- ClasGen Eye Drops is indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.

- Instill one drop of this drug twice a day in each eye approximately 12 hours apart. This drug can be used concomitantly with artificial tears, allowing a 15 minute interval between products.  Discard vial after use.

4.4.1 Warning

 - As for this drug, there has been no research data for patients who have medical histories related to vesicular keratitis.

- As for patients who use punctal plug or administer topical anti-inflammatory drug, there has been no increase making tears observed.

4.4.2 General precaution

 - This drug should be used for ophthalmic disease.

- Do not touch tip of container to eyes as this may injure the eyes.

<No clinically relevant interactions have been described.>

- Teratogenic effects: 300mg/kg/day of cyclosporine were administered to rats and rabbits orally, but there was no evidence observed that this drug might occur deformity. As for rats and rabbits, when it is regarded that this dosage is absorbed all, it is around 300,000 times bigger than daily dosage (0.001mg/kg/day) from a person of 60kg who administered the drug one drop on eyes (28㎕).

- Non-teratogenic effects:

① As for the reproductive toxicity study from rats and rabbits, the adverse reaction was observed only from the dosage of toxicity in the mothers’ body. The oral solution of cyclosporine (USP) with toxicity dosage (Rats: 30mg/kg/day, Rabbits: 100mg/kg/day) lead to late development for skeleton as well as weight loss and increase of death from pup. Also, the toxicity was observed for initial development and pup. When it is regarded that all administered dosage is absorbed totally, it is around each 30,000 times and 100,000 times bigger than daily dosage (0.001mg/kg/day) of a person who administered the drug one drop (28㎕) on each eye.

② The evidence related to toxicity was not observed from rats and rabbits which administered cyclosporine with dosage of each 17mg/kg/day and 30mg/kg/day orally. This dosage is around each 17,000 times and 30,000 times bigger than daily dosage of human.

③ From 15 days after pregnancy to 21 days after partus, the put death rate was increased from the rats which administered 45mg/kg/day (toxicity level from mother’s body of cyclosporine). When it is regarded that all administered dosage is absorbed totally, it is 45,000 times bigger than daily dosage (0.001mg/kg/day) of human.

④ No clinical study data for pregnant woman yet. Therefore, this drug should be administered carefully when it is needed definitely.

⑤ Cyclosporine is known that it is affected to the breast feeding if it is systemic administration, but for topical administration, it was not researched. Although the blood concentration is not observed, it should be careful if it is administered to pregnant woman.

Not applicable

 - Commonest adverse reaction: Ocular burning (17%)

- Other adverse reaction reported from 1 ~ 5 % patients: conjunctival hyperemia, discharge, epiphora, eye pain, foreign body sensation, pruritus, stinging and visual disturbance (Most often blurring)

- Adverse reaction from post marketing: Difficult to estimate the frequency or establish a causal relationship to drug exposure, but reported that there have been eye swelling, hypersensitivity (including rare cased of sever angioedema, face swelling, tongue swelling, pharyngeal edema, and dyspnea), superficial injury of the eye (from the vial tip touching the eye during administration), burning sensation, pruritus, and hives.

- Post marketing Surveillance in domestic market

In South Korea market, the adverse reaction has been studied with 895 patients who have ophthalmic infection for 6 years after launching the product, and the symptom incident was 7.82% without a casual relation (70 patients/895 patients, 93 cases). Among those cases, the adverse reaction, which should be considered of its casual relation, was 6.48% (58 patients/ 895 patients, 76 cases) and it was reported that there were burning sensation from applied parts (26 cases), not effectiveness (11 cases), eye dry (7 cases), ophtalmalgia (7 cases), hyperaemia conjunctivae (6 cases), dysaesthesia from eyes (5 cases), tiredness from eyes (3 cases), stimulation from eyes (3 cases), secretion from eyes (2 cases), pruritus from applied parts (2 cases), corneal erosion (1 case), sticky eyes (1 case), epiphora (1 case), edema from eyes (1 case).

Severe adverse reaction was not reported, but there were some unexpected adverse reactions (2.68% - 24 patients/895patients, 27 cases) which are effectiveness (11 cases), dry eye (7 cases), tiredness from eyes (3 cases) stimulation from eyes (3 cases), corneal erosion (1 case), sticky eyes (1 case) and edema from eyes (1 case).

- Excipients: This drug contains phosphate. As for some patients who have severe corneal damage, it was reported that there could be cornea calcification for these patients very rarely when used phosphate. (0.01%).

Not applicable

- Product Name: ClasGen Eye Drops

- CAS#: 59865-13-3

- Chemical Name: Cyclosporine

Absorption

The absorption of cyclosporine after topical ocular administration of a castor oil emulsion formulation has been studied in two nonclinical species; rabbit and dog.  Both species had significant absorption of cyclosporine in nictitating membrane, conjunctiva and cornea with substantially less detected in other ocular tissues.  Some accumulation was observed in cornea, lens and iris-ciliary body but limited in conjunctiva and sclera after multiple dosing. Systemic absorption after topical ocular administration in these two species was minimal with maximal plasma concentrations of less than 1 ng/mL.  In humans, ophthalmic cyclosporine castor oil emulsions results in very low systemic levels of cyclosporine as well.

Bioavailability of cyclosporine varies considerably after administration with standard oral formulations with a mean value of 30% and range of 1 to 89%.  Food intake may have substantial effect on the rate and extent of absorption with standard oral formulations.

Distribution

Cyclosporine after topical ocular administration distributed poorly into intraocular tissues, e.g. cornea and conjunctiva from extraocular tissues, e.g. iris-ciliary body and aqueous humor in both rabbit and dog.  Limited contralateral distribution from the treated to the untreated eye was observed in rabbit most notably detected in lens, choroid-retina, vitreous humor, lacrimal gland and optic nerve.

Cyclosporine is widely distributed systemically after intravenous administration with a volume of distribution ranging from 0.9 to 4.8 L/kg.  Cyclosporine is bound to erythrocytes with a blood: plasma ratio of 2. Plasma protein binding is approximately 80% with most binding to lipoproteins.

Biotransformation

Biotransformation of cyclosporine in ocular tissues after topical ocular administration was not detected. After oral dosing, cyclosporine is extensively metabolized which includes hydroxylation and demethylation of the parent drug in the liver primarily by CYP3A4.  The interpatient variability of cyclosporine disposition after oral administration is large, and drug-drug interactions (DDIs) with CYP3A4 inhibitors and inducers significantly contribute to this variability.  In addition, cyclosporine and some of its metabolites are known P-glycoprotein substrates and/or inhibitors; however, P-glycoprotein expression and cyclosporine disposition studies have generated inconclusive results.

Elimination

Calculated half-life of cyclosporine after topical ocular administration of castor oil emulsion (0.2%) varied among the tissues and species (rabbit or dog) and ranged from 14.6 hours (lacrimal gland of the dog) to 44 hours (iris-ciliary body of the rabbit).

Systemically, cyclosporine and its metabolites are eliminated through biliary excretion with renal excretion as a minor pathway.  Less than 1% of the dose is eliminated unchanged in the urine while only 6% of the dose was eliminated in the urine as parent drug and metabolites.  The elimination half-life of cyclosporine in healthy volunteers after systemic dosing averaged 6.3 hours.

Linearity/non-linearity

With increasing doses of cyclosporine in topical ocular castor oil emulsions from 0.05% to 0.4%, dose proportionality was found in some ocular tissues but not in others.

Pharmacokinetic/pharmacodynamic relationship(s)

No pharmacokinetic/pharmacodynamics relationship has been described for cyclosporine after topical ocular administration.

Pharmacokinetics of special populations

Renal failure and hemodialysis do not affect the pharmacokinetics of cyclosporine.  Severe liver disease decreases the absorption of cyclosporine as well as increasing serum half-life after systemic dosing.  Pharmacokinetics of cyclosporine after oral dosing is influenced by age.  Pediatric patients appear to clear the drug more rapidly than adults. 

- Non-clinical data reveal no special hazards, at the indicated route and dose, for humans based on conventional studies evaluating repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.

This drug contains following excipients: Concentrated Glycerin (used as an isotonic agent), Monobasic Sodium Phosphate Monohydrate (used as a pH adjuster), Dibasic Sodium Phosphate Hydrate (used as a pH adjuster), Polyoxyl 35 castor oil (used as a solvent), Ethanol (used as a solvent) and Water for injection (used as a solvent).

Not applicable

Store in an airtight container below 30°C

Should be protected from light.

 0.4 mL x 30 EA

- To avoid contamination, never touch the tip of the vial to any surface.

- Use before the expiration date marked on the product.

- Do not use if the product changes color.

- TAMPER EVIDENT: Do not use if security seal is damaged or missing. Do not use if package has been opened or damaged.

- If swallowed, get medical help.

- Keep out of the reach of children.

- Store at room temperature.

- One individual single-use vial is to be used immediately after opening.