Dorzolamide Hydrochloride/ Timolol Maleate

Registered South African indications:

• Elevated intra-ocular pressure
  - In ocular hypertension 
  - In open-angle glaucoma 
  - In pseudoexfoliative glaucoma 
  - In other secondary open-angle glaucomas when concomitant therapy is appropriate 

Contraindications

South African recommendations

• Hypersensitivity to dorzolamide, timolol, or to any of the excipients
• 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, and cardiogenic shock
• Severe renal impairment (CrCl<30ml/min)
• Hyperchloraemic acidosis
• Dorzolamide/ timolol ophthalmic drops contain the preservative benzalkonium chloride, which may be deposited in soft contact lenses. Therefore, dorzolamide/ timolol ophthalmic drops 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
• Safety of dorzolamide/ timolol ophthalmic drops in pregnant women has not been established
• Safety of dorzolamide/ timolol ophthalmic drops in lactating women has not been established

Recommendations in other jurisdictions

• Hypersensitivity to one or both active substances or to any of the excipients
• 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<30ml/min)
• Hyperchloraemic acidosis

Cautions

• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (Recommendations in other jurisdictions)
• Mild to moderate renal impairment (CrCl≥30ml/min)
• Hepatic impairment
• Cardiovascular disease
• Severe peripheral circulatory disorders
• Mild to moderate chronic obstructive pulmonary disease
• Abrupt withdrawal in patients with coronary heart disease
• Hypoglycaemia
• Labile diabetes mellitus
• Hyperthyroidism
• Corneal diseases
• Surgical anaesthesia
• Myasthenia gravis
• History of renal calculi
• Acute closed angle glaucoma
• History of intraocular surgery
• Low endothelial cell count
• Concomitant use of contact lenses

Forms avail. in SA and covered in this monograph: opd

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

• Elevated intra-ocular pressure
  - In ocular hypertension
  - In open-angle glaucoma
  - In pseudoexfoliative glaucoma
  - In other secondary open-angle glaucomas when concomitant therapy is appropriate

Dorzolamide/ Timolol
5/20 (mg/ml)

• Ophthalmic (opd): 1 drop in affected eye(s), 12hrly

If switching from another ophthalmic antiglaucoma agent to dorzolamide/ timolol ophthalmic drops, discontinue the other agent after the final dose of the day and initiate dorzolamide/ timolol ophthalmic drops from the next day

If an additional topical ophthalmic agent is being used, administer dorzolamide/ timolol ophthalmic drops at least 10 minutes apart from the other medication to avoid interference

Using nasolacrimal occlusion or closing the eyelids for 2 minutes after administration can reduce systemic absorption, potentially decreasing systemic adverse reactions and increasing local activity

For ophthalmic use only

Paed. forms avail. in SA and covered in this monograph: opd

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

• Elevated intra-ocular pressure
  - In ocular hypertension
  - In open-angle glaucoma
  - In pseudoexfoliative glaucoma
  - In other secondary open-angle glaucomas when concomitant therapy is appropriate

Younger than 2 years

• Not established for use

Older than 2 years

• No specific recommendations for paediatric use have been provided

Although dorzolamide/ timolol ophthalmic drops have been used in children 2-6 years of age, data on safety and efficacy are insufficient to recommend a safe and effective dose

Pregnancy

South African recommendations

• Contraindicated
• The safety of dorzolamide/ timolol ophthalmic drops has not been established for use in pregnant women
• Consequently, dorzolamide/ timolol ophthalmic drops should not be used during pregnancy

Recommendations in other jurisdictions

• Caution; not recommended
• Dorzolamide/ timolol ophthalmic solution should not be used during pregnancy
• For dorzolamide, no adequate clinical data from exposed pregnancies are available, with teratogenic effects observed in rabbits at doses that caused maternal toxicity
• There are no adequate data available for the use of timolol in pregnant women, and it should only be used during pregnancy if it is clearly necessary
• To reduce the systemic absorption of timolol, adherence to specific instructions typically provided with the medication is important
• Epidemiological studies have not revealed malformative effects, but there is a risk for intrauterine growth retardation when beta-blockers like timolol are administered orally
• Signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress, and hypoglycaemia) have been observed in newborns when beta-blockers have been administered until delivery
• If this medicinal product is administered until delivery, the newborn should be carefully monitored during the first few days of life

Breastfeeding

South African recommendations

• Contraindicated
• The safety of dorzolamide/ timolol ophthalmic drops has not been established for use in lactating women

Recommendations in other jurisdictions

• Caution; not recommended
• 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, including timolol, are excreted in breast milk, but at therapeutic doses of timolol in eye drops, it is unlikely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant
• To reduce systemic absorption of timolol, adherence to specific instructions typically provided with the medication is important
• If treatment with dorzolamide/ timolol eye drops, solution is required, then lactation is not recommended

Renal Impairment

• Mild to moderate (CrCl≥30ml/min): Caution; no information available
• Severe (CrCl<30ml/min): Contraindicated

Hepatic Impairment

• Caution; no information available

Elderly

• No dose adjustment recommended

Central Nervous System Disorders

• Depression
• Insomnia
• Nightmares
• Memory loss
• Headache
• Dizziness
• Paraesthesia
• Syncope
• Myasthenia gravis
• Decreased libido
• Cerebrovascular accident
• Cerebral ischaemia
• Decreased libido
• Sexual dysfunction
• Fatigue

Cardiovascular Disorders

• Bradycardia
• Chest pain
• Palpitation
• Oedema
• Arrhythmia
• Congestive cardiac failure
• Cardiac arrest
• Heart block
• Atrioventricular block
• Hypotension
• Claudication
• Raynaud's phenomenon
• Cold hands and feet

Respiratory Disorders

• Sinusitis
• Shortness of breath
• Respiratory failure
• Rhinitis
• Bronchospasm
• Epistaxis
• Dyspnoea
• Cough

Gastrointestinal Disorders

• Dysgeusia
• Nausea and vomiting
• Dyspepsia
• Diarrhoea
• Throat irritation
• Dry mouth
• Abdominal pain

Genitourinary Disorders

• Urolithiasis
• Peyronie's disease

Endocrine and Metabolic Disorders

• Hypoglycaemia

Musculoskeletal Disorders

• Systemic lupus erythematosus
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Urticaria
• Pruritus
• Rash
• Contact dermatitis
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Alopecia
• Psoriasiform rash
• Exacerbation of psoriasis

Immune, Blood and Lymphatic System Disorders

• Systemic allergic reactions
• Angioedema
• Anaphylaxis

Sensory Disorders

• Conjunctival injection
• Blurred vision
• Corneal erosion
• Tearing
• Eyelid inflammation
• Eyelid irritation
• Iridocyclitis
• Ocular irritation
• Ocular pain
• Transient myopia
• Corneal oedema
• Ocular hypotony
• Choroidal detachment
• Blepharitis
• Keratitis
• Decreased corneal sensitivity
• Dry eyes
• Refractive changes
• Ptosis
• Diplopia
• Tinnitus

• Calcium channel blockers
• Catecholamine-depleting medicines 
• Beta blockers
• Antiarrhythmics
• Digitalis glycosides
• Parasympathomimetics
• Guanethidine
• Narcotics
• Monoamine oxidase inhibitors
• CYP2D6 inhibitors
• Adrenaline
• Antidiabetic agents
• Clonidine

None routine

Timolol
Timolol maleate is a non-selective beta-adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic activity. It combines reversibly with the beta-adrenergic receptor, and this inhibits the usual biologic response that would occur with stimulation of that receptor. Timolol maleate reduces elevated and normal intraocular pressure whether or not associated with glaucoma and has with little or no effect on accommodation or pupil size.

Dorzolamide
Dorzolamide is a sulfonamide and a highly specific carbonic anhydrase II (CA-II) inhibitor, which is the main CA isoenzyme involved in aqueous humor secretion. Inhibition of CA-II in the ciliary processes of the eye decreases aqueous humor secretion which reduces intraocular pressure.

COMBINATION PREPARATIONS

Dorzolamide/ Timolol

Eye drops (per ml) 20mg/5mg

• Cosopt (Mundipharma) originator
• Glauopt Co (Pharmacare)
• Glaumide Co (Actor)
• Ocudor Co (Pharma Dynamics)