Product Monograph - Acuvail
RECENT MAJOR LABEL CHANGES
None at the time of the most recent authorization.
TABLE OF CONTENTS
Sections or subsections that are not applicable at the time of authorization are not listed.
RECENT MAJOR LABEL CHANGES ........................................................................................... 2
TABLE OF CONTENTS ............................................................................................................. 2
PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 4
1 INDICATIONS .............................................................................................................. 4
1.1 Pediatrics ................................................................................................................... 4
1.2 Geriatrics ................................................................................................................... 4
2 CONTRAINDICATIONS ................................................................................................. 4
4 DOSAGE AND ADMINISTRATION ................................................................................. 4
4.1 Dosing Considerations .............................................................................................. 4
4.2 Recommended Dose and Dosage Adjustment ......................................................... 4
4.4 Administration .......................................................................................................... 5
4.5 Missed Dose .............................................................................................................. 5
5 OVERDOSAGE ............................................................................................................. 5
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 5
7 WARNINGS AND PRECAUTIONS .................................................................................. 5
7.1 Special Populations ................................................................................................... 6
7.1.1 Pregnant Women ................................................................................................ 6
7.1.2 Breast-feeding ..................................................................................................... 7
7.1.3 Pediatrics ............................................................................................................. 7
7.1.4 Geriatrics ............................................................................................................. 7
8 ADVERSE REACTIONS.................................................................................................. 7
8.1 Adverse Reactions Overview .................................................................................... 7
8.2 Clinical Trial Adverse Reactions ................................................................................ 7
8.3 Less Common Clinical Trial Adverse Reactions (≤1%) ............................................... 9
8.4 Abnormal Hematologic and Clinical Chemistry Findings ........................................ 10
8.5 Post-Market Adverse Reactions .............................................................................. 10 9 DRUG INTERACTIONS ............................................................................................... 10
9.2 Drug Interactions Overview .................................................................................... 10
9.3 Drug-Behavioural Interactions ................................................................................ 11
9.4 Drug-Drug Interactions ........................................................................................... 11
9.5 Drug-Food Interactions ........................................................................................... 12
9.6 Drug-Herb Interactions ........................................................................................... 12
9.7 Drug-Laboratory Test Interactions.......................................................................... 12
10 CLINICAL PHARMACOLOGY ....................................................................................... 12
10.1 Mechanism of Action ........................................................................................ 12
10.2 Pharmacodynamics ........................................................................................... 13
10.3 Pharmacokinetics .............................................................................................. 13
11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 14
12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 14
PART II: SCIENTIFIC INFORMATION ...................................................................................... 15
13 PHARMACEUTICAL INFORMATION ........................................................................... 15
14 CLINICAL TRIALS ....................................................................................................... 15
14.1 Clinical Trial by Indication ................................................................................. 15
Pain and Inflammation Following Cataract Surgery ......................................................... 15
15 MICROBIOLOGY ....................................................................................................... 17
16 NON-CLINICAL TOXICOLOGY ..................................................................................... 17
PATIENT MEDICATION INFORMATION ................................................................................. 20
PART I: HEALTH PROFESSIONAL INFORMATION
1 INDICATIONS
ACUVAIL® (ketorolac tromethamine ophthalmic solution) is indicated for:
- the treatment of pain and inflammation following cataract surgery.
1.1 Pediatrics
Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
1.2 Geriatrics
Geriatrics (> 65 years of age): No overall differences in safety or effectiveness have been observed between elderly and other adult patients.
2 CONTRAINDICATIONS
- Ketorolac tromethamine ophthalmic solution is contraindicated in patients who are hypersensitive to ketorolac, to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, component of the container, or to other nonsteroidal anti-inflammatory drugs (NSAIDs). For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
4 DOSAGE AND ADMINISTRATION
4.1 Dosing Considerations
- There are no data specific for patients with hepatic or renal impairment and therefore specific dosage recommendations cannot be made.
- Concomitant Topical Ocular Therapy: If more than one topical ophthalmic medication is being used, such as antibiotics, alpha-agonists, beta-blockers, cycloplegics, or mydriatics, the medications must be administered at least 5 minutes apart.
- Concomitant Topical Ocular Therapy: Because the administration of ACUVAIL in conjunction with prostaglandin analogues (e.g., Lumigan®, Travatan®, Xalatan®) has not been studied, use only if the benefit outweighs any potential risk.
4.2 Recommended Dose and Dosage Adjustment
- The recommended dose of ACUVAIL is one drop to be applied to the affected eye twice daily beginning 1 day prior to cataract surgery, continued on the day of surgery and through the first two weeks of the postoperative period.
- Approximately two hours prior to surgery, one drop is to be administered approximately every twenty minutes for a total of three drops. Prior to discharge one additional drop is to be administered.
Health Canada has not authorized an indication for pediatric use.
4.4 Administration
Single-use vial
The solution from one single-use vial is to be used immediately after opening for administration to the affected eye(s), and the remaining contents should be discarded immediately after administration. Each vial is intended only for a single treatment in the affected eye(s). To avoid injury and contamination of the eye drops, the tip of the unit-dose vial should not touch the eye or any other surface.
Contact Lens Wear
ACUVAIL solution should not be administered while wearing contact lenses.
If contact lens use is recommended by the physician, they should be removed prior to instillation of ACUVAIL solution and may be re-inserted 15 minutes following administration.
4.5 Missed Dose
If a dose of this medication is missed, it should be taken as soon as possible. However, if it is almost time for the next dose, the missed dose should be skipped and the regular dosing schedule resumed. Doses should not be doubled.
5 OVERDOSAGE
There is no data on overdosage with ACUVAIL or ketorolac tromethamine. If ACUVAIL is accidentally ingested, drink fluids to dilute.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
Table 1 – Dosage Forms, Strengths, Composition and Packaging
ACUVAIL is available as a sterile preservative-free solution supplied in clear, low density polyethylene, single-use vials as follows: follows: 30 single-use vials, 0.4 mL each.
The ACUVAIL solution has a pH of approximately 6.8, and an osmolality of approximately 285 mOsml/kg.
7 WARNINGS AND PRECAUTIONS
General
There exists the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs. See 8.5 Post-Market Adverse Reactions. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.
| Route of | Dosage Form / Strength/ | Non-medicinal Ingredients | ||||
| Administration | Composition | |||||
| Ophthalmic | Solution Ketorolac tromethamine 0.45% w/v | Carboxymethylcellulose sodium, sodium chloride, sodium citrate dihydrate and purified water with sodium hydroxide and/or hydrochloric acid to adjust pH. | ||||
Topical NSAIDs may slow or delay healing (see 7 WARNINGS AND PRECAUTIONS, Ophthalmologic). Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems.
Carcinogenesis and Mutagenesis
See 16 NON-CLINICAL TOXICOLOGY section.
Driving and Operating Machinery
Based on the pharmacodynamic profile, ketorolac is not expected to influence a patient’s ability to drive or operate machinery. As with any ocular medication, if transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machinery.
Hematologic
Bleeding
With some NSAIDs, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly applied NSAIDs may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery.
It is recommended that ACUVAIL be used with caution in patients with known bleeding tendencies or who are receiving other medications, which may prolong bleeding time.
Ophthalmologic
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.
Topical NSAIDs should be used with caution in patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time as they may be at increased risk for corneal adverse events which may become sight threatening.
Post-marketing experience with topical NSAIDs also suggests that use more than 24 hours prior to surgery or use beyond 14 days post-surgery may increase patient risk for the occurrence and severity of corneal adverse events.
Delayed Healing
All topical NSAIDs may slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems.
7.1 Special Populations
7.1.1 Pregnant Women
There are no adequate studies in pregnant women. Therefore, ACUVAIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Ketorolac tromethamine, administered orally during organogenesis, was not teratogenic in rats and rabbits at doses approximately 600 times and 1700 times the typical clinical daily dose of ACUVAIL, respectively. Ketorolac tromethamine resulted in dystocia and increased pup mortality in rats, when administered at oral doses up to approximately 300 times the typical clinical daily dose of ACUVAIL. See 16 NON-CLINICAL TOXICOLOGY.
Because of the known nonteratogenic effects of prostaglandin-inhibiting drugs on the fetal cardiovascular system of rats (closure of the ductus arteriosus), the use of ACUVAIL during late pregnancy should be avoided.
7.1.2 Breast-feeding
Ketorolac tromethamine ophthalmic solutions are not recommended for treatment of nursing mothers.
Secretion of ketorolac tromethamine in human milk after systemic administration is limited. The milk-to-plasma ratio of ketorolac tromethamine concentrations ranged between 0.015 and 0.037 in a study of 10 women.
7.1.3 Pediatrics
Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
7.1.4 Geriatrics
Geriatrics (> 65 years of age): No overall differences in safety or effectiveness have been observed between elderly and other adult patients.
8 ADVERSE REACTIONS
8.1 Adverse Reactions Overview
In the two Phase 3 clinical studies conducted with ACUVAIL, the most frequently occurring adverse drug reactions were IOP increased (5.8%) and AC cell (5.2%). Most treatment-related adverse events were ocular and were mild or moderate. All serious adverse events were non-ocular and none were related to treatment. Twelve patients (3.6%) discontinued from the studies. The most common adverse event leading to study discontinuation was anterior chamber inflammation.
8.2 Clinical Trial Adverse Reactions
Clinical trials are conducted under very specific conditions. Therefore, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
Two randomized, double-masked, phase 3 studies of identical design (191578-005 and 191578-006) evaluated the efficacy and safety of ACUVAIL as compared with vehicle in the treatment of pain and inflammation following cataract surgery. Together in these trials, 511 patients were randomized with only 493 receiving either ACUVAIL (N=330) or the vehicle (N=163) starting on the day before surgery. A total of 309 patients were exposed to ACUVAIL twice daily for 14 days (93.6% of the 330).
Overall, the incidence of adverse events was statistically significantly higher in the vehicle group (48.5 %, 79/163), as compared to the ACUVAIL group (35.2%, 116/330).
Intraocular pressure (IOP) increased was the most commonly reported adverse event, and was significantly more frequent in patients treated with ACUVAIL (5.8%) as compared to those treated with the vehicle (1.8%, p<0.05). Conjunctival hyperemia, eye pain, photophobia, and anterior chamber inflammation were significantly more frequently reported with the vehicle (p<0.05).
IOP measurements performed during the study revealed that increases in IOP ≥ 10 mm Hg were recorded in 32 patients treated with ACUVAIL (9.7%), as compared to 7 patients treated with the vehicle (4.3%). These cases were mostly reported at day 1 (or day 3) and not present afterwards since they were reversible, either spontaneously or after drug treatment. No increased IOP-related complications were reported.
Some of the adverse events may have been the result of the cataract surgical procedure itself. Therefore, the adverse events presented in the following Table 2 may or may not be related to the use of ACUVAIL.
Table 2 – Adverse Events (occurring in ≥ 3 patients) by Decreasing Incidence (n [%]) organized by System Organ Class (SOC) of MedDRA
| ACUVAIL | Placebo | |||||
| n = 330 | n = 163 | |||||
| (%) | (%)* | |||||
Eye disorders AC cell Conjunctival hyperaemia Eye pain Iritis AC flare Corneal oedema Foreign body sensation in eyes Lacrimation increased Conjunctival haemorrhage Vision blurred Photophobia Conjunctival oedema Eye irritation Eye pruritus Vitreous detachment Posterior capsule rupture Vitreous floaters AC fibrin Macular oedema Punctate keratitis | 17 (5.2) 15 (4.5) 14 (4.2) 14 (4.2) 12 (3.6) 11 (3.3) 11 (3.3) 4 (1.2) 4 (1.2) 4 (1.2) 3 (0.9) 3 (0.9) 3 (0.9) 3 (0.9) 3 (0.9) 3 (0.9) 3 (0.9) 2 (0.6) 2 (0.6) 2 (0.6) | 10 (6.1) 23 (14.1)* 25 (15.3)* 12 (7.4) 8 (4.9) 10 (6.1) 9 (5.5) 4 (2.5) 1 (0.6) 1 (0.6) 16 (9.8)* 4 (2.5) 4 (2.5) 3 (1.8) 1 (0.6) 0 (0.0) 0 (0.0) 2 (1.2) 1 (0.6) 1 (0.6) | ||||
| ACUVAIL | Placebo | |||||
| n = 330 | n = 163 | |||||
| (%) | (%)* | |||||
| AC inflammation Iris haemorrhage Eyelid oedema Uveitis | 1 (0.3) 1 (0.3) 0 (0.0) 0 (0.0) | 6 (3.7)* 2 (1.2) 3 (1.8)* 3 (1.8)* | ||||
Gastrointestinal Nausea | 2 (0.6) | 1 (0.6) | ||||
General disorders and administration site conditions Facial pain | 0 (0.0) | 3 (1.8)* | ||||
Injury, poisoning and procedural complications Cataract operation complication Corneal abrasion | 3 (0.9) 2 (0.6) | 1 (0.6) 1 (0.6) | ||||
Investigations IOP increased | 19 (5.8) | 3 (1.8)† | ||||
Nervous system disorders Headache | 10 (3.0) | 6 (3.7) | ||||
*: statistically significantly higher rate (p<0.05) in the vehicle group †: statistically significantly higher rate (p<0.05) in the ACUVAIL group | ||||||
8.3 Less Common Clinical Trial Adverse Reactions (≤1%)
Adverse events observed at an incidence of ≤1% in the 2 pooled phase 3 studies are provided below. Some of the adverse events may have been the result of the cataract surgical procedure itself. Therefore, the adverse events presented below may or may not be related to the use of ACUVAIL.
Cardiac disorders: atrial fibrillation, angina unstable, bradycardia, cardiac arrest, coronary artery occlusion
Eye Disorders: photophobia, conjunctival oedema, eye irritation, eye pruritus, vitreous detachment, posterior capsule rupture, vitreous floaters, anterior chamber fibrin, macular oedema, punctate keratitis, photopsia, pupillary disorder, visual disturbance, anterior chamber inflammation, iris haemorrhage, erythema of eyelid, maculopathy, asthenopia, conjunctivitis allergic, corneal disorder, Dellen, eyelids pruritus, instillation site irritation, keratoconjunctivitis sicca, lenticular opacities, ocular hyperaemia, pupillary deformity, retinal tear, trichiasis, vitreous disorder, vitreous prolapse
Gastrointestinal disorders: nausea
Infections and infestations: urinary tract infection, bronchitis, hypopyon, nasopharyngitis, rhinitis, upper respiratory tract infection
Injury, poisoning and procedural complications: corneal abrasion, cataract operation complication, eye operation complication fall, limb injury periorbital haematoma, post procedural haemorrhage, procedural headache, procedural nausea
Musculoskeletal and connective tissue disorders: back pain, pain in extremity
Nervous system disorders: sinus headache
Psychiatric disorders: confusional state
Reproductive system and breast disorders: prostatic pain
Respiratory, thoracic and mediastinal disorders: rhinorrhoea, sneezing
8.4 Abnormal Hematologic and Clinical Chemistry Findings
Clinical laboratory evaluations were not performed for any of the clinical studies. No laboratory abnormalities were reported as adverse events in any of the clinical studies.
8.5 Post-Market Adverse Reactions
The following adverse events have been reported since marketing but due to the expected underreporting from spontaneous sources, the frequencies are unknown:
Eye disorders: eye swelling, eye oedema
Treatment-related eye irritation has been observed following the use of ACULAR (ketorolac tromethamine 0.5%).
Post-marketing experiences with ACULAR (ketorolac tromethamine 0.5%), suggest that topical NSAIDs used by patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface disease, rheumatoid arthritis, or repeat ocular surgeries within a short period of time may be at an increased risk of corneal adverse events. These may include keratitis, epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration or corneal perforation. There were also case reports of ulcerative keratitis with the use of ACUVAIL, some of which were serious.
Post-marketing experience with topical NSAIDs also suggests that use more than 24 hour prior to surgery or use beyond 14 days post-surgery may increase patient risk for the occurrence and severity of corneal adverse events.
There have been post-marketing reports of bronchospasm or exacerbation of asthma, in patients, who have either a known hypersensitivity to aspirin/NSAIDs or a past medical history of asthma, associated with the use of ACULAR (ketorolac tromethamine 0.5%) which may be contributory (see 7 WARNINGS AND PRECAUTIONS of the ACULAR/ACULAR LS Product Monograph).
9 DRUG INTERACTIONS
9.2 Drug Interactions Overview
No interaction studies were conducted.
9.3 Drug-Behavioural Interactions
No formal drug-behavioural interaction studies were conducted.
9.4 Drug-Drug Interactions
The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).
Table 3 – Summary of Effect of Co-administered Drugs on Exposure to ACUVAIL
| Co-administered drug | Source of | Effect | Clinical comment | ||
| Evidence | |||||
| Acetylsalicylic acid | T | Potential for cross- sensitivity | Caution should be exercised when using ketorolac tromethamine in individuals with previously exhibited sensitivities to these drugs. | ||
| Phenylacetic acid derivatives | T | Potential for cross- sensitivity | Caution should be exercised when using ketorolac tromethamine in individuals with previously exhibited sensitivities to these drugs. | ||
| Other NSAIDs | T | Potential for cross- sensitivity | Caution should be exercised when using ketorolac tromethamine in individuals with previously exhibited sensitivities to other NSAIDs. | ||
| Topical steroids | T | Potential for healing problems | Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems. (See 7 WARNINGS AND PRECAUTIONS, Ophthalmologic) | ||
| NSAIDs | T | Potential for increased bleeding time due to interference with thrombocyte aggregation | Recommended that 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. (See 7 WARNINGS AND PRECAUTIONS, Hematologic) | ||
| Co-administered drug | Source of | Effect | Clinical comment | ||
| Evidence | |||||
| NSAIDs | T | Potential for increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery | Recommended that 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. (See 7 WARNINGS AND PRECAUTIONS, Hematologic) | ||
| Legend: T = Theoretical | |||||
Ketorolac tromethamine ophthalmic solution may be administered in conjunction with other topical ophthalmic medications such as alpha-agonists, antibiotics, beta blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics.
9.5 Drug-Food Interactions
Interactions with food have not been established.
9.6 Drug-Herb Interactions
Interactions with herbal products have not been established.
9.7 Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
10 CLINICAL PHARMACOLOGY
10.1 Mechanism of Action
Ketorolac tromethamine is a non-steroidal, anti-inflammatory agent with analgesic and anti-inflammatory activity mediated by peripheral effects. The mechanism of its action is thought to be due to its ability to inhibit prostaglandin biosynthesis. Ketorolac tromethamine given systemically does not cause pupil constriction.
Ketorolac tromethamine has demonstrated anti-inflammatory activity when applied topically in several animal models of ocular inflammation. It significantly inhibited the inflammatory responses to silver nitrate-induced cauterization of the corneas of rat eyes at concentrations of 0.25% and 0.5%. Concentrations of ketorolac ranging from 0.02% to 0.5% blocked vascular permeability changes caused by endotoxin-induced uveitis in the eyes of rabbits. Using the same model, ketorolac also blocked endotoxin-induced elevation of aqueous humor PGE2. It prevented the development of increased intraocular pressure induced in rabbits with topically applied arachidonic acid. Ketorolac did not inhibit rabbit lens aldose reductase in vitro.
10.2 Pharmacodynamics
Ketorolac tromethamine ophthalmic solution prevented the development of increased intraocular pressure induced in rabbits with topically applied arachidonic acid. Ketorolac did not inhibit rabbit lens’ aldose reductase in vitro.
Ketorolac tromethamine ophthalmic solution did not enhance the spread of ocular infections induced in rabbits with Candida albicans, herpes simplex virus type one, or Pseudomonas aeruginosa.
10.3 Pharmacokinetics
Absorption
In human studies, penetration of the drug is rapid after application to the eye. The relationship between the concentrations of solution administered and the amount of drug that penetrates the cornea is roughly linear.
Two drops (0.1 mL) of 0.5% ketorolac tromethamine ophthalmic solution, instilled into the eyes of patients 12 hours and 1 hour prior to cataract extraction, achieved measurable levels in 8 of 9 patients’ eyes. The mean ketorolac concentration was 95 ng/mL in the aqueous humor and the range was 40 ng/mL to 170 ng/mL. The mean concentration of PGE2 was 80 pg/mL in the aqueous humor of eyes receiving vehicle and 28 pg/mL in the eyes receiving 0.5% ketorolac tromethamine ophthalmic solution.
One drop (0.05 mL) of 0.5% ketorolac tromethamine ophthalmic solution was instilled into one eye and one drop of the vehicle into the other eye three times daily. for 21 days in 26 healthy subjects. Only 5 of 26 subjects had detectable amount of ketorolac in their plasma (range 10.7 ng/mL and 22.5 ng/mL) when tested 15 minutes after the morning dose on day 10.
When ketorolac is given systemically to relieve pain, the average plasma level following chronic systemic treatment was approximately 850 ng/mL.
In animal studies, ketorolac tromethamine levels in plasma were measured in four rabbits after administration in one eye, of one drop 5 times daily of 0.45% ketorolac tromethamine formulated in a CMC-based ophthalmic solution. Ketorolac tromethamine was detectable in plasma at relatively low levels (see Table 4).
Table 4 – Plasma Ketorolac Pharmacokinetics in NZW rabbits after unilateral topical ocular administration of 0.45% Ketorolac Tromethamine (one drop five times daily), Report PK-07-090
| Species | Study Day | Dose (%w/v) | Cmax | Tmax | AUC0-t |
| n/timepoint | (ng/mL) | (hr) | (ng·hr/mL) | ||
| 4F | 1 | 0.45 | 99.0 (15.0) | 0.500 | 260 (46) |
| 28 | 0.45 | 111 (41) | 0.500 | 372 (125) | |
Cmax: Mean (±SD) AUC: Composite area under the curve (±SE) F: Female | |||||
Based on indirect comparison, systemic ketorolac exposure levels achieved following ocular administration of ACUVAIL solution are probably not significantly different from levels achieved with 0.5% ketorolac tromethamine ophthalmic solution.
Following a single topical ocular instillation of 0.45% ketorolac tromethamine in rabbits (N=2/group), ketorolac was absorbed into the aqueous humor with Tmax occurring 2 hours post-dose. The bioavailability of ketorolac increased in aqueous humor to approximately 200%, as compared with ACULAR LS (ketorolac tromethamine 0.4%).
Distribution
Animal studies have shown that 14C-labelled ophthalmic solution 0.5% was found to be extensively distributed in ocular tissues with major portions retained in the cornea and sclera.
Metabolism
Although no studies have been conducted regarding the sites of metabolism for ophthalmic ketorolac, studies of systemic administration have shown that the drug is metabolized in the liver.
Excretion
Results of studies in rabbits and cynomolgus monkeys suggest that the major route of drug elimination from the eye is probably through intraocular blood flow after distribution from the aqueous humor to the iris-ciliary body.
Special Populations and Conditions
- Pediatrics: Safety and effectiveness in pediatric patients have not been established.
- Geriatrics: No overall differences in safety or effectiveness have been observed between elderly and other adult patients.
- Hepatic Insufficiency: Ketorolac tromethamine has not been studied in patients with hepatic impairment.
- Renal Insufficiency: Ketorolac tromethamine has not been studied in patients with renal impairment.
11 STORAGE, STABILITY AND DISPOSAL
ACUVAIL should be stored at room temperature (15 to 30°C). Store the vials in the pouch, protected from light. Fold pouch ends closed.
12 SPECIAL HANDLING INSTRUCTIONS
There are no special handling instructions.
PART II: SCIENTIFIC INFORMATION
13 PHARMACEUTICAL INFORMATION
Drug Substance
Proper name: ketorolac tromethamine ophthalmic solution 0.45%
Chemical name: (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-
(hydroxymethyl)-1,3-propanediol (1:1)
2-amino-2-(hydroxymethyl)propane-1,3-diol (1RS)-5-benzoyl-2,3-dihydro-1H- pyrrolizine-1-carboxylate
Molecular formula and molecular mass: C19H24N2O6 ; 376.41
Structural formula:
Physicochemical properties: 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.
14 CLINICAL TRIALS
14.1 Clinical Trial by Indication
Pain and Inflammation Following Cataract Surgery
Table 5 – Summary of patient demographics for clinical trials in treatment of pain and inflammation following cataract surgery
| Study # | Study Design | Dosage, route of administration and duration | Study | Mean age (range) | Sex (M/F) | Race | |
| subjects (n) | |||||||
| (entered / | |||||||
| completed) | |||||||
| 191578-005 | Multicenter, randomized, double-masked, parallel group comparison study | ACUVAIL ophthalmic BID vehicle BID 16 days | 248/201 | 68 (40-89) | 107 (43%) / 141 (57%) | Caucasians: 220 (89%) Others: 28 (11%) | |
C N C
O
O
OH HO OH
OH
NH2
.
| Study # | Study Design | Dosage, route of administration and duration | Study subjects (n) (entered / completed) | Mean age (range) | Sex (M/F) | Race | |
| in patients with cataract surgery | |||||||
| 191578-006 | Multicenter, randomized, double-masked, parallel group comparison study in patients with cataract surgery | ACUVAIL ophthalmic BID vehicle BID 16 days | 263/222 | 68 (28-94) | 111 (42%) / 152 (58%) | Caucasians: 216 (82%) Others: 47 (18%) | |
Two multicenter, randomized, double-masked, parallel group comparison studies (191578-005 and 191578-006) of identical design including 511 patients assessed the effects of ACUVAIL on a summed ocular inflammation score (SOIS) of anterior chamber cell and flare (primary efficacy), ocular pain relief and analysis of pupil size (secondary efficacy endpoints) following cataract extraction with posterior chamber intraocular lens (IOL) implantation. All patients had planned unilateral, single procedure, uncomplicated phacoemulsification extracapsular cataract extraction with posterior chamber IOL implant under topical or intracameral anesthesia at the start of the procedure with no capsular staining during phacoemulsification.
One drop was administered twice daily beginning 1 day prior to cataract surgery and continued on the day of surgery and through the first two weeks post-surgery. On the day of surgery, two hours prior to surgery, one drop was administered every 20 minutes for a total of three drops. Prior to discharge, one additional drop was also administered.
Patient demographics and baseline characteristics were similar across studies and were not significantly different across treatment groups for age, sex, or race (Table 5).
Table 6 – Results of Studies 191579-005 and 191578-006 in Treatment of pain and inflammation following cataract surgery (Modified Intent-to-Treat Population)
| Primary Endpoint | Secondary Endpoints | |||||||||||
| Study | Treatment Arm P-Value | # Enrolled/ Completed | Day 14 SOIS = 0 | Day 1 Pain Score = 0 (b) | Mean Pupil Area | |||||||
| Post-I&A | ||||||||||||
| Placement (b) | ||||||||||||
| 191578-005 | Ketorolac 0.45% BID Vehicle BID P-value(a) | 155/144 79/57 — | 69/149 (46.3%) 20/78 (25.6%) 0.002 | 114/152 (75.0%) 32/78 (41.0%) < 0.001 | 41.8 mm2 41.1 mm2 0.706 | |||||||
| Primary Endpoint | Secondary Endpoints | ||||||||||||
| Study | Treatment Arm P-Value | # Enrolled/ Completed | Day 14 SOIS = 0 | Day 1 Pain Score = 0 (b) | Mean Pupil Area | ||||||||
| Post-I&A | |||||||||||||
| Placement (b) | |||||||||||||
| 191578-006 | Ketorolac 0.45% BID Vehicle BID P-value (a) | 173/163 82/59 — | 98/169 (58.0%) 21/77 (27.3%) < 0.001 | 119/170 (70.0%) 30/78 (38.5%) < 0.001 | 37.9 mm2 36.5 mm2 0.413 | ||||||||
BID = twice daily; I&A = irrigation and aspiration; SOIS = summed ocular inflammation score. (a) P-values for SOIS Score and Pain Score are from a 2-sided Pearson’s chi-square test. P-values for pupil area are from a 1-way analysis of variance model. (b) For secondary efficacy variables gate keeping method was employed to address multiple testing. | |||||||||||||
Together in these trials, 511 patients were randomized with only 493 receiving either ACUVAIL (N=330) or the vehicle (N=163) starting on the day before surgery. A total of 309 patients were exposed to ACUVAIL twice daily for 14 days (93.6% of the 330).
For the primary efficacy endpoint in both studies, patients receiving ACUVAIL had a statistically significantly higher incidence (46.3% to 58.0%) of clearing of anterior chamber inflammation (SOIS = 0 on day 14) compared with patients receiving vehicle (25.6% to 27.3%). For the secondary efficacy endpoints, ACUVAIL was statistically significantly superior to vehicle in resolving ocular pain at day 1 post-cataract surgery in both studies. No significant difference was observed between ACUVAIL and vehicle in the inhibition of surgically induced miosis post-I&A (irrigation and aspiration) in either study.
15 MICROBIOLOGY
No microbiological information is required for this drug product.
16 NON-CLINICAL TOXICOLOGY
Acute toxicity: Two single-day studies in New Zealand White (NZW) rabbits were treated with a topical ocular drop of ketorolac tromethamine at 0.45% or its vehicle for up to 6 drops for one day. In one study, no drug-related ocular effects were observed. In another study, slight drug- and pH-related effects on ocular discomfort but no significant drug- or vehicle-related effects were recorded.
Other studies performed with other ketorolac ophthalmic solutions in support of ACULAR 0.5% ophthalmic solution are presented below.
Table 7 – Acute Toxicity
| Species Strain Regimen Group Size | Route | Mortality | Clinical |
| Preservative | Concentration* | Ophthalmology | |
| (mg/mL) | |||
Rabbit New Zealand One dose in right eye followed by a 72-hour observation 3 females 0.01% BAC | Ocular | ||
| 2.5 | 0/3 | NDE | |
| 5.0 | 0/3 | NDE | |
| 10.0 | 0/3 | NDE | |
| 20.0 | 0/3 | NDE | |
| 40.0 | 0/3 | NDE | |
Rabbit New Zealand One dose every 30 min for a total of 12 doses to both eyes. Eyes were examined after the last dose and on days 1, 2, 3 and 6 following dosing 6 males 0.01% BAC | Ocular | ||
| Saline control | 0/6 | NDE | |
| Vehicle control | 0/6 | ||
| 5.0 | 0/6 | ||
*Volume = 0.1 mL/eye NDE: No drug effect (no indications of irritation or toxicity) BAC: Benzalkonium chloride | |||
Sub chronic toxicity: In a 1-month study, NZW rabbits received either ketorolac tromethamine 0.45% or the vehicle in the left eye 5 drops per day for 28 days (with 9 drops per day on day 2 and day3). No significant treatment-related findings were noted as per the clinical observations, tonometry, ophthalmic examinations, and pathology examinations (study TX07042).
In a 6-day ocular wound healing study (N=10 per group), after anterior keratectomy, NZW rabbits were administered ketorolac tromethamine ophthalmic solutions 0.45% or 0.35%, or ACULAR LS (0.40%), up to 4 times daily. Both 0.45% ketorolac tromethamine and ACULAR LS resulted in a statistically significant delay in corneal wound healing in comparison with the controls. On day 6, the wound area was 1.3 mm2 with the blank control (2% of its baseline size), as compared with 6 mm2 with the 0.45% formulation (11% of its baseline size). Comparable delays were seen with ACULAR LS, and the 0.35% ketorolac tromethamine formulation (study TX07062).
Long-term toxicity: The following studies were performed with other ketorolac tromethamine ophthalmic solutions in support of ACULAR 0.5% ophthalmic solution. Note that some of these solutions contained Benzalkonium chloride (BAC).
Ketorolac ophthalmic solution was evaluated in rabbits (pigmented and non-pigmented) in studies up to 6 weeks, and in monkeys in studies lasting up to 6 months.
The results of the preclinical toxicology studies indicate no adverse drug-related effects to ketorolac tromethamine. No adverse effects were observed in monkeys following 6 months of treatment with a thimerosal-preserved formulation. However, in studies with the BAC formulation, corneal fluorescein staining, accompanied by thinning of the epithelium, was seen in vehicle-treated and drug-treated animals. The Dutch Belted rabbit was most sensitive to these effects, with the New Zealand rabbit and the monkey showing decreasing sensitivities. Since the effects were seen primarily in vehicle and low-dose groups and since similar effects have been reported for BAC, the corneal changes were attributed to the preservative. The difference in sensitivity shown by the rabbit compared to the primate may be explained physiologically because of the greater blinking rate and lacrimal response to irritation in primates, including humans. In fact, formulations containing 0.01% BAC are well tolerated by humans and are approved as over-the-counter ophthalmic medications.
Carcinogenicity: 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 respectively 900 times and 300 times higher than the typical human topical ophthalmic daily dose of 0.324 mg given twice daily to an affected eye on a mg/kg basis.
Genotoxicity: 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, ketorolac tromethamine did result in an increased incidence in chromosomal aberrations in Chinese hamster ovary cells.
Reproductive and Developmental Toxicology: Ketorolac tromethamine did not impair fertility when administered orally to male and female rats at doses up 9 mg/kg/day and 16 mg/kg/day, respectively. These doses are respectively 1500 and 2700 times higher than the typical human topical ophthalmic daily dose.
Ketorolac tromethamine, administered orally during organogenesis, was not teratogenic at doses of 3.6 mg/kg/day in rabbits, and 10 mg/kg/day in rats; that is, approximately 600 times and 1700 times higher respectively than the typical human topical ophthalmic daily dose. When administered to rats after Day 17 of gestation at oral doses up to 1.5 mg/kg/day (approximately 300 times the typical human topical ophthalmic daily dose), ketorolac tromethamine resulted in dystocia and increased pup mortality.