Product Index

Qualitative and Quantitative Composition

Each ml contains:

Moxifloxacin Hydrochloride IP

Equivalent to Moxifloxacin……………. 0.5% w/v

Ketorolac Tromethamine IP…………0.5% w/v

Isotonic Aqueous Vehicle ......................q.s

Dosage Form and Strength

Ophthalmic Solution (Preservative free) of moxifloxacin 0.5% and ketorolac 0.5%

Clinical Particulars

Therapeutic Indications

Non-steroidal anti-inflammatory drug (NSAID) responsive inflammatory ocular conditions for which a NSAID is indicated and where superficial bacterial ocular infection or the risk of bacterial ocular infection exists and where the inherent risk of NSAID use in certain infective conjunctivitides is accepted to obtain a diminution in oedema and inflammation.

Topical NSAID like ketorolac tromethamine is indicated for the treatment of postoperative inflammation in patients who have undergone cataract extraction.

The use of a combination drug with an anti-infective component is indicated where the risk of superficial ocular infection is high or where there is an expectation that potentially dangerous numbers of bacteria will be present in the eye.

Posology and Method of Administration

Instil one drop in the affected eye three times a day or as directed by the physician.

Contraindications

Moxifloxacin and ketorolac ophthalmic solution is contraindicated in patients with a history of hypersensitivity to moxifloxacin, to other quinolones, ketorolac or to any of the components in this medication.

The potential exists for cross-sensitivity to acetylsalicylic acid and other NSAIDs. Ketorolac is contraindicated in individuals who have previously exhibited sensitivities to these drugs.

Special Warnings and Precautions for Use

For Topical Ophthalmic Use Only

NOT FOR INJECTION. Moxifloxacin and ketorolac ophthalmic solution should not be injected subconjunctivally, nor should it be introduced directly into the anterior chamber of the eye.

Moxifloxacin

Hypersensitivity Reactions

In patients receiving systemically administered quinolones, including moxifloxacin, serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported, some following the first dose. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial oedema), airway obstruction, dyspnea, urticaria, and itching. If an allergic reaction to moxifloxacin occurs, discontinue use of the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment. Oxygen and airway management should be administered as clinically indicated.

Growth of Resistance Organisms with Prolonged Use

As with other anti-infectives, prolonged use may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit-lamp biomicroscopy, and where appropriate, fluorescein staining. Patients should be advised not to wear contact lenses if they have signs or symptoms of bacterial conjunctivitis.

Avoidance of Contact Lens Wear

Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis.

Tendon Inflammation

Tendon inflammation and rupture may occur with systemic fluoroquinolone therapy including moxifloxacin, particularly in older patients and those treated concurrently with corticosteroids. Following ophthalmic administration of moxifloxacin ophthalmic solution, plasma concentrations of moxifloxacin are much lower than after therapeutic oral doses of moxifloxacin, however, caution should be exercised and treatment with moxifloxacin ophthalmic solution should be discontinued at the first sign of tendon inflammation.

Avoid Empirical Treatment of Gonococcal Conjunctivitis

Moxifloxacin should not be used for the prophylaxis or empiric treatment of gonococcal conjunctivitis, including gonococcal ophthalmia neonatorum, because of the prevalence of fluoroquinolone-resistant Neisseria gonorrhoeae. Patients with eye infections caused by Neisseria gonorrhoeae should receive appropriate systemic treatment.

Not Recommended in Neonates

Data are very limited to establish efficacy and safety of moxifloxacin in the treatment of conjunctivitis in neonates. Therefore use of this medicinal product to treat conjunctivitis in neonates is not recommended.

Neonates with ophthalmia neonatorum should receive appropriate treatment for their condition, e.g. systemic treatment in cases caused by Chlamydia trachomatis or Neisseria gonorrhoeae.

The medicinal product is not recommended for the treatment of Chlamydia trachomatis in patients less than 2 years of age as it has not been evaluated in such patients. Patients older than 2 years of age with eye infections caused by Chlamydia trachomatis should receive appropriate systemic treatment.

Ketorolac Tromethamine

Delayed Healing

Topical NSAIDs may slow or delay healing.Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems.

Cross-Sensitivity or Hypersensitivity

There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs. There have been reports of bronchospasm or exacerbation of asthma in patients with the use of ketorolac tromethamine ophthalmic solution in patients who have either a known hypersensitivity to aspirin/NSAIDs or a past medical history of asthma. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.

Increased Bleeding Time

With some NSAIDs, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly applied NSAIDs may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery.

It is recommended that ketorolac ophthalmic solution should be used with caution in patients with known bleeding tendencies or who are receiving other medications, which may prolong bleeding time.

Corneal Effects

Use of topical NSAIDs may result in keratitis. In some susceptible patients, continued use of topical NSAIDs may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration or corneal perforation. These events may be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs and should be closely monitored for corneal health.

Post-marketing experience with topical NSAIDs suggests that patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time may be at increased risk for corneal adverse events which may become sight threatening. Topical NSAIDs should be used with caution in these patients.

Post-marketing experience with topical NSAIDs also suggests that use more than 1 day prior to surgery or use beyond 14 days post-surgery may increase patient risk for the occurrence and severity of corneal adverse events.

Other

In common with other anti-inflammatory drugs, ketorolac may mask the usual signs of infection.

Concomitant use of ketorolac and topical corticosteroids should be exercised with caution in patients susceptible to corneal epithelial breakdown.

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures to avoid injury and contamination of eye drops.

Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Ketorolac ophthalmic solution should not be administered while wearing contact lenses.

Drug interactions

Moxifloxacin

Drug-drug interaction studies have not been conducted with moxifloxacin. In vitro studies indicate that moxifloxacin does not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2 indicating that moxifloxacin is unlikely to alter the pharmacokinetics of drugs metabolized by this cytochrome P450 isozymes.

Given the low systemic concentration of moxifloxacin following topical ocular administration of the medicinal product, drug interactions are unlikely to occur.

Ketorolac Tromethamine

No interaction studies have been performed.

Ketorolac has been safely administered with systemic and ophthalmic medications such as antibiotics, sedatives, beta blockers, carbonic anhydrase inhibitors, miotics, mydriatics, local anaesthetics and cycloplegics.

Ketorolac may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical corticosteroids may increase the potential for healing problems.

Use in Special Population

Pregnant Women

There are no adequate and well-controlled studies in pregnant women. Hence, MOXICIP KT ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Lactating Women

Because many drugs are excreted in human milk, caution should be exercised when MOXICIP KT ophthalmic solution is administered to a nursing mother.

Paediatric Patients

Safety and efficacy in paediatric patients below the age of two years have not been established.

There is no evidence that the ophthalmic administration of moxifloxacin has any effect on weight bearing joints, even though oral administration of some quinolones has been shown to cause arthropathy in immature animals.

Geriatric Patients

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Effects on Ability to Drive and Use Machines

As with any eye drops, temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs at instillation, the patient should wait until their vision clears before driving or using machinery.

Undesirable Effects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Moxifloxacin

The most frequently reported ocular adverse events were conjunctivitis, decreased visual acuity, dry eye, keratitis, ocular discomfort, ocular hyperaemia, ocular pain, ocular pruritus, subconjunctival haemorrhage, and tearing. These events occurred in approximately 1-6% of patients.

Non-ocular adverse events reported at a rate of 1-4% were fever, increased cough, infection, otitis media, pharyngitis, rash, and rhinitis.

In clinical studies involving 2,252 patients, Moxifloxacin ophthalmic solution was administered up to 8 times a day, with 1,900 of these patients receiving treatment three times daily. The overall safety population that received the medicinal product consisted of 1,389 patients from the United States and Canada, 586 patients from Japan and 277 patients from India. No serious ophthalmic or systemic undesirable effects related to the medicinal product were reported in any of the clinical studies. The most frequently reported treatment-related undesirable effects with the medicinal product were eye irritation and eye pain, occurring at an overall incidence of 1 to 2%. These reactions were mild in 96% of those patients who experienced them, with only 1 patient discontinuing therapy as a result.

The following undesirable effects were assessed to be treatment-related and are 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 <1/1000), or very rare (<1/10,000) or not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in decreasing order of seriousness.

System Organ Classification	Frequency	Adverse reactions
Blood and lymphatic system disorders	Rare	haemoglobin decreased
Immune system disorders	Not known	hypersensitivity
Nervous system disorders	Uncommon Rare Not known	headache paresthesia dizziness
Eye disorders	Common   Uncommon       Rare         Not known	eye pain, eye irritation   punctate keratitis, dry eye, conjunctival haemorrhage, ocular hyperaemia, eye pruritus, eyelid oedema, ocular discomfort,   corneal epithelium defect, corneal disorder, conjunctivitis, blepharitis, eye swelling, conjunctival oedema, vision blurred, visual acuity reduced, asthenopia, erythema of eyelid    endophthalmitis, ulcerative keratitis, corneal erosion, corneal abrasion, intraocular pressure increased, corneal opacity, corneal infiltrates, corneal deposits, eye allergy, keratitis, corneal oedema, photophobia, , eyelid oedema, lacrimation increased, eye discharge, foreign body sensation in eyes
Cardiac disorders	Not known	palpitations
Respiratory, thoracic and mediastinal disorders	Rare   Not known	nasal discomfort, pharyngolaryngeal pain, sensation of foreign body (throat) dyspnoea
Gastrointestinal disorders	Uncommon Rare Not known	dysgeusia vomiting nausea
Hepatobiliary disorders	Rare	alanine aminotransferase increased, gamma-glutamyltransferase increased
Skin and subcutaneous tissue disorders	Not known	erythema, rash, pruritus, urticaria

Ruptures of the shoulder, hand, Achilles, or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving systemic fluoroquinolones. Studies and post marketing experience with systemic quinolones indicate that a risk of these ruptures may be increased in patients receiving corticosteroids, especially geriatric patients and in tendons under high stress, including Achilles tendon.

Systemic Absorption of fluoroquinolones has been reported to cause following adverse effects:

The drug may cause low blood sugar and mental health related side effects. Low blood sugar levels, also called hypoglycemia, can lead to coma. The mental health side effects more prominent and more consistent across the systemic fluoroquinolone drug class are as mentioned below;

• Disturbances in attention

• Disorientation
• Agitation
• Nervousness
• Memory impairment
• Serious disturbances in mental abilities called delirium

Paediatric Population

In clinical trials, moxifloxacin 0.5% ophthalmic solution has shown to be safe in pediatric patients, including neonates. In patients under 18 years old, the two most frequent adverse reactions were eye irritation and eye pain, both occurring at an incidence rate of 0.9%.

Based on data from clinical trials involving pediatric patients, including neonates, the type and severity of adverse reactions in the pediatric population are similar to those in adults.

Ketorolac tromethamine

The most frequent adverse events reported with the use of ketorolac tromethamine ophthalmic solution have been transient stinging and burning on instillation. These events were reported by up to 40% of patients participating in clinical trials.

Other adverse events occurring approximately 1% to 10% of the time during treatment with ketorolac tromethamine ophthalmic solutions included allergic reactions, corneal oedema, iritis, ocular inflammation, ocular irritation, superficial keratitis and superficial ocular infections.

Other adverse events reported rarely with the use of ketorolac tromethamine include: corneal infiltrates, corneal ulcer, eye dryness, headaches, and visual disturbance (blurry vision).

Post-marketing Experience

The following adverse reactions have been identified during post-marketing use of ketorolac tromethamine ophthalmic solution 0.5% in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to topical ketorolac tromethamine 0.5%, or a combination of these factors, include bronchospasm or exacerbation of asthma, corneal erosion, corneal perforation, corneal thinning and epithelial breakdown.

The frequency of adverse reactions documented during clinical trials of ketorolac tromethamine and through post-marketing experience is given below and is defined as follows: 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); Not Known (cannot be estimated from available data).

Immune system disorders

Common: Hypersensitivity including localised allergic reactions

Nervous system disorders

Uncommon: Headache

Eye Disorders

Very common: Eye irritation (including burning sensation), Eye pain (including stinging)

Common: Superficial (punctate) keratitis, eye and/or eyelid oedema, ocular pruritus, conjunctival hyperaemia, eye infection, eye inflammation, iritis, keratic precipitates, retinal haemorrhage, cystoid macular oedema, eye trauma, increased intraocular pressure, blurred and/or diminished vision

Uncommon: Corneal ulcer, corneal infiltrates, eye dryness, epiphora,

Not known: Corneal damage, e.g. thinning, erosion, epithelial breakdown and perforation*, ulcerative keratitis, eye swelling, ocular hyperaemia

Respiratory, thoracic and mediastinal disorders

Not known: Bronchospasm or exacerbation of asthma**

*Occasional post-marketing reports of corneal damage including corneal thinning, corneal erosion, epithelial breakdown and corneal perforation have been received. These occurred mainly in patients using concomitant topical corticosteroids and/or with predisposing co-morbidity.

**There have been post-marketing reports of bronchospasm or exacerbation of asthma, in patients, who have either a known hypersensitivity to aspirin/NSAIDs or a past medical history of asthma, associated with the use of ketorolac which may be contributory.

None of the typical adverse reactions reported with the systemic NSAIDs (including ketorolac) have been observed at the doses used in topical ophthalmic therapy.

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product.

Overdose

No case of overdose has been reported. Overdose is unlikely to occur via the recommended method of administration. If accidentally ingested, drink fluids to dilute.

Pharmacological Properties

Mechanism of Action

Moxifloxacin

Moxifloxacin is a member of the fluoroquinolone class of anti-infective drugs. The antibacterial action of moxifloxacin results from inhibition of the topoisomerase II (DNA gyrase) and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division.

Ketorolac Tromethamine

Ketorolac tromethamine is a non-steroidal anti-inflammatory drug which, when administered systemically, has demonstrated analgesic, anti-inflammatory, and anti-pyretic activity. The mechanism of its action is thought to be due to its ability to inhibit prostaglandin biosynthesis.

Pharmacodynamic properties

Moxifloxacin

The mechanism of action for quinolones, including moxifloxacin, is different from that of macrolides, aminoglycosides, or tetracyclines. Therefore, moxifloxacin may be active against pathogens that are resistant to these antibiotics and these antibiotics may be active against pathogens that are resistant to moxifloxacin. There is no cross-resistance between moxifloxacin and the aforementioned classes of antibiotics. Cross-resistance has been observed between systemic moxifloxacin and some other quinolones.

In vitro resistance to moxifloxacin develops via multiple-step mutations. Resistance to moxifloxacin occurs in vitro at a general frequency of between 1.8 × 10⁻⁹ to < 1 × 10⁻¹¹ for Gram-positive bacteria.

In Gram-negative bacteria, moxifloxacin resistance can be due to mutations in mar (multiple antibiotic resistance) and the qnr (quinolone resistance) gene systems. Resistance is also associated with expression of bacteria efflux proteins and inactivating enzymes. Cross-resistance with beta-lactams, macrolides and aminoglycosides is not expected due to differences in mode of action

Susceptibility Testing Breakpoints

There are no pharmacological data correlated with clinical outcome for moxifloxacin administered as a topical agent. As a result, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) suggests the following epidemiological cut-off values (ECOFF mg/l) derived from MIC distribution curves to indicate susceptibility to topical moxifloxacin.

Corynebacterium	ND
Staphylococcus aureus	0.25 mg/l
Staphylococcus, coagulase-negative	0.25 mg/l
Streptococcus pneumoniae	0.5 mg/l
Streptococcus pyogenes	0.5 mg/l
Streptococcus, viridans group	0.5 mg/l
Enterobacter spp.	0.25 mg/l
Haemophilus influenzae	0.125 mg/l
Klebsiella spp.	0.25 mg/l
Moraxella catarrhalis	0.25 mg/l
Morganella morganii	0.25 mg/l
Neisseria gonorrhoeae	0.032 mg/l
Pseudomonas aeruginosa	4 mg/l
Serratia marcescens	1 mg/l

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of moxifloxacin in at least some types of infections is questionable.

Moxifloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections:

Aerobic Gram-positive microorganisms

Corynebacterium species¹

Micrococcus luteus¹

Staphylococcus aureus (methicillin susceptible)

Staphylococcus epidermidis

Staphylococcus haemolyticus

Staphylococcus hominis

Staphylococcus warneri¹

Streptococcus pneumoniae

Streptococcus viridans group

Aerobic Gram-negative microorganisms

Acinetobacter lwoffii¹

Haemophilus influenzae

Haemophilus parainfluenzae¹

Other microorganisms

Chlamydia trachomatis

¹Efficacy for this organism was studied in fewer than 10 infections.

The following in vitro data are also available, but their clinical significance in ophthalmic infections is unknown. The safety and effectiveness of moxifloxacin ophthalmic solution in treating ophthalmological infections due to these microorganisms have not been established in adequate and well-controlled trials.

The following organisms are considered susceptible when evaluated using systemic breakpoints. However, a correlation between the in vitro systemic breakpoint and ophthalmological efficacy has not been established. The list of organisms is provided as guidance only in assessing the potential treatment of conjunctival infections. Moxifloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 2 microgram/ml or less (systemic susceptible breakpoint) against most (≥ 90%) strains of the following ocular pathogens.

Aerobic Gram-positive microorganisms
Listeria monocytogenes
Staphylococcus saprophyticus
Streptococcus agalactiae
Streptococcus mitis
Streptococcus pyogenes
Streptococcus Group C, G and F

Aerobic Gram-negative microorganisms
Acinetobacter baumannii
Acinetobacter calcoaceticus
Citrobacter freundii
Citrobacter koseri
Enterobacter aerogenes
Enterobacter cloacae
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
Moraxella catarrhalis
Morganella morganii
Neisseria gonorrhoeae
Proteus mirabilis
Proteus vulgaris
Pseudomonas stutzeri

Anaerobic microorganisms
Clostridium perfringens
Fusobacterium species
Prevotella species
Propionibacterium acnes

Other microorganisms
Chlamydia pneumoniae
Legionella pneumophila
Mycobacterium avium
Mycobacterium marinum
Mycoplasma pneumoniae

Species for which acquired resistance may be a problem:

Aerobic Gram-positive microorganisms

Staphylococcus aureus (methicillin resistant)

Staphylococcus, coagulase-negative species (methicillin resistant)

Aerobic Gram-negative microorganisms:

Neisseria gonorrhoeae

Other microorganisms:

None

Inherently resistant organisms include:

Aerobic Gram-negative microorganisms

Pseudomonas aeruginosa

Other microorganisms

None

Ketorolac tromethamine

Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug which, when administered systemically, has demonstrated analgesic, anti-inflammatory, and antipyretic activity. Ketorolac inhibits the cyclo-oxygenase enzyme essential for biosynthesis of prostaglandins. Ketorolac has been shown to reduce prostaglandin levels in the aqueous humour after topical ophthalmic administration.

Ketorolac tromethamine given systemically does not cause pupil constriction. Results from clinical studies indicate that ketorolac tromethamine has no significant effect on intraocular pressure.

Pharmacokinetics Properties

Moxifloxacin

Plasma concentrations of moxifloxacin were measured in healthy adult male and female subjects who received bilateral topical ocular doses of Moxifloxacin three times a day. The mean steady-state C_max (2.7 ng/mL) and estimated daily exposure AUC (45 ng·hr/mL) values were 1,600 and 1,000 times lower than the mean C_max and AUC reported after therapeutic 400 mg oral doses of moxifloxacin. The plasma half-life of moxifloxacin was estimated to be 13 hours.

Ketorolac Tromethamine

Two drops of 0.5% ketorolac tromethamine ophthalmic solution instilled into the eyes of patients 12 hours and 1 hour prior to cataract extraction achieved a mean ketorolac concentration of 95 ng/mL in the aqueous humor of 8 of 9 eyes tested (range 40 to 170 ng/mL).

One drop of 0.5% ketorolac tromethamine ophthalmic solution was instilled into 1 eye and 1 drop of vehicle into the other eye TID in 26 healthy subjects. Five (5) of 26 subjects had detectable concentrations of ketorolac in their plasma (range 11 to 23 ng/mL) at Day 10 during topical ocular treatment. The range of concentrations following TID dosing of 0.5% ketorolac tromethamine ophthalmic solution are approximately 4 to 8% of the steady state mean minimum plasma concentration observed following four times daily oral administration of 10 mg ketorolac in humans (290 ± 70 ng/mL).

a) General Characteristics

Absorption

Rabbit Aqueous Humor Bioavailability
Mean concentration of total radioactivity	0.856 μg-equiv./ml @ 0.5 hr
	1.607 μg-equiv./ml @ 2 hr
Tmax	3.38 hr
Cmax	1.905 μg-equiv./ml
AUC (0-8 hr)	9.39 μg-equiv. hr/ml
Total AUC	13.53 μg-equiv. hr/ml
Half-life	3.77 hr
Absolute ocular bioavailability	3.7%

After topical ocular doses in the rabbit the half life of total radioactivity in aqueous humor was longer than after intracameral injection. This suggests that topical dosing may lead to a "reservoir" effect in the corneal epithelium and continued flux of drug from the reservoir into the aqueous humor.

Distribution

After ophthalmic doses were administered to rabbits, peak concentrations of radioactivity were achieved within 1 hour in the ocular tissues and were highest in the cornea (6.06 mcg-eq/ml). At 1 hour, the majority of the radioactivity (0.9% of administered dose) was recovered from the sclera (0.58%) and cornea (0.24%), and smaller amounts were recovered from the aqueous humor (0.026%), vitreous humor (0.023%), retina-choroid (0.018%), iris-ciliary body (0.007%) and lens (0.002%).

Relative to plasma AUC values, the AUC's in rabbits were higher for cornea (104 fold), sclera (27 fold), iris-ciliary body (5.8 fold), retina-choroid (5.6 fold), aqueous humor (3.3 fold) and approximately one-half in the vitreous humor and lens. After ophthalmic administration, concentrations of drug-related radioactivity were higher in the ocular tissues and lower in plasma compared with those after IV dosing.

Systemic Absorption

After ophthalmic doses in the rabbit, ketorolac was absorbed rapidly into the systemic circulation (T_max, 15 min). Plasma half-lives after ophthalmic doses (6.6 - 6.9 hr) were longer than those after IV administration (1.1 hr), suggesting that removal of drug from eye into the venous circulation may be rate-limiting. By comparison of drug levels in aqueous humor after intracameral injection vs. plasma levels after IV administration, ketorolac was shown to clear more rapidly from plasma (6 ml/min) than from the anterior chamber (11 mcl/min).

In the cynomolgus monkey, peak plasma levels of ketorolac occurred at 1.1 hr after the ophthalmic dose. The plasma half-life of ketorolac was similar after ophthalmic (1.8 hr) and IV doses (1.6 hr). The majority of the ophthalmic dose was excreted in urine (66% in rabbit and 75% in monkey) and a small amount in faeces (11% in rabbit and 2% in monkey). The extent of systemic absorption after ophthalmic dosing averaged 73% in the rabbit and 76% in the cynomolgus monkey.

Metabolism

After ophthalmic administration in rabbits, ketorolac represented the major component (more than 90%) of radioactivity in aqueous humor and plasma and the p-hydroxy metabolite accounted for 5% of radioactivity in plasma. Ketorolac was also the major component (96%) of plasma radioactivity after ophthalmic dosing in monkeys. After ophthalmic dosing in the rabbit, 72%, 17% and 6% of the total radioactivity in urine was comprised of intact ketorolac, p-hydroxy ketorolac and other polar metabolites, respectively. After IV dosing, the relative proportions of total radioactivity in urine averaged 6% as intact ketorolac, 68% as p-hydroxy ketorolac and 22% as polar metabolites. In the monkey, intact ketorolac and its polar metabolite accounted for 32% and 65% of the total radioactivity in urine, respectively, after ophthalmic dosing, and 50% and 49% of the radioactivity in urine, respectively, after IV dosing. Thus, the metabolism of ketorolac was qualitatively similar after ophthalmic and IV administration in the monkey and rabbit.

B) Characteristics In Patients

Ketorolac tromethamine solutions (0.1% or 0.5%) or vehicle were instilled into the eyes of patients approximately 12 hours and 1 hour prior to surgery. Concentrations of ketorolac in aqueous humor sampled at the time of surgery were at the lower limit of detection (40 ng/ml) in 1 patient and below the quantitation limit in 7 patients dosed with 0.1% ketorolac tromethamine. The average aqueous humor level of ketorolac in patients treated with 0.5% ketorolac tromethamine was 95 ng/ml. Concentrations of PGE2 in aqueous humor were 80 pg/ml, 40 pg/ml and 28 pg/ml in patients treated with vehicle, 0.1% ketorolac tromethamine and 0.5% ketorolac tromethamine, respectively.

In the 21-day multiple dose (TID) tolerance study in healthy subjects, only 1 of 13 subjects had a detectable plasma level pre-dose (0.021 μg/ml). In another group of 13 subjects, only 4 subjects showed very low plasma levels of ketorolac (0.011 to 0.023 μg/ml) 15 minutes after the ocular dose. Thus, higher levels of ketorolac in the aqueous humor and very low or no detectable plasma levels after ophthalmic doses, suggest that the use of ketorolac tromethamine by the ophthalmic route in treatment of ocular disorders results in quite low systemic absorption in patients

Non-Clinical Properties

Moxifloxacin

Animal Toxicology or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to determine the carcinogenic potential of moxifloxacin have not been performed. However, in an accelerated study with initiators and promoters, moxifloxacin was not carcinogenic in rats following up to 38 weeks of oral dosing at 500 mg/kg/day (approximately 21,700 times the highest recommended total daily human ophthalmic dose for a 50 kg person, on a mg/kg basis). Moxifloxacin was not mutagenic in four bacterial strains used in the Ames Salmonella reversion assay. As with other quinolones, the positive response observed with moxifloxacin in strain TA 102 using the same assay may be due to the inhibition of DNA gyrase. Moxifloxacin was not mutagenic in the CHO/HGPRT mammalian cell gene mutation assay. An equivocal result was obtained in the same assay when v79 cells were used. Moxifloxacin was clastogenic in the v79 chromosome aberration assay, but it did not induce unscheduled DNA synthesis in cultured rat hepatocytes. There was no evidence of genotoxicity in vivo in a micronucleus test or a dominant lethal test in mice. Moxifloxacin had no effect on fertility in male and female rats at oral doses as high as 500 mg/kg/day, approximately 21,700 times the highest recommended total daily human ophthalmic dose. At 500 mg/kg orally there were slight effects on sperm morphology (head-tail separation) in male rats and on the estrous cycle in female rats

Ketorolac Tromethamine

Carcinogenesis , Mutagenesis, Impairment of Fertility

Ketorolac tromethamine was not carcinogenic in either rats given up to 5 mg/kg/day orally for 24 months or in mice given 2 mg/kg/day orally for 18 months. These doses are approximately 125 times and 50 times higher respectively than the maximum recommended human topical ophthalmic daily dose given as QID for itching to affected eyes on a mg/kg basis.

Ketorolac tromethamine was not mutagenic in vitro in the Ames assay or in forward mutation assays. Similarly, it did not result in an in vitro increase in unscheduled DNA synthesis or an in vivo increase in chromosome breakage in mice. However, ketorolac tromethamine did result in an increased incidence in chromosomal aberrations in Chinese hamster ovary cells. Ketorolac tromethamine did not impair fertility when administered orally to male and female rats at doses up to 9 mg/kg/day and 16 mg/kg/day, respectively. These doses respectively 225 and 400 times higher than the typical human topical ophthalmic daily dose.

Pre-clinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Acute, sub-acute and chronic studies of ketorolac tromethamine in experimental animals have established the safety of the drug. In addition, octoxinol 40 was separately evaluated for its ocular safety. Ketorolac tromethamine was found to be non-irritating, it did not demonstrate a local anaesthetic effect, it did not influence the healing of experimental corneal wounds in rabbits, it did not enhance the spread of experimental ocular infections of Candida albicans, Herpes simplex virus type one, or Pseudomonas aeruginosa in rabbits, and it did not increase the ocular pressure of normal rabbit eyes.

Description

MOXICIP KT ophthalmic solution is a topical sterile multidose combination of nonsteroidal anti-inflammatory drug (NSAID) and antibiotic for ophthalmic use.

MOXICIP KT ophthalmic solution contains moxifloxacin hydrochloride 0.5% w/v and ketorolac tromethamine 0.5% w/v. Moxifloxacin hydrochloride is an 8-methoxy fluoroquinolone anti-infective, with a diazabicyclononyl ring at the C7 position. Chemical Name: 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-pyridin-6-yl]-4-oxo-3-quinoline carboxylic acid, monohydrochloride.

Ketorolac tromethamine is a member of the pyrrolo-pyrrole group of NSAIDs for ophthalmic use. Its chemical name is (±)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1) and it has the following structure:

 

Pharmaceutical Particulars

Incompatibilities

Not applicable.

Packaging Information

MOXICIP KT eye drops: Vial of 5ml

Storage and Handling Instructions

Store in a cool dry place. Protect from light.

Patient Counselling Information

Avoid Contamination of the Product

Advise patients not to touch the dropper tip to any surface to avoid contaminating the contents. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

To avoid the potential for cross-contamination, the patient should be advised to use one bottle for each eye following bilateral ocular surgery. The use of the same bottle of topical eye drops for both eyes following bilateral ocular surgery is not recommended.

Contact Lens Wear

Patients should be advised that MOXICIP KT ophthalmic solution should not be administered while wearing contact lenses.

Potential for Hypersensitivity Reactions

Systemically administered quinolones including moxifloxacin have been associated with hypersensitivity reactions, even following a single dose. Instruct patients to discontinue use immediately and contact their physician at the first sign of a rash or allergic reaction.

Slow or Delayed Healing

Patients should be informed of the possibility that slow or delayed healing may occur while using NSAIDs.

Intercurrent Ocular Conditions

Patients should be advised that if they develop an intercurrent ocular condition (e.g., trauma or infection) or have ocular surgery, they should immediately seek their physician's advice concerning the continued use of this product

Concomitant Topical Ocular Therapy

Patients should be advised that if more than one topical ophthalmic medication is being used, the medicines should be administered at least 5 minutes apart.

Details of Manufacturer

Manufactured by CIPLA Ltd.

E-65/66 MIDC, Solapur- 413006, India.

Details of Permission or Licence Number with Date

28A-PD/3280-A and 18/04/2018

Date of Revision

October 2019