APPACIPRO _{Eye Drops
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(Ciprofloxacin Ophthalmic Solution USP)

THIS LEAFLET CONTAINS IMPORTANT PRODUCT USE AND SAFETY INFORMATION, PLEASE READ CAREFULLY AND RETAIN FOR FURTHER FUTURE REFERENCE

DESCRIPTION:

Appacipro Eye Drops (Ciprofloxacin Ophthalmic Solution USP 0.3% w/v) is a synthetic, sterile, multiple dose, antimicrobial for topical ophthalmic use. Ciprofloxacin is a fluoroquinolone antibacterial active against a broad spectrum of gram-positive and gram-negative ocular pathogens. It is available as the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,4-dihydro-4- oxo-7-(1-piperazinyl)-3- quinoline-carboxylic acid. It is a faint to light yellow crystalline powder with a molecular weight of 385.8. Its empirical   formula   is  C17H18FN3O3HClH2O. Ciprofloxacin differs from other quinolones in that it has a fluorine atom at the 6-position, a piperazine moiety at the 7-position, and a cyclopropyl ring at the 1-position.

COMPOSITION:

Each ML Contains :

• Ciprofloxacin   Hydrochloride   USP
• Eq. to Ciprofloxacin     0.3 % w/v
• Benzalkonium Chloride Solution USP 0.02% w/v
  (As preservative)
• Sterile Aqueous Vehicle                                 q.s.
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INDICATIONS AND USAGE

Appacipro Eye Drops(Ciprofloxacin Ophthalmic SolutionUSP 0.3% w/v) is indicated for the treatment of infections causedby susceptible strainsof the designated microorganisms in the conditions listed below:
CornealUlcers:  Pseudomon aeruginosa
 Serratia marcescens*
 Staphylococcus aureus  Staphylococcus epidermidis
 Streptococcus pneumoniae  Streptococcus (Viridans Group)
*Efficacy for this organism was studied in fewer than 10 infections.

CLINICAL PHARMACOLOGY

a)Therapeutic indications

Adults, newborn infants(0-27 days), infantsand toddlers (28 days to 23 months),children (2-11 years) and adolescents (12-16 years).Appacipro Eye Drops(Ciprofloxacin Ophthalmic SolutionUSP 0.3% w/v) is indicated for the treatment of corneal ulcers and superficial infections of the eye and adnexa caused by susceptible strains of bacteria.Consideration should be given to official guidance on the appropriate use of antibacterial agents.

a)  Dosage and Administration

Adults, newborn infants(0-27 days), infantsand toddlers (28 days to 23 months),children (2-11 years) and adolescents (12-16 years).Corneal Ulcers:Appacipro Eye Drops (Ciprofloxacin Ophthalmic SolutionUSP 0.3% w/v) must be administered in the following     intervals,     even     during     night     time: On the firstday, instil 2 drops into the affectedeye every 15 minutes for the firstsix hours and then 2 drops into the affectedeye every 30 minutes for the remainder of the day.On the second day, instil 2 drops in the affected eye hourly.On the third through the fourteenth day, place two dropsin the affected eye every 4 hours. If the patient needs to be treated longerthan 14 days,the dosing regimenis at the discretion of the attending physician.Superficial               Ocular   Infection: The usual dose is one or two drops in the affectedeye(s) four times a day. In severeinfections, the dosagefor the first two days may be one or two drops every two hours during waking hours.For either indication a maximum durationof therapy of 21 days is recommended. The dosage in children above the age of 1 year is the same as for adults.Use                 in                 children Safety and effectiveness of Appacipro Eye Drops (Ciprofloxacin Ophthalmic Solution USP 0.3% w/v) were determined in 230 childrenbetween the ages of 0 and 12 years of age. No serious adversedrug reaction was reported in this groupof patients.Use   in  renal  and  hepatic      impairment Nostudies have been performed using Appacipro Eye Drops (Ciprofloxacin OphthalmicSolution USP 0.3% w/v) in patients with kidney or liver problems.

c) Contraindications                                

a) A history of hypersensitivity to Ciprofloxacin or any other component of the medication is a contraindication to its use. A historyof hypersensitivity to other quinolones may also contraindicate the use of Ciprofloxacin.

d) Warning

a) The clinical experience in children less than one year old, particularly in neonates is very limited.The use of AppaciproEye Drops (Ciprofloxacin Ophthalmic Solution USP 0.3% w/v) in neonates withophthalmia neonatorum of gonococcal or chalamydial originis not recommended as it has not been evaluated in such patients.Neonates with ophthalmia neonatorum should receiveappropriate treatment for their condition. When using Appacipro Eye Drops (Ciprofloxacin Ophthalmic Solution USP 0.3% w/v) one shouldtake into account the risk of rhinopharyngealpassage which can contribute to the occurrence and the diffusion of bacterial                              resistance. Serious and occasionally fatalhypersensitivity (anaphylactic) reactions, some following the first dose,were observed in patients receiving treatment based on systematicallyadministered quinolones. Some reactionswere accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial oedema,dyspnoea, urticaria and itching. Only a few patients had a historyof hypersensitivity reactions . Serious acutehypersensitivity reactions to ciprofloxacin may require immediate emergencytreatment. Oxygen and airway management should be administered where clinically indicated. Appacipro Eye Drops(Ciprofloxacin Ophthalmic SolutionUSP 0.3% w/v) should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.As with all antibacterialpreparations prolonged use may lead to overgrowth of non-susceptible bacterial strainsor fungi. If superinfection occurs,appropriate therapy shouldbe initiated.Tendoninflammation and rupture may occur with systemic fluoroquinolone therapyincluding ciprofloxacin, particularly in elderly patients and those treated concurrently withcorticosteroids. Therefore, treatment with Appacipro Eye Drops (CiprofloxacinOphthalmic Solution USP 0.3% w/v) should be discontinued at the first sign of tendon inflammation .In patients with corneal ulcer andfrequent administration of Appacipro Eye Drops (Ciprofloxacin Ophthalmic Solution USP 0.3% w/v), white topical ocularprecipitates (medication residue)have been observedwhich resolved after continued application of Appacipro Eye Drops(Ciprofloxacin Ophthalmic Solution USP 0.3% w/v). The precipitatedoes not preclude the continued application ofAppacipro Eye Drops (Ciprofloxacin Ophthalmic Solution USP 0.3% w/v) nor does itadversely affect the clinical course of the recovery process. The onset of the precipitate was within 24 hours to 7 days after starting therapy. Resolution of the precipitate variedfrom immediately to 13 days after therapycommencing.Contact lens wear is not recommended during treatment of an ocular infection. Therefore, patients should be advised not to wear contact lensesduring treatment with Appacipro Eye Drops (Ciprofloxacin Ophthalmic Solution USP 0.3% w/v).Appacipro Eye Drops (Ciprofloxacin Ophthalmic Solution USP 0.3% w/v) contains Benzalkonium chloride which may cause irritation and is known to discoloursoft contact lenses.Avoid contact with soft contact lenses.In case patientsare allowed to wear contactlenses they shouldbe instructed to remove them prior to application of Appacipro Eye Drops (Ciprofloxacin Ophthalmic Solution USP 0.3% w/v) and wait at least15 minutes beforereinsertion.b) Interaction with othermedicinal products andother forms of interactionSpecific drug interaction studieshave not been conducted with ophthalmic Ciprofloxacin. Given the low systemic concentration of Ciprofloxacinfollowing topical ocular administration of the product, drug interactions are unlikely to occur.If more than one topicalophthalmic medicinal productis being used, the medicinesmust be administered at least 5 minutesapart. Eye ointmentsshould be administered last.

f) Fertility, pregnancy and lactation

 Fertility

Studies have not been performedin humans to evaluate the effect of topical administration of Ciprofloxacin on fertility. Oral administration in animals does not indicatedirect harmful effectswith respect to fertility.Pregnancy                                   There are no adequate data from the use of Appacipro Eye Drops (Ciprofloxacin Ophthalmic Solution USP 0.3% w/v) in pregnantwoman. Animal studiesdo not indicate direct harmfuleffects with respectto reproductive toxicity.Systemic exposure to Ciprofloxacin after topical use is expectedto be low.As a precautionary measure, it ispreferable to avoid the use of Appacipro Eye Drops (Ciprofloxacin Ophthalmic Solution USP 0.3% w/v) duringpregnancy, unless the therapeutic benefit is expected to outweigh the potential risk to the fetus.BreastfeedingOrally administered Ciprofloxacinis excreted in the human milk. It is unknown whether Ciprofloxacin is excreted in human breast milk followingtopical ocular or otic administration. Arisk to the suckling child cannot beexcluded. Therefore, caution should be exercised when Appacipro Eye Drops(Ciprofloxacin Ophthalmic SolutionUSP 0.3% w/v) is administered to nursing women.

g) Undesirable

a) In clinical trials,the most frequently reported adverse drug reactions were ocular discomfort, dysgeusia and cornealdeposits occurring approximately in 6%, 3% and 3% of patientsrespectively.Tabulated summary of adverse reactionsThe adversereactions listed beloware classified according to the following convention: very common(≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥1/1,000 to <1/100),rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannotbe estimated from the availabledata). Within each frequency-grouping, adverse reactions are presented in orderof decreasing seriousness. The adverse reactions have been observedduring clinical trialsand post-marketing experience.

The following undesirable effects were reported in association with the ophthalmic use of Appacipro Eye Drops (Ciprofloxacin Ophthalmic Solution USP 0.3% w/v):

Description of selected adverse eventsWith locally appliedfluoroquinolones (generalized) rash, toxic epidermolysis, dermatitisexfoliative, Stevens-Johnson syndromeand urticaria occurvery rarely.Serious andoccasionally fatal hypersensitivity (anaphylactic) reactions, some followingthe first dose, have been reported in patientsreceiving systemic quinolone therapy. Some reactions were accompanied by cardiovascularcollapse, loss of consciousness, tingling, pharyngeal or facial oedema,dyspnoea, urticaria, and itching.Ruptures of the shoulder, hand,Achilles, or other tendons that required surgical repair or resulted in prolongeddisability have been reported in patients receivingsystemic fluoroquinolones. Studiesand post marketing experience with systemicfluoroquinolones indicate that the risk of these ruptures may be increased in patients receivingcorticosteroids, especially geriatric patients and in tendons under high stress, including the Achilles tendon. To date, clinical and post marketing data have not demonstrateda clear association between Appacipro Eye Drops (CiprofloxacinOphthalmic Solution USP 0.3% w/v) and musculoskeletal and connective tissue adverse reactions.In isolated casesblurred vision, decreased visual acuity and medication residuehave been observedwith ophthalmic Ciprofloxacin .Moderate to severephototoxicity has been observed in patients treatedwith systemic quinolones. Nevertheless, phototoxic reactions to ciprofloxacin are uncommon.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Mechanism of ActionAppacipro Eye Drops (CiprofloxacinOphthalmic Solution USP 0.3% w/v), solution contains the fluoroquinolone ciprofloxacin. The cidal and inhibitory activityof Ciprofloxacin againstbacteria results from an interference with the DNA gyrase, an enzyme neededby the bacterium for the synthesis of DNA. Thus the vital information from the bacterialchromosomes cannot be transcribed which causes a breakdown of the bacterial metabolism. Ciprofloxacin has in vitro activity againsta wide range of Gram-positive and Gram- negativebacteria.Mechanism             of             Resistance Fluoroquinolone resistance, particularly Ciprofloxacin, requires significant geneticchanges in one or more of five major bacterialmechanisms: a) enzymesfor DNA synthesis, b) protecting proteins, c) cell permeability, d) drug efflux,or e) plasmid-mediated aminoglycoside 6'-N-acetyltransferase.Fluoroquinolones, includingCiprofloxacin, differ in chemical structure and mode of action from aminoglycosides, β-lactam antibiotics,macrolides, tetracyclines, sulfonamides, trimethoprim, and chloramphenicol. Therefore, organisms resistantto these drugs may be susceptible to Ciprofloxacin.Susceptibility              to              Ciprofloxacin: The prevalence of acquired resistance may vary geographically and with time for selectedspecies and local informationon resistance is desirable,particularly when treating severe infections.As necessary, expertadvice should be sought when the local prevalence of resistance is such that the utilityof the agent in at least some types of infections is questionable.The presentation below lists bacterial species recovered from externalocular infections of the eye.

PHARMACOKINETIC PROPERTIES

Appacipro Eye Drops (Ciprofloxacin Ophthalmic Solution USP 0.3% w/v) solution is rapidly absorbed into the eye following topical ocular administration. Systemic levels are low following topical administration. Plasma levels of Ciprofloxacin in human subjects following 2 drops of 0.3% Ciprofloxacin solution every 2 hours for two days and then every four hours for 5 days ranged from non-quantifiable (<1.0ng/mL) to 4.7 ng/mL. The mean peak Ciprofloxacin plasma level obtained in this study is approximately 450-fold less than that seen following a single oral dose of 250 mg Ciprofloxacin. The systemic pharmacokinetic properties of Ciprofloxacin have been well studied. Ciprofloxacin widely distributes to tissues of the body. The apparent volume of distribution at steady state is 1.7 to 5.0 l/kg. Serum protein binding is 20-40%. The half-life of Ciprofloxacin in serum is 3-5 hours. Both Ciprofloxacin and its four primary metabolites are excreted in urine and faeces. Renal clearance accounts for approximately two-thirds of the total serum clearance with biliary and faecal routes accounting for the remaining percentages. In patients with impaired renal function, the elimination half-life of Ciprofloxacin is only moderately increased due to extrarenal routes of elimination. Similarly, in patients with severely reduced liver function the elimination half-life is only slightly longer. There are no pharmacokinetic data available in respect of use in children.

PACKAGING AND STORAGE

Preserve in tight containers, protected from light, at room temperature.

SHELF LIFE

24   Months   (Unopened   Container)
To be used within one month after opening the container.

HOW SUPPLIED

Appacipro Eye Drops (Ciprofloxacin Ophthalmic SolutionUSP 0.3% w/v) sterile solution is available in10mL/5mL poly bottle.
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