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DORZOLAMIDE 20MG/ML AND TIMOLOL 5MG/ML EYE DROPS SOLUTION

Active substance(s): DORZOLAMIDE HYDROCHLORIDE / TIMOLOL MALEATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 22.26 mg of dorzolamide hydrochloride corresponding to 20 mg
dorzolamide and 6.83 mg of Timolol maleate corresponding to 5 mg Timolol.
Excipients with known effect
Benzalkonium chloride 0.075 mg/ml.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Eye drops, solution.
Clear, colourless slightly viscous solution.

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 in the (conjunctival sac of the) affected eye(s) two times daily.
If another topical ophthalmic agent is being used, Dorzolamide 20 mg/ml and Timolol
5 mg/ml and the other agent should be administered at least ten minutes apart.
The dosage of this eye drop should not exceed twice daily.
If one dose is missed, treatment should continue with the next dose as normal. The
duration of the treatment should be as recommended by the doctor.
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.
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 two 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

4.3



First wash your hands.



Avoid touching the eye (or any other surface) with the tip of the bottle.



If you wear soft contact lenses, they should be removed before using the eye drops
and wait at least 15 minutes before reinserting.



These drops are supplied in a plastic bottle with an insert cap assembly, with a
tamper proof dust cover. When using the bottle for the first time, snap of the dust
cover by turning it clockwise to break the seal.



Unscrew the inner cap.



Tilt your head back and look at the ceiling.



Pull the lower eyelid gently downwards to form a pocket between your eyelid and
eye.



Hold the bottle upside down above the eye and gently squeeze the bottle to release
a drop into your eye. DO NOT TOUCH YOUR EYE OR EYELID WITH THE
DROPPER TIP.



Keep the affected eye closed and press your fingertip against the inside corner of
the closed eye, and hold for 2 minutes. This is important because it reduces the
amount of drug that goes into the rest of your body.



Repeat for the other eye if instructed to do so by your doctor.



Recap the bottle after every use, tighten the inner cap on the nozzle.

Contraindications
Dorzolamide 20 mg/ml and Timolol 5 mg/ml 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 pace-maker, 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 the beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary
and other adverse reactions seen with systemic beta-adrenergic blocking agents may
occur. The 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.
Dorzolamide 20 mg/ml and Timolol 5 mg/ml 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
Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops, Solution 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 sulphonamides. Therefore, the same types of adverse reactions found with systemic
administration of sulphonamides 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 Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye
Drops Solution. If such reactions occur, discontinuation of Dorzolamide 20 mg/ml and
Timolol 5 mg/ml 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 dose 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 betablocking 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 betablocker 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 this medicinal
product, urolithiasis has been reported infrequently. Because Dorzolamide 20 mg/ml
and Timolol 5 mg/ml Eye Drops, Solution contains 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. Dorzolamide 20 mg/ml and
Timolol 5 mg/ml Eye Drops Solution has not been studied in patients with acute angleclosure 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 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 drugs, 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.
Contact Lens UseDorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution
contains the preservative benzalkonium chloride which may cause eye irritation.
Remove contact lenses prior to application and wait at least 15 minutes before
reinsertion. Benzalkonium chloride is known to discolour soft contact lenses.
Paediatric population
See section 5.1

4.5

Interaction with other medicinal products and other forms of interaction
No specific drug interaction studies have been performed with Dorzolamide 20 mg/ml
and Timolol 5 mg/ml Eye Drops Solution.
In clinical studies, Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution
was used concomitantly with the following systemic medications without evidence of
adverse interactions: ACE-inhibitors, calcium channel blockers, diuretics, non-steroidal
anti-inflammatory drugs 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 beta
adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis
glycosides, parasympathomimetics, guanethidine, 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 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 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 betablockers have been administered until delivery. If Dorzolamide 20 mg/ml and Timolol
5 mg/ml Eye Drops Solution 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 the systemic
absorption, see section 4.2.
If treatment with Dorzolamide 20 mg/ml and Timolol 5 mg/ml 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 clinical studies for Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution
the observed adverse reactions have been consistent with those that were reported
previously with dorzolamide hydrochloride and/or timolol maleate.
In clinical studies, 1035 patients were treated with Dorzolamide 20 mg/ml and
Timolol 5 mg/ml Eye Drops Solution. Approximately 2.4% of all patients discontinued
therapy 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).
Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic
circulation; this may cause similar undesirable effects as seen with systemic betablocking agents. Incidence of systemic ADRs after topical ophthalmic administration
is lower than for systemic administration.
The following adverse reactions have been reported with Dorzolamide 20 mg/ml and
Timolol 5 mg/ml Eye Drops Solution or one of its components either during clinical
trials or during post-marketing experience.
[Very Common: (≥ 1/10), Common: (≥ 1/100 to <1/10), Uncommon:( ≥ 1/1,000 to
<1/100), Rare: (≥ 1/10,000 to < 1/1,000)], very rare(<1/10,000) and not known
(cannot be estimated from the available data)

System
Organ
Class
(MedDRA)
Immune
system

Formulation

Dorzolamide
20 mg/ml and

Very
Commo
n

Common

Uncommon

Rare

signs and
symptoms

Not
Known**

disorders

Metabolism
and
nutrition
disorders
Psychiatric
disorders

Nervous
system
disorders

Eye
disorders

Timolol 5 mg
/ml Eye
Drops
Solution

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

Timolol
maleate eye
drops,
solution

signs and
symptoms
of allergic
reactions
including
angioedema
, urticaria,
localized
and
generalized
rash,
anaphylaxis

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

Dorzolamide burning
20 mg/ml and and

Pruritus

hypoglycae
mia

depression*

insomnia*,
nightmares*
, memory
loss
dizziness*,
paraesthesia
*

dizziness*,
syncope*

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

headache*

headache*

conjunctiv
al

Timolol
5 mg/ml Eye
Drops
Solution

Dorzolamide
hydrochloride
eye drops,
solution

Timolol
maleate eye
drops,
solution

Ear and
labyrinth
disorders
Cardiac

Timolol
maleate eye
drops,
solution
Timolol

stinging

injection,
blurred
vision,
corneal
erosion,
ocular
itching,
tearing
eyelid
iridocyclitis
inflammati *
on*, eyelid
irritation*

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

irritation
including
redness*,
pain,*
eyelid
crusting*,
transient
myopia
(which
resolved
upon
discontinuat
ion of
therapy),
corneal
oedema*,
ocular
hypotony*,
choroidal
detachment
(following
filtration
surgery)*
visual
ptosis,
disturbances diplopia,
including
choroidal
refractive
detachment
changes
following
(due to
filtration
withdrawal surgery*
of miotic
(see special
therapy in
warning and
some
precautions
cases)*
for use 4.4)

itching,
tearing,
redness,
blurred
vision,
corneal
erosion

tinnitus*

bradycardia

chest pain*,

atrioventric

disorders

maleate eye
drops,
solution

Vascular
disorders

Timolol
maleate eye
drops,
solution

Respiratory
, thoracic,
and
mediastinal
disorders

Dorzolamide
20 mg/ml and
Timolol
5 mg/ml Eye
Drops
Solution

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

Gastrointestinal
disorders

Dorzolamide dysgeusi
20 mg/ml and a
Timolol
5 mg/ml Eye
Drops
Solution

*

palpitation*, ular block,
oedema*,
cardiac
arrhythmia* failure
, congestive
heart
failure*,
heart block,
cardiac
arrest*
hypotension
*,
claudication
, Raynaud’s
phenomeno
n*, cold
hands and
feet*
shortness of
breath,
respiratory
failure,
rhinitis,
rarely
bronchospas
m
epistaxis*

sinusitis

dyspnoea*

bronchospas
m
(predomina
ntly
in patients
with preexisting
bronchospas
tic
disease)*,
respiratory
failure,
cough*

Skin and
subcutaneo
us tissue
disorders

Dorzolamide
hydrochloride
eye drops,
solution
Timolol
maleate eye
drops,
solution
Dorzolamide
20 mg/ml and
Timolol
5 mg/ml Eye
Drops
Solution

nausea*

throat
irritation,
dry mouth*
nausea*,
dyspepsia*

Timolol
maleate eye
drops,
solution

Dorzolamide
20 mg/ml and
Timolol
5 mg/ml Eye
Drops
Solution
Reproducti Timolol
maleate eye
ve system
drops,
and breast
solution
disorders
Dorzolamide
General
hydrochloride
disorders
eye drops,
and
administrati solution
on site
conditions
Timolol
maleate eye
drops,

dysgeusia,
abdominal
pain,
vomiting

contact
dermatitis,
StevensJohnson
syndrome,
toxic
epidermal
necrolysis
rash*

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

Musculoske
letal and
connective
tissue
disorders
Renal and
urinary
disorders

diarrhoea,
dry mouth*

alopecia*,
psoriasifor
m rash or
exacerbatio
n of
psoriasis*
systemic
lupus
erythematos
us

skin rash

Peyronie’s
disease*,
decreased
libido

sexual
dysfunction

myalgia

urolithiasis

asthenia/fa
tigue*

asthenia/
fatigue*

solution

*These adverse reactions were also observed with Dorzolamide 20 mg/ml and Timolol
5 mg/ml Eye Drops Solution during post-marketing experience.
**Additional adverse reactions have been seen with ophthalmic beta-blockers and may
potentially occur with Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops
Solution.
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 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 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution.
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.

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Antiglaucoma preparations and miotics, Beta blocking
agents, Timolol, combinations, ATC code: S01ED51
Mechanism of Action
Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 non-selective
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 20 mg/ml and Timolol 5 mg/ml Eye
Drops Solution 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. It also reduces intra-ocular
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 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution
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 enrollment. In an
analysis of the combined studies, the IOP-lowering effect of Dorzolamide 20 mg/ml
and Timolol 5 mg/ml Eye Drops Solution b.i.d. was greater than that of monotherapy
with either 2% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOP-lowering effect of
Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution
b.i.d. was demonstrated when measured at various time points throughout the day and
this effect was maintained during long-term administration.
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 20 mg/ml and Timolol 5 mg/ml Eye
Drops Solution in an open label phase. Efficacy in those patients has not been
established. In this small group of patients, twice daily administration of Dorzolamide
20 mg/ml and Timolol 5 mg/ml Eye Drops Solution 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 (CAI). 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 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Hydroxyethyl Cellulose,
Mannitol,
Sodium citrate,
Benzalkonium Chloride,
Sodium hydroxide (to adjust pH),
Water for Injections.

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years.
The product should be used no longer than 28 days after first opening the container.
.

6.4

Special precautions for storage
For storage conditions before and after first opening (see Section 6.3).
Do not store above 25°C.
Keep the bottle in the outer carton, in order to protect from light.

6.5

Nature and contents of container
5 ml solution filled in 5 ml LDPE bottle with insert-cap assembly comprising of a
dark blue coloured screw cap over a LDPE nozzle with tamper-evident LDPE
dustcover sealing the bottle cap. One such bottle is packed in a carton.
Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution is available in the
following packaging configuration:
1 x 5 ml (single 5 ml bottle).

6.6

Special precautions for disposal and other handling
No special requirements.

7

MARKETING AUTHORISATION HOLDER
FDC Pharma,
Unit 6 Fulcrum 1,
Solent Way, Whiteley,
Fareham, Hampshire,
PO15 7FE.
United Kingdom.

8

MARKETING AUTHORISATION NUMBER(S)
PL 35638/0005.

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
16/06/2011

10

DATE OF REVISION OF THE TEXT
30/11/2016

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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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