Timolol Maleate

Registered South African indications:

• Elevated intraocular pressure, including:
  - Ocular hypertension
  - Chronic open-angle glaucoma
  - Aphakia and glaucoma
  - Secondary glaucoma (some cases)
  - Narrow angles and a history of spontaneous or iatrogenically induced narrow-angle closure in the opposite eye, in whom reduction of intraocular pressure is necessary
  - Paediatric glaucoma (who are inadequately controlled with other anti-glaucoma therapy)

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to other beta-blocking agents
• Reactive airway disease including bronchial asthma or a history of bronchial asthma
• Presence or history of severe chronic obstructive pulmonary disease
• Sinus bradycardia
• Sick sinus syndrome
• Sino-atrial block
• Second- and third-degree atrioventricular block not controlled with pace-maker
• Overt cardiac failure
• Cardiogenic shock
• Untreated pheochromocytoma (gel)
• Corneal dystrophies (gel)

Cautions 

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Cardiovascular diseases 
  - Coronary heart disease
  - Prinzmetal's angina
  - Cardiac failure
• Hypotension
• Risk of rebound hypertension (gel)
• First-degree heart block
• History of severe cardiac disease
• Heart rate below 50-55 beats per minute at rest or if the patient presents bradycardia-related symptoms (gel)
• Severe peripheral circulatory disturbance/ disorders
  - Severe forms of Raynaud's disease or Raynaud's syndrome
• Mild/ moderate chronic obstructive pulmonary disease (COPD)
• Patients subject to spontaneous hypoglycaemia or with labile diabetes
• Metabolic acidosis (gel)
• Hyperthyroidism
• Corneal diseases
• Use after filtration procedures
• Surgical anaesthesia
• Angle-closure glaucoma
• Disruption of the ocular epithelial surface
• Young patients with glaucoma
• Neonates, infants and younger children
• Patients with dry eye
• Patients where the cornea may be compromised
• Prolonged use
• History of atopy or severe anaphylactic reaction to a variety of allergens
• Psoriasis (gel)
• Use with lenses made with material other than polymethylmethacrylate (PMMA) or with soft contact lenses
• Treated pheochromocytoma (without concomitant α-adrenoceptor blocking therapy) (gel)
• Coadministration with a systemic beta-blocking agent
• Coadministration with systemic beta-agonists e.g. epinephrine (adrenaline)
• Coadministration with other topical beta-adrenergic blocking agents
• May impair ability to drive and operate machinery

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

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Reduction of elevated intra-ocular pressure in various conditions 
- Ocular hypertension
- Chronic open-angle glaucoma

• Ophthalmic (opd (sol)): 0.25% sol. 1 drop into affected eye(s), 12hrly; If clinical response not adequate: 0.5% sol. 1 drop into affected eye(s), 12hrly
• Ophthalmic (opd (gellan sol)): 0.25% sol. 1 drop into affected eye(s), dly; If clinical response not adequate: 0.5% sol. 1 drop into affected eye(s), dly
• Ophthalmic (gel): 1 drop into affected eye(s), dly in the morning

- Chronic open-angle glaucoma, including aphakic patients
- Some patients with secondary glaucoma

• Ophthalmic (opd (sol)): 0.25% sol. 1 drop into affected eye(s), 12hrly; If clinical response not adequate: 0.5% sol. 1 drop into affected eye(s), 12hrly
• Ophthalmic (opd (gellan sol)): 0.25% sol. 1 drop into affected eye(s), dly; If clinical response not adequate: 0.5% sol. 1 drop into affected eye(s), dly

---

Intraocular pressure should be reassessed approximately four weeks after starting treatment because response to timolol eye drops may take a few weeks to stabilise

---

Timolol may be used with other agent(s) for lowering intra-ocular pressure. The use of two topical beta-adrenergic blocking agents is not recommended

---

Ophthalmic (opd): Provided that the intra-ocular pressure is maintained at satisfactory levels, many patients can then be placed on once a day therapy

---

See additional prescribing points for recommendations on transferring from other agents

---

South African manufacturer recommendations

Reduction of elevated intra-ocular pressure in various conditions
- Ocular hypertension
- Chronic open-angle glaucoma
- Aphakic glaucoma
- Some patients with secondary glaucoma

• Ophthalmic (opd (sol)): 0.25% sol. 1 drop into affected eye(s), 12hrly; If clinical response not adequate: 0.5% sol. 1 drop into affected eye(s), 12hrly
• Ophthalmic (opd (gellan sol)): 0.25% sol. 1 drop into affected eye(s), dly; If clinical response not adequate: 0.5% sol. 1 drop into affected eye(s), dly
• Ophthalmic (gel): 1 drop into affected eye(s), dly

---

Ophthalmic (gel):

- The gel should be instilled into the conjunctival cul-de-sac and can be used over a long period of time
- If other eye drops are being used, there must be an interval of at least 5 minutes between instillations so that the active substance is not washed out. Eye drops should be applied before the ophthalmic gel
- As it takes some time to stabilise the effect, it is recommended that the intraocular pressure is checked 3-4 weeks after the start of treatment
- The intraocular pressure should also be measured regularly thereafter because the response to timolol may change

---

- Narrow angles and a history of spontaneous or iatrogenically induced narrow-angle closure in the opposite eye  

• Ophthalmic (opd (sol)): 0.25% sol. 1 drop into affected eye(s), 12hrly; If clinical response not adequate: 0.5% sol. 1 drop into affected eye(s), 12hrly
• Ophthalmic (opd (gellan sol)): 0.25% sol. 1 drop into affected eye(s), dly; If clinical response not adequate: 0.5% sol. 1 drop into affected eye(s), dly

---

Ophthalmic (opd): If needed, concomitant therapy with other agent(s) for lowering intraocular pressure may be given with timolol. The use of two topical beta-adrenergic blocking agents is not recommended

---

Ophthalmic (sol): Since in some patients the pressure-lowering response to timolol may require a few weeks to stabilise, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment. If the intraocular pressure is maintained at satisfactory levels, many patients can be placed on once-a-day therapy

---

Ophthalmic (gel): As it takes some time to stabilise the effect, it is recommended that the intraocular pressure is checked 3-4 weeks after the start of treatment

---

Ophthalmic (gellan sol): Other topical medications should be administered no less than 10mins before ophthalmic gellan sol

---

Contact lenses should be removed before application of timolol and not reinserted earlier than 15mins (sol) or 30mins (gellan sol and gel) after use

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

Paed. dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Primary congenital and primary juvenile glaucoma
- When used for a transitional period while decision is made on a surgical approach
- In the case of failed surgery while awaiting further options

• Ophthalmic (opd (sol)): No specific dosage recommendations available (See notes below)
• Ophthalmic (opd (gellan sol)): Not indicated for use in children 
• Ophthalmic (gel): Not recommended for use

---

Ophthalmic (sol):

- Clinicians should strongly evaluate the risks and benefits when considering medical therapy with timolol in paediatric patients. A detailed paediatric history and examination to determine the presence of systemic abnormalities should precede the use of timolol
- No specific dosage recommendation can be given as there is only limited clinical data
- However, if benefit outweighs the risk, it is recommended to use the lowest active agent concentration available once daily. If the intraocular pressure could not be sufficiently controlled, a careful up titration to a maximum of two drops daily per affected eye has to be considered. If applied twice daily, an interval of 12 hours should be preferred
- Furthermore, the patients, especially neonates, should be closely observed after the first dose for one to two hours in the office and closely monitored for ocular and systemic side effects
- With regard to paediatric use, the 0.1% active agent concentration might already be sufficient (not currently available in South Africa)

---

Ophthalmic (gel):

- There is no experience in children and adolescents. This eye gel is therefore not recommended in such patients
- If the ophthalmologist considers it necessary, ophthalmic timolol gel may be combined with one or more other anti-glaucoma treatments (local and/or systemic route of administration)
- However, the combination of two beta-blocker eye drops is not recommended
- The other eye drops should be administered at least 15 minutes before ophthalmic timolol gel. The eye gel should be the last medication instilled
- Nonetheless, response to ophthalmic timolol gel may take several weeks to stabilise intraocular pressure, therefore the monitoring of the treatment should include intraocular pressure assessment after a treatment period of approximately four weeks

---

South African manufacturer recommendations

Paediatric glaucoma
- In patients inadequately controlled with other anti-glaucoma therapy

Premature infants or neonates

• Not recommended for use

Children

• Ophthalmic (opd (sol)): See adult dosage

Reduction of elevated intra-ocular pressure in various conditions
- Ocular hypertension
- Chronic open-angle glaucoma
- Aphakic glaucoma
- Some patients with secondary glaucoma

Younger than 12 years

• Ophthalmic (gel): Not recommended for use

Older than 12 years

• Ophthalmic (gel): See adult dosage

---

According to South African manufacturer recommendations, the use of the timolol (gellan sol) is not established for use for any indications

Pregnancy 

• Caution
• There are no adequate data for the use of timolol maleate in pregnant women. Timolol should not be used during pregnancy unless clearly necessary
• 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 timolol is administered until delivery, the neonate should be carefully monitored during the first days of life

Breastfeeding 

• Caution
• Timolol is detectable in human milk. A decision for breastfeeding mothers, either to stop taking timolol or stop breastfeeding, should be based on the importance of the drug to the mother

Renal Impairment

• Caution; no information available

Hepatic Impairment 

• Caution; no information available 

Elderly 

• No dose adjustment recommended

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Prohibited - In certain sports

  Prohibited - In  and out of competition: 
  Archery (WA)
  Shooting (ISSF) (IPC)

Prohibited - In competition: 
Automobile (FIA)
Billiards (all disciplines) (WCBS)
Darts (WDF)
Golf (IGF)
Skiing/ Snowboarding (FIS) in ski jumping, freestyle aerials/ halfpipe and snowboard halfpipe/big air
Underwater sports (CMAS) in constant-weight apnoea with or without fins, dynamic apnoea with and without fins, free immersion apnoea, Jump Blue apnoea, spearfishing, static apnoea, target shooting and variable weight apnoea 

Central Nervous System Disorders 

• Depression
• Insomnia
• Nightmares
• Memory loss
• Hallucination
• Diminished concentration
• Increased dreaming
• Syncope
• Cerebrovascular accident
• Cerebral ischemia
• Headache
• Dizziness
• Increase in signs and symptoms of myasthenia gravis
• Paraesthesia
• Local weakness
• Asthenia

Cardiovascular Disorders

• Bradycardia
• Chest pain
• Arrhythmia
• Congestive heart failure
• Palpitations
• Cardiac arrest
• Cardiac failure
• Oedema
• Atrioventricular block (second- or third-degree)
• Sino-atrial block
• Pulmonary oedema
• Worsening of arterial insufficiency
• Worsening of angina pectoris
• Vasodilation
• Intermittent claudication
• Hypotension
• Raynaud's phenomenon
• Cold hands and feet
• Decreased exercise tolerance

Respiratory Disorders

• Bronchospasm
• Respiratory failure
• Dyspnoea
• Cough
• Rales

Gastrointestinal Disorders

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

Genitourinary Disorders 

• Micturition difficulties
• Peyronie's disease
• Sexual dysfunction
  - Impotence
• Decreased libido

Endocrine and Metabolic Disorders  

• Hypoglycaemia
• Hyperglycaemia

Musculoskeletal Disorders 

• Myalgia
• Arthralgia

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Alopecia
• Psoriasiform rash or exacerbation of psoriasis
• Skin rash
• Sweating
• Exfoliative dermatitis

Immune, Blood and Lymphatic System Disorders 

• Systemic lupus erythematosus
• Allergic reactions
  - Anaphylaxis
  - Angioedema
  - Urticaria
  - Localised and generalised rash
  - Anaphylactic reaction
• Non-thrombocytopenic purpura

Sensory Disorders

• Ocular irritation
  - Burning
  - Stinging
  - Itching
  - Tearing
  - Redness
• Conjunctivitis
• Conjunctival hyperaemia
• Blepharitis
• Keratitis
• Dry eyes
• Decreased corneal sensitivity
• Blurred vision
• Corneal erosion
• Visual disturbance
  - Refractive changes
• Diplopia
• Ptosis
• Choroidal detachment (following filtration surgery)
• Corneal calcification
• Tinnitus
• Vertigo

Others

• Extremity pain
• Decreased exercise tolerance

---

Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic beta-blocking agents. Incidence of systemic adverse reactions after topical ophthalmic administration is lower than for systemic administration

• Central antihypertensive agents
• Calcium channel blockers
• Dihydropyridine derivatives
• Nifedipine
• Verapamil
• Diltiazem
• Beta-adrenergic blocking agents
• Antiarrhythmics
• Class I antiarrhythmics
• Amiodarone
• Digitalis glycosides
• Rauwolfia alkaloids
• Parasympathomimetics
• Guanethidine
• Epinephrine (adrenaline)
• CYP2D6 inhibitors
• Quinidine
• Fluoxetine
• Paroxetine
• Clonidine
• Catecholamine-depleting drugs
• Reserpine
• Bepridil
• Fingolimod
• Volatile halogenated anaesthetic agents
• Baclofen
• Insulin
• Oral hypoglycaemic agents
• Glinides
• Gliptines
• Lidocaine
• Agents that may cause torsades de pointes
• Propafenone
• Alpha-blockers intended for urological use
• Antihypertensive alpha-blockers
• Amifostine
• Imipraminic antidepressants
• Neuroleptics
• Non-steroidal anti-inflammatory drugs
• Other bradycardial drugs
• Dihydropyridines
• Dipyridamole
• Pilocarpine (systemic)
• Nitro derivatives

---

Although the quantity of beta-blockers which passes into the systemic circulation is low after ocular instillation, the risk of drug interactions is still present. It is therefore advisable to keep in mind the above interactions observed with beta-blockers given by general route

• Intraocular pressure
• Blood pressure

Additional observations

• Systemic effects of beta-blockade 
• Signs of cardiac failure (patients with a history of severe cardiac disease)
• Pulse rate  (patients with a history of severe cardiac disease)

Transferring from other agents

Transfer from another topical beta-blocking agent to the timolol eye drops (solution)

• When another topical beta-blocking agent is being used, discontinue its use after a full day of therapy and start treatment with timolol eye drops 0.25% the next day with one drop in each affected eye twice a day. The dosage may be increased to one drop of 0.5% solution in each affected eye twice a day, if the response is not adequate

Transfer from a single anti-glaucoma agent other than a topical beta-blocking agent to the timolol eye drops (solution) 

• When transferring a patient from a single anti-glaucoma agent other than a topical beta-blocking agent, continue the agent and add one drop of timolol eye drops 0.25% in each affected eye twice a day. On the following day, discontinue the previous agent completely, and continue with timolol eye drops If a higher dosage of timolol eye drop is required, substitute one drop of 0.5% solution in each affected eye twice a day

Transfer from timolol eye drops (solution) to timolol eye drops (gellan solution)

• Discontinue timolol eye drops (solution) after a full day of therapy, starting treatment with the same concentration of timolol eye drops (gellan solution) on the following day

Transfer from another topical beta-blocking agent to the timolol eye drops (gellan solution)

• When another topical beta-blocking agent is being used, discontinue its use after a full day of therapy and start treatment with timolol eye drops (gellan solution) the next day with one drop of 0.25% timolol eye drops (gellan solution) in each affected eye once a day. The dosage may be increased to one drop of 0.5% solution in each affected eye once a day if the response is not adequate

Transfer from a single anti-glaucoma agent other than a topical beta-blocking agent to the timolol eye drops (gellan solution) 

• When transferring a patient from a single anti-glaucoma agent other than a topical beta-blocking agent, continue the agent and add one drop of 0.25% timolol eye drops (gellan solution) in each affected eye once a day. On the following day, discontinue the previous agent completely, and continue with timolol eye drops (gellan solution). If a higher dosage is required, substitute one drop of 0.5% solution in each affected eye once a day

Transfer from another anti-glaucoma eye drop to timolol eye gel 

• When timolol eye gel  is used to replace another anti-glaucoma eye drops, this eye drops should be discontinued after a full day of therapy, and timolol eye gel  should be started the next day at the dosage of one drop in the affected eye (or eyes) once a day, in the morning
• If timolol eye gel is replacing a combination of anti-glaucoma treatments, only one drug should be withdrawn at a time

Transfer from another anti-glaucoma eye drops (not a beta-blocker eye drops) to timolol eye gel 

• If the anti-glaucoma drug being replaced is not a beta-blocker eye drops, it should be continued and one drop of timolol eye gel should be instilled in the affected eye (or eyes), once a day. The following day, stop taking the previous drug completely

Replacing miotic eye drops

• When timolol eye gel is used to replace miotic eye drops, testing of refraction may prove necessary when the effects of the miotics have disappeared
• Medical prescription should be combined with the monitoring of intraocular pressure, particularly when the treatment is initiated

Method of administration

• 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
• Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures
• When using the gellan solution, invert the closed container and shake once before each use. It is not necessary to shake the container more than once
• 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 eye and subsequent loss of vision may result from using contaminated solutions

Effects on investigations

• Antinuclear antibodies positive (gel)

Timolol maleate is a non-selective beta-adrenergic receptor blocking agent that combines reversibly with the beta-adrenergic receptor, and thus inhibits the usual biologic response that would occur with stimulation of that receptor. This specific competitive antagonism blocks stimulation of the beta-adrenergic stimulating (agonist) activity, whether these originate from an endogenous or exogenous source. Timolol maleate does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic activity.

Eye drops (sol) (per ml) 2.5mg 

• Timoptol 0.25% (Mundipharma) Originator

Eye drops (sol) (per ml) 5mg 

• Glaucosan 0.5% (Sandoz)
• Occumol 0.5% (Gulf Drug)
• Timoptol 0.5% (Mundipharma) Originator

Eye drops (gellan sol) (per ml) 2.5mg

• Timoptol-xe 2.5ml  (Mundipharma)

Eye drops (gellan sol) (per ml) 5mg

• Timoptol-xe 2.5ml (Mundipharma)

Eye gel (per g) 1mg

• Nyogel (Adcock Ingram)

COMBINATION PREPARATIONS

Bimatoprost/ Timolol

Eye drops (per ml) 3mg/5mg

• Ganfort (Allergan) originator

Latanprost/ Timolol

Eye drops (per ml) 50μg/5μg

• Xalacom (Pfizer) originator

Dorzolamide/ Timolol

Eye drops (per ml)  20mg/5mg

• Cosopt (MSD) originator
• Glauopt Co (Pharmacare)
• Glaumide Co (Actor)

Travoprost/ Timolol

Eye drops (per ml) 40μg/5mg

• Duotrav Eye drop (Alcon) originator

Brinzolamide/ Timolol

Eye drops (per ml) 10mg/5mg

• Azarga (Alcon) originator

Brimonidine tartrate/ Timolol

Eye drops (per ml) 2mg/5mg

• Combigan (Allergan) originator