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EYLAMDO 20MG/ML +5MG/ML EYE DROPS SOLUTION.

Active substance(s): DORZOLAMIDE HYDROCHLORIDE / TIMOLOL MALEATE / DORZOLAMIDE HYDROCHLORIDE / TIMOLOL MALEATE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Eylamdo 20mg/ml + 5mg/ml eye drops, solution

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 20 mg of dorzolamide (as hydrochloride) and 5 mg of timolol (as
maleate).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Eye drops, solution
Clear, colourless, slightly viscous aqueous solution, with a pH between 5.0 and 6.0,
and an osmolality of 242-323 mOsM/Kg.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Indicated in the treatment of elevated intraocular pressure (IOP) in patients with
open-angle glaucoma or pseudoexfoliative glaucoma when topical beta-blocker
monotherapy is not sufficient.

4.2

Posology and method of administration
Posology

The dose is one drop of Eylamdo eye drops solution in the (conjunctival sac of the)
affected eye(s) two times daily.
If another topical ophthalmic agent is being used, Eylamdo eye drops solution and the
other agent should be administered at least ten minutes apart.
Eylamdo eye drops solution is a sterile solution that does not contain a preservative.
The solution from the multi-dose container can be used for up to 28 days after first
opening for administration to the affected eye(s).
Patients should be instructed to wash their hands before use and avoid allowing the
tip of the container to come into contact with the eye or surrounding structures as this
could cause injury to the eye.
Patients should also be instructed that ocular solutions, if handled improperly, can
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.
When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic
absorption is reduced. This may result in a decrease in systemic side effects and an
increase in local activity.
Paediatric population
Efficacy in paediatric patients has not been established.
Safety in paediatric patients below the age of 2 years has not been established. (For
information regarding safety in paediatric patients ≥ 2 and < 6 years of age, see
section 5.1)
Method of administration
Before instillation of the eye drops
-

Users should be instructed to wash their hands before opening the bottle.

-

Users should also be instructed to not use this medicine if they notice that the
tamper-proof seal on the bottle neck is broken before they first use it.

-

When used for the first time, before delivering a drop to the eye, the patient
should practise using the dropper bottle by squeezing it slowly to deliver one
drop away from the eye.

-

When the patient is confident they can deliver one drop at a time, the patient
should adopt a position that is the most comfortable for the instillation of the
drops (the patient can sit down, lie on their back, or stand in front of a mirror).

Instillation

1. The bottle should be held directly below the cap and the cap should be turned to
open the bottle. To avoid contamination of the solution, the tip of the bottle must not
touch anything.

2. The patient should tilt their head backwards and hold the bottle above their eye.
3. The patient should pull the lower eyelid down and look up. The bottle should be
squeezed gently in the middle and a drop should be allowed to fall into the patient’s
eye. Please note that there might be a few seconds delay between squeezing and the
drop coming out. The bottle must not be squeezed too hard.
Patients should be instructed to seek advice from their doctor, pharmacist or nurse if
they are not sure how to administer their medicine.

4. The patient should blink a few times so that the drop spreads over their eye.

5. Instructions 2. – 4. should be repeated for delivery into the other eye, if required.
The patient should be clearly instructed if one eye only requires treatment, and if so,
which eye is affected.
6. After each use and prior to recapping, the bottle should be shaken once in a
downwards direction, without touching the dropper tip, in order to remove any
residual liquid on the tip. This is necessary in order to ensure delivery of subsequent
drops.

7. At the end of the 28-day in-use shelf life of the medicine, there will be some
Eylamdo left in the bottle. Using the excess medicine remaining in the bottle after the
patient has completed the course of treatment should not be attempted. Patients must
not use the eye drops for longer than 28 days after first opening the bottle.

4.3

Contraindications
Eylamdo eye drops solution is contraindicated in patients with:


reactive airway disease, including bronchial asthma or a history of bronchial
asthma, or severe chronic obstructive pulmonary disease



sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third
degree atrioventricular block not controlled with pacemaker, overt cardiac
failure, cardiogenic shock



severe renal impairment (CrCl < 30 ml/min) or hyperchloraemic acidosis



hypersensitivity to one or both active substances or to any of the excipients
listed in section 6.1.

The above are based on the components and are not unique to the combination.

4.4

Special warnings and precautions for use
Cardiovascular/Respiratory Reactions
Like other topically applied ophthalmic agents timolol is absorbed systemically. Due
to beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary
and other adverse reactions seen with systemic beta-adrenergic blocking agents may
occur. Incidence of systemic ADRs after topical ophthalmic administration is lower
than for systemic administration. To reduce the systemic absorption, see section 4.2.
Cardiac disorders
In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's
angina and cardiac failure) and hypotension therapy with beta-blockers should be
critically assessed and the therapy with other active substances should be considered.

Patients with cardiovascular diseases should be watched for signs of deterioration of
these diseases and of adverse reactions.
Due to its negative effect on conduction time, beta-blockers should only be given
with caution to patients with first degree heart block.
Vascular disorders
Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of
Raynaud's disease or Raynaud's syndrome) should be treated with caution.
Respiratory disorders
Respiratory reactions, including death due to bronchospasm in patients with asthma
have been reported following administration of some ophthalmic beta-blockers.
Eylamdo eye drops solution should be used with caution, in patients with
mild/moderate chronic obstructive pulmonary disease (COPD) and only if the
potential benefit outweighs the potential risk.
Hepatic Impairment
This medicinal product has not been studied in patients with hepatic impairment and
should therefore be used with caution in such patients.
Immunology and Hypersensitivity
As with other topically-applied ophthalmic agents, this medicinal product may be
absorbed systemically. Dorzolamide contains a sulfonamido group, which also occurs
in sulfonamides. Therefore, the same types of adverse reactions found with systemic
administration of sulfonamides may occur with topical administration, including
severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If
signs of serious reactions or hypersensitivity occur, discontinue use of this
preparation.
Local ocular adverse effects, similar to those observed with dorzolamide
hydrochloride eye drops, have been seen with this medicinal product. If such
reactions occur, discontinuation of Eylamdo eye drops solution should be considered.
While taking beta-blockers, patients with a history of atopy or a history of severe
anaphylactic reaction to a variety of allergens may be more reactive to repeated
challenge with such allergens and may be unresponsive to the usual doses of
adrenaline used to treat anaphylactic reactions.
Concomitant Therapy
The effect on intra-ocular pressure or the known effects of systemic beta-blockade
may be potentiated when timolol is given to the patients already receiving a systemic
beta-blocking agent. The response of these patients should be closely observed. The
use of two topical beta-adrenergic blocking agents is not recommended (see section
4.5).
The use of dorzolamide and oral carbonic anhydrase inhibitors is not recommended.

Withdrawal of Therapy
As with systemic beta-blockers, if discontinuation of ophthalmic timolol is needed in
patients with coronary heart disease, therapy should be withdrawn gradually.
Additional Effects of Beta-Blockade
Hypoglycaemia/diabetes
Beta-blockers should be administered with caution in patients subject to spontaneous
hypoglycaemia or to patients with labile diabetes, as beta-blockers may mask the
signs and symptoms of acute hypoglycaemia.
Beta-blockers may also mask the signs of hyperthyroidism. Abrupt withdrawal of
beta-blocker therapy may precipitate a worsening of symptoms.
Corneal diseases
Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases
should be treated with caution.
Surgical anaesthesia
Beta-blocking ophthalmological preparations may block systemic beta-agonist effects
e.g. of adrenaline. The anaesthesiologist should be informed when the patient is
receiving timolol.
Therapy with beta-blockers may aggravate symptoms of myasthenia gravis.
Additional Effects of Carbonic Anhydrase Inhibition
Therapy with oral carbonic anhydrase inhibitors has been associated with urolithiasis
as a result of acid-base disturbances, especially in patients with a prior history of
renal calculi. Although no acid-base disturbances have been observed with
Dorzolamide/Timolol (preserved formulation), urolithiasis has been reported
infrequently. Because Dorzolamide/Timolol preservative-free contains a topical
carbonic anhydrase inhibitor that is absorbed systemically, patients with a prior
history of renal calculi may be at increased risk of urolithiasis while using this
medicinal product.
Other
The management of patients with acute angle-closure glaucoma requires therapeutic
interventions in addition to ocular hypotensive agents. This medicinal product has not
been studied in patients with acute angle-closure glaucoma.
Corneal oedema and irreversible corneal decompensation have been reported in
patients with pre-existing chronic corneal defects and/or a history of intraocular

surgery while using dorzolamide. There is an increased potential for developing
corneal oedema in patients with low endothelial cell counts. Precautions should be
used when prescribing Dorzolamide/Timolol to these groups of patients.
Choroidal detachment has been reported with administration of aqueous suppressant
therapies (e.g. timolol, acetazolamide) after filtration procedures.
As with the use of other antiglaucoma medicines, diminished responsiveness to
ophthalmic timolol maleate after prolonged therapy has been reported in some
patients. However, in clinical studies in which 164 patients have been followed for at
least three years, no significant difference in mean intraocular pressure has been
observed after initial stabilisation.
Patients with a history of contact hypersensitivity to silver should not use this product
as dispensed drops may contain traces of silver from the container.
Contact Lens Use
This medicinal product has not been studied in patients wearing contact lenses.
Paediatric population
See section 5.1.

4.5

Interaction with other medicinal products and other forms of interaction
Specific medicine interaction studies have not been performed with
Dorzolamide/Timolol preservative-free.
In a clinical study, this medicinal product was used concomitantly with the following
systemic medications without evidence of adverse interactions: ACE-inhibitors,
calcium channel blockers, diuretics, non-steroidal anti-inflammatory medicines
including aspirin, and hormones (e.g., oestrogen, insulin, thyroxine).
There is a potential for additive effects resulting in hypotension and/or marked
bradycardia when ophthalmic beta-blockers solution is administered concomitantly
with oral calcium channel blockers, catecholamine-depleting medicines or betaadrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis
glycosides, parasympathomimetics, quanethidine, narcotics, and monoamine oxidase
(MAO) inhibitors.
Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been
reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine,
fluoxetine, paroxetine) and timolol.

Although Dorzolamide/Timolol (preserved formulation) alone has little or no effect
on pupil size, mydriasis resulting from concomitant use of ophthalmic beta-blockers
and adrenaline (epinephrine) has been reported occasionally.
Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents.
Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which
can follow the withdrawal of clonidine.

4.6

Fertility, pregnancy and lactation
Pregnancy
Dorzolamide/Timolol should not be used during pregnancy.
Dorzolamide
No adequate clinical data in exposed pregnancies are available. In rabbits,
dorzolamide produced teratogenic effect at maternotoxic doses (see section 5.3).
Timolol
There are no adequate data for the use of timolol in pregnant women. Timolol should
not be used during pregnancy unless clearly necessary. To reduce the systemic
absorption, see section 4.2.
Epidemiological studies have not revealed malformative effects but show a risk for
intra uterine growth retardation when beta-blockers are administered by the oral
route. In addition, signs and symptoms of beta-blockade (e.g. bradycardia,
hypotension, respiratory distress and hypoglycaemia) have been observed in the
neonate when beta-blockers have been administered until delivery. If this medicinal
product is administered until delivery, the neonate should be carefully monitored
during the first days of life.
Breast-feeding
It is not known whether dorzolamide is excreted in human milk. In lactating rats
receiving dorzolamide, decreases in the body weight gain of offspring were observed.
Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in
eye drops it is not likely that sufficient amounts would be present in breast milk to
produce clinical symptoms of beta-blockade in the infant. To reduce systemic
absorption, see section 4.2. If treatment with Eylamdo eye drops solution is required,
then lactation is not recommended.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed. Possible side effects such as blurred vision may affect some patients'
ability to drive and/or operate machinery.

4.8

Undesirable effects
In a clinical study for Dorzolamide/Timolol preservative-free the observed adverse
reactions have been consistent with those that were reported previously with
Dorzolamide/Timolol (preserved formulation), dorzolamide hydrochloride and/or
timolol maleate.
During clinical studies, 1035 patients were treated with Dorzolamide/Timolol
(preserved formulation). Approximately 2.4% of all patients discontinued therapy
with Dorzolamide/Timolol (preserved formulation) because of local ocular adverse
reactions; approximately 1.2% of all patients discontinued because of local adverse
reactions suggestive of allergy or hypersensitivity (such as lid inflammation and
conjunctivitis).
Dorzolamide/Timolol preservative-free has been shown to have a similar safety
profile to Dorzolamide/Timolol (preservative containing formulation) in a repeat dose
double-masked, comparative study.
Like other topically applied ophthalmic medicines, timolol is absorbed into the
systemic circulation. This may cause similar undesirable effects as seen with systemic
beta-blocking agents. Incidence of systemic ADRs after topical ophthalmic
administration is lower than for systemic administration.
The following adverse reactions have been reported with Dorzolamide/Timolol
preservative-free or one of its components either during clinical trials or during postmarketing experience:
[Very Common: (≥ 1/10), Common: (≥ 1/100, <1/10), Uncommon: (≥ 1/1000,
<1/100), and Rare: (≥ 1/10,000, <1/1000), Not known (cannot be estimated from the
available data)]

System Organ
Class
(MedDRA)

Formulation

Immune system Dorzolamide/T
imolol
disorders
Preservative-

Very
Common

Common

Uncommon

Rare

signs and
symptoms of
systemic

Not
Known**

Free

allergic
reactions,
including
angioedema,
urticaria,
pruritus, rash,
anaphylaxis

Timolol
maleate eye
drops, solution

signs and
symptoms of
allergic
reactions
including
angioedema,
urticaria,
localised and
generalised
rash,
anaphylaxis

Hypoglycaemia

Metabolism
and nutrition
disorders

Timolol
maleate eye
drops, solution

Psychiatric
disorders

Timolol
maleate eye
drops, solution

Nervous system
disorders

Dorzolamide
hydrochloride
eye drops,
solution

headache*

dizziness*,
paraesthesia*

Timolol
maleate eye
drops, solution

headache* dizziness*,
syncope*

paraesthesia*,
increase in
signs and
symptoms of
myasthenia
gravis,
decreased
libido*,
cerebrovascula
r accident*,
cerebral
ischaemia

Dorzolamide/T burning and
stinging
imolol
PreservativeFree

conjunctiv
al
injection,
blurred
vision,
corneal
erosion,
ocular
itching,

Eye disorders

pruritus

depression*

insomnia*,
nightmares*,
memory loss

foreign body
sensation in
eye

tearing
Dorzolamide
hydrochloride
eye drops,
solution

eyelid
inflammat
ion*,
eyelid
irritation*

iridocyclitis*

irritation
foreign body
including
sensation in
redness*,
eye
pain*, eyelid
crusting*,
transient
myopia (which
resolved upon
discontinuatio
n of therapy),
corneal
oedema*,
ocular
hypotony*,
choroidal
detachment
(following
filtration
surgery)*

Timolol
maleate eye
drops, solution

signs and
symptoms
of ocular
irritation
including
blepharitis
*,
keratitis*,
decreased
corneal
sensitivity
, and dry
eyes*

visual
disturbances
including
refractive
changes (due
to
withdrawal
of miotic
therapy in
some cases)*

ptosis,
diplopia,
choroidal
detachment
following
filtration
surgery* (see
Special
warning and
precautions for
use 4.4)

Ear and
labyrinth
disorders

Timolol
maleate eye
drops, solution

Cardiac
disorders

Timolol
maleate eye
drops, solution

Vascular
disorders

Timolol
maleate eye
drops, solution

itching,
tearing,
redness,
blurred
vision,
corneal
erosion

tinnitus*

bradycardia*

chest pain*,
palpitation*,
oedema*,
arrhythmia*,
congestive
heart failure*,
cardiac arrest*,
heart block
hypotension*,
claudication,
Raynaud's
phenomenon*,
cold hands and
feet*

Atrioventricular
block,
cardiac
failure

Respiratory,
thoracic, and
mediastinal
disorders

Dorzolamide/
Timolol
PreservativeFree

sinusitis

shortness of
dyspnoea
breath,
respiratory
failure,
rhinitis, rarely
bronchospasm

Dorzolamide
hydrochloride
eye drops,
solution

epistaxis*

Timolol
maleate eye
drops, solution

Gastrointestina
l disorders

Dorzolamide/
Timolol
PreservativeFree
Dorzolamide
hydrochloride
eye drops,
solution
Timolol
maleate eye
drops, solution

Skin and
subcutaneous
tissue disorders

dyspnoea*

dyspnoea

bronchospasm
(predominantl
y in patients
with
pre-existing
bronchospastic
disease)*,
respiratory
failure, cough*

dysgeusia

nausea*

throat
irritation, dry
mouth*
nausea*,
dyspepsia*

diarrhoea, dry
mouth*

Dorzolamide/
Timolol
PreservativeFree

contact
dermatitis,
StevensJohnson
syndrome,
toxic
epidermal
necrolysis

Dorzolamide
hydrochloride
eye drops,
solution

rash*

Timolol
maleate eye
drops, solution

alopecia*,
psoriasiform
rash or
exacerbation
of psoriasis*

dysgeusia,
abdominal
pain,
vomiting

skin rash

Musculoskeleta
l and
connective
tissue disorders

Timolol
maleate eye
drops, solution

Renal and
urinary
disorders

Dorzolamide/
Timolol
PreservativeFree

Reproductive
system and
breast
disorders

Timolol
maleate eye
drops, solution

General
disorders and
administration
site conditions

Dorzolamide
hydrochloride
eye drops,
solution

systemic lupus
erythematosus

myalgia

Peyronie's
disease*,
decreased
libido

sexual
dysfunction

urolithiasis

asthenia/
fatigue*

Timolol
maleate eye
drops, solution

asthenia/
fatigue*

*These adverse reactions were also observed with Dorzolamide/ Timolol (preserved
formulation) during post-marketing experience.
**Additional adverse reactions have been seen with ophthalmic beta-blockers and
may potentially occur with Dorzolamide/ Timolol preservative-free.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
No data are available in humans in regard to overdose by accidental or deliberate
ingestion of Dorzolamide/ Timolol (preserved formulation) or Dorzolamide/ Timolol
preservative-free.
Symptoms
There have been reports of inadvertent overdoses with timolol maleate ophthalmic
solution resulting in systemic effects similar to those seen with systemic betaadrenergic blocking agents such as dizziness, headache, shortness of breath,
bradycardia, bronchospasm, and cardiac arrest. The most common signs and
symptoms to be expected with overdoses of dorzolamide are electrolyte imbalance,
development of an acidotic state, and possibly central nervous system effects.

Only limited information is available with regard to human overdose by accidental or
deliberate ingestion of dorzolamide hydrochloride. With oral ingestion, somnolence
has been reported. With topical application the following have been reported: nausea,
dizziness, headache, fatigue, abnormal dreams, and dysphagia.
Treatment
Treatment should be symptomatic and supportive. Serum electrolyte levels
(particularly potassium) and blood pH levels should be monitored. Studies have
shown that timolol does not dialyse readily.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Antiglaucoma preparations and miotics, Beta blocking
agents, Timolol, combinations, ATC code: S01E D51.
Mechanism of action
Dorzolamide/ Timolol is comprised of two components: dorzolamide hydrochloride
and timolol maleate. Each of these two components decreases elevated intraocular
pressure by reducing aqueous humor secretion, but does so by a different mechanism
of action.
Dorzolamide hydrochloride is a potent inhibitor of human carbonic anhydrase II.
Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous
humor secretion, presumably by slowing the formation of bicarbonate ions with
subsequent reduction in sodium and fluid transport. Timolol maleate is a nonselective beta-adrenergic receptor blocking agent. The precise mechanism of action of
timolol maleate in lowering intraocular pressure is not clearly established at this time,
although a fluorescein study and tonography studies indicate that the predominant
action may be related to reduced aqueous formation. However, in some studies a
slight increase in outflow facility was also observed. The combined effect of these
two agents results in additional intraocular pressure reduction (IOP) compared to
either component administered alone.
Following topical administration, Dorzolamide/ Timolol preservative-free reduces
elevated intraocular pressure, whether or not associated with glaucoma. Elevated
intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage
and glaucomatous visual field loss. This medicinal product reduces intraocular
pressure without the common side effects of miotics such as night blindness,
accommodative spasm and pupillary constriction.
Pharmacodynamic effects

Clinical Effects
Clinical studies of up to 15 months duration were conducted to compare the IOPlowering effect of Dorzolamide/Timolol (preserved formulation) b.i.d. (dosed
morning and bedtime) to individually- and concomitantly-administered 0.5% timolol
and 2.0% dorzolamide in patients with glaucoma or ocular hypertension for whom
concomitant therapy was considered appropriate in the trials. This included both
untreated patients and patients inadequately controlled with timolol monotherapy.
The majority of patients were treated with topical beta-blocker monotherapy prior to
study enrolment. In an analysis of the combined studies, the IOP-lowering effect of
Dorzolamide/Timolol (preserved formulation) b.i.d. was greater than that of
monotherapy with either 2% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOPlowering effect of Dorzolamide/Timolol (preserved formulation) b.i.d. was equivalent
to that of concomitant therapy with dorzolamide b.i.d. and timolol b.i.d. The IOPlowering effect of Dorzolamide/ Timolol (preserved formulation) b.i.d. was
demonstrated when measured at various time points throughout the day and this effect
was maintained during long-term administration.
In an active-treatment-controlled, parallel, double-masked study in 261 patients with
elevated intraocular pressure ≥ 22 mmHg in one or both eyes, Dorzolamide/Timolol
preservative-free had an IOP-lowering effect equivalent to that of
Dorzolamide/Timolol (preserved formulation). The safety profile of
Dorzolamide/Timolol Preservative-Free was similar to Dorzolamide/Timolol
(preserved formulation).
Paediatric population
A 3 month controlled study, with the primary objective of documenting the safety of
2% dorzolamide hydrochloride ophthalmic solution in children under the age of 6
years has been conducted. In this study, 30 patients under 6 and greater than or equal
to 2 years of age whose IOP was not adequately controlled with monotherapy by
dorzolamide or timolol received Dorzolamide/Timolol (preserved formulation) in an
open label phase. Efficacy in those patients has not been established. In this small
group of patients, twice daily administration of Dorzolamide/Timolol (preserved
formulation) was generally well tolerated with 19 patients completing the treatment
period and 11 patients discontinuing for surgery, a change in medication, or other
reasons.

5.2

Pharmacokinetic properties
Dorzolamide Hydrochloride
Unlike oral carbonic anhydrase inhibitors, topical administration of dorzolamide
hydrochloride allows for the active substance to exert its effects directly in the eye at
substantially lower doses and therefore with less systemic exposure. In clinical trials,
this resulted in a reduction in IOP without the acid-base disturbances or alterations in
electrolytes characteristic of oral carbonic anhydrase inhibitors.

When topically applied, dorzolamide reaches the systemic circulation. To assess the
potential for systemic carbonic anhydrase inhibition following topical administration,
active substance and metabolite concentrations in red blood cells (RBCs) and plasma
and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates
in RBCs during chronic dosing as a result of selective binding to CA-II while
extremely low concentrations of free active substance in plasma are maintained. The
parent active substance forms a single N-desethyl metabolite that inhibits CA-II less
potently than the parent active substance but also inhibits a less active isoenzyme
(CA-I). The metabolite also accumulates in RBCs where it binds primarily to CA-I.
Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide
is primarily excreted unchanged in the urine; the metabolite is also excreted in urine.
After dosing ends, dorzolamide washes out of RBCs non-linearly, resulting in a rapid
decline of active substance concentration initially, followed by a slower elimination
phase with a half-life of about four months.
When dorzolamide was given orally to simulate the maximum systemic exposure
after long term topical ocular administration, steady state was reached within 13
weeks. At steady state, there was virtually no free active substance or metabolite in
plasma; CA inhibition in RBCs was less than that anticipated to be necessary for a
pharmacological effect on renal function or respiration. Similar pharmacokinetic
results were observed after chronic, topical administration of dorzolamide
hydrochloride. However, some elderly patients with renal impairment (estimated
CrCl 30-60 ml/min) had higher metabolite concentrations in RBCs, but no
meaningful differences in carbonic anhydrase inhibition and no clinically significant
systemic side effects were directly attributable to this finding.
Timolol Maleate
In a study of plasma active substance concentration in six subjects, the systemic
exposure to timolol was determined following twice daily topical administration of
timolol maleate ophthalmic solution 0.5%. The mean peak plasma concentration
following morning dosing was 0.46 ng/ml and following afternoon dosing was 0.35
ng/ml.

5.3

Preclinical safety data
The ocular and systemic safety profile of the individual components is well
established.
Dorzolamide
In rabbits given maternotoxic doses of dorzolamide associated with metabolic
acidosis, malformations of the vertebral bodies were observed.
Timolol
Animal studies have not shown teratogenic effect.

Furthermore, no adverse ocular effects were seen in animals treated topically with
dorzolamide hydrochloride and timolol maleate ophthalmic solution or with
concomitantly-administered dorzolamide hydrochloride and timolol maleate. In vitro
and in vivo studies with each of the components did not reveal a mutagenic potential.
Therefore, no significant risk for human safety is expected with therapeutic doses of
dorzolamide/timolol preservative-free.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Hydroxyethyl cellulose
Mannitol
Sodium citrate
Sodium hydroxide
Water for injection

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.
After first opening, the product may be stored for a maximum of 28 days.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions after first opening of the medicinal product, see section 6.3.

6.5

Nature and contents of container
5 ml solution in a white opaque 11 ml LDPE bottle and white Novelia nozzle (HDPE
and silicone) with a white HDPE cap.
Pack sizes: 1, 3 or 6 bottles in cardbox.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements for disposal.

7

MARKETING AUTHORISATION HOLDER
Aspire Pharma Ltd
Unit 4, Rotherbrook Court,
Bedford Road,
Petersfield,
Hampshire,
GU32 3QG
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 35533/0117

9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
12/12/2016

10

DATE OF REVISION OF THE TEXT
21/12/2016

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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