VI.2 Elements for a public summary VI.2.1 Overview of disease epidemiology The term ocular hypertension usually refers to any situation in which the pressure inside the eye, called intraocular pressure, is higher than normal. Eye pressure is measured in millimeters of mercury (mm Hg). Normal eye pressure ranges from 10-21 mm Hg. Ocular hypertension is an eye pressure of greater than 21 mm Hg. Ocular hypertension should not be considered a disease by itself. Instead, ocular hypertension is a term that is used to describe individuals who should be observed more closely than the general population for the onset of glaucoma. Recent data on people with ocular hypertension from the Ocular Hypertension Treatment Study have shown that they have an average estimated risk of 10% of developing glaucoma over 5 years. This risk may be decreased to 5% (a 50% decrease in risk) if eye pressure is lowered by medications or laser surgery. However, the risk may become even less than 1% per year because of significantly improved techniques for detecting glaucomatous damage. Glaucoma is the second leading cause of blindness in the world (after cataracts) and the leading cause of blindness among African-Americans. Open-angle glaucoma is the most common type of glaucoma among populations of European or African descent, whereas angle-closure glaucoma is more common among populations of Asian descent. It is estimated that there are 44.7 million people with open-angle glaucoma worldwide in 2010, and that this number will increase to 58.6 million in 2020. It is estimated that there are 2.8 million people with open-angle glaucoma in the United States (US) in 2010, and that the number will increase to 3.4 million in 2020. The Barbados Eye Study found ocular hypertension present more frequently in women. Mean intraocular pressure (IOP) slowly rises with increasing age. Age older than 40 years is considered a risk factor for the development of ocular hypertension and primary open-angle glaucoma (POAG). Black subjects had almost 3 times the age-adjusted prevalence of glaucoma than white subjects.
Aphakia is the absence of the lens of the eye, due to surgical removal, a perforating wound or ulcer, or hereditary anomaly. Short term or permanent increases in intraocular pressure occurs in patients with aphakia, with studies reporting from 6% to 26% of patients developing this problem. The reported incidence varies with the duration of follow-up after cataract surgery. A longer follow-up period has been associated with a higher incidence of glaucoma. Glaucoma can occur at any time after hereditary cataract surgery; therefore, paediatric aphakic patients should be routinely monitored for glaucoma throughout their lives. Secondary glaucoma refers to any form of glaucoma in which there is an identifiable cause of increased eye pressure, resulting in optic nerve damage and vision loss. It may be caused by e.g. an eye injury, inflammation, certain drugs such as steroids, and advanced cases of cataract or diabetes.about 20% of all glaucoma cases may be classed as secondary glaucoma. Glaucomas are a heterogeneous group of eye conditions that may appear from as early as birth to very late age of onset in life. The primary type of glaucomas affecting children and juveniles are less frequent, but their prevalence affecting older people of 70 years progressively increases to ~5%. Primary congenital glaucoma is a rare eye disorder usually manifested at birth or early childhood (before 3 years of age) and accounts for 0.01 0.04% of total blindness. The only known risk factors of the disease are genetic - consanguinity and affected siblings. The risk of congenital glaucoma in the second child is approximately 5%, and the risk increases to 25% with two affected siblings. Primary juvenile glaucoma is also a rare eye disorder, with an estimated occurrence of 1 per 50,000 persons, when compared in frequency to other types of childhood glaucoma. Juvenileonset glaucoma may appear during the first two decades of life with unknown frequency and is related, like the primary congenital glaucoma, with heredity factors. VI.2.2 Summary of treatment benefits A variety of options are available to treat glaucoma. These include eye drops, laser procedures, and surgery. All are intended to decrease eye pressure and, thereby, protect the optic nerve. Drugs to treat glaucoma are classified by their active ingredient. These include: prostaglandin analogs, beta blockers, alpha agonists, and carbonic anhydrase inhibitors. In addition, combination drugs are available for patients who require more than one type of medication. Beta blockers such as timolol are the second most often used class of medication and work by decreasing production of fluid from the eye. They have systemic side effects that can be minimized by closing the eyes following application or using a technique called punctual occlusion that prevents the drug from entering the tear drainage duct and systemic circulation. In contrast to prostaglandin analogs, they are not associated with changes to the eye itself (e.g. change in iris color and growth of eyelashes). Timolol is also used in combination with a carbonic anhydrase inhibitor (dorzolamide) and also with an alpha agonist (brimonidine) in patients who require more than one type of medication.
There are many studies comparing safety and efficacy of timolol maleate with other drugs using to treat glaucoma. Timolol has been shown safe and effective alone or in combination formulations. [Timolol] 2.5 and 5 mg/ml preservative free eye drops, solution does not contain preservative. Thus, there is no risk with contact lenses neither eye irritation that may occur by the preservative himself. VI.2.3 Unknowns relating to treatment benefits Due to limited data in the paediatric population, timolol could only be recommended for use in primary congenital and primary juvenile glaucoma in short term treatment. VI.2.4 Summary of safety concerns Important identified risks Risk What is known Preventability Safety concern in lay language (medical term) Worsening of heart problems (Deterioration of cardiovascular diseases) Patients with poor blood circulation disease (such as Raynaud s disease or Raynaud s syndrome) Brief summary in lay language Inhibition by beta-adrenergic receptor blockade (timolol) may precipitate more severe failure in individuals with a history of severe cardiac diseases such as coronary heart diseases, Prizmental s angina and cardiac failure. In addition, in patients without a history of cardiac failure continued depression of the myocardium with betablocking agents over a period of time can, in some cases, lead to cardiac failure. In cardiac tissues, beta blockade (timolol) causes a reduction in inotropic as well as chronotropic activity, which may further depress cardiac Whether risk can be minimised or mitigated, and how Cardiac failure should be adequately controlled before beginning therapy with the medication. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates monitored. Treatment should be discontinued immediately after apparition of symptoms and patient should ask for physician advice.
(Peripheral circulatory disorders) Patients with breathing problems, asthma or chronic obstructive pulmonary disease (Bronchospasm) Very low level of blood sugar, diabetes (Acute hypoglycaemia) Overactivity of the thyroid gland (Masking signs) hyperthyroidism output and blood pressure in patients with peripheral circulatory disorders. Timolol is a drug widely used for lowering increased intaocular pressure. It is an effective treatment mode, but as much as 80% of the ophthalmic dose can be absorbed into the systemic circulation. This may cause adverse systemic effects such as bradycardia, lowering of blood pressure, constriction of the airways in the lungs (predominantly in patients with pre-existing disease), difficulty breathing, shortness of breath, wheezing, cough. Beta-adrenergic receptor blocking agents may mask symptoms of hypoglycaemia such as tremors, tachycardia and blood pressure changes. In addition, the nonselective beta-blockers (e.g., propranolol, pindolol, timolol) may potentiate insulin-induced hypoglycaemia and suspending the recovery of normal blood glucose levels. Beta-adrenergic receptor blocking agents (such as timolol) are used to alleviate symptoms of hyperthyroidism such as tachycardia, anxiety, tremor and heat intolerance. Thus, use of timolol eye drops, because of it systemic absorption, may mask hyperthyroidism symptoms. Complications due to hyperthyroidism, such heart problems, brittle bones, thyrotoxic crisis, myasthenia gravis Medication should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) as bronchospasm may be life-threatening in patients with asthma. Treatment should be discontinued immediately after apparition of symptoms and patient should ask for physician advice. Timolol should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile diabetes Physician should be aware if patient had or has overactivity of the thyroid gland
Irritation of the eye - dry eyes (Corneal toxicity dry eye) Abnormality in heart s rhythm (Conduction abnormality) Problem in the surface layer of the eye, eye surgery (Choroidal detachment) Signs and symptoms of eye irritation (e.g. burning, stinging, itching, tearing, redness), inflammation of the eyelid, inflammation in the cornea, blurred vision, decreased corneal sensitivity, dry eyes, corneal erosion (damage to the front layer of the eyeball), drooping of the upper eyelid (making the eye stay half closed) double vision, sensitivity to light, discharge from the eye, pain in the eye, have been reported Ophthalmic timolol can induce atrioventricular block, sinus bradycardia demonstrated in ECG, and expressed as syncope or dizziness. The most of them are reversible. Choroidal detachment is the separation of the choroid from the sclera of the eye as a result of leakage of fluid from the vessels of the choroid. It occurs when pressure inside the eyeball is very low, usually after trauma or intraocular surgery. Ophthalmologist should evaluate the risks and benefits of ophthalmic medications before initiating therapy, identify the minimum dosages necessary to achieve a therapeutic benefit, and monitor patients for local and systemic adverse effects Physician should be known if patient low blood pressure. Beta-blocker such as timolol, should not administer with a category of drugs named calcium-channel blockers Choroidal detachment cases have been reported following timolol treatment. Management of eyes with chronic or recurrent choroidal detachment should include stopping all forms of aqueous suppressant therapy. Timolol administration together with adrenaline (Co-administration with adrenaline) In case of surgical anaesthesia, both the anesthesiologist and the ophthalmologist must be aware that eyedrops are readily absorbed through hyperemic incised conjunctivae. Although small in volume, these drops contain highly concentrated medication that can produce systemic results. The anaesthesiologist should be informed when the patient is receiving timolol.
Allergic reaction (Hypersensitivity to any allergen) Beta-blockers, such as timolol, in patients with 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. Treatment should be discontinued immediately after apparition of an allergic symptom. Patient should ask physician advice. Appearance of calcium on the cornea (Corneal calcification) Allergic reaction such as swelling beneath the skin that can occur in areas such as the face and limbs, and can obstruct the airway which may cause difficulty swallowing or breathing, hives or itchy rash, localized and generalized rash, itchiness may occur Severe sudden life-threatening has been recorded but their frequency (not known) cannot be established from the available data at the moment. Phosphates are widely used as part of the buffering system in ophthalmic drop preparations. However, recent studies have shown that phosphate buffer play a role in the process of corneal calcification. Serious ocular diseases, such as band keratopathy (a corneal disease) derived from the appearance of calcium on the central cornea may occur Cases of corneal calcification have been reported very rarely in association with the use of phosphate eye containing eye drops in some patients with significantly damaged corneas. Thus, of phosphate-buffered medications should be used cautionally. Important potential risks Risk Bacterial keratitis What is known (Including reason why it is considered a potential risk) Bacterial keratitis is an infection of the cornea (the clear, round dome covering the eye's iris and pupil) that causes pain, reduced vision, light sensitivity and tearing or discharge from the eye. It is an important cause of visual loss. The aetiology is diverse: bacterial, fungal, viral, protozoal or it may be polymicrobial in nature. Prescribed topical ocular medications
can become contaminated and result in bacterial keratitis especially gram-negative infection with Pseudomonas, Serratia and Proteus species. Missing information Risk No adequate and well controlled studies in pregnant women What is known There are no adequate data for the use of timolol in pregnant women. Timolol should not be used during pregnancy unless clearly necessary. Systemic absorption of topically administered β-blockers can be reduced by nasolacrimal occlusion and by keeping the eyes closed as long as possible (e.g. for 3-5 minutes) after instillation of drops. Epidemiological studies have not revealed malformative effects but show a risk for intra uterine growth retardation when betablockers 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. No studies in patients wearing contact lenses [Invented name] has not been studied in patients using contact lenses. [Invented name] should not be used while using soft contact lenses. The lenses should only be inserted 15 minutes after the drip. Exposure in paediatric patients There is only very limited data available on the use of Timolol (2.5, 5 mg/ml twice daily one drop) in the paediatric population. In one small, double masked, randomized, published clinical study conducted for a treatment period of up to 12 weeks on 105 children (n=71 on Timolol) aged 12 days 5 years the data have shown to some extent evidence, that Timolol in the indication primary congenital and primary juvenile glaucoma is effective in short term treatment. Thus, timolol could only be recommended for use in primary congenital and primary juvenile glaucoma for a transitional period while a decision is made on a surgical approach and in case of failed surgery while awaiting further options. VI.2.5 Summary of risk minimisation measures by safety concern
All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimisation measures. This medicine has no additional risk minimisation measures. VI.2.6 Planned post authorisation development plan Not applicable VI.2.7 Summary of changes to the risk management plan over time Version Date Safety concerns Change 1.0 18.07.2014 Important identified risks Deterioration of cardiovascular diseases Peripheral circulatory disorders Bronchospasm Acute hypoglycaemia Masking Hyperthyroidism signs Corneal toxicity dry eye Conduction abnormality adverse events Choroidal detachment Co-administration with epinephrine Hypersensitivity to any allergen Corneal calcification Important potential risks Bacterial keratinitis associated with the use of the multidose containers of topical ophthalmic Initial version
products Usage of medicinal product longer than 28 days after first opening the container Missing information No adequate and well controlled studies in pregnant women No studies in patients wearing contact lenses Exposure in paediatric patients 2.0 25.02.2015 Important identified risks Deterioration of cardiovascular diseases Peripheral circulatory disorders Bronchospasm Acute hypoglycaemia Masking Hyperthyroidism signs Corneal toxicity dry eye Conduction abnormality adverse events Choroidal detachment Co-administration with epinephrine Hypersensitivity to any allergen Corneal calcification Bacterial keratitis Important potential risks None Missing information Use in pregnant women No studies in patients wearing contact lenses Implementation of day 106 answers
Exposure in paediatric patients 3.0 27.10.2015 Important identified risks Deterioration of cardiovascular diseases Peripheral circulatory disorders Bronchospasm Acute hypoglycaemia Masking Hyperthyroidism signs Corneal toxicity dry eye Conduction abnormality adverse events Choroidal detachment Co-administration with adrenaline Hypersensitivity to any allergen Corneal calcification Important potential risks Bacterial keratitis Implementation of day 160 answers Missing information Use in pregnant women No studies in patients wearing contact lenses Exposure in paediatric patients