For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Gatifloxacin Eye Drops 0.3% w/v

GATIQUIN Eye Drops

Qualitative and Quantitative Composition

Each ml contains:

Gatifloxacin……………….. 0.3% w/v

Benzalkonium chloride IP… 0.005% w/v

(As preservative)

Aqueous vehicle….q.s

Dosage Form and Strength

Ophthalmic solution of Gatifloxacin 0.3% w/v

Clinical Particulars

Therapeutic Indications

Gatifloxacin ophthalmic solution 0.3% w/v is indicated for the treatment of bacterial conjunctivitis caused by susceptible strains of the following organisms:

Aerobic Gram-Positive Bacteria

Corynebacterium propinquum*

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus mitis group*

Streptococcus pneumoniae

Aerobic Gram-Negative Bacteria:

Haemophilus influenzae

* Efficacy for these organisms were studied in fewer than 10 infections

 

Posology and Method of Administration

The recommended dosage regimen is:

Days 1 and 2: Instil one drop every two hours in the affected eye(s) while awake, up to eight times daily.

Days 3 through 7: Instil one drop up to four times daily while awake.

Contraindications

Gatifloxacin ophthalmic solution is contraindicated in patients with a history of hypersensitivity to gatifloxacin, to other quinolones or to any of the components in this medication.

Special Warnings and Precautions for Use

NOT SUITABLE FOR INJECTION. FOR TOPICAL OPHTHALMIC USE ONLY.

Gatifloxacin ophthalmic solution should not be injected sub-conjunctivally, nor should it be introduced directly in the anterior chamber of the eye. Gatifloxacin ophthalmic solution may cause corneal endothelial cell injury if introduced directly into the anterior chamber of the eye.

Hypersensitivity

In patients receiving systemic quinolones, including gatifloxacin, serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial oedema), airway obstruction, dyspnea, urticaria, and itching. Patients receiving topical gatifloxacin have experienced hypersensitivity reactions including anaphylactic reactions, angioedema (including pharyngeal, laryngeal, or facial edema), dyspnea, urticaria, and itching, even following a single dose. There have been reports of Steven-Johnson syndrome and anaphylactic reaction reported in associated with topical gatifloxacin use. If an allergic reaction to gatifloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment. Oxygen and airway management should be administered as clinically indicated.

As with all antibiotics, serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have been reported in patients receiving systemic quinolone therapy. These events may be severe and generally occur following administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome); vasculitis, arthralgia, myalgia, serum sickness; allergic pneumonitis, interstitial nephritis; acute renal insufficiency or failure; hepatitis, jaundice, acute hepatic necrosis or failure; anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

As with all topical ophthalmic drugs, there is a potential for a systemic reaction. Urticaria has been reported in patients receiving Gatifloxacin ophthalmic solution.

Growth of Resistant Organisms with Prolonged Use

As with other anti-infectives, prolonged use of Gatifloxacin ophthalmic solution may result in the overgrowth of non-susceptible organisms, including fungi. If super-infection 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.

Use with Contact Lenses

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

Arthropathy

As with other members of the quinolone class, gatifloxacin has caused arthropathy and/or chondrodysplasia in juvenile rats and dogs when given systemically. Arthrotoxic and osteotoxic potential of Gatifloxacin ophthalmic solution was not assessed in animals.

Drug Interactions

Specific drug interaction studies have not been conducted with gatifloxacin 0.3% ophthalmic solution. Limited information is available on the concurrent use of gatifloxacin 0.3% ophthalmic solution with other ophthalmic products. However, the systemic administration of some quinolones has been shown to elevate plasma concentrations of theophylline, interfere with the metabolism of caffeine, and enhance the effects of the oral anti-coagulant warfarin and its derivatives, and has been associated with transient elevations in serum creatinine in patients receiving systemic cyclosporine concomitantly.

Use in Special Population

Pregnant Women

Risk Summary

Because there are no adequate and well-controlled studies in pregnant women, gatifloxacin 0.3% ophthalmic solution should not be used during pregnancy. This drug should not be used in pregnant women unless, in the physician’s opinion, the potential benefit to the mother justifies the potential risk to the fetus.

Oral and intravenous studies in pregnant animals indicate that gatifloxacin crosses the placenta and that reproductive and fetal effects occur at doses of 150 mg/kg/day, which cause maternal toxicity. Administration of oral gatifloxacin to pregnant rats and rabbits throughout organogenesis did not produce adverse development outcomes at clinically relevant doses. Administration of gatifloxacin to rats during late gestation through lactation did not produce adverse maternal, fetal or neonatal effects at clinically relevant doses.

Data

Animal Data

Oral administration of gatifloxacin to pregnant rats throughout organogenesis produced teratogenic effects in rat fetuses, including skeletal/craniofacial malformations, delayed ossification, atrial enlargement, and reduced fetal weight, at doses greater than or equal to 150 mg/kg/day (approximately 1010-fold higher than the maximum recommended human ophthalmic dose [MRHOD] for gatifloxacin 0.3% ophthalmic solution of 0.024 mg/kg/day, on a mg/m² basis). No teratogenic effects were observed in rat or rabbit fetuses at doses of gatifloxacin up to 50 mg/kg/day (approximately 335- and 675-fold higher than the MRHOD, respectively, on a mg/m² basis).

In a perinatal/postnatal study in rats, oral administration of gatifloxacin during late gestation through lactation produced an increase in late gestation fetal loss and neonatal/perinatal mortality at 200 mg/kg/day (approximately 1350-fold higher than the MRHOD on a mg/m² basis).

Lactating Women

Risk Summary

There is no information regarding the presence of gatifloxacin 0.3% ophthalmic solution in human milk, the effect of gatifloxacin on breastfed infants, or the effect of gatifloxacin on milk production. Gatifloxacin was found in the breast milk of rats following oral administration of gatifloxacin during lactation. However, systemic levels of gatifloxacin following topical ocular administration are low, and it is not known whether gatifloxacin would be present in maternal milk at measurable levels following topical ocular administration. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for gatifloxacin 0.3% ophthalmic solution and any potential adverse effects on the breastfed child from gatifloxacin 0.3% ophthalmic solution. Gatifloxacin 0.3% ophthalmic solution should not be used by nursing mothers.

Pediatric Patients

Safety and effectiveness in infants below the age of one year have not been established.

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

If transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machinery.

Undesirable Effects

Clinical Studies Experience

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

In clinical studies with gatifloxacin 0.3% ophthalmic solution, the most frequently reported adverse events in the overall study population were conjunctival irritation, increased lacrimation, keratitis and papillary conjunctivitis. These events occurred in approximately 5%–10% of patients. Other reported reactions occurring in 1%–4% of patients were chemosis, conjunctival hemorrhage, dry eye, eye discharge, eye irritation, eye pain, eyelid edema, headache, red eye, reduced visual acuity, and taste disturbance.

An additional adverse reaction reported with gatifloxacin ophthalmic solution in other clinical studies includes worsening of the conjunctivitis.

For each indication the frequency of adverse reactions arising from clinical experience is given as follows: Very common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1000, <1/100); Rare (≥1/10000, <1/1000); Very rare (<1/10000).

Eye Disorders

Very common: Conjunctivitis NEC¹

Common: Punctate keratitis, papillary conjunctivitis, increased lacrimation, conjunctival

disorder NOS², eyelid edema, reduced visual acuity, red eye, eye irritation, eye pain, eye discharge, dry eye NEC¹, conjunctival hemorrhage.

Uncommon: Chemosis

Skin and Subcutaneous Tissue Disorders

Common: Erythema NEC¹

Uncommon: Contact dermatitis

Gastrointestinal Disorders

Common: Taste disturbance

Nervous System Disorders

Common: Headache NOS²

¹ NEC = not elsewhere classified

² NOS = not otherwise specified

In clinical studies, 364 patients were treated with gatifloxacin ophthalmic solution 0.3% for up to 5 days. Treatment-related adverse events were reported for 14.6% (53/364) of patients. The most frequently reported treatment-related adverse events occurring in 0.5% to 5% of patients treated with gatifloxacin are listed below:

Table 1: Percent of Patients in Phase 3 Trials with Treatment-Related Adverse Events Reported by 0.5% to 5% of Patients in the Active Treatment Arm

Body System Preferred Term	Gatifloxacin N = 364
Ocular
Superficial punctate keratitis	4.4%
Eye irritation	1.9%
Dry eye	1.6%
Eyelid edema	1.4%
Lacrimation increased	1.4%
Visual acuity reduced	1.1%
Eye pain	0.8%
Conjunctivitis papillary	0.8%
Eye discharge	0.5%
Other (non-ocular)
Erythema	0.8%
Dermatitis, contact	0.5%
Taste disturbance	1.4%
Rhinorrhoea	0.5%
Edema	0.5%

 

Other treatment-related adverse events occurring in less than 0.5% of patients included, conjunctival disorder, conjunctivitis, chemosis, conjunctival cyst, conjunctival hemorrhage, corneal deposits, eye disorder, photophobia, subepithelial opacities, blurred vision, dermatitis, generalized urticaria, nausea, sore throat, sneezing, dizziness, and iritis.

Gatifloxacin 0.3% ophthalmic solution was discontinued due to an adverse event, either related or unrelated to the drug, in 1.6% (6/364) of patients.

Post-marketing Experience

The following adverse reactions have been identified during post-approval use of gatifloxacin ophthalmic solution 0.3%. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions include: anaphylactic reactions and angioedema (including pharyngeal, oral or facial edema), blepharitis, dyspnea, eye pruritus, eye swelling (including corneal and conjunctival edema), hypersensitivity, nausea, pruritus (including pruritus generalized), rash, urticaria, vision blurred, conjunctival/ocular hyperemia, eye irritation, eye pain, macular edema, eye redness, eyelid edema, keratoconjunctivitis, allergic, endophthalmitis, corneal disorder, uveitis, corneal ulcer, allergic reactions including pruritis and angioneurotic edema and neurological events including headache, tinnitus, tremor and oral parasthesia. Rare cases of corneal melts and perforation have been reported in patients with multiple confounding factors including pre-existing large corneal ulcer, corneal thinning, undiagnosed dacryocystitis, and use of multiple topical medications. Thus, it is difficult to determine the relationship of the events to gatifloxacin 0.3% ophthalmic solution.

In one case, an elderly female with chronic conjunctivitis due to methicillin-resistant Staphylococcus aureus and a history of dacrocystitis, reported corneal perforation. This patient was using multiple concomitant antibiotics and had demonstrated evidence of a corneal defect associated with the infection prior to using gatifloxacin 0.3% ophthalmic solution and continued using gatifloxacin 0.3% ophthalmic solution during a successful post-operative repair healing period.

If your patients experience any side effects, you can 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

Topical overdosage of gatifloxacin 0.3% ophthalmic solution is considered to be a remote possibility. Discontinue medication when heavy or protracted use is suspected. A topical overdosage may be flushed from the eye(s) with warm tap water.

Pharmacological Properties

Mechanism of Action

Gatifloxacin, quinolone antimicrobial drug, is an an 8-methoxyfluoroquinolone with a 3-methylpiperazinyl substituent at C7. The antibacterial action of gatifloxacin results from inhibition of 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

The mechanism of action of fluoroquinolones, including gatifloxacin, is different from that of aminoglycoside, macrolide, and tetracycline antibiotics. Therefore, gatifloxacin may be active against pathogens that are resistant to these antibiotics and these antibiotics may be active against pathogens that are resistant to gatifloxacin. There is no cross-resistance between gatifloxacin and the aforementioned classes of antibiotics. Cross-resistance has been observed between systemic gatifloxacin and some other fluoroquinolones.

Resistance to gatifloxacin in vitro develops via multiple-step mutations. Resistance to gatifloxacin in vitro occurs at a general frequency of between 1 × 10^-7 to 10^-10. The most common reported species showing resistance are methicillin resistant Staphylococcus aureus (0%-54%), Pseudomonas aeruginosa (0%-13%), Enterobacteriaceae (0%-3,4%) and coagulase negative Staphylococci sp. (0%-8 %).

Gatifloxacin has been shown to be active against most strains of the following organisms both in vitro and clinically, in conjunctival infections as described in indication section. In vitro activity does not necessarily imply in vivo activity.

Aerobes, Gram-Positive
Corynebacterium propinquum*
Staphylococcus aureus (variable sensitivity)
Staphylococcus epidermidis
Streptococcus mitis*
Streptococcus pneumoniae

Aerobes, Gram-Negative
Haemophilus influenzae

*Efficacy for this organism was studied in fewer than ten infections.

The following in vitro data are available, but their clinical significance in ophthalmic infections is unknown.

The safety and effectiveness of gatifloxacin 0.3% ophthalmic solution in treating ophthalmic infections due to the following organisms has not been established in adequate and well-controlled clinical 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 following list of organisms is provided as guidance only in assessing the potential treatment of conjunctival infections. Gatifloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 2 μg/mL or less (systemic susceptible breakpoint) against most (≥ 90%) strains of the following ocular pathogens:

Aerobes, Gram-Positive
Listeria monocytogenes
Staphylococcus saprophyticus
Streptococcus agalactiae
Streptococcus pyogenes
Streptococcus viridans Group
Streptococcus Groups C, F, G

Aerobes, Gram-Negative
Acinetobacter lwoffii
Enterobacter aerogenes
Enterobacter cloacae
Escherichia coli
Citrobacter freundii
Citrobacter koseri
Haemophilus parainfluenzae
Klebsiella oxytoca
Klebsiella pneumoniae
Moraxella catarrhalis
Morganella morganii
Neisseria gonorrhoeae
Neisseria meningitidis
Proteus mirabilis
Proteus vulgaris
Serratia marcescens
Vibrio cholerae
Yersinia enterocolitica

Other Microorganisms
Chlamydia pneumoniae
Legionella pneumophila
Mycobacterium marinum
Mycobacterium fortuitum
Mycoplasma pneumonia

Anaerobic Microorganisms
Bacteroides fragilis
Clostridium perfringens

Clinical Studies

In a randomized, double-masked, multicentre clinical trial, where patients were dosed for 5 days, gatifloxacin 0.3% ophthalmic solution was superior to its vehicle on days 5–7 in patients with conjunctivitis and positive conjunctival cultures. Clinical outcomes for the trial demonstrated clinical cure of 77% (40/52) for the gatifloxacin-treated group versus 58% (28/48) for the placebo-treated group. Microbiological outcomes for the same clinical trial demonstrated a statistically superior eradication rate for causative pathogens of 92% (48/52) for gatifloxacin versus 72% (34/48) for placebo. Please note that microbiological eradication does not always correlate with clinical outcome in anti-infective trials.

In a randomized, double-masked, multicenter clinical trial of pediatric patients with bacterial conjunctivitis between birth and 31 days of age, patients were dosed with gatifloxacin 0.3% ophthalmic solution or another anti-infective agent for 7 days. Clinical outcomes for the trial demonstrated clinical cure of 79% (44/56) for the gatifloxacin-treated group.

Pharmacokinetic Properties

Gatifloxacin ophthalmic solution 0.3% or 0.5% was administered to one eye of 6 healthy male subjects, each in an escalated dosing regimen starting with a single two-drop dose, then two drops four times daily for 7 days, and finally two drops eight times daily for 3 days. At all-time points, serum gatifloxacin levels were below the lower limit of quantification (5 ng/mL) in all subjects.

Nonclinical Properties

Animal Toxicology or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

There was no increase in neoplasms among B6C3F1 mice given gatifloxacin in the diet for 18 months at doses averaging 81 mg/kg/day in males and 90 mg/kg/day in females. These doses are approximately 290-fold higher than the maximum recommended human ophthalmic dose (MRHOD) of 0.024 mg/kg/day gatifloxacin 0.3% ophthalmic solution in a 60 kg human (on a mg/m² basis).

A statistically significant increase in the incidence of large granular lymphocyte (LGL) leukemia was seen in male rats treated with 100 mg/kg/day (approximately 675-fold higher than the MRHOD, on a mg/m² basis). Fischer 344 rats have a high spontaneous background rate of LGL leukemia and the incidence in high-dose males only slightly exceeded the historical control range established for this strain. There was no increase in neoplasms among Fischer 344 rats given gatifloxacin in the diet for 2 years at doses averaging 47 mg/kg/day in males and 139 mg/kg/day in females (approximately 315-fold and 935-foldhigher, respectively, than the MRHOD, on a mg/m² basis).  

Mutagenesis

In genetic toxicity tests, gatifloxacin was positive in 1 of 5 strains used in bacterial reverse mutation assays; Salmonella strain TA102. Gatifloxacin was positive in in vitro mammalian cell mutation and chromosome aberration assays. Gatifloxacin was positive in in vitro unscheduled DNA synthesis in rat hepatocytes but not human leukocytes. Gatifloxacin was negative in in vivo micronucleus tests in mice, cytogenetics test in rats, and DNA repair test in rats. The genotoxic findings are similar to findings obtained with other quinolones and may be due to the pharmacologic inhibitory effects of high concentrations of gatifloxacin on eukaryotic type II DNA topoisomerase.

Impairment of Fertility

There were no adverse effects on fertility or reproduction in rats given gatifloxacin orally at doses up to 200 mg/kg/day (approximately 1350-fold higher than the MRHOD, on a mg/m² basis).

Description

GATIQUIN is a quinolone antimicrobial topical ophthalmic solution of gatifloxacin for the treatment of bacterial conjunctivitis. Its chemical name is (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3quinolinecarboxylic acid, sesquihydrate. Its molecular formula is C₁₉H₂₂FN₃O₄ · 1.5 H₂O, and its molecular weight is 402.42. Its chemical structure is:

Pharmaceutical Particulars

Incompatibility

Data not available.

Shelf-Life

As on the pack.

Packaging Information

GATIQUIN Eye Drops: 5 ml FFS vial

Storage and Handling Instructions

Store below 30°C, in a dark place.

Patient Counselling Information

Avoiding Contamination of the Product

Advise patients to avoid contaminating the applicator tip with material from the eye, fingers or other source.

Potential for Hypersensitivity Reactions

Advise patients to discontinue use immediately and contact your physician at the first sign of a rash or allergic reaction.

Details of Manufacturer

Manufactured by Aditi Pharmaceuticals Pvt. Ltd.

E- 65/66, M.I.D.C., Solapur – 413006

Marketed By Cipla Ltd.

Registered Office:

Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai – 400 013, India.

Details of Permission or Licence Number with Date

M.L. 904 dated 16.11.1987

Date of Revision

13.06.2023