Cyclosporine; Uses, Dosage, Side Effects, Drug Interactions

Cyclosporine is a calcineurin inhibitor and potent immunosuppressive agent used largely as a means of prophylaxis against cellular rejection after solid organ transplantation. Cyclosporine therapy can be associated with mild elevations in serum bilirubin and transient serum enzyme elevations, and to rare instances of clinically apparent cholestatic liver injury.

Cyclosporine is a natural cyclic polypeptide immunosuppressant isolated from the fungus Beauveria nivea. The exact mechanism of action of cyclosporine is not known but may involve binding to the cellular protein cyclophilin, resulting in inhibition of the enzyme calcineurin. This agent appears to specifically and reversibly inhibit immunocompetent lymphocytes in the G0-or G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited with T-helper cells as the primary target. Cyclosporine also inhibits lymphokine production and release

It is used by mouth and injection into a vein for rheumatoid arthritis, psoriasis, Crohn’s disease, nephrotic syndrome, and in organ transplants to prevent rejection. It is also used as eye drops for keratoconjunctivitis sicca (dry eyes).

Mechanism of action of Cyclosporine

Cyclosporine suppresses some humoral immunity but is more effective against T cell-dependent immune mechanisms such as those underlying transplant rejection & some forms of autoimmunity. It preferentially inhibits antigen-triggered signal transduction in T lymphocytes, blunting expression of many lymphokines, including /(interleukin-2)/ IL-2, as well as expression of antiapoptotic proteins. Cyclosporine forms a complex with cyclophilin, a cytoplasmic receptor protein present in target cells. This complex binds to calcineurin, inhibiting Ca2+ stimulated dephosphorylation of the cytosolic component of NFAT. When the cytoplasmic component of NFAT is dephosphorylated, it translocates to the nucleus, where it complexes with nuclear components required for complete T-cell activation, including transactivation of IL-2 & other lymphokine genes. Calcineurin enzymatic activity is inhibited following physical interaction with the cyclosporine/cyclophilin complex. This results in the blockade of NFAT dephosphorylation; thus, the cytoplasmic component of NFAT does not enter the nucleus, gene transcription is not activated, & the T lymphocyte fails to respond to specific antigenic stimulation Cyclosporine also increases expression of transforming growth fact /beta/ (TGF-B), a potent inhibitor of IL-2-stimulated T-cell proliferation & generation of cytotoxic T lymphocytes

or

Cyclosporine binds to cyclophilin. The complex then inhibits calcineurin which is normally responsible for activating transcription of interleukin 2. Cyclosporine also inhibits lymphokine production and interleukin release. In ophthalmic applications, the precise mechanism of action is not known. Cyclosporine emulsion is thought to act as a partial immunomodulator in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. Used in immunosuppression for prophylactic treatment of organ transplants, cyclosporine exerts specific and reversible inhibition of immunocompetent lymphocytes in the G0-or G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T1-helper cell is the main target, although the T1-suppressor cell may also be suppressed. Sandimmune (cyclosporine) also inhibits lymphokine production and release including interleukin-2.

Indications of Cyclosporine

• Psoriatic arthritis
• Ankylosing Spondylities
• Steroid induce arthritis
• Multiple joints pain
• Rheumatoid Arthritis
• Juvenile idiopathic arthritis
• Ulcerative colitis
• Crohn’s disease
• Idiopathic thrombocytopenic purpura
• Inflammatory bowel disease
• Organ transplant, rejection prophylaxis
• Organ transplant, rejection reversal
• Bone marrow transplant rejection
• Glomerulonephritis minimal lesion
• Glomerulosclerosis, focal segmental
• Graft versus host disease
• Heart transplant rejection
• Idiopathic thrombocytopenic purpura
• Interstitial cystitis
• Kidney transplant rejection
• Liver transplant rejection
• Nephritis, lupus
• Psoriasis
• Severe ulcerative colitis
• Uveitis
• Refractory ulcerative colitis
• Severe, active rheumatoid arthritis
• Severe, recalcitrant plaque psoriasis
• Suppressed tear production

Therapeutic Uses 

Contra-Indications of Cyclosporine

• Malignant tumor or cancer
• Tumor
• high cholesterol
• high amount of triglyceride in the blood
• low amount of magnesium in the blood
• the high amount of potassium in the blood
• pseudotumor cerebri
• Disorder of the brain
• high blood pressure
• Severe uncontrolled high blood pressure
• Thrombotic thrombocytopenic purpura
• Liver problems
• Kidney damage
• kidney disease with the reduction in kidney function
• seizures
• High amount of bilirubin in the blood
• High amount of uric acid in the blood
• Abnormal liver function tests
• Malignant Lymphoma
• Poisoning by immune suppression drug cyclosporine
• Progressive disease in the white matter of the brain
• Hyperchloremic Acidosis
• BK virus reactivation causing kidney problems
• A compromised immune system
• Abnormal kidney function
• High blood pressure
• Cancer, or a history of cancer (other than basal or squamous cell skin cancers)
• Severe gout
• Pregnant or breastfeeding
• Undergoing radiation treatments

Dosages of Cyclosporine

• Strengths:  25 mg; 50 mg; 100 mg;  100 mg/mL; 50 mg/mL; 100 mg/mL.

Rheumatoid Arthritis

• Initial dose: 1.25 mg/kg orally 2 times a day; onset of action usually occurs between 4 and 8 weeks
• Titration: If the insufficient benefit is seen and tolerability is good at the initial dose (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5 to 0.75 mg/kg/day after 8 weeks and again after 12 weeks
• Maximum dose: 4 mg/kg/day orally in 2 divided doses; if no benefit is seen by 16 weeks, therapy should be discontinued

Organ Transplant – Rejection Prophylaxis 

• Initial dose: Give 4 to 12 hours prior to transplantation or postoperatively; the initial dose varies depending on the organ and concomitant immunosuppressives.

Newly transplants patients

• Renal: 9 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses
• Liver: 8 mg/kg/day (plus or minus 4 mg/kg/day) orally in 2 divided doses
• Heart: 7 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses

Psoriasis

• Initial dose: 1.25 mg/kg orally 2 times a day for at least 4 weeks
• Titration: If insufficient benefit is seen at 4 weeks and tolerability is good at the initial dose, the dose may be increased by 0.5 mg/kg/day at 2-week intervals based on patient response.
• Maximum dose: 4 mg/kg/day in 2 divided doses

Note: Doses below 2.5 mg/kg/day may also be effective.

Pediatric Organ Transplant – Rejection

ORAL FORMULATION (MODIFIED)

1 year and older

• Initial dose: Give 4 to 12 hours prior to transplantation or postoperatively; the initial dose varies depending on the organ and concomitant immunosuppressives.

Newly transplant patients

• Renal: 9 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses
• Liver: 8 mg/kg/day (plus or minus 4 mg/kg/day) orally in 2 divided doses
• Heart: 7 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses

Side Effects of Cyclosporine

The most common

• stomach pain
• nausea, vomiting
• diarrhoea
• agitation, including aggressive behaviour and/or hostility
• headache
• muscle, bone or joint pain
• high blood pressure
• skin sensitivity
• high cholesterol
• excessive hair growth
• irritability, restlessness, feeling anxious
• depression
• tingling or burning sensation in the arms or legs

More common

• Abdominal or stomach pain or tenderness
• back pain
• black, tarry stools
• blurred vision
• chest pain
• Sweating
• Blurred vision
• Dizziness.
• slower heart rate
• diarrhea
• dry eyes
• hair loss
• nausea
• weakness or tiredness

Common

• Cough producing mucus
• difficulty with breathing
• tightness in the chest
• Abdominal or stomach pain and tenderness
• blistering, peeling, or loosening of the skin
• Anxiety
• dry mouth
• irritability
• shaking
• sleepiness or unusual drowsiness
• trouble sleeping
• unusual dream blood in the urine
• Decreased appetite

Drug Interactions of Cyclosporine

Cyclosporine may interact with following drugs,supplement & may change the efficacy of drugs

• antihistamines (e.g,. cetirizine, doxylamine, diphenhydramine, hydroxyzine, loratadine)
• H2 antagonists (e.g., famotidine, ranitidine)
• antipsychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
• antiseizure medications (e.g., clobazam,  phenobarbital, phenytoin,   valproic acid, )
• angiotensin-converting enzyme inhibitors (ACEIs; e.g., ramipril, lisinopril)
• angiotensin receptor blockers (ARBs; e.g., candesartan, irbesartan, losartan)
• aripiprazole
• “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
• baclofen
• fusidic acid
• barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
• benzodiazepines (e.g., alprazolam, diazepam, lorazepam)
• calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
• domperidone
• “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
• famotidine
• gabapentin
• ipratropium
• ketotifen
• levodopa
• macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
• magnesium sulfate
• methylphenidate
• mirtazapine
• monoamine oxidase inhibitors (MAOIs; e.g. rasagiline, selegiline, tranylcypromine)
• muscle relaxants (e.g., cyclobenzaprine, methocarbamol, orphenadrine)
• non-steroidal anti-inflammatory medications (NSAIDs; e.g., diclofenac, ibuprofen, naproxen)
• orphenadrine
• quinolone antibiotics (e.g., levofloxacin, norfloxacin, moxifloxacin)
• selective serotonin reuptake inhibitors (SSRIs; e.g., paroxetine, fluoxetine, citalopram)
• serotonin antagonists (anti-emetic medications; e.g., granisetron, ondansetron)
• sotalol
• tapentadol
• thiazide diuretics (water pills; e.g., hydrochlorothiazide, indapamide, )
• thioridazine
• multivitamins/minerals
• mycophenolate
• selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine, paroxetine, sertraline)
• macrolide antibiotics (e.g., clarithromycin, erythromycin)
• tolterodine
• tramadol
• trimethoprim
• “statin” anti-cholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
• tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine, trimipramine)
• “triptan” migraine medications (e.g., eletriptan, sumatriptan)
• tryptophan
• tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
• vardenafil

Pregnancy & Lactation of Cyclosporine

FDA Pregnancy Category C

Pregnancy

This medication should be used during pregnancy only if the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately. Do not stop taking this medication without guidance from your doctor.

Lactation

This medication passes into breast milk. If you are a breastfeeding mother and are taking cyclosporine, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding.

References

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