CIPLOX-D Eye/Ear Drops (Ciprofloxacin + Dexamethasone sodium )

Table of Content

Qualitative and Quantitative Composition

CIPLOX-D Eye/Ear Drops

Ciprofloxacin HCL IP equivalent to ciprofloxacin IP…...............................................0.3% w/v
Dexamethasone Sodium Phosphate IP equivalent to Dexamethasone……….........0.1% w/v

Benzalkonium Chloride NF…...................................................................................0.01% w/v

Sterile aqueous vehicle …........................................................................................q.s.

Dosage Form(S) and Strength(S)

Ciprofloxacin (0.3% w/v) and Dexamethasone (0.1% w/v) eye/ear drops

Clinical Particulars

Therapeutic Indications

For Ophthalmic use

CIPLOX-D Eye/Ear Drops are indicated for the treatment of post-operative inflammatory conditions of the eyes.

For Otic use

Acute Otitis Media (AOM) with tympanostomy tubes due to Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Pseudomonas aeruginosa.

Acute Otitis Externa (AOE), due to Staphylococcus aureus and Pseudomonas aeruginosa.

Posology and Method of Administration

For Ophthalmic use

One or two drops of CIPLOX-D Eye/Ear Drops to be instilled into the conjunctival sac every 4–6 hours.

For Otic use

CIPLOX-D Eye/Ear Drops to be Instilled four drops into the affected ear twice daily, for seven days.

Contraindications

  • A history of hypersensitivity to ciprofloxacin, dexamethasone or any other component of the medication is a contraindication to its use.
  • A history of hypersensitivity to other quinolones may also contraindicate the use of ciprofloxacin.
  • Use is contraindicated in herpes simplex and other viral diseases of the cornea and conjunctiva, fungal disease, ocular tuberculosis, untreated purulent infections, patients with a history of acute epithelial herpes simplex keratitis or hypersensitivity to any component of the preparation.
  • Use is contraindicated in viral infections of the external canal, including herpes simplex infections and fungal otic infections.

Special Warnings and Precaution for Use

General

NOT FOR INJECTION INTO THE EYE.

FOR TOPICAL USE ONLY.

The clinical experience in children less than 1 year old, particularly in neonates, is very limited. The use of CIPLOX D Eye/Ear Drops in neonates with ophthalmia neonatorum of gonococcal or chalamydial origin is not recommended as it has not been evaluated in such patients. Neonates with ophthalmia neonatorum should receive appropriate treatment for their condition.

When using CIPLOX D Eye/Ear Drops one should take into account the risk of rhinopharyngeal passage, which can contribute to the occurrence and the diffusion of bacterial resistance.

Serious, and occasionally fatal, hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial oedema, dyspnoea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions.

Serious acute anaphylactic reactions require immediate emergency treatment with epinephrine and other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.

CIPLOX D Eye/Ear Drops should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

As with all antibacterial preparations, prolonged use may lead to overgrowth of non-susceptible bacterial strains or fungi. If superinfection occurs, appropriate therapy should be initiated.

Remove contact lenses before using. During therapy, soft contact lenses should not be worn.

Ciprofloxacin

As with other antibacterial preparations, prolonged use of ciprofloxacin may result in overgrowth of non-susceptible organisms, including fungi. If super-infection occurs, appropriate therapy should be initiated. Whenever clinical judgement dictates, the patient should be examined with the aid of magnification, such as slit-lamp
biomicroscopy and, where appropriate, fluorescein staining.

Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity reaction.

In clinical studies of patients with bacterial corneal ulcers, a white crystalline precipitate located in the superficial portion of the corneal defect was observed in 35 (16.6%) of 210 patients. The onset of the precipitate was within 24 hours to 7 days after starting therapy. In 1 patient, the precipitate was immediately irrigated out upon its appearance. In 17 patients, resolution of the precipitate was seen in 1–8 days (in 7 days if treated within the first 24–72 hours). In 5 patients, resolution was noted in 10–13 days. In 9 patients, exact resolution days were unavailable; however, at follow-up examinations, 18–44 days after onset of the event, complete resolution of the precipitate was noted. In 3 patients, outcome information was unavailable. The precipitate did not preclude continued use of ciprofloxacin, nor did it adversely affect the clinical course of the ulcer or visual outcome.

Tendon inflammation and rupture may occur with systemic fluoroquinolone therapy, including ciprofloxacin, particularly in elderly patients and those treated concurrently with corticosteroids. Therefore, treatment with ciprofloxacin eye/ear drops should be discontinued at the first sign of tendon inflammation.

During therapy, soft contact lenses should not be worn. Contact lens wear is not recommended during treatment of an ocular infection. Therefore, patients should be advised not to wear contact lenses during treatment with CIPLOX D Eye/Ear Drops.

Dexamethasone

General

The possibility of persistent fungal infections of the cornea should be considered after prolonged corticosteroid dosing. There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.

Warnings

Prolonged use may result in ocular hypertension and/or glaucoma, with damage to the optic nerve, defects in visual acuity and fields of vision, and posterior subcapsular cataract formation. Prolonged use may suppress the host response and, thus, increase the hazard of secondary ocular infections. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical corticosteroids. In acute purulent conditions of the eye or ear, corticosteroids may mask infection or enhance existing infection. If these products are used for 10 days or longer, intraocular pressure should be routinely monitored even though it may be difficult in children and uncooperative patients.

Employment of corticosteroid medication in the treatment of herpes simplex other than epithelial herpes simplex keratitis, in which it is contraindicated, requires great caution; periodic slit-lamp microscopy is essential.

Hypersensitivity Reactions

CIPLOX D Eye/Ear Drops should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolones. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal, or facial edema), airway obstruction, dyspnea, urticaria, and itching.

Continued or Recurrent Otorrhea

If otorrhea persists after a full course of therapy, or if two or more episodes of otorrhea occur within six months, further evaluation is recommended to exclude an underlying condition such as cholesteatoma, foreign body, or a tumor.

Drug Interactions

Specific drug interaction studies have not been conducted with ciprofloxacin and dexamethasone eye/ear drops. However, the systemic administration of some quinolones has been shown to elevate plasma concentrations of theophylline, interfere with the metabolism of caffeine, enhance the effects of the oral anticoagulant, warfarin and its derivatives, and has been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly.

Use in Special Populations

Pregnancy

Category C

Reproduction studies have been performed in rats and mice at doses up to 6 times the usual daily human oral dose and have revealed no evidence of impaired fertility or harm to the foetus due to ciprofloxacin. In rabbits, as with most antimicrobial agents, ciprofloxacin (30 and 100 mg/kg orally) produced gastrointestinal disturbances resulting in maternal weight loss and an increased incidence of abortion. No teratogenicity was observed at either dose. After intravenous administration, at doses up to 20 mg/kg, no maternal toxicity was produced and no embryotoxicity or teratogenicity was observed.

There are no adequate and well-controlled studies in pregnant women. CIPLOX D Eye/Ear Drops should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Dexamethasone has been shown to be teratogenic in mice and rabbits following topical ophthalmic application in multiples of the therapeutic dose. In the mouse, corticosteroids produce foetal resorptions and a specific abnormality, cleft palate. In the rabbit, corticosteroids have produced foetal resorptions and multiple abnormalities involving the head, ears, limbs, palate, etc.

There are no adequate or well-controlled studies in pregnant women. Dexamethasone sodium phosphate eye/ear drops should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the embryo or foetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be observed carefully for signs of hypoadrenalism.

Lactating Women

It is not known whether topically applied ciprofloxacin is excreted in human milk; however, it is known that orally administered ciprofloxacin is excreted in the milk of lactating rats and oral ciprofloxacin has been reported in human breast milk after a single 500 mg dose.

Topically applied steroids are absorbed systemically. Therefore, because of the potential for serious adverse reactions in nursing infants from dexamethasone sodium phosphate, caution should be exercised when CIPLOX D Eye/Ear Drops are administered to a nursing mother. A decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Paediatric Patients

Safety and effectiveness of ciprofloxacin eye/ear drops have been established in all ages. Although ciprofloxacin and other quinolones cause arthropathy in immature animals after oral administration, topical ocular administration of ciprofloxacin to immature animals did not cause any arthropathy and there is no evidence that the administered dosage form has any effect on the weight-bearing joints.

Safety and effectiveness of dexamethasone in paediatric patients have not been established.

Geriatric Patients

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

Fertility

Studies have not been performed in humans to evaluate the effect of topical administration of ciprofloxacin on fertility. Oral administration in animals does not indicate direct harmful effects with respect to fertility.

Effects on Ability to Drive and Use Machines

This product has no or negligible influence on the ability to drive or use machines.

Temporarily blurred vision or other visual disturbances may affect the ability to drive or use machines. If transient blurred vision occurs upon instillation, the patient must wait until the vision clears before driving or using machinery.

Undesirable Effects

Ciprofloxacin

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

The most frequently reported drug-related adverse reaction was local burning and discomfort. In corneal ulcer studies with frequent administration of the drug, white crystalline precipitates were seen in approximately 17% of patients. Other reactions occurring in less than 10% of patients included lid margin crusting, crystals/scales, foreign body sensation, itching, conjunctival hyperaemia, and a bad taste following instillation. Additional events occurring in less than 1% of patients included corneal staining, keratopathy/keratitis, allergic reactions, lid oedema, tearing, photophobia, corneal infiltrates, nausea and decreased vision. Hypersensitivity reactions cannot be excluded.

The adverse reactions listed below 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 <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The adverse reactions have been observed during clinical trials and postmarketing experience.

The following undesirable effects were reported in association with the use of ciprofloxacin eye/ear drops:

System Organ Classification

MedDRA Preferred Term (v. 15.1)

Infections and infestations

Rare: hordeolum, rhinitis

Immune system disorders

Rare: hypersensitivity

Nervous system disorders

Common: dysgeusia
Uncommon: headache
Rare: dizziness

Eye disorders

Common: corneal deposits, ocular discomfort, ocular hyperaemia

 

Uncommon: keratopathy, corneal infiltrates, corneal staining, photophobia, visual acuity reduced, eyelid oedema, blurred vision, eye pain, dry eye, eye swelling, eye pruritus, foreign body sensation in eyes, lacrimation increased, eye discharge, eyelid margin crusting, eyelid exfoliation, conjunctival oedema, erythema of eyelid

 

Rare: ocular toxicity, punctate keratitis, keratitis, conjunctivitis, corneal disorder, corneal epithelium defect, diplopia, hypoaesthesia eye, asthenopia, eye irritation, eye inflammation, conjunctival hyperaemia

Ear and labyrinth disorders

Rare: ear pain

Respiratory, thoracic and mediastinal disorders

Rare: paranasal sinus hypersecretion, rhinitis

Gastrointestinal disorders

Uncommon: nausea

Rare: diarrhoea, abdominal pain

Skin and subcutaneous tissue disorders

Rare: dermatitis

General disorders and administration site conditions

Rare: drug intolerance

Musculoskeletal and connective tissue disorders

Not known: tendon disorder

Investigations

Rare: laboratory test abnormal

Description of Selected Adverse Events

With locally applied fluoroquinolones, (generalised) rash, toxic epidermolysis, dermatitis exfoliative, Stevens-Johnson syndrome and urticaria occur very rarely.

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

In patients with corneal ulcers and frequent administration of the drug, white precipitates have been seen with locally applied fluoroquinolones; (generalised) rash, toxic epidermolysis, dermatitis exfoliative, Stevens-Johnson syndrome and urticaria occur very rarely.

Ruptures of the shoulder, hand, Achilles’ tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving systemic fluoroquinolones. Studies and postmarketing experience with systemic fluoroquinolones indicate that the risk of these ruptures may be increased in patients receiving corticosteroids, especially geriatric patients and in tendons under high stress, including the Achilles’ tendon. To date, clinical and postmarketing data have not demonstrated a clear association between ciprofloxacin eye/ear drops and musculoskeletal and connective tissue adverse reactions.

In isolated cases, blurred vision, decreased visual acuity and medication residue have been observed with ophthalmic ciprofloxacin.

Safety and effectiveness of ciprofloxacin eye/ear drops were determined in 230 children between the ages of 0 and 12 years. No serious adverse drug reaction was reported in this group of patients.

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

Dexamethasone

Glaucoma with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, perforation of the globe have been reported.

Rarely, filtering blebs have been reported when topical steroids have been used following cataract surgery.

Rarely, stinging or burning may occur.

The following undesirable effects 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 <1/1,000), 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.

Endocrine Disorders

  • NOT KNOWN (cannot be estimated from the available data): Cushing's syndrome, adrenal suppression

Ocular disorders

  • VERY COMMON (>1/10): intraocular pressure increased (after 2 weeks of treatment).
  • COMMON (>1/100, <1/10): ocular discomfort after instillation, irritation, burning, eye pruritus and blurred vision. These symptoms are mild and transient with no consequences.
  • UNCOMMON (>1/1,000, <1/100): signs and symptoms of allergic or hypersensitive reactions can occur. The following corticoid specific undesirable effects can occur: delay in healing, risk of posterior subcapsular cataract formation, opportunist infections and glaucoma.
  • VERY RARE (<1/10,000, including isolated reports): conjunctivitis, eyelid oedema, corticoid-induced uveitis, keratitis, corneal thinning, corneal oedema and ulcerations. Cases of corneal calcification have been reported in association with the use of phosphate-containing eye drops in some patients with significantly damaged corneas. Due to the steroid component, in diseases causing thinning of the cornea or sclera, there is a higher risk for perforation, especially after topical long treatments.

General Disorders and Administration Site Conditions

  • UNCOMMON (>1/1,000, <1/100): after long treatment posology, systemic absorption can occur with an inhibition of the adrenal function.

Clinical Trials Experience

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.

In Phases II and III clinical trials, a total of 937 patients were treated with CIPLOX D Eye/Ear Drops. This included 400 patients with acute otitis media with tympanostomy tubes (AOMT) and 537 patients with Acute Otitis Externa (AOE). The reported adverse reactions are listed below:

Acute Otitis Media in Pediatric Patients with Tympanostomy Tubes

The following adverse reactions occurred in 0.5% or more of the patients with non-intact tympanic membranes.

Adverse Reactions Incidence (N =400)

Ear discomfort 3.0%

Ear pain 2.3%

Ear precipitate (residue) 0.5%

Irritability 0.5%

Taste Perversion 0.5%

The following adverse reactions were each reported in a single patient: tympanostomy tube blockage; ear pruritus; tinnitus; oral moniliasis; crying; dizziness; and erythema.

Acute Otitis Externa

The following adverse reactions occurred in 0.4% or more of the patients with intact tympanic membranes.

Adverse Reactions Incidence (N = 537)

Ear pruritus 1.5%

Ear debris 0.6%

Superimposed ear infection 0.6%

Ear congestion 0.4%

Ear pain 0.4%

Erythema 0.4%

The following adverse reactions were each reported in a single patient: ear discomfort; decreased hearing; and ear disorder (tingling).

Post-marketing Experience

The following adverse reactions have been identified during post approval use of

CIPLOX D Eye/Ear Drops. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions include: auricular swelling, headache, hypersensitivity, otorrhea, skin exfoliation, rash erythematous, and vomiting.

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 Programme of India (PvPI) by calling on 1800 267 7779 (Cipla number) or you can report to PvPI on 1800 180 3024. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

A topical overdose of ciprofloxacin dexamethasone eye/ear drops may be flushed from the eye(s) with lukewarm tap water or drops may be wiped away with a clean tissue.

No toxic effects are to be expected with an ear overdose with this product.

Pharmacological Properties

Mechanism of Action

The bactericidal action of ciprofloxacin results from inhibition of the enzyme, DNA gyrase, which is required for the synthesis of bacterial DNA.

Dexamethasone is a highly potent and long-acting glucocorticoid. It has an approximately 7 times greater anti-inflammatory potency than prednisolone, another commonly prescribed corticosteroid.

Pharmacodynamic Properties

Ciprofloxacin: Pharmacotherapeutic Group – Ophthalmologicals, Other Antiinfectives. ATC Code: S01A X13.

Dexamethasone: Pharmacotherapeutic group: Corticosteroids, plain, ATC code: S01 BA01

CIPLOX D Eye/Ear Drops contain the fluoroquinolone, ciprofloxacin. The bactericidal and inhibitory activity of ciprofloxacin against bacteria results from an interference with the DNA gyrase, an enzyme needed by the bacterium for the synthesis of DNA. Thus, the vital information from the bacterial chromosomes cannot be transcribed which causes a breakdown of the bacterial metabolism. Ciprofloxacin has in vitro activity against a wide range of Gram-positive and Gram-negative bacteria.

Mechanism of Resistance

Fluoroquinolone resistance, particularly ciprofloxacin, requires significant genetic changes in one or more of five major bacterial mechanisms: a) enzymes for DNA synthesis, b) protecting proteins, c) cell permeability, d) drug efflux, or e) plasmid-mediated aminoglycoside 6'-N-acetyltransferase, AAC (6')-Ib.

Fluoroquinolones, including ciprofloxacin, differ in chemical structure and mode of action from aminoglycosides, β-lactam antibiotics, macrolides, tetracyclines, sulfonamides, trimethoprim, and chloramphenicol. Therefore, organisms resistant to these drugs may be susceptible to ciprofloxacin.

Breakpoints

There are no official topical ocular breakpoints for ciprofloxacin and although systemic breakpoints have been used, their relevance to topical therapy is doubtful. The EUCAST clinical MIC breakpoints used for this antibiotic are the following:

Staphylococcus species

S ≤1 mg/l, R ≥1 mg/l

Streptococcus pneumoniae

S ≤0.125 mg/l, R ≥2 mg/l

Haemophilus influenzae

S ≤0.5 mg/l, R ≥0.5 mg/l

Moraxella catarrhalis

S ≤0.5 mg/l, R ≥0.5 mg/l

Pseudomonas aeruginosa

S ≤0.5 mg/l, R ≥1 mg/l

 

Susceptibility to Ciprofloxacin

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 the agent in at least some types of infections is questionable. The presentation below lists bacterial species recovered from external ocular infections of the eye.

Commonly Susceptible Species

AEROBIC GRAM-POSITIVE MICROORGANISMS

Corynebacterium accolens

Corynebacterium auris

Corynebacterium propinquum

Corynebacterium psudodiphtheriticum

Corynebacterium striatum

Staphylococcus aureus (methicillin-susceptible – MSSA)

Staphylococcus capitis

Staphylococcus epidermidis (methicillin-susceptible – MSSE)

Staphylococcus hominis

Staphylococcus saprophyticus

Staphylococcus warneri

Streptococcus pneumoniae

Streptococcus viridans Group

AEROBIC GRAM-NEGATIVE MICROORGANISMS

Acinetobacter species

Haemophilus influenzae

Moraxella catarrhalis

Pseudomonas aeruginosa

Serratia marcescens

Species for Which Acquired Resistance May Be a Problem

AEROBIC GRAM-POSITIVE MICROORGANISMS

Staphylococcus aureus (methicillin-resistant – MRSA)

Staphylococcus epidermidis (methicillin-resistant – MRSE)

Staphylococcus lugdunensis

AEROBIC GRAM-NEGATIVE MICROORGANISMS

None

OTHER MICROORGANISMS

None

Inherently Resistant Organisms

AEROBIC GRAM-POSITIVE MICROORGANISMS

Corynebacterium jeikium

AEROBIC GRAM-NEGATIVE MICROORGANISMS

None

OTHER MICROORGANISMS

None

CIPLOX D Eye/Ear Drops also contain dexamethasone, a highly potent and long-acting glucocorticoid. It has an approximately 7 times greater anti-inflammatory potency than prednisolone, another commonly prescribed corticosteroid.

The actions of corticosteroids are mediated by the binding of the corticosteroid molecules to receptor molecules located within sensitive cells. Corticosteroid receptors are present in human trabecular meshwork cells and in rabbit iris ciliary body tissue.

Corticosteroids will inhibit phospholipase A2, thereby preventing the generation of substances that mediate inflammation, e.g. prostaglandins. Corticosteroids also produce a marked, though transient, lymphocytopaenia. This depletion is due to redistribution of the cells, with the T lymphocytes being affected to a greater degree than the B lymphocytes. Lymphokine production is reduced, as is the sensitivity of macrophages to activation by lymphokines.

Corticosteroids also retard epithelial regeneration, diminish post-inflammatory neo- vascularisation and reduce the excessive permeability of inflamed capillaries to normal levels.

The actions of corticosteroids, as described above, are exhibited by dexamethasone and they all contribute to its anti-inflammatory effect.

Pharmacokinetic Properties

Ciprofloxacin

Ciprofloxacin in CIPLOX D Eye/Ear Drops 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 two drops of 0.3% ciprofloxacin solution every 2 hours for 2 days and then every 4 hours for 5 days ranged from non-quantifiable (<1.0 ng/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 1.7–5.0 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 extra-renal 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 with respect to use in children.

Dexamethasone

Absorption

When administered topically into the eye, dexamethasone is absorbed into the aqueous humour, cornea, iris, choroid, ciliary body and retina. Systemic absorption occurs but may be significant only at higher dosages or in extended paediatric therapy. Up to 90% of dexamethasone is absorbed when given by mouth; peak plasma levels are reached between 1 and 2 hours after ingestion and show wide individual variations.

Distribution

Tissue distribution studies in animals show a high uptake of dexamethasone by the liver, kidneys and adrenal glands; a volume of distribution has been quoted as 0.58 l/kg. In man, over 60% of circulating steroids are excreted in the urine within 24 hours, largely as unconjugated steroid.

Biotransformation

Dexamethasone sodium phosphate is rapidly converted to dexamethasone within the circulation. Up to 77% of dexamethasone is bound to plasma proteins, mainly albumin. This percentage, unlike cortisol, remains practically unchanged with increasing steroid concentrations. The mean plasma half-life of dexamethasone is 3.6 ± 0.9 hours.

Elimination

Dexamethasone also appears to be cleared more rapidly from the circulation of the foetus and neonate than in the mother; plasma dexamethasone levels in the foetus and the mother have been found in the ratio of 0.32:1.

Non-Clinical Properties

Animal Toxicology or Pharmacology

Ciprofloxacin

After topical application of ciprofloxacin 0.3%, (one drop every 30 minutes for a total of six doses), the concentration of ciprofloxacin achieved in the aqueous humour of rabbits when the corneal epithelium was intact was 4.8 μg/mL; when debrided, it was 12.9 μg/mL.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Non-clinical developmental toxicity was observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.

Dexamethasone

Repeat-dose topical ocular safety studies with dexamethasone in rabbits have shown systemic corticosteroid effects. Such effects are considered to be unlikely when dexamethasone eye drops are used as recommended.

Dexamethasone was clastogenic in the in vitro human lymphocyte assay and in vivo in the mouse micronucleus assay at doses in excess of those obtained following topical application. Conventional carcinogenicity studies with dexamethasone have not been performed.

Dexamethasone has been found to be teratogenic in animal models. Dexamethasone induced abnormalities of foetal development, including cleft palate, intra-uterine growth retardation and effects on brain growth and development.

Guinea pigs dosed in the middle ear with ciprofloxacin dexamethasone ear drops for one month exhibited no drug-related structural or functional changes of the cochlear hair cells and no lesions in the ossicles.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of dexamethasone sodium phosphate eye/ear drops.

Description

CIPLOX D Eye/Ear Drops contain ciprofloxacin, which is a fluoroquinolone antibacterial active against a broad spectrum of Gram-positive and Gram-negative ocular pathogens, and dexamethasone sodium phosphate, a corticosteroid that suppresses the inflammatory response to a variety of agents.

Pharmaceutical Particulars

Incompatibilities

Incompatible with alkaline solutions.

Shelf-Life

As on the pack

Packaging Information

CIPLOX D Eye/Ear Drops…………………. Vial of 10 mL

Storage and Handling Instructions

Store in a cool, dark place.

Protect from light.

Keep out of the reach of children.

Patient Counselling Information

  • What is CIPLOX D Eye/ Ear Drops?

Each drop of CIPLOX D Eye/Ear Drops contains ciprofloxacin a quinolone antibiotic, and dexamethasone a corticosteroid that suppress inflammation. CIPLOX D Eye/Ear Drops is indicated to use for post-operative inflammatory condition of eyes and Acute Otitis Media with tympanostomy tubes and Acute Otitis Externa.

  • Do not use CIPLOX D Eye/Ear Drops if you have allergy to:

Do not use CIPLOX D Eye/Ear Drops If you are allergic (hypersensitive) to ciprofloxacin and/or dexamethasone or any other quinolone antibiotic or to any of the other key ingredients

  • Before you take this medicine, tell your HCP about other medication.

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. If you are using more than one type of eye medicine, the medicines must be used at least 5 minutes apart. Eye ointments should be used last. Tell your doctor if you are using ritanovir or cobicistat as this may increase the amount of dexamethasone in the blood.

  • How should I use CIPLOX D Eye/Ear Drops?

Always use CIPLOX D Eye/Ear Drops exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

  • What are the possible side effects?

Like all medicines, CIPLOX D Eye/Ear Drops can cause side effects, although not everybody gets them.

You may experience some or all the following effects in your eye(s):

Common (1 to 10 users in 100)

  • White deposits on the eye surface (cornea)
  • Discomfort (stinging or burning, gritty feeling in the eye, irritation)
  • Redness, watering of the eyes

Uncommon (1 to 10 users in 1,000)

  • Damage to the eye surface (cornea)
  • Sensitivity to light
  • Blurred vision
  • Swelling of the eye or eyelid, pain
  • Dry eye
  • Itchiness
  • Eye discharge
  • Eyelid crusting
  • Eyelids scales
  • Eyelid redness
  • Poor vision
  • Watery eyes
  • Red eyes

Rare (1 to 10 users in 10,000)

  • Damage of the eye
  • Inflammation
  • Double vision
  • Decreased eye sensation
  • Tired eyes, stye

Topical corticosteroids should not be used for longer than 1 week except under ophthalmic supervision.

If you notice white particles in your eyes, continue to use CIPLOX D Eye/Ear Drops but tell your doctor immediately.

You may also experience effects in other areas of your body such as the following:

Common: bad taste.

Uncommon: headache, nausea.

Rare: hypersensitivity, dizziness, ear pain, inflammation inside the nose, nasal sinus discharge, diarrhoea, abdominal pain, skin inflammation, tendon disorder.

If you experience an allergic reaction, stop using CIPLOX D Eye/Ear Drops and tell your doctor.

Middle Ear Infections: The most common side effect is ear discomfort or pain. Other side effects include: white, flaking, scaling material in the ear, irritability and abnormal taste in the mouth.

Outer Ear Canal Infections: The most common side effect is itching of the ear. Other side effects include: flaking, scaling material in the ear, fungal infection of the treated ear, feeling of fullness of plugging in the ear, ear pain and skin rash.

Other side effects include discharge from the ear, vomiting, headache, skin peeling and swelling of the ear.

  • How should I store CIPLOX D Eye/Ear Drops?
  • Keep out of the reach and sight of children.
  • Do not store above 25°C.
  • Do not refrigerate or freeze.
  • Keep the bottle tightly closed.
  • Do not use the drops after the expiry date (marked ‘EXP’) on the bottle and the carton. The expiry date refers to the last day of that month
  • General information about the safe and effective use of CIPLOX D Eye/Ear Drops

CIPLOX D Eye/Ear Drops contains ciprofloxacin, which belongs to a group of medicines known as quinolone antibiotics, and dexamethasone, which belongs to the group of corticosteroids that suppres inflammation. It is used for the treatment of post-operative inflammatory conditions of the eyes and the ears.

Ask your doctor for advice and take special care.

  • Use CIPLOX D Eye/Ear Drops only in your eyes and or ears.
  • As with any antibiotic, use of CIPLOX D Eye/Ear Drops for a long time may lead to other infections. If your symptoms get worse or suddenly return, tell your doctor. You may become more susceptible to other infections with the use of this medicine, especially after prolonged use.
  • If you notice the first signs of a skin rash or any other allergic reaction, including hives, itching and breathing problems, stop treatment and immediately contact your doctor. If you have a serious allergic reaction, then you may need emergency treatment.
  • If you feel pain, swelling or inflammation while or shortly after taking this medicine, stop treatment and contact your doctor.
  • If you are elderly or if you are taking medicines called ‘corticosteroids’ used to treat conditions such as pain and inflammation, asthma or skin problems, then you have a higher risk of getting tendon problems during treatment with CIPLOX D Eye/Ear Drops. If you experience any inflammation or inflammatory condition, stop treatment and immediately consult your doctor.

Do not use CIPLOX D Eye/Ear Drops:

  • In case of tuberculosis.
  • In cases of damaged cornea (such as perforation of the cornea), ulceration, lesions with incomplete formation of the covering tissue.
  • In cases of increased intraocular pressure caused by glucocorticosteroids (these belong to the group of corticosteroids).
  • if allergic to other steroids.
  • If has a viral infection of the outer ear canal, including herpes simplex (often called a cold sore).
  • if has a fungal ear infection.
  • If has a parasitic ear infection.

Pregnancy and breastfeeding

If you are pregnant or might get pregnant, or if you are breastfeeding a baby, talk to your doctor before you use CIPLOX D Eye/Ear Drops.

Driving and using machines

If your sight is temporarily blurred or affected in any way following use of CIPLOX D Eye/Ear Drops you should not drive or operate machinery until your vision is clear again.

Important information if you wear contact lenses

There is a preservative in CIPLOX D Eye/Ear Drops (benzalkonium chloride) that may cause eye irritation and can discolour soft contact lenses. Do not wear contact lenses (hard or soft) during treatment with CIPLOX D Eye/Ear Drops. If you do continue to wear your lenses, you must remove them before using CIPLOX D Eye/Ear Drops and wait at least 15 minutes after use before putting your lenses back in.

  • What are the ingredients in CIPLOX D Eye/Ear Drops?

CIPLOX D Eye/Ear Drops contains Ciprofloxacin 0.3% and Dexamethasone Sodium 0.1% along with Benzalkonium Chloride, NF 0.01% as preservative.

  • Any other information

The preservative in CIPLOX D Eye/Ear Drops, benzalkonium chloride, may irritate your skin.

Details of Manufacturer

Mfd. By CIPLA LTD.

C-116 B, Road No.8,

Vishwakarma Industrial Area, Jaipur 302 013

At:  SP-918, phase III,

Bhiwandi – 301 019

ADITI PHARMACEUTICALS PVT LTD (709103)

E 65/66, M.I.D.C., Akkalkot Road, Solapur-413006

District: SOLAPUR

Details of Permission or Licence Number With Date

RAJ – 1704-A & Date: 11/11/2016

28A-PD/3280-A & Date: 18/04/2018

Date of Revision

07/11/2019