Apo-Cyclosporine Oral

In the U.S.

• Gengraf
• Neoral
• SandIMMUNE

In Canada

• Apo-cycloSPORINE

Available Dosage Forms:

• Capsule, Liquid Filled
• Solution
• Capsule

Therapeutic Class: Immune Suppressant

Pharmacologic Class: Calcineurin Inhibitor

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies on the relationship of age to the effects of cyclosporine have not been performed in children receiving organ transplants. However, no pediatric-specific problems have been documented to date.

Appropriate studies have not been performed on the relationship of age to the effects of cyclosporine in children with rheumatoid arthritis or psoriasis. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of cyclosporine in the elderly. However, elderly patients are more likely to have high blood pressure or age-related kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving cyclosporine.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amifampridine
• Bosentan
• Colchicine
• Dronedarone
• Grazoprevir
• Lercanidipine
• Mifepristone
• Pitavastatin
• Simvastatin
• Sitaxsentan

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aceclofenac
• Acemetacin
• Afatinib
• Alefacept
• Alfalfa
• Aliskiren
• Amlodipine
• Amtolmetin Guacil
• Aspirin
• Atorvastatin
• Bacillus of Calmette and Guerin Vaccine, Live
• Betrixaban
• Black Cohosh
• Blinatumomab
• Bromfenac
• Bufexamac
• Bupropion
• Carbamazepine
• Caspofungin
• Celecoxib
• Ceritinib
• Cerivastatin
• Cholic Acid
• Choline Salicylate
• Clonixin
• Cobicistat
• Conivaptan
• Crizotinib
• Cyclophosphamide
• Dabigatran Etexilate
• Dasabuvir
• Deflazacort
• Dexibuprofen
• Dexketoprofen
• Diclofenac
• Diflunisal
• Diltiazem
• Diphtheria Toxoid, Adsorbed
• Dipyrone
• Domperidone
• Donepezil
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Droxicam
• Efavirenz
• Eliglustat
• Eluxadoline
• Enzalutamide
• Etodolac
• Etofenamate
• Etoposide
• Etoricoxib
• Etravirine
• Felbinac
• Felodipine
• Fenoprofen
• Fepradinol
• Feprazone
• Floctafenine
• Fluconazole
• Flufenamic Acid
• Flurbiprofen
• Foscarnet
• Golimumab
• Guselkumab
• Haemophilus B Vaccine
• Hepatitis A Vaccine, Inactivated
• Ibuprofen
• Ibuprofen Lysine
• Idelalisib
• Indomethacin
• Infliximab
• Influenza Virus Vaccine
• Isavuconazonium Sulfate
• Itraconazole
• Ketoprofen
• Ketorolac
• Lanreotide
• Lornoxicam
• Lovastatin
• Loxoprofen
• Lumacaftor
• Lumiracoxib
• Lyme Disease Vaccine (Recombinant OspA)
• Measles Virus Vaccine, Live
• Meclofenamate
• Mefenamic Acid
• Meloxicam
• Meningococcal Vaccine
• Morniflumate
• Morphine
• Morphine Sulfate Liposome
• Mumps Virus Vaccine, Live
• Mycophenolic Acid
• Nabumetone
• Nafcillin
• Naproxen
• Nepafenac
• Netupitant
• Nicardipine
• Niflumic Acid
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Octreotide
• Ombitasvir
• Orlistat
• Oxaprozin
• Oxyphenbutazone
• Parecoxib
• Paritaprevir
• Pazopanib
• Perindopril
• Pertussis Vaccine
• Phenylbutazone
• Piketoprofen
• Piperaquine
• Piroxicam
• Pitolisant
• Pixantrone
• Plague Vaccine
• Pneumococcal Vaccine, Diphtheria Conjugate
• Pneumococcal Vaccine Polyvalent
• Poliovirus Vaccine, Live
• Posaconazole
• Pravastatin
• Proglumetacin
• Propionic Acid
• Propyphenazone
• Proquazone
• Pyrazinamide
• Rabies Vaccine
• Ranolazine
• Red Yeast Rice
• Ribociclib
• Rifabutin
• Rifampin
• Ritonavir
• Rofecoxib
• Rosuvastatin
• Rotavirus Vaccine, Live
• Rubella Virus Vaccine, Live
• Salicylic Acid
• Salsalate
• Secukinumab
• Silodosin
• Simeprevir
• Smallpox Vaccine
• Sodium Salicylate
• St John's Wort
• Sulfinpyrazone
• Sulindac
• Tacrolimus
• Telaprevir
• Telithromycin
• Tenoxicam
• Tetanus Toxoid
• Tiaprofenic Acid
• Tolfenamic Acid
• Tolmetin
• Topotecan
• Typhoid Vaccine, Live
• Valdecoxib
• Varicella Virus Vaccine
• Venetoclax
• Vilazodone
• Vincristine
• Vincristine Sulfate Liposome
• Voriconazole
• Yellow Fever Vaccine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acetazolamide
• Allopurinol
• Ambrisentan
• Amiodarone
• Amphotericin B
• Amphotericin B Cholesteryl Sulfate Complex
• Amphotericin B Lipid Complex
• Amphotericin B Liposome
• Amprenavir
• Azathioprine
• Boceprevir
• Bromocriptine
• Chloramphenicol
• Chloroquine
• Cimetidine
• Ciprofloxacin
• Cisapride
• Clarithromycin
• Clindamycin
• Clonidine
• Colesevelam
• Dalfopristin
• Danazol
• Desogestrel
• Dienogest
• Digoxin
• Dirithromycin
• Drospirenone
• Erythromycin
• Estradiol Cypionate
• Estradiol Valerate
• Ethinyl Estradiol
• Ethynodiol Diacetate
• Etonogestrel
• Ezetimibe
• Famotidine
• Fenofibrate
• Fluvoxamine
• Fosamprenavir
• Fosphenytoin
• Furosemide
• Glipizide
• Glyburide
• Imipenem
• Indinavir
• Josamycin
• Ketoconazole
• Levonorgestrel
• Medroxyprogesterone Acetate
• Melphalan
• Mercaptopurine
• Mestranol
• Methotrexate
• Methylprednisolone
• Metoclopramide
• Metronidazole
• Mibefradil
• Midazolam
• Miokamycin
• Modafinil
• Mycophenolate Mofetil
• Nefazodone
• Nelfinavir
• Nevirapine
• Norelgestromin
• Norethindrone
• Norfloxacin
• Norgestimate
• Norgestrel
• Oxypurinol
• Phenytoin
• Probucol
• Propafenone
• Quinine
• Quinupristin
• Repaglinide
• Rifapentine
• Saquinavir
• Sirolimus
• Sulfadiazine
• Sulfasalazine
• Terbinafine
• Tobramycin
• Tolterodine
• Troglitazone
• Verapamil
• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice
• Pomelo Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Abnormal kidney function or
• Cancer or
• Hypertension (high blood pressure), uncontrolled—Rheumatoid arthritis patients who also have these conditions should not receive Neoral®.

• Alcohol abuse, or history of or
• Epilepsy (seizures) or
• Liver disease—This medicine contains alcohol, which can make these conditions worse.

• Anemia or
• Bleeding problems or
• Brain disease (eg, encephalopathy) or
• Cancer or
• Eye or visual problems (eg, papilloedema) or
• Hyperkalemia (high potassium in the blood) or
• Hypertension (high blood pressure) or
• Hyperuricemia (too much uric acid in the blood) or
• Kidney disease or
• Precancerous skin changes or
• Seizures, history of or
• Thrombocytopenia (low number of platelets)—Use with caution. May make these conditions worse.

• Infection—May decrease body's ability to fight an infection.

Applies to cyclosporine: compounding powder, injectable solution, oral capsule, oral liquid, oral solution

Renal

BK virus associated nephropathy has been associated with serious outcomes, including deteriorating renal function and renal graft loss.

Elevations in serum creatinine and BUN are common during cyclosporine therapy and do not necessarily indicate allograft rejection.

In addition, cyclosporine-induced hyperuricemia may predispose the patient to renal calculi.

Renal insufficiency is dose-related. It is often accompanied by hypertension. Cyclosporine causes a reversible reduction in renal blood flow and glomerular filtration rate. The mechanism of cyclosporine-induced nephrotoxicity is now considered to be vasoconstriction of the afferent arterioles. ET1 is also considered to be a key substance of cyclosporine-induced nephrotoxicity. Mild nephrotoxicity generally responds to reductions in cyclosporine doses. A chronic, progressive nephrotoxicity may also occur in which discontinuation of cyclosporine fails to alleviate the renal insufficiency. Renal biopsies from these patients may demonstrate interstitial fibrosis, tubular atrophy, global or segmental glomerulosclerosis, or smooth vascular muscle damage. It has been suggested that higher cumulative doses or high cyclosporine trough levels may be associated with the development of interstitial fibrosis.

Renal function should be closely monitored. Differentiation between cyclosporine-induced nephrotoxicity, allograft rejection, and other causes of impaired renal function should be made before considering cyclosporine dosage adjustments.

The use of nonsteroidal anti-inflammatory agents in combination with cyclosporine may increase the risk of renal toxicity, especially in rheumatoid arthritis patients. Intact renal prostaglandins are necessary for maintaining adequate renal blood flow in patients treated with cyclosporine. Renal deterioration may occur independent of changes in cyclosporine levels.[Ref]

Renal side effects including renal insufficiency (up to 38%) and BK virus associated nephropathy have been reported. A chronic, progressive, irreversible nephrotoxicity has also been reported. Elevations in serum creatinine and BUN are common during cyclosporine therapy and do not necessarily indicate allograft rejection. A case of hemolytic uremic syndrome (HUS) associated with cyclosporine therapy has been reported. A fatal case of acute tubular necrosis has been reported. In addition, cyclosporine-induced hyperuricemia may predispose the patient to renal calculi.[Ref]

Nervous system

Seizures in patients on cyclosporine therapy may be associated with hypomagnesemia or concomitant high-dose corticosteroids. In addition, hypercholesterolemia and hypertension may contribute to cyclosporine neurotoxicity. Hypomagnesemia and hypercholesterolemia allow easier diffusion of cyclosporine across the blood-brain barrier potentiating neurotoxicity.

A review of cyclosporine-induced neurotoxicity revealed a 10% incidence after liver transplantation. Intravenous administration of cyclosporine was associated with more severe reactions such as psychosis, however severe reactions occurred rarely. MRI abnormalities were seldom found. Only 61% of patients that experienced neurotoxicity (n=46) had cyclosporine trough levels suggestive of toxicity. Temporary discontinuation and lowering the dose of cyclosporine resolved the neurotoxicity. Three patients were successfully switched to tacrolimus therapy without return of neurotoxicity. No patient exhibited abnormal magnesium levels.

The speech disorder leading to mutism which has been associated with cyclosporine therapy was reversible. Symptoms resolved within 1 to 2 weeks after withdrawal of the cyclosporine.

The permanent blindness which was reported in one patient was suspected to be due to neurotoxicity associated with elevated cyclosporine levels. Dechallenge with cyclosporine did not reverse the blindness . The blindness occurred over a 36 hour period 3 weeks following a kidney-pancreas transplant. The cyclosporine trough level was at its highest on the day of complete blindness (495 ng/mL). The mechanism by which cyclosporine induces neurologic blindness is unknown.[Ref]

Nervous system side effects of cyclosporine have included tremors (12% to 55%) and headache (2% to 15%). Depression, somnolence, decreased visual acuity, confusion, paresthesias, seizures, and a reversible speech disorder leading to mutism have also been associated with cyclosporine therapy. Three cases of leukoencephalopathy have also been reported. Postmarketing reports of migraine headache have been reported.[Ref]

Dermatologic

Dermatologic side effects of cyclosporine have included hypertrichosis (30%), acne (1% to 8%), and pruritus. Cyclosporine has been associated with pilosebaceous lesions, including hypertrichosis, epidermal cysts, keratosis pilaris, acne, folliculitis, sebaceous gland hyperplasia, and cutaneous malignancies. A case of erythroderma resembling Sezary syndrome with lymphocytic infiltrates of the skin has been reported. Cases of folliculodystrophy and pseudoporphyria have also been reported.

Postmarketing 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.[Ref]

Hepatic

Hepatic side effects have been common, occurring in up to 50% of patients, and are generally mild and self-limited, and manifest as elevated bilirubin, serum transaminases, and alkaline phosphatase values. In addition, cholestatic jaundice has been reported. Postmarketing reports of cholestasis, jaundice, hepatitis and liver failure with serious and/or fatal outcomes have been reported.[Ref]

Hematologic

Hematologic side effects have included leukopenia (less than 1% to 6%), anemia, and thrombocytopenia.[Ref]

A syndrome characterized by thrombocytopenia and microangiopathic anemia is reported in some patients and may result in allograft rejection.[Ref]

Metabolic

Metabolic side effects of cyclosporine have included significant hyperkalemia, which is sometimes associated with hyperchloremic metabolic acidosis.[Ref]

Gastrointestinal

Gastrointestinal side effects have included gum hyperplasia (4% to 16%), diarrhea (3% to 8%), nausea and vomiting (2% to 10%), anorexia, abdominal discomfort, and rare reports of upper gastrointestinal bleeding. Pancreatitis has also been reported rarely.[Ref]

The incidence of gum hyperplasia is lower with the microemulsion form of cyclosporine. A 14 day course of metronidazole 750 mg three times a day has been effective in remitting gum hyperplasia in patients with rheumatoid arthritis. No increase in serum cyclosporine levels and creatinine levels were observed during metronidazole therapy. The effect of metronidazole on gum hyperplasia may be due to its antibacterial activity, although data is lacking.[Ref]

Cardiovascular

One study has reported that reduced basal and stimulated nitrous oxide production in cyclosporine-treated renal transplant recipients. The authors stated that this suggests endothelial dysfunction, and may explain the increased risk of premature atherosclerosis and cardiovascular death. They felt this might also provide, at least in part, a potential mechanism to explain cyclosporine-induced hypertension.[Ref]

Cardiovascular side effects have included hypertension (50%) induced by cyclosporine. Myocardial infarction has also been reported rarely.[Ref]

Endocrine

Endocrine side effects of cyclosporine have included hypertriglyceridemia, increases in serum prolactin, decreases in serum testosterone, gynecomastia, hyperglycemia, and hypertrichosis. Cremophor EL (polyoxyethylated castor oil), the vehicle for the intravenous form of cyclosporine, may cause hyperlipidemia and electrophoretic abnormalities of lipoproteins. These effects are reversible upon cessation of therapy, but usually do not necessitate drug withdrawal.[Ref]

Other

Other side effects including a significant risk of acute rejection and death and/or graft loss have been reported in one study of 108 living related renal transplant recipients when cyclosporine was withdrawn after an average of twelve and a half months after transplantation because of economic constraints. One case of trichomegaly has been reported. A case of calcineurin inhibitor induced pain syndrome (CIPS) has also been reported.[Ref]

Hypersensitivity

Anaphylaxis, manifest as acute dyspnea, tachypnea, pruritus, rash, and chest discomfort has been reported in rare cases after intravenous administration of cyclosporine. The vehicle, Cremophor EL, is suspected of inducing anaphylaxis as some patients who experienced anaphylaxis following IV administration were subsequently safely treated with oral dosage forms. Intravenous cyclosporine should be reserved for those patients who are unable to tolerate oral medications. If this route is necessary, continuous observation for at least the first 30 minutes of the infusion is recommended.[Ref]

Hypersensitivity side effects to cyclosporine have occurred in less than 2% of patients.[Ref]

Ocular

A rare manifestation of neurotoxicity induced by cyclosporine (which has occurred in transplant patients more frequently than in other indications) is optic disc edema including papilledema, with possible visual impairment, secondary to benign intracranial hypertension.[Ref]

Ocular side effects have included reports of pseudotumor cerebri, which resolved rapidly upon discontinuation of cyclosporine, and optic disk edema. Permanent blindness has been reported in one patient. A case of cyclosporine-induced retinal toxic blindness has also been reported.[Ref]

Oncologic

The development of neoplasms, particularly lymphomas and skin malignancies, is more likely in immunosuppressed patients.

Whether neoplasms are more likely due to underlying disease, the immunosuppressed state, or to cyclosporine itself is somewhat speculative. In a large study, an increased incidence of lymphoma and Kaposi's sarcoma was found in patients treated with cyclosporine relative to those treated with a combination of azathioprine and prednisone. In some reported cases of B-cell lymphoma, the Epstein-Barr virus genome was found in the malignant cells, suggesting opportunistic infection during a cyclosporine-induced immunosuppressed state.[Ref]

Oncologic side effects including one fatal case of metastatic angiosarcoma during cyclosporine and prednisone immunosuppression (after kidney transplantation) have been reported.[Ref]

Immunologic

Immunologic side effects have included an increased patient susceptibility to opportunistic infections due to cyclosporine-induced immunosuppression. Postmarketing reports of progressive multifocal leukoencephalopathy (PML), sometimes fatal; and polyoma virus associated nephropathy (PVAN), especially BK virus resulting in graft loss have been reported.[Ref]

Accelerated hepatitis B and C infections, sometimes resulting in hepatic necrosis, Pneumocystis pneumoniae infections, as well as other viral, fungal, and bacterial infections have been reported in patients treated with cyclosporine. An in vitro study demonstrated enhanced intracellular cytomegalovirus production and virus spread, indicating an increased risk of CMV infection in cyclosporine-treated patients.[Ref]

Local

Local side effects including a case of recurrent infusion phlebitis have been reported.[Ref]

Respiratory

The death was part caused by an anaphylactic reaction which may have actually been a reaction to the Cremophor EL (polyoxyethylated castor oil) used as the vehicle for the intravenous formulation.[Ref]

Respiratory side effects have included respiratory arrest and aspiration pneumonia in one patient that lead to the death of that patient.[Ref]

Some side effects of cyclosporine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

IV: 2 to 4 mg/kg/day IV infusion once a day over 4 to 6 hours or
1 to 2 mg/kg IV infusion twice a day over 4 to 6 hours or
2 to 4 mg/kg/day as a continuous IV infusion over 24 hours.
Capsules: 8 to 12 mg/kg/day orally in 2 divided doses.
Solution: 8 to 12 mg/kg orally once a day.
Doses are usually titrated downward with time to maintenance doses as low as 3 to 5 mg/kg/day. All doses should be adjusted to achieve the desired therapeutic concentration.

When refractory to corticosteroids: 4 mg/kg/day via continuous IV infusion. The dose should be titrated gradually to achieve clinical efficacy while avoiding unacceptable toxicity. Therapy should be continued for 7 to 14 days. In successful treatments, oral therapy should be instituted after 14 days of IV therapy and continued for 3 to 6 months.

Some clinicians have found a dose of 2 mg/kg/day via continuous IV infusion to be equally effective to the 4 mg/kg/day dosage regimen.

Careful monitoring of cyclosporine blood or plasma concentrations is necessary to avoid exacerbation of renal impairment.

A supplemental dose is not necessary with hemodialysis or peritoneal dialysis.

Cyclosporine is not removed by hemodialysis.

Adjunct therapy with adrenal corticosteroids is recommended initially for organ rejection prophylaxis.