Cyclosporine

Today's med: Cyclosporine (SYE kloe spor een)

(brand names: Gengraf, Neoral, SandIMMUNE)

Drug Class: Immunosuppressant agent, Calcineurin Inhibitor

Other Drugs in this class: Tacrolimus, Pimecrolimus

Action: Inhibition of production and release of interleukin II and inhibits interleukin II-induced activation of resting T-lymphocytes.

Indications: Prophylaxis of organ rejection in kidney, liver, and heart transplants, has been used with azathioprine and/or corticosteroids; severe, active rheumatoid arthritis (RA) not responsive to methotrexate alone; severe, recalcitrant plaque psoriasis in nonimmunocompromised adults unresponsive to or unable to tolerate other systemic therapy

Use: Unlabeled

Allogenic stem cell transplants for prevention and treatment of graft-versus-host disease; also used in some cases of severe autoimmune disease (eg, SLE) that are resistant to corticosteroids and other therapy; focal segmental glomerulosclerosis; severe ulcerative colitis

Contraindications: Hypersensitivity to cyclosporine or any component of the formulation. I.V. cyclosporine is contraindicated in hypersensitivity to polyoxyethylated castor oil (Cremophor® EL).

Rheumatoid arthritis and psoriasis: Abnormal renal function, uncontrolled hypertension, malignancies. Concomitant treatment with PUVA or UVB therapy, methotrexate, other immunosuppressive agents, coal tar, or radiation therapy are also contraindications for use in patients with psoriasis.

Adverse Effects: Adverse reactions reported with systemic use, including rheumatoid arthritis, psoriasis, and transplantation (kidney, liver, and heart). Percentages noted include the highest frequency regardless of indication/dosage. Frequencies may vary for specific conditions or formulation.

>10%:  Cardiovascular: Hypertension (8% to 53%), edema (5% to 14%)

Central nervous system: Headache (2% to 25%)

Dermatologic: Hirsutism (21% to 45%), hypertrichosis (5% to 19%)

Endocrine & metabolic: Triglycerides increased (15%), female reproductive disorder (9% to 11%)

Gastrointestinal: Nausea (23%), diarrhea (3% to 13%), gum hyperplasia (2% to 16%), abdominal discomfort (<1% to 15%), dyspepsia (2% to 12%)

Neuromuscular & skeletal: Tremor (7% to 55%), paresthesia (1% to 11%), leg cramps/muscle contractions (2% to 12%)

Renal: Renal dysfunction/nephropathy (10% to 38%), creatinine increased (16% to ≥50%)

Respiratory: Upper respiratory infection (1% to 14%)

Miscellaneous: Infection (3% to 25%)

1% to 10%:

Cardiovascular: Chest pain (4% to 6%), arrhythmia (2% to 5%), flushes (<1% to 5%), abnormal heart sounds, cardiac failure, glomerular capillary thrombosis, MI, peripheral ischemia

Central nervous system: Dizziness (8%), pain (6%), convulsions (1% to 5%), insomnia (4%), psychiatric events (4% to 5%), pain (3% to 4%), depression (1% to 6%), migraine (2% to 3%), anxiety, confusion, fever, hypoesthesia, emotional lability, impaired concentration, lethargy, malaise, nervousness, paranoia, somnolence, vertigo

Dermatologic: Purpura (3% to 4%), acne (1% to 6%), brittle fingernails, hair breaking, abnormal pigmentation, angioedema, cellulitis, dermatitis, dry skin, eczema, folliculitis, keratosis, pruritus, rash, skin disorder, skin malignancies, urticaria

Endocrine & metabolic: Gynecomastia (<1% to 4%), menstrual disorder (1% to 3%), breast fibroadenosis, breast pain, hyper-/hypoglycemia, diabetes mellitus, goiter, hot flashes, hyperkalemia, hyperuricemia, hypomagnesemia, libido increased/decreased

Gastrointestinal: Vomiting (2% to 10%), flatulence (5%), gingivitis (up to 4%), cramps (up to 4%), anorexia, constipation, dry mouth, dysphagia, enanthema, eructation, esophagitis, gastric ulcer, gastritis, gastroenteritis, gastrointestinal bleeding (upper), gingival bleeding, glossitis, mouth sores, peptic ulcer, pancreatitis, swallowing difficulty, salivary gland enlargement, taste perversion, tongue disorder, gum hyperplasia, weight loss/gain

Genitourinary: Leukorrhea (1%), abnormal urine, micturition increased, micturition urgency, nocturia, polyuria, pyelonephritis, urinary incontinence, uterine hemorrhage

Hematologic: Leukopenia (<1% to 6%), anemia, bleeding disorder, clotting disorder, platelet disorder, red blood cell disorder, thrombocytopenia

Hepatic: Hepatotoxicity (<1% to 7%), hyperbilirubinemia

Neuromuscular & skeletal: Arthralgia (1% to 6%), bone fracture, joint dislocation, joint pain, muscle pain, myalgia, neuropathy, stiffness, synovial cyst, tendon disorder, tingling, weakness

Ocular: Abnormal vision, cataract, conjunctivitis, eye pain, visual disturbance

Otic: Deafness, hearing loss, tinnitus, vestibular disorder

Renal: BUN increased, hematuria, renal abscess

Respiratory: Sinusitis (<1% to 7%), bronchospasm (up to 5%), cough (3% to 5%), pharyngitis (3% to 5%), dyspnea (1% to 5%), rhinitis (up to 5%), abnormal chest sounds, epistaxis, respiratory infection, pneumonia (up to 1%)

Miscellaneous: Flu-like syndrome (8% to 10%), lymphoma (<1% to 6% reported in transplant), abscess, allergic reactions, bacterial infection, carcinoma, diaphoresis increased, fungal infection, herpes simplex, herpes zoster, hiccups, lymphadenopathy, moniliasis, night sweats, tonsillitis, viral infection

Postmarketing and/or case reports (any indication): Anaphylaxis/anaphylactoid reaction (possibly associated with Cremophor® EL vehicle in injection formulation), benign intracranial hypertension, cholesterol increased, death (due to renal deterioration), encephalopathy, gout, hyperbilirubinemia, hyperkalemia, impaired consciousness, infections (increased risk; including JC virus and BK virus), migraine headache, neurotoxicity, papilloedema, polyoma virus-associated nephropathy (PVAN), progressive multifocal leukoencephalopathy (PML), pulmonary edema (noncardiogenic), reversible posterior leukoencephalopathy syndrome (RPLS), thrombotic microangiopathy

Warnings: Hepatotoxicity, Hyperkalemia, Hypertension, Hyperuricemia, Infection, Lymphoma and other malignancies, Nephrotoxicity, Neurotoxicity, Skin cancer, Thrombotic microangiopathy.

Standard Dosing: Neoral®/Gengraf® and Sandimmune® are not bioequivalent and cannot be used interchangeably. Children: Transplant: Refer to adult dosing; children may require, and are able to tolerate, larger doses than adults. Adults: Newly-transplanted patients: Adjunct therapy with corticosteroids is recommended. Initial dose should be given 4-12 hours prior to transplant or may be given postoperatively; adjust initial dose to achieve desired plasma concentration

Oral: Dose is dependent upon type of transplant and formulation:

Cyclosporine (modified):

Renal: 9 ± 3 mg/kg/day, divided twice daily

Liver: 8 ± 4 mg/kg/day, divided twice daily

Heart: 7 ± 3 mg/kg/day, divided twice daily

Cyclosporine (non-modified): Initial doses of 10-14 mg/kg/day have been used for renal transplants (the manufacturer’s labeling includes dosing from initial clinical trials of 15 mg/kg/day [range: 14-18 mg/kg/day]; however, this higher dosing level is rarely used any longer). Continue initial dose daily for 1-2 weeks; taper by 5% per week to a maintenance dose of 5-10 mg/kg/day; some renal transplant patients may be dosed as low as 3 mg/kg/day

Note: When using the non-modified formulation, cyclosporine levels may increase in liver transplant patients when the T-tube is closed; dose may need decreased

I.V.: Cyclosporine (non-modified): Manufacturer's labeling: Initial dose: 5-6 mg/kg/day or one-third of the oral dose as a single dose, infused over 2-6 hours; use should be limited to patients unable to take capsules or oral solution; patients should be switched to an oral dosage form as soon as possible

Note: Many transplant centers administer cyclosporine as "divided dose" infusions (in 2-3 doses/day) or as a continuous (24-hour) infusion; dosages range from 3-7.5 mg/kg/day. Specific institutional protocols should be consulted.

Rheumatoid arthritis: Oral: Cyclosporine (modified): Initial dose: 2.5 mg/kg/day, divided twice daily; salicylates, NSAIDs, and oral glucocorticoids may be continued (refer to Drug Interactions); dose may be increased by 0.5-0.75 mg/kg/day if insufficient response is seen after 8 weeks of treatment; additional dosage increases may be made again at 12 weeks (maximum dose: 4 mg/kg/day). Discontinue if no benefit is seen by 16 weeks of therapy.

Psoriasis: Oral: Cyclosporine (modified): Initial dose: 2.5 mg/kg/day, divided twice daily; dose may be increased by 0.5 mg/kg/day if insufficient response is seen after 4 weeks of treatment. Additional dosage increases may be made every 2 weeks if needed (maximum dose: 4 mg/kg/day). Discontinue if no benefit is seen by 6 weeks of therapy. Once patients are adequately controlled, the dose should be decreased to the lowest effective dose. Doses lower than 2.5 mg/kg/day may be effective. Treatment longer than 1 year is not recommended.

Note: Increase the frequency of blood pressure monitoring after each alteration in dosage of cyclosporine. Cyclosporine dosage should be decreased by 25% to 50% in patients with no history of hypertension who develop sustained hypertension during therapy and, if hypertension persists, treatment with cyclosporine should be discontinued.

Focal segmental glomerulosclerosis (unlabeled use): Oral: Initial: 3.5-5 mg/kg/day divided every 12 hours (in combination with oral prednisone) (Braun, 2008; Cattran, 1999)

Lupus nephritis (unlabeled use): Oral: Initial: 4 mg/kg/day for 1 month (reduce dose if trough concentrations >200 ng/mL); reduce dose by 0.5 mg/kg every 2 weeks to a maintenance dose of 2.5-3 mg/kg/day (Moroni, 2006)

Severe ulcerative colitis (steroid-refractory) (unlabeled use):

I.V.: Cyclosporine (non-modified): 2-4 mg/kg/day, infused continuously over 24 hours. (Lichtiger, 1994; Van Assche, 2003). Note: Some studies suggest no therapeutic difference between low-dose (2 mg/kg) and high-dose (4 mg/kg) cyclosporine regimens (Van Assche, 2003).

Oral: Cyclosporine (modified): 2.3-3 mg/kg every 12 hours (De Saussure 2005; Weber 2006)

Note: Patients responsive to I.V. therapy should be switched to oral therapy when possible.

*Administer this medication consistently with relation to time of day and meals. Avoid grapefruit juice with oral cyclosporine use.

Drug interactions: Link: http://www.drugs.com/drug-interactions/cyclosporine.html

A total of 730 drugs (2952 brand and generic names) are known to interact with cyclosporine.

• 123 major drug interactions (365 brand and generic names)
• 557 moderate drug interactions (2392 brand and generic names)
• 50 minor drug interactions (195 brand and generic names)

Show all medications in the database that may interact with cyclosporine.

CYP3A4 Inhibitors.

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

There is also an opthalmic version.  Indications: Increase tear production when suppressed tear production is presumed to be due to keratoconjunctivitis sicca-associated ocular inflammation (in patients not already using topical anti-inflammatory drugs or punctal plugs)