Ketoflox

Ketorolac Tromethamine:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Ketoflox (Ketorolac Tromethamine) reviews

1 INDICATIONS AND USAGE

Ketoflox (Ketorolac Tromethamine) ophthalmic solution is indicated for the temporary relief of ocular itching due to seasonal allergic conjunctivitis. Ketoflox (Ketorolac Tromethamine) ophthalmic solution is also indicated for the treatment of postoperative inflammation in patients who have undergone cataract extraction.

Ketoflox (Ketorolac Tromethamine) ophthalmic solution is a nonsteroidal, anti-inflammatory indicated for:

• The treatment of inflammation following cataract surgery.
• The temporary relief of ocular itching due to seasonal allergic conjunctivitis (1).

2 DOSAGE AND ADMINISTRATION

One drop of Ketoflox should be applied to the affected eye(s) four times a day for relief of ocular itching due to seasonal allergic conjunctivitis.

For the treatment of postoperative inflammation in patients who have undergone cataract extraction, one drop of Ketoflox (Ketorolac Tromethamine) should be applied to the affected eye four times daily beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative period. (2.1)

2.1 Recommended Dosing

Patient Dosing

The recommended dose of Ketoflox (Ketorolac Tromethamine) ophthalmic solution is one drop four times a day to the affected eye(s) for relief of ocular itching due to seasonal allergic conjunctivitis.

For the treatment of postoperative inflammation in patients who have undergone cataract extraction, one drop of Ketoflox (Ketorolac Tromethamine) ^{ophthalmic solution should be applied to the affected eye four times daily beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative period.}

2.2 Use with Other Topical Medications

Ketoflox (Ketorolac Tromethamine) ^{ophthalmic solution has been safely administered in conjunction with other ophthalmic medications such as antibiotics, alpha-agonists, beta blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics. Drops should be administered at least 5 minutes apart.}

3 DOSAGE FORMS AND STRENGTHS

Ketoflox (Ketorolac Tromethamine) Ophthalmic Solution 0.5% is supplied sterile in white opaque LDPE plastic bottles with white opaque droppers with grey opaque ophthalmic HDPE plastic caps as follows

• 11 mL size bottle filled with 5 mL or 10 mL Ketoflox (Ketorolac Tromethamine) ophthalmic solution, 0.5%.

Ophthalmic solution containing 5 mg/mL Ketoflox (Ketorolac Tromethamine). (3)

• 11 mL size bottle filled with 5 mL or 10 mL Ketoflox (Ketorolac Tromethamine) ophthalmic solution, 0.5%.

4 CONTRAINDICATIONS

Ketoflox (Ketorolac Tromethamine) solution is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formulation.

Hypersensitivity to any component of this product. (4)

5 WARNINGS AND PRECAUTIONS

• Delayed healing
• Cross-sensitivity or hypersensitivity (5.2)
• Increased bleeding time due to interference with thrombocyte aggregation (5.3)
• Corneal effects including keratitis (5.4)

5.1 Delayed Healing

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems.

5.2 Cross-Sensitivity or Hypersensitivity

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

5.3 Increased Bleeding Time

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

It is recommended that Ketoflox (Ketorolac Tromethamine) ophthalmic solution be used with caution in patients with known bleeding tendencies or who are receiving other medications, which may prolong bleeding time.

5.4 Corneal Effects

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

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

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

5.5 Contact Lens Wear

Ketoflox (Ketorolac Tromethamine) should not be administered while wearing contact lenses.

6 ADVERSE REACTIONS

The most frequent adverse reactions reported by up to 40% of patients participating in clinical trials have been transient stinging and burning on instillation.

To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 the rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The most frequent adverse reactions reported with the use of Ketoflox (Ketorolac Tromethamine) ophthalmic solutions have been transient stinging and burning on instillation. These reactions were reported by up to 40% of patients participating in clinical trials.

Other adverse reactions occurring approximately 1 to 10% of the time during treatment with Ketoflox (Ketorolac Tromethamine) ophthalmic solutions included allergic reactions, corneal edema, iritis, ocular inflammation, ocular irritation, superficial keratitis, and superficial ocular infections.

Other adverse reactions reported rarely with the use of Ketoflox (Ketorolac Tromethamine) ophthalmic solutions included: corneal infiltrates, corneal ulcer, eye dryness, headaches, and visual disturbance (blurry vision).

6.2 Postmarketing Experience

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C

Pregnancy Category C: Ketoflox, administered during organogenesis, was not teratogenic in rabbits and rats at oral doses of 3.6 mg/kg/day and 10 mg/kg/day, respectively. These doses are approximately 100 times and 250 times higher respectively than the maximum recommended human topical ophthalmic daily dose of 2 mg (5 mg/mL x 0.05 mL/drop, x 4 drops x 2 eyes) to affected eyes on a mg/kg basis. Additionally, when administered to rats after Day 17 of gestation at oral doses up to 1.5 mg/kg/day (approximately 40 times the typical human topical ophthalmic daily dose), Ketoflox (Ketorolac Tromethamine) resulted in dystocia and increased pup mortality. There are no adequate and well-controlled studies in pregnant women. Ketoflox (Ketorolac Tromethamine) solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Because of the known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), the use of Ketoflox (Ketorolac Tromethamine) solution solution during late pregnancy should be avoided.

8.3 Nursing Mothers

Because many drugs are excreted in human milk, caution should be exercised when Ketoflox (Ketorolac Tromethamine) is administered to a nursing woman.

8.4 Pediatric Use

Safety and efficacy in pediatric patients below the age of 2 have not been established.

8.5 Geriatric Use

No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients.

11 DESCRIPTION

Ketoflox (Ketorolac Tromethamine) ophthalmic solution 0.5% is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs) for ophthalmic use. Its chemical name is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1) and it has the following structure

Ketoflox (Ketorolac Tromethamine) Ophthalmic solution is supplied as a sterile isotonic aqueous 0.5% solution, with a pH of 7.4. Ketoflox (Ketorolac Tromethamine) Ophthalmic Solution is a racemic mixture of R-(+) and S-(-) - Ketoflox (Ketorolac Tromethamine). Ketoflox (Ketorolac Tromethamine) may exist in three crystal forms. All forms are equally soluble in water. The pKa of ketorolac is 3.5. This white to off-white crystalline substance discolors on prolonged exposure to light. The molecular weight of Ketoflox (Ketorolac Tromethamine) is 376.41. The osmolality of Ketoflox (Ketorolac Tromethamine) Ophthalmic Solution is 290 mOsmol/kg.

Each mL of Ketoflox (Ketorolac Tromethamine) Ophthalmic Solution contains: Active: Ketoflox (Ketorolac Tromethamine) 0.5%. Preservative: Benzalkonium chloride 0.01%. Inactives: Edetate disodium dihydrate 0.1%; octoxynol 40; sodium chloride; hydrochloric acid and/or sodium hydroxide to adjust the pH; and water for injection.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

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

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Ketoflox (Ketorolac Tromethamine) was not mutagenic in vitro in the Ames assay or in forward mutation assays. Similarly, it did not result in an in vitro increase in unscheduled DNA synthesis or an in vivo increase in chromosome breakage in mice. However, Ketoflox (Ketorolac Tromethamine) did result in an increased incidence in chromosomal aberrations in Chinese hamster ovary cells.

Ketoflox (Ketorolac Tromethamine) did not impair fertility when administered orally to male and female rats at doses up to 9 mg/kg/day and 16 mg/kg/day, respectively. These doses are respectively 225 and 400 times higher than the typical human topical ophthalmic daily dose.

14 CLINICAL STUDIES

Two controlled clinical studies showed that Ketoflox (Ketorolac Tromethamine) ophthalmic solution was significantly more effective than its vehicle in relieving ocular itching caused by seasonal allergic conjunctivitis.

Two controlled clinical studies showed that patients treated for two weeks with Ketoflox (Ketorolac Tromethamine) ophthalmic solution were less likely to have measurable signs of inflammation (cell and flare) than patients treated with its vehicle.

Results from clinical studies indicate that Ketoflox (Ketorolac Tromethamine) has no significant effect upon intraocular pressure; however, changes in intraocular pressure may occur following cataract surgery.

16 HOW SUPPLIED/STORAGE AND HANDLING

Ketoflox (Ketorolac Tromethamine) Ophthalmic Solution 0.5% is supplied sterile in white opaque LDPE plastic bottles with white opaque droppers with grey opaque ophthalmic HDPE plastic caps as follows: 5 mL - NDC 60505-1003-1 and 10 mL - NDC 60505-1003-2.

Store at 20° to 25°C (68° to 77°F). Protect from light.

17 PATIENT COUNSELING INFORMATION

17.1 Slow or Delayed Healing

Patients should be informed of the possibility that slow or delayed healing may occur while using nonsteroidal anti-inflammatory drugs.

17.2 Avoiding Contamination of the Product

Patients should be instructed to avoid allowing the tip of the bottle to contact the eye or surrounding structures because this could cause the tip to become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

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

17.3 Contact Lens Wear

Patients should be advised that Ketoflox solution should not be administered while wearing contact lenses.

17.4 Intercurrent Ocular Conditions

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

17.5 Concomitant Topical Ocular Therapy

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

Rx only.

Apotex Inc.

Ketoflox (Ketorolac Tromethamine) Ophthalmic Solution 0.5%

October 2015

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

PRINCIPAL DISPLAY PANEL - 0.5% BOTTLE LABEL

APOTEX CORP. NDC 60505-1003-1

Ketoflox (Ketorolac Tromethamine) OPHTHALMIC SOLUTION 0.5%

Rx only

5 ml

Ofloxacin:

• Pharmacological action
• Pharmacokinetics
• Why is Ketoflox prescribed?
• Dosage and administration
• Ketoflox (Ofloxacin) side effects, adverse reactions
• Ketoflox contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Ketoflox drug interactions
• Ketoflox in case of emergency / overdose
• Ketoflox (Ofloxacin) reviews

Pharmacological action

Ketoflox is an antimicrobial agents of broad-spectrum action type from fluoroquinolone group. Bactericidal action of Ketoflox (Ofloxacin) is due to blockage of the enzyme DNA gyrase in bacterial cells. This medication is highly active against most of gram-negative bacteria: Escherichia coli, Salmonella spp., Shigella spp., Proteus spp., Morganella morganii, Klebsiella spp. (including Klebsiella pneumoniae), Enterobacter spp., Serratia spp., Citrobacter spp., Yersinia spp., Providencia spp., Haemophilus influenzae, Neisseria gonorrhoeae, Neisseria meningitidis, Mycoplasma spp., Legionella pneumophila, Acinetobacter spp., and Chlamydia spp.

Ketoflox (Ofloxacin) is active against some gram-positive bacteria (including Staphylococcus spp., Streptococcus spp., especially beta-hemolytic streptococci).

Enterococcus faecalis, Streptococcus pneumoniae, Pseudomonas spp. are moderately susceptible to Ketoflox (Ofloxacin).

Anaerobic bacteria (except Bacteroides ureolyticus) are insensitive to Ketoflox (Ofloxacin).

This drug is resistant to beta-lactamases.

Pharmacokinetics

After oral administration Ketoflox (Ofloxacin) is rapidly and completely absorbed from the gastrointestinal tract. Ingestion has a little effect on the extent of absorption but may slow its speed. C_max plasma levels reached in 2 hours.

The protein binding is 25%. Ketoflox (Ofloxacin) is widely distributed in tissues and body fluids (organs of urinary system, reproductive organs, prostate, lung, ENT organs, gall bladder, bone, skin).This medicine is excreted in the urine in unchanged form (about 80% in 24 h). A small portion of the active substance (4%) is excreted in the feces. T_1/2 is 6 h.

Why is Ketoflox prescribed?

Infectious-inflammatory diseases caused by microorganisms sensitive to Ketoflox (Ofloxacin), including: diseases of the lower respiratory tract, ear, nose, throat, skin, soft tissues, bones, joints, infectious and inflammatory diseases of the abdominal organs (except bacterial enteritis) and pelvic infection, kidney and urinary tract, prostatitis, gonorrhea.

Dosage and administration

Dosing regimen of Ketoflox is individual. Daily dose of 200-800 mg, the multiplicity of application 2 times / day. For patients with impaired renal function (creatinine clearance 20-50 ml / min), the first dose is 200 mg, then 100 mg every 24 hours. When CC is less than 20 ml / min, the first dose is 200 mg, then 100 mg every 48 hours.

Ketoflox (Ofloxacin) side effects, adverse reactions

Digestive system: nausea, vomiting, diarrhea, abdominal pain and cramps, appetite loss, dry mouth, flatulence, gastrointestinal dysfunction, constipation; rarely - liver damage, liver necrosis, jaundice, hepatitis, intestinal perforation, pseudomembranous colitis, bleeding from the gastrointestinal tract, disorders of the oral mucosa, heartburn, elevated liver enzymes, including GGT and LDH, increased serum bilirubin.

CNS and peripheral nervous system: insomnia, dizziness, fatigue, drowsiness, nervousness; rarely - convulsions, anxiety, cognitive changes, depression, abnormal dreams, euphoria, hallucinations, paresthesia, syncope, tremor, confusion, nystagmus, suicidal thoughts or attempts, disorientation, psychotic reactions, paranoia, phobia, agitation, aggressiveness, emotional instability, peripheral neuropathy, ataxia, incoordination, exacerbation of extrapyramidal disorders, speech disorder.

Allergic reactions: skin rash, itching, rarely - angioedema, urticaria, vasculitis, allergic pneumonitis, anaphylactic shock, erythema multiforme, Stevens-Johnson syndrome, erythema nodosum, exfoliative dermatitis, toxic epidermal necrolysis, conjunctivitis.

Sexual system: an itch on the external genitalia in women, vaginitis, vaginal discharge; rare - burning, irritation, pain and rash in the genital area of women, dysmenorrhea, menorrhagia, metrorrhagia, vaginal candidiasis.

Cardiovascular system: rarely - heart failure, edema, hypertension, hypotension, palpitation, vasodilatation, cerebral thrombosis, pulmonary edema, and tachycardia.

Urinary system: rarely - dysuria, urinary frequency, urinary retention, anuria, polyuria formation of kidney stones, kidney failure, nephritis, hematuria, albuminuria, candiduria.

Musculoskeletal system: rarely - arthralgia, myalgia, tendonitis, muscle weakness, exacerbation of myasthenia gravis.

Metabolism: rarely - thirst, weight loss, hyper- or hypoglycemia (especially in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents), acidosis, increase in serum triglycerides, cholesterol, potassium.

Respiratory system: rarely - cough, runny nose, respiratory failure, dyspnea, bronchospasm, stridor.

Sensory organs: rarely - hearing loss, tinnit, diplopia, nystagmus, impaired clarity of vision, disturbances of taste, smell, photophobia.

Dermatological reactions: rarely - photosensitivity, hyperpigmentation, vesicle-bullous eruption.

Hematopoietic system: rarely - anemia, hemorrhage, pancytopenia, agranulocytosis, leukopenia, reversible suppression of bone marrow hematopoiesis, thrombocytopenia, thrombocytopenic purpura, petechiae, ecchymosis, increased prothrombin time.

Other: chest pain, sore throat, fever, body aches, rarely - fatigue, chills, malaise, epistaxis, increased sweating.

Ketoflox contraindications

Pregnancy, lactation, childhood and adolescence to 18 years, increased sensitivity to Ketoflox (Ofloxacin) or other quinolone derivatives.

Using during pregnancy and breastfeeding

Ketoflox is contraindicated during pregnancy and lactation.

Category effects on the fetus by FDA - C.

Special instructions

Use with caution in patients with impaired renal function and liver.

During the period of treatment required to conduct monitoring of blood glucose. Long-term therapy is necessary to periodically monitor the kidney function, liver and peripheral blood picture.

When using Ketoflox (Ofloxacin) it should be ensure adequate hydration of the body, the patient should be subjected to ultraviolet irradiation.

In experimental studies the mutagenic potential was not been identified. Long-term studies to determine the carcinogenicity of Ketoflox (Ofloxacin) were not conducted.

Safety and efficacy in children and adolescents under the age of 18 is not defined.

Use with caution in patients whose activities are connected with the necessity of high concentration of attention and quickness of psychomotor reactions.

Ketoflox drug interactions

Simultaneous administration of Ketoflox (Ofloxacin) with: