cyclosporine (Rx)

Brand and Other Names:Neoral, Sandimmune, more...Gengraf
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 25mg (Gengraf, Neoral, Sandimmune)
  • 50mg (Gengraf, Sandimmune)
  • 100mg (Gengraf, Neoral, Sandimmune)

oral solution

  • 100mg/mL (Gengraf, Neoral, Sandimmune)

injectable solution

  • 50mg/mL (Sandimmune)
more...

Solid Organ Transplantation

Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants; has been used in combination with azathioprine and corticosteroids

Adjust dosage according to trough levels, general dosage guidelines listed below

Oral

  • 4-12 hr pre-transplant: 15 mg/kg PO for 1 dose 
  • 1-2 wk post-transplant: 15 mg/kg/day PO divided BID
  • Reduce 5% per wk until: 5-10 mg/kg/day PO divided BID

IV

  • 4-12 hr pre-transplant IV: 5-6 mg/kg IV for 1 dose over 2-6 hours
  • Post-transplant, until can tolerate oral therapy: 5-6 mg/kg IV qDay

Rheumatoid Arthritis

Indicated for severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate; may be used in combination with methotrexate

Gengraf or Neoral: 1.25 mg/kg PO BID; may increase by 0.5-0.75 mg/kg/day after 8 weeks and again after 12 wk if needed, not to exceed 4 mg/kg/day 

Discontinue if no improvement observed by 16 wk

Decrease dose by 25-50% at any time to control adverse effects (eg, hypertension, elevations in serum creatine >30% pretreatment level

Psoriasis

Indicated for treatment of adult, nonimmunocompromised patients with severe, recalcitrant, plaque psoriasis who have failed to respond to at least 1 systemic therapy (eg, PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated

Gengraf or Neoral: 1.25 mg/kg PO BID; may increase by 0.5 mg/kg/day after 4 wk and q2wk if needed, not to exceed 4 mg/kg/day  

Discontinue if no improvement observed at 6 weeks on maximum daily dose of 4 mg/kg/day

Decrease dose by 25-50% at any time to control adverse effects (eg, hypertension, elevations in serum creatine >30% pretreatment level

Orphan Designations

ALS

  • Treatment of amyotropohic lateral sclerosis and its variants
  • Orphan sponsor: Maas Biolab,LLC; Tecnology Ventures, Corporation Technopolis 1155 University Blvd., SE; Albuquerque, NM 87106

Traumatic Brain Injury

  • Treatment of moderate-to-severe traumatic brain injury
  • Orphan sponsor: NeuroVive Pharmaceutical AB, Biomedical Center SE-221 84; Lund, Sweden

Lung Transplant

  • Prophylaxis of organ rejection in patients receiving allogeneic lung transplant
  • Treatment of acute rejection in recipients of allogeneic lung transplants
  • Orphan sponsor: APT Pharmaceuticals, Inc; 700 Airport Blvd, Suite 350; Burlingame, CA 94010

GVHD

  • Prophylaxis and treatment of graft versus host disease
  • Orphan sponsor: Sigmoid Pharma LTD; Dublin City University; Ireland

Lung Allograft Rejection

  • Liposomal: For aerosolized administration in the prevention and treatment of lung allograft rejection
  • Orphan sponsor: Vernon Knight, M.D.; Baylor College of Medicine, Dept. of Molecular Phy, One Baylor Plaza; Houston, TX 77030

Pulmonary Rejection With BMT

  • Liposomal: For aerosolized administration in the prevention and treatment of pulmonary rejection events associated with bone marrow transplant (BMT)
  • Orphan sponsor: Vernon Knight, M.D.; Baylor College of Medicine, Dept. of Molecular Phy, One Baylor Plaza; Houston, TX 77030

Bronchioitis Obliterans (Orphan)

  • Liposomal cyclosporine for inhalation
  • Orphan sponsor: PARI Pharma GmbH; Moosstrasse 3; Germany

Dosage Forms & Strengths

capsule

  • 25mg (Gengraf, Neoral, Sandimmune)
  • 50mg (Gengraf, Sandimmune)
  • 100mg (Gengraf, Neoral, Sandimmune)

oral solution

  • 100mg/mL (Gengraf, Neoral, Sandimmune)

injectable solution

  • 50mg/mL (Sandimmune)
more...

Solid Organ Transplantation (Off-Label)

Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants; has been used in combination with azathioprine and corticosteroids

Children as young as 6 months have received cyclosporine to prevent solid organ transplant rejection

Dosage is same as adults, although children may require higher mg/kg dose than adults

Adjust dosage according to trough levels, general dosage guidelines listed below

Oral

  • 4-12 hr pretransplant: 15 mg/kg PO for 1 dose 
  • 1-2 wk post-transplant: 15 mg/kg/day PO divided BID
  • Reduce 5% per wk until: 5-10 mg/kg/day PO divided BID

IV

  • 4-12 hr pre-transplant IV: 5-6 mg/kg IV for 1 dose over 2-6 hr
  • Posttransplant, until can tolerate oral therapy: 5-6 mg/kg IV qDay
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Interactions

Interaction Checker

and cyclosporine

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Tremor (12-55%)

            Nephrotoxicity (32%)

            Hypertension (26%)

            Infection (3-25%)

            Headache (2-25%)

            Nausea (23%)

            Hirsutism (21%)

            Hypertrichosis (5-19%)

            Female reproductive disorder (5-19%)

            Gum hyperplasia (2-16%)

            Triglycerides increased (15%)

            Abdominal discomfort (1-15%)

            URI (1-14%)

            Diarrhea (3-13%)

            Dyspepsia (2-12%)

            Leg cramps (2-12%)

            Parathesia (1-11%)

            1-10%

            Acne

            Convulsions

            Pruitus

            Hyperkalemia, hypomagnesemia

            Pancreatitis

            Hepatotoxicity

            Flu-like syndrome

            Frequency Not Defined

            Leukopenia

            Thrombocytopenia

            Anaphylaxis

            Glomerular capillary thrombosis

            Hypomagnesemia

            Migraine

            Hyponatremia

            Postmarketing Reports

            Pain in lower extremities

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            Warnings

            Black Box Warnings

            Should be prescribed only by physicians who have experience with immunosuppression in solid organ transplant recipients and can provide necessary follow-up and appropriate monitoring

            Coadministration with other immunosuppressants in kidney, liver, and heart transplant recipients, but risk of infection and neoplasia may be increased

            Increased risk for development of lymphomas and other malignancies, particularly those of the skin; avoid excess UV light exposure

            Increased risk appears related to the intensity and duration of immunosuppression rather than to the use of specific agents; oversuppression of the immune system may result in infection or malignancy; caution with regimens containing multiple immunosuppressants

            Sandimmune and Neoral are not bioequivalent and should not be interchanged without physician approval; Neoral (capsules and oral solution) has increased bioavailability compared with Sandimmune (capsules and oral solution)

            For a given trough concentration, cyclosporine exposure will be greater with Neoral than with Sandimmune

            Sandimmune has decreased bioavailability compared with Neoral and erratic absorption; requires careful monitoring of blood levels and subsequent dosage adjustments

            Patients with psoriasis who have been treated with PUVA, methotrexate or immunosuppressants, UVB, coal tar, or radiation are at increased risk for skin malignancies, hypertension, and renal dysfunction

            Contraindications

            Hypersensitivity

            Breastfeeding

            (RA/Psoriasis use): Abnormal renal function, uncontrolled HTN, malignancies

            (Psoriasis use) Concomitant PUVA, UVB radiation, coal tar, methotrexate, other immunosuppressants

            Cautions

            Injection: monitor closely for at least 30 min

            Risk of hepatotoxicity and nephrotoxicity

            Myelosuppression may be severe and prolonged; monitor complete blood and platelet counts

            Potential increase risk for optic disk edema and infusion-related anaphylactic reactions

            Some malignancies caused by cyclosporine immunosuppression may be fatal (eg, lymphoma)

            Serious and fatal cerebral, gastrointestinal and pulmonary hemorrhage; monitor platelets and coagulation parameters and treat accordingly

            Anticipate and monitor for signs and symptoms of tumor lysis syndrome occur; treat promptly

            Monitor for and discontinue promptly if systemic inflammatory response or capillary leak syndrome suspected

            Monitor for signs and symptoms of infection; severe and fatal sepsis as a result of bone marrow suppression; discontinue therapy promptly if infection occur

            Monitor for and discontinue if venous occlusive disease of the liver suspected

            Monitor liver enzymes and discontinue therapy at first signs of severe hepatotoxicity; fatal hepatotoxicity may occur

            Monitor renal function and interrupt or discontinue if creatinine levels increase or acute renal failure occur

            Increased risk for serious infection with fatal outcome because of immunosuppression, including activation of latent viruses, eg, BK virus-induced nephropathy

            Patients with psoriasis who received coal tar, PUVA, methotrexate, or other immunosuppressants have higher risk of skin cancer with Neoral

            Discontinue therapy if exfoliative or bullous rash suspected or if Stevens-Johnson syndrome or toxic epidermal necrolysis suspected

            Monitor for signs and symptoms of enterocolitis and treat promptly

            Extensively metabolized by CYP3A isoenzymes, in particular CYP3A4, and is a substrate of the multidrug efflux transporter P-glycoprotein (P-gp); various agents are known to either increase or decrease plasma or whole blood of cyclosporine levels usually by inhibition or induction of CYP3A4 or P-gp or both

            Occasionally, patients develop a syndrome of thrombocytopenia and thrombotic microangiopathic hemolytic anemia may result in graft failure

            Significant hyperkalemia and hyperuricemia may occur

            Neurotoxicity may occur, particularly with high dose methylprednisolone; caution with other drugs that may cause neurotoxicity

            Mild or moderate hypertension and rarely severe hypertension may occur; incidence decreases over time; antihypertensive therapy may be required in recipients of kidney, liver, and heart allografts treated with cyclosporine; potassium-sparing diuretics should not be used to treat cyclosporine associated hypertension as cyclosporine may cause hyperkalemia; calcium antagonists can be effective but can interfere with cyclosporine metabolism

            Gingival hyperplasia may occur; avoid concomitant nifedipine administration in patients who develop gingival hyperplasia

            Seizures may occur when used in combination with high-dose corticosteroids

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            Pregnancy & Lactation

            Pregnancy Category: C; take into consideration alcohol content of various cyclosporine formulations

            Lactation: excreted in breast milk, do not nurse

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Calcineurin inhibitor

            Suppresses cellular and humoral immunity (mainly T cells)

            Absorption

            Bioavailability: Neoral >Sandimmune

            Peak plasma time: Neoral 1.5-2 hr; Sandimmune 3.5 hr

            Onset: unknown

            Duration: unknown

            Distribution

            Protein Bound: 90%

            Vd: 13 L/kg

            Metabolism

            Via hepatic CYP3A4

            Metabolites: AM1, AM9, AM4N

            Enzymes inhibited: CYP3A4 and P-gp

            Elimination

            Half-Life: 8.4-27 hr

            Clearance: 5-7 mL/min/kg

            Excretion: Mainly bile and feces; 6% urine

            Pharmacogenomics

            Substrate of CYP3A4 and CYP3A5

            Genetic variant in CYP3A4 containing an A- to G- mutation (called CYP3A4-V or CYP3A4*1B) is associated with impaired enzyme activity

            Frequency of this mutation is 4% in the white population, but 67% in the black population

            This may be important in the early postsurgical phase when trying to establish adequate therapeutic serum levels

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            Administration

            IV Incompatibilities

            Additive: MgSO4

            Y-site: amphotericin B cholesteryl sulfate

            IV Compatibilities

            Solution: NS, D5W

            Additive: ciprofloxacin

            Y-site: gatifloxacin, linezolid, propofol, sargramostim

            IV Preparation

            Dilute 1 mL (50 mg) of concentrated inj soln in 20-100 mL of D5W or NS

            Stability of injection of parenteral admixture at room temp (25°C) is 6 hr in PVC; 24 hr in Excel, PAB containers, or glass

            Polyoxyethylated castor oil surfactant in cyclosporine injection may leach phthalate from PVC containers such as bags and tubing

            Actual amount of DEHP plasticizer leached from PVC containers and administration sets may vary in clinical situations, depending on surfactant concentration, bag size, & contact time

            IV Administration

            Following dilution, infuse over 2-6 hr

            Continuously monitor for at least the first 30 min of the infusion, and then frequently thereafter

            Anaphylaxis possible with IV use; reserve only for patients unable to take oral form

            Maintain airway; other supportive measures & agents for treating anaphylaxis should be present

            Oral Administration

            Neoral and Sandimmune are NOT bioequivalent, exercise caution if switching between brands/generics

            Storage

            Store ampules at controlled room temp; do not refrigerate

            Protect ampules from light

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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