Medication Guide App

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

Active substance: TIMOLOL MALEATE

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Transcript
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 include Benzalkonium chloride 0.0075% w/v.
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
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.

Usage Instructions:

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
• Hold the bottle upside down above the eye and gently squeeze the bottle to
release a drop into your eye
• 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 necessary
• Recap the bottle after every use, tighten the inner cap on the nozzle.
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).

4.3

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, severe chronic obstructive pulmonary disease
• Sinus bradycardia, sick sinus syndrome, sino-atrial block, second or thirddegree atrioventricular block not controlled with pace-maker. Overt cardiac
failure, cardiogenic shock
• Severe renal impairment (CrCl < 30 ml/min) or hyperchloraemic acidosis
• Hypersensitivity to the active substances, or to any of the excipients.
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 dorzolamide and timolol may be
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 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.
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.
Corneal diseases
Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases
should be treated with caution.
Other beta-blocking agents
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).
Choroidal detachment
Choroidal detachment has been reported with administration of aqueous suppressant
therapy (e.g. timolol, acetazolamide) after filtration procedures.
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.
Additional Effects of Beta-Blockade
Beta-blockers may also mask the signs of hyperthyroidism. Abrupt withdrawal of
beta-blocker therapy may precipitate a worsening of symptoms.
Therapy with beta-blockers may aggravate symptoms of myasthenia gravis.
Hepatic Impairment

Dorzolamide 20 mg/ml and Timolol 5 mg/ml 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 should be considered.
Anaphylactic reactions
While taking beta-blockers, patients with 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 unresponsive to the usual dose of adrenaline used
to treat anaphylactic reactions.
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 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 20 mg/ml and Timolol 5 mg/ml Eye Drops, urolithiasis has been
reported infrequently. Because it contains topical carbonicanhydrase inhibitor that is
absorbed systemically, patients with a prior history of renal calculi may be at
increased risk of urolithiasis while using this eye drops.
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
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. Topical dorzolamide should be used with caution
in such patients.
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.

Information about the preservative
Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution contains the
preservative benzalkonium chloride. Benzalkonium Chloride may cause eye
irritation. Use of benzalkonium chloride with soft contact lenses should be avoided.
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.
In clinical studies, Dorzolamide 20 mg/ml and Timolol 5 mg/ml was used
concomitantly with the following systemic medications without evidence of adverse
interactions: ACE-inhibitors, calcium channel blockers, diuretics, non-steroidal antiinflammatory 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, 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.
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 beta-blockers 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.
Lactation
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.

Undesirable effects
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).
No adverse experiences specific to Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye
Drops Solution have been observed; adverse reactions have been limited to those that
were reported previously with dorzolamide hydrochloride and/or timolol maleate.
Timolol, like other topically applied ophthalmic drugs, 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.
Listed adverse reactions include reactions seen with Dorzolamide 20 mg/ml and
Timolol 5 mg/ml Eye Drops Solution or one of its components and within the class of
ophthalmic beta-blockers 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)






Immune system disorders:



4.8

Timolol maleate eye drops, solution:
Rare: Systemic allergic reactions including angioedema, urticaria, localized and
generalized rash, pruritus, anaphylactic reaction
Metabolism and nutrition disorders:
Timolol maleate eye drops, solution:
Not known: hypoglycaemia
Psychiatric disorders:
Timolol maleate eye drops, solution:
Uncommon: depression
Rare: insomnia, nightmares, memory loss
Nervous system disorders:
Dorzolamide hydrochloride eye drops, solution:
Common: headache
Rare: dizziness, paraesthesia
Timolol maleate eye drops, solution:
Common: headache
Uncommon: dizziness, syncope
Rare: paraesthesia, increase in signs and symptoms of myasthenia gravis,
cerebrovascular accident, cerebral ischaemia
Eye disorders:
Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution
Very Common: burning and stinging
Common: conjunctival injection, blurred vision, corneal erosion, ocular itching,
tearing
Dorzolamide hydrochloride eye drops, solution:
Common: eyelid inflammation, eyelid irritation
Uncommon: iridocyclitis
Rare: irritation including redness, pain, eyelid crusting, transient myopia (which
resolved upon discontinuation of therapy), corneal oedema, ocular hypotony,
choroidal detachment (following filtration surgery)
Timolol maleate eye drops, solution:
Very Common: burning and stinging
Common: signs and symptoms of ocular irritation (e.g. itching and tearing)
blepharitis, keratitis, blurred vision, decreased corneal sensitivity, dry eyes, corneal
erosion
Uncommon: visual disturbances including refractive changes (due to withdrawal of
miotic therapy in some cases)
Rare: ptosis, diplopia, choroidal detachment following filtration surgery (see section
4.4)
Not Known: redness
Ear and labyrinth disorders:
Timolol maleate eye drops, solution:
Rare: tinnitus
Cardiac disorders:
Timolol maleate eye drops, solution:
Uncommon: bradycardia

Rare: chest pain, palpitation, oedema, arrhythmia, congestive heart failure,
atrioventricular block, cardiac arrest
Not known: cardiac failure
Vascular disorders:
Timolol maleate eye drops, solution:
Rare: hypotension, claudication, Raynaud’s phenomenon, cold hands and feet
Respiratory, thoracic, and mediastinal disorders:
Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution
Common: sinusitis
Rare: dyspnoea, respiratory failure, rhinitis
Dorzolamide hydrochloride eye drops, solution:
Rare: epistaxis
Timolol maleate eye drops, solution:
Uncommon: dyspnoea
Rare: bronchospasm (predominantly in patients with pre-existing bronchospastic
disease), cough
Gastrointestinal disorders:
Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution
Very Common: dysgeusia
Dorzolamide hydrochloride eye drops, solution:
Common: nausea
Rare: throat irritation, dry mouth
Timolol maleate eye drops, solution:
Very Common: dysgeusia
Uncommon: nausea, dyspepsia,
Rare: diarrhoea, dry mouth
Not known: abdominal pain, vomiting
Skin and subcutaneous tissue disorders:
Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution
Rare: contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis
Dorzolamide hydrochloride eye drops, solution:
Rare: rash
Timolol maleate eye drops, solution:
Rare: alopecia, psoriasiform rash or exacerbation of psoriasis
Not known: skin rash
Musculoskeletal and connective tissue disorders:
Timolol maleate eye drops, solution:
Rare: systemic lupus erythematosus
Not known: myalgia
Renal and urinary disorders:
Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution
Uncommon: urolithiasis

Reproductive system and breast disorders:
Timolol maleate eye drops, solution:
Rare: Peyronie’s disease, decreased libido
Not Known: sexual dysfunction
General disorders and administration site conditions:
Dorzolamide hydrochloride eye drops, solution:
Common: asthenia/fatigue
Timolol maleate eye drops, solution:
Uncommon: asthenia/ fatigue
Laboratory findings
Dorzolamide 20 mg/ml and Timolol 5 mg/ml Eye Drops Solution was not associated
with clinically meaningful electrolyte disturbances in clinical studies.

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 beta
adrenergic 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: 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
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 (IOP) reduction
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 IOP-lowering 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 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 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
None.

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
02/12/2013

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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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