Sigmasporin

Uses

This drug is used to increase tear production in patients whose tear production issuppressed due to ocular inflammation associated with dry eye syndrome(keratoconjunctivitis sicca).

Sigmasporin is also used to associated treatment for these conditions: Atopic Dermatitis (AD), Bone Marrow Transplant Rejection, Chronic transplant rejection, Connective Tissue Disorders, Glomerulosclerosis, Focal Segmental, Graft Versus Host Disease (GVHD), Heart Transplant Rejection, Idiopathic Thrombocytopenic Purpura, Interstitial Cystitis, Juvenile Idiopathic Arthritis (JIA), Kidney Transplant Rejection, Liver Transplant Rejection, Nephritis, Lupus, Nephrotic Syndrome, Ocular Rosacea, Rejection, Transplant, Severe Ulcerative Colitis, Steroid Dependent Nephrotic Syndrome, Steroid Resistant Nephrotic Syndrome, Uveitis, Vernal Keratoconjunctivitis, Blistering disorder, Refractory Ulcerative colitis, Severe, active Rheumatoid arthritis, Severe, recalcitrant Plaque psoriasis, Suppressed tear production

How Sigmasporin works

Sigmasporin is a calcineurin inhibitor that inhibits T cell activation. Its binding to the receptor cyclophilin-1 inside cells produces a complex known as cyclosporine-cyclophilin. This complex subsequently inhibits calcineurin, which in turn stops the dephosphorylation as well as the activation of the nuclear factor of activated T cells (NF-AT) that normally cause inflammatory reactions. NF-AT is a transcription factor that promotes the production of cytokines such as IL-2, IL-4, interferon-gamma and TNF-alpha, all of which are involved in the inflammatory process. Specifically, the inhibition of IL-2, which is necessary for T cell activation or proliferation, is believed to be responsible for cyclosporine's immunosuppressive actions. In addition to the above, the inhibition of NF-AT leads to lower levels of other factors associated with T helper cell function and thymocyte development.

Dosage

Sigmasporin dosage

Instill one drop of this drug twice a day in each eye approximately 12 hours apart. Itcan be used concomitantly with artificial tears, allowing a 15 minute interval betweenproducts

Side Effects

The most common adverse event is ocular burning. Other events reported includeconjunctival hyperemia, discharge, epiphora, eye pain, foreign body sensation,pruritus, stinging and visual disturbance (most often blurring).

Toxicity

The oral LD50 in rats is 1480 mg/kg and the TDLO in humans is 12 mg/kg.

Overdose information

In cases of overdose with oral cyclosporine, forced emesis and gastric lavage are recommended 2 hours after ingestion. There are little data available in the literature regarding overdoses with cyclosporine, but hepatotoxicity and nephrotoxicity may occur. One case report of an cyclosporine overdose due to medical error was made involving a 26 year old female and noted the occurrence of nausea, flushing, tremor, vertigo and vomiting, which resolved within about 1 day. Anorexia and a feeling of increased body girth were also experienced by this patient and resolved within about 2 weeks. When overdose with cyclosporine is observed, it is important to consider that dialysis and charcoal, hemoperfusion are not effective techniques to remove cyclosporine from the body.

Precaution

This drug should not be administered while wearing contact lenses. Patients withdecreased tear production typically should not wear contact lenses. If contact lensesare worn, they should be removed prior to the administration of the emulsion. Lensesmay be reinserted 15 minutes following administration of this medication.This drug may cause blurred vision. Do not drive, use machinery, or do any activitythat requires clear vision until you are sure you can perform such activities safely.

Food Interaction

• Avoid grapefruit products.
• Avoid potassium-containing products. Taking products that increase serum potassium may increase the risk of hyperkalemia.
• Avoid St. John's Wort.
• Take at the same time every day. Take consistently with regard to food.

[Moderate] GENERALLY AVOID: Administration with grapefruit juice (compared to water or orange juice) has been shown to increase blood concentrations of cyclosporine with a relatively high degree of interpatient variability.

The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

GENERALLY AVOID: Administration with red wine or purple grape juice may decrease blood concentrations of cyclosporine.

In 12 healthy volunteers, 12 ounces total of a merlot consumed 15 minutes prior to and during cyclosporine administration (single 8 mg

The time to reach peak concentration (Tmax) doubled, and oral clearance increased 50%.

Similarly, one study were 12 healthy patients were administered purple grape juice and a single dose of cyclosporine showed a 30% and a 36% decrease in cyclosporine systemic exposure (AUC) and peak blood concentration (Cmax), respectively.

The exact mechanism of interaction is unknown but may involve decreased cyclosporine absorption.

MONITOR: Food has been found to have variable effects on the absorption of cyclosporine.

There have been reports of impaired, unchanged, and enhanced absorption during administration with meals relative to the fasting state.

The mechanisms are unclear.

Some investigators found an association with the fat content of food.

In one study, increased fat intake resulted in significantly increased cyclosporine bioavailability and clearance.

However, the AUC and pharmacodynamics of cyclosporine were not significantly affected, thus clinical relevance of these findings may be minimal.

MANAGEMENT: Patients receiving cyclosporine therapy should be advised to either refrain from or avoid fluctuations in the consumption of grapefruits and grapefruit juice.

Until more data are available, the consumption of red wine or purple grape juice should preferably be avoided or limited.

All oral formulations of cyclosporine should be administered on a consistent schedule with regard to time of day and relation to meals so as to avoid large fluctuations in plasma drug levels.

Sigmasporin Hypertension interaction

[Major] The use of cyclosporine is contraindicated in patients with rheumatoid arthritis or psoriasis with uncontrolled hypertension.

Hypertension, possibly due to renal vasoconstriction, has occurred in 50% of patients receiving cyclosporine.

Antihypertensive therapy may be necessary for kidney, liver, and heart transplant recipients treated with cyclosporine.

Hypertension may decline with continued used, but has persisted in some patients.

Sigmasporin Drug Interaction

Major: atorvastatin, atorvastatinModerate: aspirin, aspirin, mycophenolate mofetil, mycophenolate mofetil, furosemide, furosemideUnknown: omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, pregabalin, pregabalin, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol, cetirizine, cetirizine

Sigmasporin Disease Interaction

Major: hypertension, renal dysfunctionModerate: hepatic dysfunction, malabsorption syndrome

Volume of Distribution

The distribution of cyclosporine in the blood consists of 33%-47% in plasma, 4%-9% in the lymphocytes, 5%-12% in the granulocytes, and 41%-58% in the erythrocytes. The reported volume of distribution of cyclosporine ranges from 4-8 L/kg. It concentrates mainly in leucocyte-rich tissues as well as tissues that contain high amounts of fat because it is highly lipophilic. Sigmasporin, in the eye drop formulation, crosses the blood-retinal barrier.

Elimination Route

The absorption of cyclosporine occurs mainly in the intestine. Absorption of cyclosporine is highly variable with a peak bioavailability of 30% sometimes occurring 1-8 hours after administration with a second peak observed in certain patients. The absorption of cyclosporine from the GI tract has been found to be incomplete, likely due to first pass effects. Cmax in both the blood and plasma occurs at approximately 3.5 hours post-dose.

The C_max of a 0.1% cyclosporine ophthalmic emulsion is 0.67 ng/mL after instilling one drop four times daily.

A note on erratic absorption

During chronic administration, the absorption of Sandimmune Soft Gelatin Capsules and Oral Solution have been observed to be erratic, according to Novartis prescribing information. Those being administered the soft gelatin capsules or oral solution over the long term should be regularly monitored by testing cyclosporine blood concentrations and adjusting the dose accordingly. When compared with the other oral forms of Sandimmune, Neoral capsules and solution have a higher rate of absorption that results in a higher Tmax and a 59% higher Cmax with a 29 % higher bioavailability.

Half Life

The half-life of cyclosporine is biphasic and very variable on different conditions but it is reported in general to last 19 hours. Prescribing information also states a terminal half-life of approximately 19 hours, but with a range between 10 to 27 hours.

Clearance

Cyclosporin shows a linear clearance profile that ranges from 0.38 to 3 Lxh/kg, however, there is substantial inter- patient variability. A 250 mg dose of cyclosporine in the oral soft gelatin capsule of a lipid micro-emulsion formulation shows an approximate clearance of 22.5 L/h.

Elimination Route

After sulfate conjugation, cyclosporine remains in the bile where it is broken down to the original compound and then re-absorbed into the circulation. Sigmasporin excretion is primarily biliary with only 3-6% of the dose (including the parent drug and metabolites) excreted in the urine while 90% of the administered dose is eliminated in the bile. From the excreted proportion, under 1% of the dose is excreted as unchanged cyclosporine.

Pregnancy & Breastfeeding use

Pregnancy category C. There are no adequate and well-controlled studies of Sigmasporin ophthalmic emulsion in pregnant women. It should be administered topregnant women if clearly needed. Sigmasporin is known to be excreted in human milk following systemic administration but excretion in human milk after topical treatment has not been investigated.

Although blood concentrations are undetectable after topical administration of Sigmasporin ophthalmic emulsion, caution should be exercised when it isadministered to a nursing woman.

Contraindication

Sigmasporin is contraindicated in patients with active ocular infections and in patients with known or suspected hypersensitivity to any of the ingredients in the formulation.

Acute Overdose

No information provided

Interaction with other Medicine

No information provided

Storage Condition

Keep out of the reach of children. Keep in a cool and dry place, away from light. Do not use more than 4 weeks after opening

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