Qualitative and Quantitative Composition

Each gm contains:

Moxifloxacin Hydrochloride equivalent to Moxifloxacin……… 5mg

Dosage Form and Strength

Eye ointment of moxifloxacin 0.5%

Clinical Particulars

Therapeutic Indications

Moxifloxacin ophthalmic ointment is indicated for the treatment of bacterial conjunctivitis caused by susceptible organisms.

Posology and Method of Administration

The recommended dosage regimen for the treatment of bacterial conjunctivitis is: Apply half-inch ribbon three times a day on the first two days. For the next five days apply half-inch ribbon two times a day.

Contraindications

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

Special Warnings and Precautions for Use

Topical Ophthalmic Use Only

MOXICIP ophthalmic ointment is for topical ophthalmic use only.

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 edema), 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.

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 administration of moxifloxacin 0.5% ophthalmic ointment, plasma concentrations of moxifloxacin are much lower than after therapeutic oral doses of moxifloxacin, however, caution should be exercised and treatment with moxifloxacin 0.5% ophthalmic ointment should be discontinued at the first sign of tendon inflammation.

Avoid Empirical Treatment of Gonococcal Conjunctivitis

Moxifloxacin 0.5% ophthalmic ointment 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.

Drug Interactions

Drug-drug interaction studies have not been conducted with MOXICIP ophthalmic ointment. 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.

Use in Special Population

Pregnant Women

Pregnancy Category C

Teratogenic Effects: Moxifloxacin was not teratogenic when administered to pregnant rats during organogenesis at oral doses as high as 500 mg/kg/day (approximately 21,700 times the highest recommended total daily human ophthalmic dose); however, decreased fetal body weights and slightly delayed fetal skeletal development were observed. There was no evidence of teratogenicity when pregnant Cynomolgus monkeys were given oral doses as high as 100 mg/kg/day (approximately 4,300 times the highest recommended total daily human ophthalmic dose). An increased incidence of smaller fetuses was observed at 100 mg/kg/day.

Since there are no adequate and well-controlled studies in pregnant women, MOXICIP ophthalmic ointment should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactating Women

Moxifloxacin has not been measured in human milk, although it can be presumed to be excreted in human milk.  Caution should be exercised when MOXICIP ophthalmic ointment is administered to a nursing mother.

Pediatric Patients

The safety and effectiveness of moxifloxacin in infants below 1 year of age 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 and effectiveness have been observed between elderly and younger patients.

Effects on Ability to Drive and Use Machines

Moxifloxacin has no or negligible influence on the ability to drive and use machines, however, as with any eye drops or eye ointment, 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.

The most frequently reported ocular adverse events were conjunctivitis, decreased visual acuity, dry eye, keratitis, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, subconjunctival hemorrhage, 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.

Summary of the Safety Profile

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 3 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.

Tabulated summary of adverse reactions

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	hemoglobin 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 hemorrhage, ocular hyperemia, eye pruritus, eyelid edema, ocular discomfort, corneal epithelium defect, corneal disorder, conjunctivitis, blepharitis, eye swelling, conjunctival edema, 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 edema, photophobia, eyelid edema, 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) dyspnea
Gastrointestional 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

Description of Selected Adverse Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following first dose, have been reported in patients receiving systemic quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial oedema), airway obstruction, dyspnoea, urticaria and itching.

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

Pediatric Population

In clinical trials, topical moxifloxacin 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 paediatric patients, including neonates, the type and severity of adverse reactions in the paediatric population are similar to those in adults.

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

The limited holding capacity of the conjunctival sac for ophthalmic products practically precludes any overdosing of the medicinal product.

The total amount of moxifloxacin in a single container is too small to induce adverse effects after accidental ingestion.

Pharmacological Properties

Mechanism of Action

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.

Pharmacodynamic Properties

Resistance

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:

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 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

Clinical Studies

In two randomized, double-masked, multicenter, controlled clinical trials in which patients were dosed 3 times a day for 4 days, moxifloxacin 0.5% ophthalmic solution produced clinical cures on day 5-6 in 66% to 69% of patients treated for bacterial conjunctivitis. Microbiological success rates for the eradication of baseline pathogens ranged from 84% to 94%.

In a randomized, double-masked, multicenter, parallel-group clinical trial of pediatric patients with bacterial conjunctivitis between birth and 31 days of age, patients were dosed with moxifloxacin 0.5% ophthalmic solution or another anti-infective agent. Clinical outcomes for the trial demonstrated a clinical cure rate of 80% at Day 9 and a microbiological eradication success rate of 92% at Day 9.

Please note that microbiologic eradication does not always correlate with clinical outcome in anti-infective trials.

Pharmacokinetic Properties

Plasma concentrations of moxifloxacin were measured in healthy adult male and female subjects who received bilateral topical ocular doses of moxifloxacin ophthalmic solution 3 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.

Nonclinical Properties

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.

Description

MOXICIP (moxifloxacin ophthalmic ointment) 0.5% is a sterile ointment for topical ophthalmic use. 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-[(4aS,7aS)-octahydro-6H-pyrrolol[3,4b]pyridin-6-yl]-4-oxo-3-quinoline carboxylic acid, monohydrochloride.

Pharmaceutical Particulars

Incompatibilities

Not applicable

Shelf-life

As on the pack

Packaging Information

MOXICIP Eye Ointment: Tube of 5 gm

Storage and Handling Instructions

Store in a cool place.

Patient Counselling Information

Risk of Contamination

Advise patients not to touch the applicator tip to any surface to avoid contaminating the contents.

Concomitant Use of Contact Lens

Advise patients not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis.

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.

Details of Manufacturer

Manufactured by CIPLA Ltd.

T-68, M.I.D.C, Tarapur, Boisar, Dist. Palghar-401502

Details of Permission Or Licence Number With Date

Permission number and date of issue: MF-6384/06

Date of Revision

October 2019