EYE:

Adults, newborn infants (0-27 days), infants and toddlers (28 days to 23 months), children (2-11 years) and adolescents (12 – 16 years)

CIPROCIN is indicated for the treatment of corneal ulcers and superficial infections of the eye and adnexa caused by susceptible strains of bacteria.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

EAR:

Adults and Children 1 year and above

CIPROCIN is indicated for acute otitis externa due to susceptible strains of bacterial species shown to be responsive to ciprofloxacin as listed in section 5.1.

Use should be under the supervision of a specialist ENT service having the facilities for regular monitoring of clinical and microbiological effects during and after administration.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

EYE:

Adults, newborn infants (0-27 days), infants and toddlers (28 days to 23 months), children (2-11 years) and adolescents (12 – 16 years)

Corneal Ulcers:

CIPROCIN must be administered in the following intervals, even during night time:

On the first day, instil 2 drops into the affected eye every 15 minutes for the first six hours and then 2 drops into the affected eye every 30 minutes for the remainder of the day.

On the second day, instil 2 drops in the affected eye hourly.

On the third through the fourteenth day, place two drops in the affected eye every 4 hours. If the patient needs to be treated longer than 14 days, the dosing regimen is at the discretion of the attending physician.

Superficial Ocular Infection:

The usual dose is one or two drops in the affected eye(s) four times a day. In severe infections, the dosage for the first two days may be one or two drops every two hours during waking hours.

For either indication a maximum duration of therapy of 21 days is recommended.

The dosage in children above the age of 1 year is the same as for adults.

Use in children

Safety and effectiveness of CIPROCIN Eye Drops were determined in 230 children between the ages of 0 and 12 years of age. No serious adverse drug reaction was reported in this group of patients.

Use in renal and hepatic impairment

No studies have been performed using CIPROCIN Eye Drops in patients with kidney or liver problems.

EAR:

Adults and children 1 year and above:

The dose is 4 drops of CIPROCIN in the ear canal twice daily for adults.

For patients requiring use of an otowick, the dose can be doubled for the first administration only (i.e., 6 drops for paediatric patients and 8 drops for adult patients).

Use in elderly

No dosage alteration in elderly patients is necessary.

In clinical studies conducted with CIPROCIN, the probability of having an adverse reaction was independent of age. No difference in patients experiencing adverse reactions was noted in patients less than 65 years of age, between 65 and 75 years of age, and greater than 75 years of age.

Use in children

The dose is 3 drops of CIPROCIN in the ear canal twice daily for children. Safety and effectiveness of CIPROCIN was determined in 139 children between the ages of one and 12 years. No serious adverse events were reported in these patients.

Safety and effectiveness in children below 1 year of age have not been established.

Use in hepatic and renal impairment

CIPROCIN has not been studied in patients with hepatic or renal impairment and is therefore not recommended in such patients.

Method of administration

The bottle should be shaken well before use.

After cap is removed, if tamper evident snap collar is loose, remove before using product.

The user should be instructed to warm the bottle just before use by holding it in the palm of the hand for a few minutes to prevent any unpleasant sensation associated with the cold suspension coming into contact with the ear.

With head tilted, instil the drops into the affected ear. Keep the head tilted on its side for around 5 minutes to enable the drops to penetrate into the external auditory canal. Repeat if necessary in the other ear.

To prevent contamination of the dropper tip and solution, care must be taken not to touch the auricle or the external ear canal, and surrounding areas, or other surfaces with the dropper tip of the bottle. Keep the bottle tightly closed when not in use.

After cap is removed, if tamper evident snap collar is loose, remove before using product.

For Ocular use only:

The clinical experience in children less than one year old, particularly in neonates is very limited. The use of CIPROCIN eye 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 CIPROCIN eye 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, were observed in patients receiving treatment based on systematically administered quinolones. 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. (See section 4.8)

Serious acute hypersensitivity reactions to ciprofloxacin may require immediate emergency treatment. Oxygen and airway management should be administered where clinically indicated.

CIPROCIN 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.

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 CIPROCIN Eye Drops should be discontinued at the first sign of tendon inflammation (See section 4.8).

In patients with corneal ulcer and frequent administration of CIPROCIN Eye Drops, white topical ocular precipitates (medication residue) have been observed which resolved after continued application of CIPROCIN Eye Drops. The precipitate does not preclude the continued application of CIPROCIN Eye Drops nor does it adversely affect the clinical course of the recovery process. The onset of the precipitate was within 24 hours to 7 days after starting therapy. Resolution of the precipitate varied from immediately to 13 days after therapy commencing.

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 CIPROCIN eye drops.

CIPROCIN Eye Drops contains benzalkonium chloride which may cause irritation and is known to discolour soft contact lenses.

Avoid contact with soft contact lenses. In case patients are allowed to wear contact lenses they should be instructed to remove them prior to application of CIPROCIN Eye Drops and wait at least 15 minutes before reinsertion.

For Otic use only:

• The safety and efficacy of this product have been established in paediatric patients 1 year and older in controlled clinical trials. Although very limited data are available in patients less than age 1 year treated for acute otitis externa, there are no differences in the disease process itself, in this patient population, which would preclude use of this product in patients less than one year of age. Based upon the very limited data, the prescribing physician should weigh the clinical benefits of use against the known and possibly unknown risks when prescribing in patients less than age 1 year.

• In otic use, meticulous medical monitoring is required in order to be able to determine in a timely manner the possible necessity of other therapeutic measures.

• 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. (See section 4.8)

• Serious 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.

• CIPROCIN should be suspended immediately at the first appearance of a skin rash or any other sign of hypersensitivity reaction and medical advice should be sought.

• Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has been observed in patients who are exposed to direct sunlight while receiving some members of the quinolone class of drugs. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs.

• As with all 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.

• Tendon inflammation and rupture may occur with systemic fluoroquinolone therapy including ciprofloxacin, particularly in elderly patients and in those treated concurrently with corticosteroids. Therefore treatment with CIPROCIN should be discontinued at the first sign of tendon inflammation (see section 4.8).

• Benzalkonium chloride, used as a preservative in this medicine is an irritant, may cause skin reactions when used topically.

Specific drug interaction studies have not been conducted with ophthalmic ciprofloxacin. Given the low systemic concentration of ciprofloxacin following topical ocular administration of the product, drug interactions are unlikely to occur.

If more than one topical ophthalmic medicinal product is being used, the medicines must be administered at least 5 minutes apart. Eye ointments should be administered last.

Specific drug interaction studies have not been conducted with otic ciprofloxacin.

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.

Given the low systemic concentration of ciprofloxacin following otic administration of the product, drug interactions are unlikely to occur.

Pregnancy

There are no adequate data from the use of CIPROCIN in pregnant woman. Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. Systemic exposure to ciprofloxacin after topical use is expected to be low.

As a precautionary measure, it is preferable to avoid the use of CIPROCIN during pregnancy, unless the therapeutic benefit is expected to outweigh the potential risk to the fetus.

Breastfeeding

Orally administered ciprofloxacin is excreted in the human milk. It is unknown whether ciprofloxacin is excreted in human breast milk following topical ocular or otic administration. A risk to the suckling child cannot be excluded. Therefore, caution should be exercised when CIPROCIN is administered to nursing women.

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.

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.

Eye :

In clinical trials, the most frequently reported adverse drug reactions were ocular discomfort, dysgeusia and corneal deposits occurring approximately in 6%, 3% and 3% of patients respectively.

Tabulated summary of adverse reactions

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 post-marketing experience.

The following undesirable effects were reported in association with the ophthalmic use of CIPROCIN:

Description of selected adverse events

With locally applied fluoroquinolones (generalized) 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 (see section 4.4). Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial oedema, dyspnoea, urticaria, and itching.

Ruptures of the shoulder, hand, Achilles, or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving systemic fluoroquinolones. Studies and post marketing 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 post marketing data have not demonstrated a clear association between CIPROCIN and musculoskeletal and connective tissue adverse reactions.

In isolated cases blurred vision, decreased visual acuity and medication residue have been observed with ophthalmic ciprofloxacin (see section 4.4).

Moderate to severe phototoxicity has been observed in patients treated with systemic quinolones. Nevertheless, phototoxic reactions to ciprofloxacin are uncommon.

Paediatric population

Safety and effectiveness of CIPROCIN 3mg/ml eye drops were determined in 230 children between the ages of 0 and 12 years of age. No serious adverse drug reaction was reported in this group of patients.

Ear:

In clinical trials the most frequently reported adverse drug reactions were ear pruritus and otorrhoea occurring approximately in1% of patients.

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 post-marketing experience.

Description of selected adverse events

In otic use the ingredients rarely are sensitising. However as with any substance that is applied to the skin, an allergic reaction to any of the ingredients of the preparation can always occur.

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.

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 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 post marketing data have not demonstrated a clear association between CIPROCIN and musculoskeletal and connective tissue adverse reactions.

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

Moderate to severe phototoxicity has been observed in patients treated with systemic quinolones. Nevertheless, phototoxic reactions to ciprofloxacin are uncommon.

Paediatric population

Safety and efficacy of CIPROCIN 3mg/ml ear drops was determined in 193 children between the ages of one and 12 years of age. No serious adverse drug reaction was reported in this group of patients.

To report any side effects

-       National Pharmacovigilance and Drug Safety Center (NPC)

• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Ext 2317-2356-2340
• Call Center: 19999
• E-mail: npc.drug@sfda.gov.sa
• Website: https://ade.sfda.gov.sa

Eye :

A topical overdose of CIPROCIN may be rinsed out from the eye(s) with lukewarm tap water. Due to the characteristics of this preparation no toxic effects are to be expected with an ocular overdose of this product, or in the event of accidental ingestion of the contents of one bottle.

Ear :

No case of overdose has been reported. No data are available in humans regarding overdosage by accidental or deliberate ingestion. Due to the characteristics of this preparation no toxic effects are to be expected with an otic overdose of this product, or in the event of accidental ingestion of the contents of one bottle.

Eye :

Pharmacotherapeutic Group – Ophthalmologicals, Other Anti-infectives

ATC Code: S01A X13

Ear :

Pharmacotherapeutic group: Otological; Anti-infectives.

ATC Code: S02A A.

Mechanism of Action

CIPROCIN eye/ear drops, solution contains the fluoroquinolone ciprofloxacin. The cidal 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:

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.

Eye :

CIPROCIN eye drops, solution is rapidly absorbed into the eye following topical ocular administration. Systemic levels are low following topical administration. Plasma levels of ciprofloxacin in human subjects following 2 drops of 0.3% ciprofloxacin solution every 2 hours for two days and then every four hours for 5 days ranged from non-quantifiable (<1.0 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 to 5.0 l/kg. Serum protein binding is 20-40%. The half-life of ciprofloxacin in serum is 3-5 hours. Both ciprofloxacin and its four primary metabolites are excreted in urine and faeces. Renal clearance accounts for approximately two-thirds of the total serum clearance with biliary and faecal routes accounting for the remaining percentages. In patients with impaired renal function, the elimination half-life of ciprofloxacin is only moderately increased due to extrarenal routes of elimination. Similarly, in patients with severely reduced liver function the elimination half-life is only slightly longer.

There are no pharmacokinetic data available in respect of use in children.

Ear :

The systemic pharmacokinetic properties of ciprofloxacin have been well studied. Ciprofloxacin widely distributes to tissues of the body, with tissue levels typically greater than levels in plasma. The apparent volume of distribution at steady state is 1.7-2.7 l/kg. Serum protein binding is 16 43%. The half life of ciprofloxacin in serum is 3-5 hours. Following oral administration of single doses ranging from 250 to 750 mg to adults with normal renal function, 15-50% of the dose is excreted in urine as unchanged drug and 10-15% as metabolites within 24 hours. Both ciprofloxacin and its four primary metabolites are excreted in urine and faeces. Renal clearance of ciprofloxacin is typically 300-479 ml/minute. Approximately 20-40% of the dose is excreted in faeces as unchanged drug and metabolites within 5 days.

In children with otitis media with tympanostomy tubes treated with ciprofloxacin 3mg/ml solution (3 drops three times daily for 14 days), plasma concentrations of ciprofloxacin were not detected (limit of quantification 5ng/ml). In children with suppurative otitis with perforated tympanic membrane, treated by ciprofloxacin 2mg/ml solution (twice daily for 7-10 days), no circulating plasma concentration of ciprofloxacin up to the limit of quantification 5ng/ml was detected. No significant systemic passage of ciprofloxacin is expected under the normal conditions of use.

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.

Sodium Chloride

Disodium Edetate

Benzalkonium Chloride Solution

Water for Injection

Not applicable

Keep out of the reach and sight of children.

Store below 30"C. protect from light.

Keep the bottle tightly closed.

Stop using the bottle 1 month after first opening to prevent infections.

5 ml plastic bottle with white plastic cap and white pilfer proof.

Keep medicines out of reach & sight of children