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.

Posology

The dose is one drop of DORZALOL in the (conjunctival sac of the) affected eye(s) two times daily.

If another topical ophthalmic agent is being used, DORZALOL and the other agent should be administered at least ten minutes apart.

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.

Patients should be informed of the correct handling of the OCUMETER PLUS bottles.

Method of administration

1. Before using the medication for the first time, be sure the Safety Strip on the front of the bottle is unbroken. A gap between the bottle and the cap is normal for an unopened bottle.
2. First wash your hands, then tear off the Safety Strip to break the seal.
3. To open the bottle, unscrew the cap by turning as indicated by the arrows on the top of the cap. Do not pull the cap directly up and away from the bottle. Pulling the cap directly up will prevent your dispenser from operating properly.
4. Tilt your head back and pull your lower eyelid down slightly to form a pocket between your eyelid and eye.
5. Invert the bottle, and press lightly with the thumb or index finger over the “Finger Push Area” until a single drop is dispensed into the eye as directed by your doctor. DO NOT TOUCH YOUR EYE OR EYELID WITH THE DROPPER TIP.
6. 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.
7. If drop dispensing is difficult after opening for the first time, replace the cap on the bottle and tighten (do not overtighten) and then remove by turning the cap in the opposite directions as indicated by the arrows on the top of the cap.
8. Repeat steps 4 & 5 with the other eye if instructed to do so by your doctor.
9. Replace the cap by turning until it is firmly touching the bottle. The arrow on the left side of the cap must be aligned with the arrow on the left side of the bottle label for proper closure. Do not overtighten or you may damage the bottle and cap.
10. The dispenser tip is designed to provide a single drop; therefore, do NOT enlarge the hole of the dispenser tip.
11. After you have used all doses, there will be some medicine left in the bottle. You should not be concerned since an extra amount of medicine has been added and you will get the full amount of DORZALOL that your doctor prescribed. Do not attempt to remove the excess medicine from the bottle.

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).

DORZALOL 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.

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.

DORZALOL 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 sulphonamides. 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 this medicinal product 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 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 this medicinal product, urolithiasis has been reported infrequently. Because DORZALOL 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 DORZALOL 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.

Contact Lens Use

This medicinal product 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.

Specific medicine interaction studies have not been performed with DORZALOL.

In clinical studies, 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 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 DORZALOL 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.

Pregnancy

DORZALOL 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 the systemic absorption, see section 4.2.

If treatment with DORZALOL is required, then lactation is not recommended.

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.

In clinical studies for DORZALOL the observed adverse reactions have been consistent with those that were reported previously with dorzolamide hydrochloride and/or timolol maleate.

During clinical studies, 1035 patients were treated with DORZALOL. Approximately 2.4% of all patients discontinued therapy with this medicinal product 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 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 DORZALOL 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: ≥ 1/1000 to <1/100), and Rare: (≥ 1/10,000 to <1/1000), Not known (cannot be estimated from the available data)]

System Organ Class (MedDRA)	Formulation	Very Common	Common	Uncommon	Rare	Not Known**
Immune system disorders	DORZALOL				signs and symptoms of systemic 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	pruritus
Metabolism and nutrition disorders	Timolol maleate eye drops, solution					hypoglycaemia
Psychiatric disorders	Timolol maleate eye drops, solution			depression*	insomnia*, nightmares*, memory loss
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*, cerebrovascular accident*, cerebral ischaemia
Eye disorders	DORZALOL	burning and stinging	conjunctival injection, blurred vision, corneal erosion, ocular itching, tearing
	Dorzolamide hydrochloride eye drops, solution		eyelid inflammation*, eyelid irritation*	iridocyclitis*	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		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)	itching, tearing, redness, blurred vision, corneal erosion
Ear and labyrinth disorders	Timolol maleate eye drops, solution				tinnitus*
Cardiac disorders	Timolol maleate eye drops, solution			bradycardia*	chest pain*, palpitation*, oedema*, arrhythmia*, congestive heart failure*, cardiac arrest*, heart block	atrioventricular block, cardiac failure
Vascular disorders	Timolol maleate eye drops, solution				hypotension*, claudication, Raynaud's phenomenon*, cold hands and feet*
Respiratory, thoracic, and mediastinal disorders	DORZALOL		sinusitis		shortness of breath, respiratory failure, rhinitis, rarely bronchospasm
	Dorzolamide hydrochloride eye drops, solution				epistaxis*
	Timolol maleate eye drops, solution			dyspnoea*	bronchospasm (predominantly in patients with pre‑existing bronchospastic disease)*, respiratory failure, cough*
Gastrointestinal disorders	DORZALOL	dysgeusia
	Dorzolamide hydrochloride eye drops, solution		nausea*		throat irritation, dry mouth*
	Timolol maleate eye drops, solution			nausea*, dyspepsia*	diarrhoea, dry mouth*	dysgeusia, abdominal pain, vomiting
Skin and subcutaneous tissue disorders	DORZALOL				contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis
	Dorzolamide hydrochloride eye drops, solution				rash*
	Timolol maleate eye drops, solution				alopecia*, psoriasiform rash or exacerbation of psoriasis*	skin rash
Musculoskeletal and connective tissue disorders	Timolol maleate eye drops, solution				systemic lupus erythematosus,	myalgia
Renal and urinary disorders	DORZALOL			urolithiasis
Reproductive system and breast disorders	Timolol maleate eye drops, solution				Peyronie's disease*, decreased libido	sexual dysfunction
General disorders and administration site conditions	Dorzolamide hydrochloride eye drops, solution		asthenia/ fatigue*
	Timolol maleate eye drops, solution			asthenia/ fatigue*

*These adverse reactions were also observed with DORZALOL during post-marketing experience.

**Additional adverse reactions have been seen with ophthalmic beta-blockers and may potentially occur with DORZALOL.

Reporting side effects

National Pharmacovigilance &amp; Drug Safety Centre (NPC)

•                  Fax: +966-11-205-7662

•                  Toll free phone: 8002490000

•                  E-mail: npc.drug@sfda.gov.sa

•                  Website: www.sfda.gov.sa/npc

No data are available in humans in regard to overdose by accidental or deliberate ingestion of DORZALOL.

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.

Pharmacotherapeutic group: Antiglaucoma preparations and miotics, Beta blocking agents, Timolol, combinations, ATC code: S01ED51

Mechanism of action

DORZALOL 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, this medicinal product 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 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 IOP-lowering effect of DORZALOL 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 DORZALOL 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 DORZALOL 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 DORZALOL 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 DORZALOL in an open label phase. Efficacy in those patients has not been established. In this small group of patients, twice daily administration of DORZALOL was generally well tolerated with 19 patients completing the treatment period and 11 patients discontinuing for surgery, a change in medication, or other reasons.

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.

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 DORZALOL.

Benzalkonium Chloride Solution (50%)

Sodium citrate

Mannitol

Natrasol 250M Pharma,

Water for injection.

Not applicable.

2 years DORZALOL should be used no longer than one month after first opening the container.

Store below 30°C. Keep in the original pack to protect from light

Once the bottle has been opened, the contents should be used within one month.

5 ml white LDPE bottle with polyethylene dropper insert and white polypropylene cap having polyethylene pilfer proof.

No special requirements.