Cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), sometimes fatal; and polyoma virus-associated nephropathy (PVAN), especially BK virus resulting in graft loss have been reported. (See WARNINGS, Polyoma Virus Infection)

Headache, including Migraine

Cases of migraine have been reported. In some cases, patients have been unable to continue cyclosporine, however, the final decision on treatment discontinuation should be made by the treating physician following the careful assessment of benefits versus risks.

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 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 Disorder 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

Psorias is

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 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.

Postmarketing Experience, Psoriasis

Cases of transformation to erythrodermic psoriasis or generalized pustular psoriasis upon either withdrawal or reduction of cyclosporine in patients with chronic plaque psoriasis have been reported.



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: 2013-05-15

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