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KETOROLAC TROMETAMOL 5 MG/ML EYE DROPS SOLUTION

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Ketorolac trometamol 5 mg/ml eye drops, solution

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of solution contains 5 mg ketorolac trometamol (0.5 % w/v)
Excipient(s): contains benzalkonium chloride 0.1 mg/ml (0.01 %w/v)
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Eye drops, solution.
Clear and colourless solution

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Ketorolac trometamol 5 mg/ml eye drops are indicated for the prophylaxis and
reduction of inflammation and associated symptoms following ocular surgery.
Ketorolac trometamol 5 mg/ml eye drops are indicated in adults.

4.2

Posology and method of administration
Posology
Post-operative inflammation:
One drop instilled into the eye three times daily starting 24 hours pre-operatively and
continuing for up to three weeks post-operatively.

Paediatric population
There is no relevant use of Ketorolac trometamol 5 mg/ml eye drops in the paediatric
population.
Method of administration
Ocular use.
Instil one drop of the solution into the inferior conjunctival sac of the eye to be
treated, while pulling the lower eyelid gently downwards and looking upwards.
No special dosage for the elderly.

4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients.
The potential exists for cross-sensitivity to acetylsalicylic acid and other non-steroidal
anti-inflammatory drugs. Ketorolac trometamol 5 mg/ml eye drops are contraindicated in individuals who have previously exhibited sensitivities to these drugs.

4.4

Special warnings and precautions for use
It is recommended that Ketorolac trometamol 5 mg/ml eye drops be used with caution
in patients with known bleeding tendencies or who are receiving other medications
which may prolong bleeding time.
In common with other anti-inflammatory drugs, Ketorolac trometamol 5 mg/ml eye
drops may mask the usual signs of infection.
All non-steroidal anti-inflammatory drugs (NSAIDs) may slow down or delay wound
healing. Concomitant use of NSAIDs and topical steroids can increase the potential
for healing problems.
Concomitant use of Ketorolac trometamol 5 mg/ml eye drops and topical
corticosteroids should be exercised with caution in patients susceptible to corneal
epithelial breakdown.
Use of topical NSAIDS may result in keratitis. In some 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 suggest 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.
The preservative in Ketorolac trometamol 5 mg/ml eye drops, benzalkonium chloride,
may cause eye irritation. Contact lenses must be removed prior to application, with at
least a 15-minute wait before reinsertion. Benzalkonium chloride is known to
discolour soft contact lenses. Contact with soft contact lenses must be avoided.
There have been post-marketing reports of bronchospasm or exacerbation of asthma
in patients, who have either a known hypersensitivity to aspirin/non-steroidal antiinflammatory drugs or a past medical history of asthma associated with the use of
Ketorolac trometamol 5 mg/ml eye drops , which may be contributory. Caution is
recommended in the use of Ketorolac trometamol 5 mg/ml eye drops in these
individuals (see section 4.8).

4.5

Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
Ketorolac trometamol 5 mg/ml eye drops have been safely administered with
systemic and ophthalmic medications such as antibiotics, sedatives, beta blockers,
carbonic anhydrase inhibitors, miotics, mydriatics, local anaesthetics and
cycloplegics.
Ketorolac trometamol 5 mg/ml eye drops may slow or delay healing. Topical
corticosteroids are also known to slow or delay healing. Concomitant use of topical
NSAIDs and topical corticosteroids may increase the potential for healing problems
(see section 4.4).
If Ketorolac trometamol 5 mg/ml eye drops are used concomitantly with other topical
eye medications there must be an interval of at least 5 minutes between the two
medications.

4.6

Fertility, pregnancy and lactation
Fertility
There are no adequate data from the use of ketorolac trometamol on fertility in
humans.
Pregnancy
There are no or a limited amount of data from the use of ketorolac trometamol in
pregnant women. Animal studies are insufficient with respect to reproductive
toxicity. Ketorolac trometamol 5 mg/ml eye drops are not recommended during
pregnancy and in women of childbearing potential not using contraception.
Breastfeeding

Ketorolac trometamol 5 mg/ml eye drops should not be used during breast-feeding.
Ketorolac trometamol is excreted in human milk after systemic administration.

4.7

Effects on ability to drive and use machines
Ketorolac trometamol 5 mg/ml eye drops have no or negligible influence on the
ability to drive and use machines.
Transient blurring of vision may occur on instillation of eye drops. Do not drive or
use machinery unless vision is clear.

Undesirable effects
Frequencies are defined as:
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)



4.8

Very rare (<1/10,000)
Not known (cannot be estimated from the available data).
The most frequent adverse events reported with the use of Ketorolac are transient
stinging and burning on instillation.

MedDRA
Very
System organ Common
class
Nervous
system
disorders
Immune
system
disorders

Eye disorders Eye irritation
(including
burning
sensation)
Eye pain
(including
stinging)

Respiratory,

Common

Uncommon

Not known

Headache

Hypersensitivity
including
localised
allergic
reactions
Superficial
(punctate)
keratitis (SPK),
eye and/or
eyelid oedema,
Ocular pruritus,
Conjunctival
hyperaemia,
Eye infection,
Eye
inflammation

Corneal ulcer ,
corneal
infiltrates,
blurred and/or
diminished
vision, eye
dryness,
Epiphora,
Iritis

Corneal
damage, e.g.
thinning,
erosion,
epithelial
breakdown
and
perforation*

Bronchospasm

thoracic and
mediastinal
disorders

or
exacerbation
of asthma**

The events listed above are classified according to their incidence in clinical trials.
*Occasional post marketing reports of corneal damage including corneal thinning,
corneal erosion, epithelial breakdown and corneal perforation have been received.
These occurred mainly in patients using concomitant topical corticosteroids and/or
with predisposing co-morbidity (see warnings and precautions section 4.4).
**There have been post-marketing reports of bronchospasm or exacerbation of
asthma, in patients, who have either a known hypersensitivity to aspirin/non-steroidal
anti-inflammatory drugs or a past medical history of asthma, associated with the use
of Ketorolac trometamol 5 mg/ml eye drops which may be contributory.
None of the typical adverse reactions reported with the use of systemic non-steroidal
anti-inflammatory agents (including ketorolac trometamol) have been observed at the
doses used in topical ophthalmic therapy.

4.9

Overdose
No case of overdose has been reported. Overdose is unlikely to occur via the
recommended method of administration.
If accidentally ingested, drink fluids to dilute.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Antiinflammatory agents, non-steroids, ATC
code: S01BC 05
Ketorolac trometamol is a non-steroidal anti-inflammatory agent
demonstrating analgesic and anti-inflammatory activity. Ketorolac trometamol
inhibits the cyclo-oxygenase enzyme essential for biosynthesis of
prostaglandins. Ketorolac has been shown to reduce prostaglandin levels in the
aqueous humour after topical ophthalmic administration.
Ketorolac trometamol given systemically does not cause pupil constriction.
Results from clinical studies indicate that ketorolac has no significant effect on
intra-ocular pressure.

5.2

Pharmacokinetic properties

a) General characteristics

Absorption
Rabbit aqueous humour bioavailability
0.856 µg-equiv./ml @ 0.5 hr
Mean concentration of total radioactivity
1.607 µg-equiv./ml @ 2 hr
Tmax
3.38 hr
Cmax
1.905 µg-equiv./ml
AUC (0-8 hr)
9.39 µg-equiv. hr/ml
Total AUC
13.53 µg-equiv. hr/ml
Half-life
3.77 hr
Absolute ocular bioavailability
3.7%
After topical ocular doses in the rabbit the half life of total radioactivity in
aqueous humor was longer than after intracameral injection. This suggests that
topical dosing may lead to a "reservoir" effect in the corneal epithelium and
continued flux of drug from the reservoir into the aqueous humor.
Distribution
After ophthalmic doses were administered to rabbits, peak concentrations of
radioactivity were achieved within 1 hour in the ocular tissues and were
highest in the cornea (6.06 µg-eq/ml). At 1 hour, the majority of the
radioactivity (0.9% of administered dose) was recovered from the sclera
(0.58%) and cornea (0.24%), and smaller amounts were recovered from the
aqueous humor (0.026%), vitreous humor (0.023%), retina-choroid (0.018%),
iris-ciliary body (0.007%) and lens (0.002%).
Relative to plasma AUC values, the AUC's in rabbits were higher for cornea
(104 fold), sclera (27 fold), iris-ciliary body (5.8 fold), retina-choroid (5.6
fold) aqueous humor (3.3 fold) and approximately one-half in the vitreous
humor and lens. After ophthalmic administration, concentrations of drugrelated radioactivity were higher in the ocular tissues and lower in plasma
compared with those after IV dosing.
Systemic Absorption
After ophthalmic doses in the rabbit, ketorolac was absorbed rapidly into the
systemic circulation (Tmax, 15 min). Plasma half-lives after ophthalmic doses
(6.6 - 6.9 hr) were longer than those after IV administration (1.1 hr),
suggesting that removal of drug from eye into the venous circulation may be
rate-limiting. By comparison of drug levels in aqueous humor after
intracameral injection vs. plasma levels after IV administration, ketorolac was
shown to clear more rapidly from plasma (6 ml/min) than from the anterior
chamber (11 µl/min).
In the cynomolgus monkey, peak plasma levels of ketorolac occurred at 1.1 hr
after the ophthalmic dose. The plasma half-life of ketorolac was similar after
ophthalmic (1.8 hr) and IV doses (1.6 hr).
The majority of the ophthalmic dose was excreted in urine (66% in rabbit and
75% in monkey) and a small amount in faeces (11% in rabbit and 2% in
monkey). The extent of systemic absorption after ophthalmic dosing averaged
73% in the rabbit and 76% in the cynomolgus monkey.
Metabolism

After ophthalmic administration in rabbits, ketorolac represented the major
component (more than 90%) of radioactivity in aqueous humor and plasma
and the p-hydroxy metabolite accounted for 5% of radioactivity in plasma.
Ketorolac was also the major component (96%) of plasma radioactivity after
ophthalmic dosing in monkeys.
After ophthalmic dosing in the rabbit, 72%, 17% and 6% of the total
radioactivity in urine was comprised of intact ketorolac, p-hydroxy ketorolac
and other polar metabolites, respectively. After IV dosing, the relative
proportions of total radioactivity in urine averaged 6% as intact ketorolac,
68% as p-hydroxy ketorolac and 22% as polar metabolites.
In the monkey, intact ketorolac and its polar metabolite accounted for 32% and
65% of the total radioactivity in urine, respectively, after ophthalmic dosing,
and 50% and 49% of the radioactivity in urine, respectively, after IV dosing.
Thus, the metabolism of ketorolac was qualitatively similar after ophthalmic
and IV administration in the monkey and rabbit.
b) Characteristics in patients
Ketorolac trometamol solutions (0.1% or 0.5%) or vehicle were instilled into
the eyes of patients approximately 12 hours and 1 hour prior to surgery.
Concentrations of ketorolac in aqueous humour sampled at the time of surgery
were at the lower limit of detection (40 ng/ml) in 1 patient and below the
quantitation limit in 7 patients dosed with 0.1% ketorolac trometamol. The
average aqueous humor level of ketorolac in patients treated with 0.5%
ketorolac trometamol was 95 ng/ml. Concentrations of PGE2 in aqueous
humour were 80 pg/ml, 40 pg/ml and 28 pg/ml in patients treated with vehicle,
0.1% ketorolac trometamol and 0.5% ketorolac trometamol, respectively.
In the 21-day multiple dose (TID) tolerance study in healthy subjects, only 1
of 13 subjects had a detectable plasma level pre-dose (0.021 µg/ml). In another
group of 13 subjects, only 4 subjects showed very low plasma levels of
ketorolac (0.011 to 0.023 µg/ml) 15 minutes after the ocular dose.
Thus, higher levels of ketorolac in the aqueous humor and very low or no
detectable plasma levels after ophthalmic doses, suggest that the use of
ketorolac trometamol by the ophthalmic route in treatment of ocular disorders
results in quite low systemic absorption in patients.

5.3

Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies
of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential,
toxicity to reproduction and development.
Acute, sub-acute and chronic studies of ketorolac in experimental animals have
established the safety of the drug. In addition, octoxynol 40 was separately evaluated
for its ocular safety. Ketorolac was found to be non-irritating, it did not demonstrate a
local anaesthetic effect, it did not influence the healing of experimental corneal
wounds in rabbits, it did not enhance the spread of experimental ocular infections of

Candida albicans, Herpes simplex virus type one, or Pseudomonas aeruginosa in
rabbits, and it did not increase the ocular pressure of normal rabbit eyes.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium chloride
Benzalkonium chloride
Edetate disodium
Octoxynol 40
Sodium hydroxide (for pH adjustment)
Water for injection

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years
After first opening: 4 weeks.

6.4

Special precautions for storage
This product does not require any special storage conditions

6.5

Nature and contents of container
White low density polyethylene (LDPE) dropper bottles with transparent LDPE
dropper tips and white high density polyethylene (HPDE) screw caps. Each bottle
contains 5 ml eye drops. It is available in packs of 1 bottle or packs of 3 bottles.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Biokanol Pharma GmbH
Kehler Str. 7,
76437 Rastatt
Germany

8

MARKETING AUTHORISATION NUMBER(S)
PL 20812/0003

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
09/08/2011

10

DATE OF REVISION OF THE TEXT
28/02/2013

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