DORZIL Eye Drops
DORZOLAMIDE EYE DROPS IP 2% w/v
COMPOSITION
Each ml contains:
Dorzolamide Hydrochloride IP equ. to Dorzolamide 2.0% w/v
Benzalkonium Chloride Solution BP 0.015% w/v (as preservative)
Water for Injections BP q.s.
DESCRIPTION
A clear, colorless to slightly viscous solution.
PHARMACODYNAMIC
Pharmacotherapeutic group: Antiglaucoma preparations and miotics, Carbonic Anhydrase
Inhibitors, dorzolamide, ATC code: S01EC03.
Mechanism of action
Carbonic anhydrase (CA) is an enzyme found in many tissues of the body including the eye.
In humans, carbonic anhydrase exists as a number of isoenzymes, the most active being
carbonic anhydrase II (CA-II) found primarily in red blood cells (RBCs) but also in other
tissues. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous
humor secretion. The result is a reduction in intra-ocular pressure (IOP).
Dorzolamide 20 mg/ml eye drops solution contains dorzolamide hydrochloride, a potent
inhibitor of human carbonic anhydrase II. Following topical ocular administration,
dorzolamide reduces elevated intra-ocular pressure, whether or not associated with glaucoma.
Elevated intra-ocular pressure is a major risk factor in the pathogenesis of optic nerve damage
and visual-field loss. Dorzolamide does not cause pupillary constriction and reduces intra-
ocular pressure without side effects such as night blindness, accommodative spasm.
Dorzolamide has minimal or no effect on pulse rate or blood pressure.
Topically applied beta-adrenergic blocking agents also reduce IOP by decreasing aqueous
humor secretion but by a different mechanism of action. Studies have shown that when
dorzolamide is added to a topical beta-blocker, additional reduction in IOP is observed; this
finding is consistent with the reported additive effects of beta-blockers and oral carbonic
anhydrase inhibitors.
PHARMACOKINETICS
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.
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.
THERAPEUTIC INDICATION
Dorzolamide eye drops solution is indicated:
as adjunctive therapy to beta-blockers,
as monotherapy in patients unresponsive to beta-blockers or in whom beta-blockers are
contraindicated,
in the treatment of elevated intra-ocular pressure in: ocular hypertension, open-angle
glaucoma, pseudo-exfoliative glaucoma.
DOSAGE AND ADMINISTRATION
When used as monotherapy, the dose is one drop of dorzolamide in the conjunctival sac
of the affected eye(s), three times daily.
When used as adjunctive therapy with an ophthalmic beta-blocker, the dose is one drop of
dorzolamide in the conjunctival sac of the affected eye(s), two times daily.
When substituting dorzolamide for another ophthalmic anti-glaucoma agent, discontinue
the other agent after proper dosing on one day, and start dorzolamide on the next day.
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.
If more than one topical ophthalmic drug is being used, the drugs should be administered
at least ten minutes apart.
Paediatric population:
Limited clinical data in paediatric patients with administration of dorzolamide three times
a day are available.
INSTRUCTION FOR USE
Apply DORZIL Eye Drops in the following way:
1. Wash your hands. Tilt your head back and look at the ceiling.
2. Gently pull the lower eyelid down until there is a small pocket.
3. Turn the bottle upside down and gently press the bottle to release drops into eyes that
needs treatment.
4. Let go of the lower lid, and close your eye for 30 seconds.
5. To avoid contamination, do not let the tip of dropper touch your eye or anything else.
6. Replace and tighten the cap straight after use.
OVERDOSE
Only limited information is available with regard to human overdose by accidental or
deliberate ingestion of dorzolamide hydrochloride.
CONTRAINDICATION
Hypersensitivity to the active substance or to the excipients.
Dorzolamide has not been studied in patients with severe renal impairment (CrCl < 30
ml/min) or with hyperchloraemic acidosis. Because dorzolamide and its metabolites are
excreted predominantly by the kidney, dorzolamide is therefore contraindicated in such
patients.
WARNING AND PRECAUTIONS
Dorzolamide has not been studied in patients with hepatic impairment and should therefore
be used with caution in such patients.
The management of patients with acute angle-closure glaucoma requires therapeutic
interventions in addition to ocular hypotensive agents. Dorzolamide has not been studied in
patients with acute angle-closure glaucoma.
Dorzolamide contains a sulphonamido group, which also occurs in sulphonamides and
although administered topically, is absorbed systemically. Therefore, the same types of
adverse reactions that are attributable to 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 the
use of this preparation.
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, urolithiasis has
been reported infrequently. Because dorzolamide is 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 dorzolamide.
There is a potential for an additive effect on the known systemic effects of carbonic
anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and
dorzolamide. The concomitant administration of dorzolamide and oral carbonic anhydrase
inhibitors is not recommended.
Corneal oedemas and irreversible corneal decompensations have been reported in patients
with pre-existing chronic corneal defects and/or a history of intra-ocular surgery while using
Dorzolamide 20 mg/ml eye drops solution. Topical dorzolamide should be used with caution
in such patients.
Choroidal detachment concomitant with ocular hypotony have been reported after filtration
procedures with administration of aqueous suppressant therapies.
Paediatric population:
Dorzolamide has not been studied in patients less than 36 weeks gestational age and less than
one week of age. Patients with significant renal tubular immaturity should only receive
dorzolamide after careful consideration of the risk benefit balance because of the possible
risk of metabolic acidosis.
PREGNANCY AND LACTATION
Pregnancy
Dorzolamide should not be used during pregnancy. There are no or limited amount of data
from the use of dorzolamide in pregnant women. In rabbits, dorzolamide produced
teratogenic effects at maternotoxic doses.
Breast-feeding
It is unknown whether dorzolamide/metabolites are excreted in human milk. Available
pharmacodynamic/toxicological data in animals have shown excretion of
dorzolamide/metabolites in milk. A decision must be made whether to discontinue breast-
feeding or to discontinue/abstain from dorzolamide therapy taking into account the benefit of
breast feeding for the child and the benefit of therapy for the woman. A risk to the
newborns/infants cannot be excluded.
Fertility
Animal data do not suggest an effect of treatment with dorzolamide on male and female
fertility. Human data are lacking.
DRUG INTERACTION
Specific drug interaction studies have not been performed with dorzolamide.
In clinical studies, dorzolamide was used concomitantly with the following medications
without evidence of adverse interactions: timolol ophthalmic solution, betaxolol ophthalmic
solution and systemic medications, including ACE-inhibitors, calcium-channel blockers,
diuretics, non-steroidal anti-inflammatory drugs including aspirin, and hormones (e.g.
oestrogen, insulin, thyroxine).
Association between dorzolamide and miotics and adrenergic agonists has not been fully
evaluated during glaucoma therapy.
ADVERSE EFFECTS
Dorzolamide was evaluated in more than 1400 individuals in controlled and uncontrolled
clinical studies. In long term studies of 1108 patients treated with dorzolamide as
monotherapy or as adjunctive therapy with an ophthalmic beta-blocker, the most frequent
cause of discontinuation (approximately 3%) from treatment with dorzolamide was drug-
related ocular adverse reactions, primarily conjunctivitis and lid reactions.
The following adverse reactions have been reported either during clinical trials or during
post-marketing experience with dorzolamide:
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), Not known: (cannot be estimated from the available data).
Nervous system Common- Headache; Rare- Dizziness Paraesthesia
Eye disorders Very common- Burning and stinging; Common- Superficial punctate keratitis,
tearing, conjunctivitis, eyelid inflammation, eye itching, eyelid irritation,
blurred vision; 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; Not known- Foreign body sensation in eye
Cardiac disorders Not known- Palpitations Tachycardia
Vascular disorders Not known- Hypertension
Respiratory, thoracic, and
mediastinal disorders
Rare- Epistaxis; Not known- Dyspnoea
Gastrointestinal disorders Common- Nausea, bitter taste; Rare- Throat irritation, dry mouth
Skin and subcutaneous
tissue disorders
Rare- Contact dermatitis, Stevens-Johnson syndrome, toxic epidermal
necrolysis
Renal and urinary
disorders
Rare- Urolithiasis
General disorders and
administration site
conditions
Common- Asthenia/fatigue; Rare- Hypersensitivity: Signs and symptoms of
local reactions (palpebral reactions) and systemic allergic reactions, including
angioedema, urticaria and pruritus, rash, shortness of breath, rarely
bronchospasm
PRESENTATION
DORZIL Eye Drops are supplied in 5 ml sterilized opaque plastic container with nozzle and
cap.
STORAGE AND OTHER INFORMATION
Store at temperature below 30 °C. Keep this medicine out of the sight and reach of children.
Do not touch the dropper tip or other dispensing tip to any surface since this may contaminate
the solution. Use the solution within one month after opening the container.