Cosopt 20/5 mg Ophthalmic solution

COSOPT u00c6 is indicated in the treatment of elevated intra-ocular pressure (IOP) in patients with ocular hypertension, open-angle glaucoma, pseudoexfoliative glaucoma or other secondary open-angle glaucomas when concomitant therapy is appropriate.

Posology
The dose is one drop of COSOPT u00c6 in the affected eye(s) two times daily. When substituting COSOPT u00c6 for another ophthalmic antiglaucoma agent(s), discontinue the other agent(s) after proper dosing on one day, and start COSOPT u00c6 on the next day. If another topical ophthalmic agent is being used, COSOPT u00c6 and the other agent should be administered at least ten minutes apart.

Paediatric population
Safety and efficacy in paediatric patients below the age of 2 years have not been established. Although COSOPT u00c6 has been used in children 2 to 6 years of age, however data on safety and efficacy are insufficient to recommend a safe and effective dose (see Paediatric Use Section 5.1). 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.

COSOPT u00c6 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, 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. COSOPT u00c6 contains the preservative benzalkonium chloride, which may be deposited in soft contact lenses; therefore, COSOPT u00c6 should not be administered while wearing these lenses. The lenses should be removed before application of the drops and not be reinserted earlier than 15 minutes after use (see section 4.4.)

Pregnancy
There are no adequate and well-controlled studies in pregnant women.

As the possibility of adverse effects on the corneal permeability, and the danger of disruption of the corneal epithelium with prolonged or repeated usage of benzalkonium chloride preserved ophthalmological preparations cannot be excluded, regular ophthalmological examination is required. Caution should be exercised in the use of benzalkonium chloride preserved topical medication over an extended period in patients with extensive ocular surface disease.

Cardiovascular / Respiratory Reactions
COSOPT u00c6 may be absorbed systemically. The timolol component is a beta-blocker. Therefore, the same types of cardiovascular, pulmonary or other adverse reactions found with systemic administration of beta-blockers may occur with COSOPT u00c6. Incidence of systemic ADRs after topical 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, Prinzmetalu2019s 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 Raynaudu2019s disease or Raynaudu2019s 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. COSOPT u00c6 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
COSOPT u00c6 has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.

Immunology and Hypersensitivity
COSOPT u00c6 may be absorbed systemically. The dorzolamide component is a sulfonamide. Therefore, the same types of adverse reactions found with systemic administration of sulfonamides may occur with COSOPT u00c6 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. In clinical studies, local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of dorzolamide hydrochloride ophthalmic solution. Some of these reactions had the clinical appearance and course of an allergic-type reaction that resolved upon discontinuation of therapy. Similar reactions have been reported with COSOPT u00c6. If such reactions are observed, discontinuation of treatment with COSOPT u00c6 should be considered.

While taking beta-blockers, including timolol, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to accidental, diagnostic, or therapeutic repeated challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

Concomitant Therapy
There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving oral and topical carbonic anhydrase inhibitors concomitantly. The concomitant administration of COSOPT u00c6 and oral carbonic anhydrase inhibitors has not been studied and is not recommended. Patients who are already receiving a beta-adrenergic blocking agent systemically and who are given COSOPT u00c6 should be observed for a potential additive effect either on the intra-ocular pressure or on the known systemic effects of beta-blockade. The use of two topical beta-adrenergic blocking agents 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 COSOPT u00c6 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.

Use in the Elderly
Of the total number of patients in clinical studies of COSOPT u00c6, 49 % were 65 years of age and over, while 13 % were 75 years of age and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Other
The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. COSOPT u00c6 has not been studied in patients with acute angle-closure glaucoma. Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide, dorzolamide) after filtration procedures. 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 COSOPT u00c6 to this group of patients. 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 stabilization.

Specific interaction studies have not been performed with COSOPT u00c6. In clinical studies, COSOPT u00c6 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. estrogen, insulin, thyroxine). However, the potential exists for additive effects and production of hypotension and/or marked bradycardia when timolol maleate ophthalmic solution is administered together with oral calcium channel blockers, catecholamine-depleting drugs 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, selective serotonin re-uptake inhibitors) and timolol. Although COSOPT u00c6 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
COSOPT u00c6 should not be used during pregnancy. The safety of this medicine in pregnant and lactating woman has not been established (see section 4.3). 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.

Breastfeeding
It is not known whether dorzolamide hydrochloride is excreted in human milk. Timolol maleate does appear in human milk. Because of the potential for serious adverse reactions on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the product.

There are side effects associated with COSOPT u00c6 that may affect your ability to drive and/or operate machinery (see section 4.8).

During clinical studies, 1 035 patients were treated with COSOPT u00c6. Approximately 2,4 % of all patients discontinued therapy with COSOPT u00c6 because of local ocular adverse reactions, approximately 1,2 % of all patients discontinued because of local adverse reactions suggestive of allergy or hypersensitivity.

The following adverse reactions have been reported with COSOPT u00c6 or one of its components either during clinical trials or during post-marketing experience: [Very Common: ( u2265 1/10), Common: ( u2265 1/100, < 1/10), Uncommon: ( u2265 1/1 000, < 1/100), Rare: ( u2265 1/10 000, < 1/1 000) and Not Known** (cannot be estimated from the available data)]

*Adverse reactions marked with an asterisk (*) were also observed with COSOPT u00c6 during post-marketing experience.

Formulation
Very Common ( u2265 1/10)
Common ( u2265 1/100 to <1/10)
Uncommon ( u2265 1/1000 to <1/100)
Rare ( u2265 1/10,000 to <1/1000)
Not Known**

Immune System disorders
Cosopt u00c6 signs and symptoms of systemic allergic reactions, including angioedema, urticaria, rash, anaphylaxis
Timolol maleate ophthalmic solution signs and symptoms of allergic reactions including angioedema, pruritus, urticaria, localised and generalised rash, anaphylaxis

Metabolism and nutrition disorders
Timolol maleate ophthalmic solution hypoglycaemia

Psychiatric disorders
Timolol maleate ophthalmic solution depression* Insomnia*, nightmares*, memory loss, hallucination

Nervous system disorders
Dorzolamide hydrochloride ophthalmic solution headache* dizziness*, paraesthesia*
Timolol maleate ophthalmic solution headache* dizziness*, syncope* paraesthesia*, increase in signs and symptoms of myasthenia gravis, decreased libido*, cerebrovascular accident*, cerebral ischaemia

Eye disorders
COSOPT u00c6 burning and stinging, conjunctival injection, blurred vision, corneal erosion, ocular itching, tearing
Dorzolamide hydrochloride ophthalmic solution eyelid inflammation*, eyelid irritation*, superficial punctuate keratitis, iridocyclitis* irritation including redness*, pain*, eyelid crusting*, transient myopia (which resolved upon discontinuation of therapy), corneal oedema*, ocular hypotony*, foreign body sensation in eye, choroidal detachment (following filtration surgery)*, signs and symptoms of local reactions including palpebral reaction
Timolol maleate ophthalmic solution signs and symptoms of ocular irritation including blepharitis*, keratitis*, decreased corneal sensitivity, dry eyes, conjunctivitis, 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 ophthalmic solution tinnitus*

Cardiac disorders
Timolol maleate ophthalmic solution bradycardia* chest pain*, palpitation*, oedema*, arrhythmia*, congestive heart failure*, cardiac arrest*, heart block, atrioventricular block, cardiac failure, tachycardia
Dorzolamide hydrochloride ophthalmic solution palpitations

Vascular disorders
Timolol maleate ophthalmic solution hypotension*, claudication, Raynaudu2019s phenomenon*, cold hands and feet* hypertension

Respiratory, thoracic, and mediastinal disorders
COSOPT u00c6 sinusitis shortness of breath, respiratory failure, rhinitis, bronchospasm
Dorzolamide hydrochloride ophthalmic solution epistaxis*
Timolol maleate ophthalmic solution dyspnoea* bronchospasm (predominantly in patients with pre-existing bronchospastic disease)*, respiratory failure, cough*

Gastro-intestinal disorders
COSOPT u00c6 dysgeusia
Dorzolamide hydrochloride ophthalmic solution nausea* throat irritation, dry mouth*
Timolol maleate ophthalmic solution nausea*, dyspepsia* diarrhoea, dry mouth* dysgeusia, abdominal pain, vomiting

Skin and subcutaneous tissue disorders
COSOPT u00c6 contact dermatitis*, Stevens-Johnson syndrome, toxic epidermal necrolysis
Dorzolamide hydrochloride ophthalmic solution rash*
Timolol maleate ophthalmic solution alopecia*, psoriasiform rash or exacerbation of psoriasis* skin rash

Musculoskeletal and connective tissue disorder
Timolol maleate ophthalmic solution systemic lupus erythematosus, myalgia

Renal disorders
COSOPT u00c6 urolithiasis

Reproductive system and breast disorders
Timolol maleate ophthalmic solution Peyronieu2019s disease*, decreased libido, sexual dysfunction

General disorders and administration site disorders
Dorzolamide hydrochloride ophthalmic solution asthenia / fatigue*
Timolol maleate ophthalmic solution asthenia / fatigue*

*These adverse reactions were also observed with COSOPT during post-marketing experience. **Additional adverse reactions have been seen with ophthalmic beta-blockers and may potentially occur with COSOPT.

Laboratory Findings
COSOPT u00c6 was not associated with clinically meaningful electrolyte disturbances.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Alternatively report to the following e-mail address: [email protected]

No data is available with regard to human overdosage by accidental or deliberate ingestion of COSOPT u00c6. Symptoms
There have been reports of inadvertent overdosage 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 overdosage of dorzolamide are electrolyte imbalance, development of an acidotic state, and possibly central nervous system effects (see undesirable effects). Only limited information is available with regard to human overdosage 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.