July 30, 2016
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Gengraf Capsules

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Gengraf Capsules




Side Effects
Interactions

SIDE EFFECTS

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 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 (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 (Gengraf®), 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®

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.

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.

Pain of lower extremities

Isolated cases of pain of lower extremities have been reported in association with cyclosporine. Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) as described in the literature.

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

Body System Preferred Term Studies 651+652 +2008 Study 302 Study 654 Study 654 Study 302 Studies 651+652 +2008
Sandimmune®†
(N=269)
Sand- ® immune
(N=155)
Methotrexate & Sandimmune®
(N=74)
Metho- trexate & 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 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

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 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   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.

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

DRUG INTERACTIONS

Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety

All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition, concomitant use of NSAIDs with cyclosporine, particularly in the setting of dehydration, may potentiate renal dysfunction. Caution should be exercised when using other drugs which are known to impair renal function. (See WARNINGS, Nephrotoxicity)

Drugs That May Potentiate Renal Dysfunction

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

During the concomitant use of a drug that may exhibit additive or synergistic renal impairment with cyclosporine, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, the dosage of the coadministered drug should be reduced or an alternative treatment considered.

Cyclosporine is extensively metabolized by CYP 3A isoenzymes, in particular CYP3A4, and is a substrate of the multidrug efflux transporter P-glycoprotein. Various agents are known to either increase or decrease plasma or whole blood concentrations of cyclosporine usually by inhibition or induction of CYP3A4 or P-glycoprotein transporter or both. Compounds that decrease cyclosporine absorption such as orlistat should be avoided. Appropriate Gengraf® dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly. (See Blood Concentration Monitoring)

Drugs That Increase Cyclosporine Concentrations

Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs
diltiazem fluconazole azithromycin methylprednisolone Allopurinol
nicardipine itraconazole clarithromycin   Amiodarone
verapamil ketoconazole erythromycin   Bromocriptine
  voriconazole quinupristin/ dalfopristin   colchicine
        danazol
        imatinib
        metoclopramide
        nefazodone
        oral contraceptives

HIV Protease inhibitors

The HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 3A 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 juice

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/Dietary Supplements
nafcillin carbamazepine bosentan
rifampin oxcarbazepine octreotide
  phenobarbital orlistat
  phenytoin sulfinpyrazone
    St. John's Wort
    terbinafine
    ticlopidine

Bosentan

Coadministration of bosentan (250 to 1000 mg every 12 hours based on tolerability) and cyclosporine (300 mg every 12 hours for 2 days then dosing to achieve a Cmin of 200 to 250 ng/mL) for 7 days in healthy subjects resulted in decreases in the cyclosporine mean dose-normalized AUC, Cmax, and trough concentration of approximately 50%, 30%, and 60%, respectively, compared to when cyclosporine was given alone (See also Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents). Coadministration of cyclosporine with bosentan should be avoided.

Boceprevir

Coadministration of boceprevir (800 mg three times daily for 7 days) and cyclosporine (100 mg single dose) in healthy subjects resulted in increases in the mean AUC and Cmax of cyclosporine approximately 2.7-fold and 2-fold, respectively, compared to when cyclosporine was given alone.

Telaprevir

Coadministration of telaprevir (750 mg every 8 hours for 11 days) with cyclosporine (10 mg on day 8) in healthy subjects resulted in increases in the mean dose-normalized AUC and Cmax of cyclosporine approximately 4.5-fold and 1.3-fold, respectively, compared to when cyclosporine (100 mg single dose) was given alone.

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

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.

Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents

Cyclosporine is an inhibitor of CYP3A4 and of multiple drug efflux transporters (e.g., P-glycoprotein) and may increase plasma concentrations of comedications that are substrates of CYP3A4, P-glycoprotein or organic anion transporter proteins.

Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins), and, aliskiren, bosentan, dabigatran, repaglinide, NSAIDs, sirolimus, etoposide, and other drugs.

See the full prescribing information of the other drug for further information and specific recommendations. The decision on coadministration of cyclosporine with other drugs or agents should be made by the healthcare provider following the careful assessment of benefits and risks.

Digoxin

Severe digitalis toxicity has been seen within days of starting cyclosporine in several patients taking digoxin. If digoxin is used concurrently with cyclosporine, serum digoxin concentrations should be monitored.

Colchicine

There are reports on the potential of cyclosporine to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction. Concomitant administration of cyclosporine and colchicine results in significant increases in colchicine plasma concentrations. If colchicine is used concurrently with cyclosporine, a reduction in the dosage of colchicine is recommended.

HMG-CoA reductase inhibitors (statins)

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.

Repaglinide

Cyclosporine may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycemia. In 12 healthy male subjects who received two doses of 100 mg cyclosporine capsule orally 12 hours apart with a single dose of 0.25 mg repaglinide tablet (one-half of a 0.5mg tablet) orally 13 hours after the cyclosporine initial dose, the repaglinide mean Cmax and AUC were increased 1.8 fold (range: 0.6 to 3.7 fold) and 2.4 fold (range 1.2 to 5.3 fold), respectively. Close monitoring of blood glucose level is advisable for a patient taking cyclosporine and repaglinide concomitantly.

Ambrisentan

Coadministration of ambrisentan (5 mg daily) and cyclosporine (100 to 150 mg twice daily initially, then dosing to achieve Cmin 150 to 200 ng/mL) for 8 days in healthy subjects resulted in mean increases in ambrisentan AUC and Cmax of approximately 2-fold and 1.5-fold, respectively, compared to ambrisentan alone. When coadministering ambrisentan with cyclosporine, the ambrisentan dose should not be titrated to the recommended maximum daily dose.

Anthracycline antibiotics

High doses of cyclosporine (e.g., at starting intravenous dose of 16 mg/kg/day) may increase the exposure to anthracycline antibiotics (e.g., doxorubicin, mitoxantrone, daunorubicin) in cancer patients.

Aliskiren

Cyclosporine alters the pharmacokinetics of aliskiren, a substrate of P-glycoprotein and CYP3A4. In 14 healthy subjects who received concomitantly single doses of cyclosporine (200 mg) and reduced dose aliskiren (75 mg), the mean Cmax of aliskiren was increased by approximately 2.5-fold (90% CI: 1.96 to 3.17) and the mean AUC by approximately 4.3 fold (90% CI: 3.52 to 5.21), compared to when these subjects received aliskiren alone. The concomitant administration of aliskiren with cyclosporine prolonged the median aliskiren elimination half-life (26 hours versus 43 to 45 hours) and the Tmax (0.5 hours versus 1.5 to 2.0 hours). The mean AUC and Cmax of cyclosporine were comparable to reported literature values. Coadministration of cyclosporine and aliskiren in these subjects also resulted in an increase in the number and/or intensity of adverse events, mainly headache, hot flush, nausea, vomiting, and somnolence. The coadministration of cyclosporine with aliskiren is not recommended.

Bosentan

In healthy subjects, coadministration of bosentan and cyclosporine resulted in time-dependent mean increases in dose-normalized bosentan trough concentrations (i.e., approximately 21-fold on day 1 and 2-fold on day 8 (steady state)) compared to when bosentan was given alone as a single dose on day 1. (See also Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety) Coadministration of cyclosporine with bosentan should be avoided.

Dabigatran

The effect of cyclosporine on dabigatran concentrations had not been formally studied. Concomitant administration of dabigatran and cyclosporine may result in increased plasma dabigatran concentrations due to the P-gp inhibitory activity of cyclosporine. Coadministration of cyclosporine with dabigatran should be avoided.

Potassium-Sparing Diuretics

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.

Nonsteroidal Anti-inflammatory Drug (NSAID) Interactions

Clinical status and serum creatinine should be closely monitored when cyclosporine is used with NSAIDs 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 concentrations of cyclosporine, it has been associated with approximate doubling of diclofenac blood concentrations 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).

Sirolimus

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 concentrations, it is recommended that sirolimus be given 4 hours after cyclosporine administration.

Nifedipine

Frequent gingival hyperplasia when nifedipine is given concurrently with cyclosporine has been reported. The concomitant use of nifedipine should be avoided in patients in whom gingival hyperplasia develops as a side effect of cyclosporine.

Methylprednisolone

Convulsions when high dose methylprednisolone is given concurrently with cyclosporine have been reported.

Other Immunosuppressive Drugs and Agents

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.

Effect of Cyclosporine on the Efficacy of Live Vaccines

During treatment with cyclosporine, vaccination may be less effective. The use of live vaccines should be avoided.

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

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

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 2/5/2016

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