1. Name Of The Medicinal Product
Nyogel 0.1%, eye gel
2. Qualitative And Quantitative Composition
1 g gel contains 1.37 mg timolol maleate, corresponding to 1 mg of timolol
Excipients: benzalkonium chloride (0.05 mg/g).
For a full list of excipients see section 6.1.
3. Pharmaceutical Form
Eye gel.
Colourless, opalescent, odourless gel, free of visible particulate matter.
4. Clinical Particulars
4.1 Therapeutic Indications
Nyogel eye gel is used to reduce elevated intraocular pressure in the following conditions:
- Ocular hypertension
- Chronic open-angle glaucoma
4.2 Posology And Method Of Administration
Adults and children over the age of 12 years:
The recommended dosage is one drop of Nyogel eye gel in the affected eye(s) daily, preferably in the morning.
Elderly
The above dosage can be used for the elderly.
Children under the age of 12 years
Paediatric use is not recommended.
All age goups
Intraocular pressure should be reassessed 2 to 4 weeks after starting treatment, because response to treatment may take a few weeks to stabilise.
If necessary, Nyogel eye gel can be used concomitantly with miotics, epinephrine and/or carbonic anhydrase inhibitors. To prevent the active substance from being washed out from the eye, an interval of at least 5 minutes between application of different drugs is required, and Nyogel eye gel should be the last one to be administered.
In case of transfer from other topical beta blocking agents: discontinue their use after a full day of therapy and start treatment with Nyogel eye gel the next day. Instill one drop in each affected eye once a day, preferably in the morning.
In case of transfer from a single antiglaucoma agent other than topical beta blocking agent:
Continue the agent and add one drop of Nyogel eye gel in each affected eye once a day. On the following day, discontinue the previous agent completely, and continue with Nyogel eye gel.
Method of administration:
Nyogel eye gel is to be instilled into the conjunctival cul-de-sac. It can be used also for long-term therapy.
For a correct dosing during application, the eye-drop bottle must be held vertically during administration.
The dispenser remains sterile until the original closure is broken. Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures as this may contaminate the gel.
When using nasolacrimal occlusion or closing the eyelids for 5 minutes the systemic absorption may be reduced. This may result in a decrease in systemic side effects and an increase in local activity.
4.3 Contraindications
As with all products containing beta-receptor agents, Nyogel eye gel is contraindicated in patients with
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4.4 Special Warnings And Precautions For Use
Like other topically applied ophthalmic drugs, timolol maleate is absorbed into the systemic circulation. This may cause similar undesirable side effects as seen with oral beta-blocking agents.
Therefore it should be used with caution in patients with metabolic acidosis.
During anaesthesia severe bradycardia and hypotension have been observed in some patients using beta-blockers. The anaesthesiologist should be informed when the patient is receiving Nyogel eye gel. A gradual withdrawal of Nyogel eye gel over 1 to 2 weeks is recommended in high risk patients (including patients with coronary heart disease) prior to scheduled surgery. Sudden withdrawal of Nyogel eye gel may lead to exacerbation of angina and development of hypertension and arrhythmias; Nyogel eye gel should therefore be discontinued at least 24 to 48 hours prior to surgery (see section 4.5 Interaction with other medicinal products and other forms of interaction).
Nyogel eye gel may cause worsening systolic heart failure or new heart failure in patients who depend on high sympathetic drive to maintain cardiac output. Cardiac failure should be adequately controlled before beginning therapy. andpatients with a history of severe cardiac disease should be monitored for early signs of possible cardiac failure. Beta
Concomitant use of amisulpride with Nyogel eye gel may lead to increased risk of ventricular arrhythmia, particularly torsades de pointes. Therefore, caution is recommended in patients with pre-existing bradycardia (see section 4.5 Interaction with other medicinal products and other forms of interaction).
Close monitoring of cardiac function and observation of the patient for bradycardia or heart block is advised when amiodarone and a beta adrenergic blocker are coadministered (see section 4.5 Interaction with other medicinal products and other forms of interaction)
Although the concentration of timolol maleate in the plasma following application of Nyogel eye gel is lower than after administration of timolol eye drops, the product should generally not be used in combination with amiodarone, calcium antagonists, (bepridil, verapamil, diltiazem) or with beta blockers (see section 4.5 Interaction with other medicinal products and other forms of interaction).
Nyogel eye gel has little or no effect on the pupil. When this eye gel is used to lower intraocular pressure in patients with angle-closure glaucoma, it should be given in combination with a miotic. In these patients, the immediate treatment objective is to open the angle by constriction of the pupil with a miotic agent.
Respiratory and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death associated with cardiac failure have been reported.
Risk of anaphylactic reactions: Patients with a history of atopy or serious anaphylactic reactions to different allergens may be more sensitive to repeated exposure to allergens. The exposure may be accidental, diagnostic or therapeutic. When Nyogel eye gel is used in such patients, the normal epinephrine dose used to treat anaphylactic reactions may be insufficient.
Nyogel eye gel contains benzalkonium chloride as a preservative. Benzalkonium chloride may cause eye irritation and is known to discolour soft contact lenses. Therefore avoid contact with soft contact lenses. Remove contact lenses prior to drug application and wait until at least 15 minutes before reinsertion.
Beta-blockers may increase the risk of rebound hypertension.
Caution should be exercised if Nyogel eye gel is used with systemic beta- blockers.
Nyogel eye gel should not be used with another topical beta-blocker.
The concomitant administration of MAO inhibitors should be avoided.
Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g. timolol, acetazolamide).
As with any glaucoma treatment, regular examination of the intraocular pressure and cornea is recommended.
Signs and symptoms of hypoglycaemia, especially tachycardia, palpitations and sweating may be masked. Diabetic patients should be advised to reinforce self-monitoring of their glycaemia at the beginning of treatment.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
1. Other eye drops
If concomitant treatment with other eye drops is used, their administration should be separated by at least a 5 minute interval and the eye gel should be administered last.
Although Nyogel eye gel has little effect on the size of the pupil, mydriasis has occasionally been reported when timolol maleate has been used with mydriatic agents such as epinephrine.
2. Other drugs
Despite the lower systemic exposure after instillation of the once daily Nyogel 0.1% eye gel compared to the twice daily timolol 0.5% eye drops, timolol maleate is absorbed systemically and interactions observed with oral beta-blockers may occur.
Amisulpride
Increased risk of ventricular arrhythmia, particularly torsades de points.
Amiodarone
Supression of compensatory sympathetic mechanisms may lead to conduction and myocardial contractility disorders.
Calcium antagonists
Bradyarrhythmias (excessive bradycardia, sinus arrest), sinoatrial or atrioventricular conduction disorders and cardiac failure via a synergistic effect.
The nature of any cardiovascular adverse effects tends to depend on the type of calcium-channel blocker used. Dihydropyridine derivatives, such as nifedipine, may lead to hypotension, whereas verapamil or diltiazem tend to cause AV conduction disturbances or left ventricular failure when used with beta-blocker.
Oral beta-blockers
When Nyogel eye gel is administered to patients receiving an oral beta-blocking agent, both the reduction in intraocular pressure and the effects of systemic beta-blockade may be intensified. The response of such patients should be closely observed.
Catecholamine-depleting drugs (e.g. reserpine)
Close observation of the patient is also recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension.
Digitalis glycosides
The concomitant use of digitalis glycosides and beta-blockers may slow down atrioventricular conduction.
Class I anti-arrhythmic drugs
Class I anti-arrhythmic drugs (e.g. disopyramide, propafenone, quinidine, lidocain i.v.) and amiodarone may have a potentiating effect on atrial conduction and thus induce a negative inotropic effect.
CYP2D6 inhibitors (e.g. quinidine, SSRIs)
Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported.
Parasypathomimetics
Increased risk of bradycardia
Volatile halogenated anaesthetic agents
Reductions in compensatory cardiovascular mechanisms by beta-blockers (beta-adrenergic inhibition may be counteracted during surgery by beta-stimulants). As a general rule do not discontinue beta-blocker therapy and in any event, avoid a sudden discontinuation. The anaesthetist should be advised of this treatment. (see section special warnings and precautions for use)
Potentiation of the systemic beta-blocking effects of eye drops and an increase in plasma levels of the beta-blocker have been reported when beta-blocker eye drops are combined with quinidine, probably due to inhibition of the beta-blocker metabolism by quinidine (described for timolol). In addition, cimetidine and hydralazine may increase the timolol maleate concentration in the plasma.
Mefloquine
Prolongation of QT interval may occur.
Clonidine and other centrally acting antihypertensive agents (methyldopa, guanfacine, moxonidine, rilmenidine)
Close observation of the patient is recommended. To avoid rebound hypertension, abrupt withdrawal of the drugs should be avoided.
Insulin, oral hypoglycaemic agents
All beta-blockers may mask certain symptoms of hypoglycaemia: palpitations and tachycardia.
Most of the non-cardioselective beta-blockers increase the frequency and severity of hypoglycaemia.
Warn the patient and particularly at the beginning of treatment, self-monitoring of glucose by the patient should be increased.
Contrast media
Iodine contrast products
4.6 Pregnancy And Lactation
Pregnancy
Clinically, to date, no teratogenic effect has been reported, and the results of controlled prospective studies performed with some beta-blockers have not shown any malformations at birth. Experimental data did not show teratogenic effect.
Beta-blockers reduce placental perfusion, which may result in foetal death or premature delivery. In addition, undesirable effects, especially hypoglycemia and bradycardia may also occur in foetuses.
In neonates born to treated mothers, beta-blocker activity persists for several days after birth and may cause bradycardia, respiratory distress and hypoglycaemia, but in general this is of no clinical consequence.
However, as a result of depressed sympathetic compensatory mechanisms, cardiac failure, requiring intensive care, may occur. Administration of intravenous fluids should be avoided to reduce the risk of precipitating acute pulmonary oedema.
Nyogel eye gel should therefore not be used during pregnancy unless there is a clear benefit. If treatment is continued until delivery, close monitoring of the neonate (for heart rate and hypoglycaemia during the first 3 to 5 days after birth) is recommended.
Breast-feeding
An occurrence of hypoglycaemia and bradycardia with poorly protein-bound beta-blockers has been described in suckling infant. Therefore, breast-feeding is not recommended while using Nyogel eye drops.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effect of this medicinal product on the ability to drive have been conducted. While driving vehicles or operating different machines, it should be taken into account that occasionally visual disturbances may occur including refractive changes, diplopia, ptosis, frequent episodes of mild and transient blurred vision and occasional episodes of dizziness or fatigue.
4.8 Undesirable Effects
Like other topically applied ophthalmic drugs, Nyogel eye gel may be absorbed into the systemic circulation. This may cause similar undesirable effects as seen with oral beta-blocking agents.
Immune system disorders:
Systemic lupus erythematosus, signs and symptoms of allergic reactions including anaphylaxis, angioedema
Metabolism and nutrition disorders:
Hypoglycaemia.
Psychiatric disorders:
Depression, insomnia, nightmares, memory loss.
Nervous system disorders
Syncope, cerebrovascular disturbances, cerebral ischaemia, dizziness, paraesthesiae, an increase in signs and symptoms of myasthenia gravis, headache.
Eye disorders:
Symptoms of ocular irritation include conjunctivitis, blepharitis, keratitis, and decreased corneal sensitivity. Blurred vision of short duration may occur in 30 to 50% of patients. Other possible reactions are eye irritation (burning), eye pain (stinging) visual disturbances, including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, eyelid ptosis and choroidal detachment following filtration surgery (see 4.4 “Special warnings and special precautions for use”. Dry eyes have been reported during beta-blocker therapy.
Cardiac disorders:
Bradycardia, atrioventricular block (complete or lower degree) or worsening of an existing atrioventricular block, cardiac failure, heart block, arrhythmia, , palpitation, cardiac arrest and chest pain..
Vascular disorders
Hypotension, Raynaud phenomenon, claudication.
Respiratory, thoracic and mediastinal disorders:
Bronchospasm (predominantly in patients with pre-existing broncho-spastic disease), respiratory failure, dyspnoea and cough.
Gastrointestinal disorders:
Nausea, vomiting, diarrhoea, dyspepsia, gastralgia, dry mouth.
Skin and subcutaeous tissue reactions disorders:
Hypersensitivity reactions, local and generalised erythema including urticaria, alopecia, psoriatiform-like lesions or exacerbation of psoriasis.
The incidence of the symptoms is low, and in most cases the symptoms have cleared after discontinuation of treatment. The use of the medication should be discontinued if any such reaction is not otherwise explicable. Benzalkonium chloride is known to cause allergy.
Musculoskeletal and connective tissue disorders
Arthropathy.
Reproductive system and breast disorders:
Sexual disfunction (such as decreased libido, impotence), syndrome of Peyronie.
General disorders and administration
Fatigue, asthenia
Biologically:
Rare cases of antinuclear antibodies have been observed during treatment with timolol maleate, only exceptionally accompanied by clinical symptoms such as systemic lupus erythematosus syndrome. The antibodies have regressed on discontinuation of the treatment.
4.9 Overdose
No data specific to this preparation are available. The most common side effects caused by beta-blocker overdosage are symptomatic bradycardia, hypotension, bronchospasm, and acute cardiovascular insufficiency.
If overdosage occurs, the following measures should be considered:
1. Administration of activated charcoal, if the preparation has been taken orally. Studies have shown that timolol maleate cannot be removed by haemodialysis.
2. Symptomatic bradycardia: Atropine sulphate, 0.25 to 2 mg intravenously, should be used to induce vagal blockade. If bradycardia persists, intravenous isoprenaline hydrochloride should be administered cautiously. In refractory cases, the use of a cardiac pacemaker should be considered.
3. Hypotension: A sympathomimetic agent such as dopamine, dobutamine or noradrenaline should be given. In refractory cases, the use of glucagon has been useful.
4. Bronchospasm: Isoprenaline hydrochloride should be given. Concomitant therapy with aminophylline may be considered.
5. Acute cardiac failure: Conventional therapy with digitalis, diuretics and oxygen should be instituted immediately. In refractory cases, the use of intravenous aminophylline is recommended.
This may be followed, if necessary, by glucagon, which has been found useful.
6. Heart blocks: Isoprenaline hydrochloride or a pacemaker should be used.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group:Antiglaucoma preparations and miotics, beta blocking agents.
ATC code: S01ED01
Timolol maleate is a non-selective beta-blocker that does not have any significant cardiac stimulating or direct cardiac depressant or local anaesthetic (membrane stabilizing) activity. When applied topically in the eye, it reduces both elevated and normal intraocular pressure. Although not all mechanisms of action of timolol maleate are known yet, it is thought to primarily reduce the production of aqueous humour.
Unlike miotics, timolol maleate reduces intraocular pressure with little effect on pupil size or visual acuity. Thus, impairment of vision or night blindness does not occur as with the use of miotics. In cataract patients, the impairment of vision, caused by lenticular opacities when the pupil is constricted, is avoided.
The onset of reduction in intraocular pressure following ocular administration of timolol maleatecan usually be detected within 30 minutes after eye drop administration. The maximum effect is achieved within about 2 hours from administration and significant lowering of intraocular pressure can be maintained for periods as long as 24 hours.
5.2 Pharmacokinetic Properties
Nyogel eye gel 0.1% is an eye-drop formulation in gel form, which due to the particular chemical characteristics, maximise the drug absorption in the eye and reduces its absorption into the systemic circulation.
The systemic absorption after topical administration of Nyogel eye gel 0.1% has been shown to be reduced by 90% as compared to timolol 0.5% eye drops. This is due to the 10 times lower daily timolol maleate dose. Nyogel eye gel 0.1% had a significantly smaller effect on the peak heart rate in an exercise test as compared to timolol 0.5% solution.
Pharmacokinetic data from studies in healthy volunteers have shown that the mean value of the maximum plasma concentration is 0.18 ng/ml when Nyogel eye gel 1mg/g is given once daily, which is approximately 10 times lower than achieved after twice daily dosage of timolol eye drops 5mg/ml.
5.3 Preclinical Safety Data
No adverse local effects were observed in rabbits or dogs receiving timolol maleate by ocular administration for 4 weeks.
Timolol maleatewas not mutagenic, and did not affect fertility in rats.
Carcinogenicity studies produced an increased incidence of phaeochromocytomas in male rats, and mammary adenomas, pulmonary tumors and benign uterine polyps in mice, but only at high oral doses.
Repeated application of timolol eye gel did not produce any local or systemic intolerance in rabbits or dogs.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Benzalkonium chloride
Sorbitol
Polyvinyl alcohol
Carbomer 974 P
Sodium acetate trihydrate
Lysine monohydrate
Water for injections
6.2 Incompatibilities
For information on use of the product with contact lenses see under 4.4.
6.3 Shelf Life
18 months. The shelf-life after first opening is 4 weeks
6.4 Special Precautions For Storage
Keep the container in the outer carton in order to protect from light. Do not store above 25 °C.
Store the dropper bottle upside down in the carton below 25°C after first opening.
Do not freeze.
Nyogel eye gel must be kept out of the reach and sight of children.
6.5 Nature And Contents Of Container
The eye-drop bottle contains 5g gel and it is made of low-density polyethylene (LDPE). The tip of the bottle is also of LDPE and the cap is of high-density polyethylene.
The following pack sizes are available: cartons containing 1 or 3 bottles of 5g. Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Novartis Pharmaceuticals UK Ltd
Frimley Business Park
Frimley, Camberley
Surrey, GU16 7SR,
UK
8. Marketing Authorisation Number(S)
PL 00101/0616
9. Date Of First Authorisation/Renewal Of The Authorisation
13 August 2001 / 29 June 2010
10. Date Of Revision Of The Text
9 November 2010
Legal Category
POM
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