Public Assessment Report Decentralised Procedure Dorzolamide

PAR Dorzolamide/Timolol 20mg/ml + 5mg/ml, Preservative-free, Single Dose Eye Drops, Solution

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Public Assessment Report

Decentralised Procedure

Dorzolamide/Timolol 20mg/ml + 5mg/ml, Preservative-Free, Single Dose Eye drops,

Solution

Dorzolamide hydrochloride and Timolol maleate

UK/H/2364/001/DC

UK licence no: PL 00289/1239

TEVA UK Limited


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Dorzolamide/Timolol 20mg/ml +5mg/ml, Preservative-Free, Single Dose Eye Drops, Solution

PL 00289/1239

LAY SUMMARY On 15th September 2010, the Concerned Member States (CMS) and the Reference Member State (RMS) agreed to grant a marketing authorisation to TEVA UK Limited for the medicinal product Dorzolamide/Timolol 20mg/ml + 5mg/ml, Preservative-free, Single Dose Eye Drops, Solution. The marketing authorisation was granted via the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS). After the national phase, a licence was granted in the UK on 2nd December 2010. This medicine is only available on prescription from your doctor. Dorzolamide /Timolol eye drops contain two active ingredients: dorzolamide and timolol. Dorzolamide belongs to a group of medicines called ‘carbonic anhydrase inhibitors’. Timolol belongs to a group of medicines called ‘beta-blockers’. These medicines lower the pressure in the eye in different ways. This medicine is prescribed to lower raised pressure within the eye in the treatment of glaucoma when beta-blocker eye drops used alone are not adequate. If left untreated this raised pressure in the eye may damage the optic nerve resulting in deterioration of vision and possible blindness. If your doctor has diagnosed raised pressure in your eye, regular eye examinations and measurements of the pressure within your eyes will be necessary. No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Dorzolamide/Timolol 20mg/ml + 5mg/ml, Preservative-free, Single Dose Eye Drops, Solution outweigh the risks, hence a Marketing Authorisation has been granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 3 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflets Page 14 Module 4: Labelling Page 18 Module 5: Scientific Discussion Page 20 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions Module 6 Steps taken after initial procedure


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Module 1

Product Name

Dorzolamide/Timolol 20 mg/ml + 5 mg/ml, Preservative-Free, Single Dose Eye Drops, Solution

Type of Application

Article 10.3, Hybrid Application

Active Substance

dorzolamide hydrochloride and timolol maleate

Form

Preservative-Free, Single Dose Eye Drops, Solution

Strength

20 mg/ml + 5 mg/ml,

MA Holder

TEVA UK Limited Brampton Road, Hampden Park, Eastbourne, East Sussex BN22 9AG United Kingdom

RMS

UK

CMSs

Austria, Bulgaria, Cyprus, Denmark, Estonia, Greece, Spain, Finland, France, Hungary, Italy, Lithuania, Latvia, The Netherlands, Poland, Portugal, Romania, Sweden, Slovenia, and Slovak Republic

Procedure Number

UK/H/2364/001/DC

Timetable

End of Procedure: 15th September 2010


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Module 2 Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Dorzolamide/Timolol 20 mg/ml + 5 mg/ml, Preservative-Free, Single Dose Eye Drops, Solution 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 20mg of dorzolamide as dorzolamide hydrochloride and 5mg of timolol as timolol maleate. For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Eye drops, solution. Single-dose container Colourless, clear, viscous solution, free from visible particles.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

This medicinal product is indicated in the treatment of elevated intra-ocular pressure (IOP) in patients with open-angle glaucoma or pseudo-exfoliative glaucoma when topical beta-blocker monotherapy is not sufficient.

4.2 Posology and method of administration

The dose is one drop of dorzolamide/timolol in the (conjunctival sac of the) affected eye(s) two times daily. If another topical ophthalmic agent is being used, dorzolamide/timolol and the other agent should be administered at least ten minutes apart. This medicinal product is a sterile solution that does not contain a preservative. The solution from one individual single dose container is to be used immediately after opening for administration to the affected eye(s). Since sterility cannot be maintained after the individual single dose container is opened, any remaining contents must be discarded immediately after administration. Please see section 6.6. Paediatric use Efficacy in paediatric patients has not been established. Safety in paediatric patients below the age of two years has not been established. (For information regarding safety in paediatric patients ≥2 and < 6 years of age, see section 5.1).

4.3 Contraindications

This medicinal product is contraindicated in patients with: 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, second- or third-degree atrioventricular block, overt cardiac failure, cardiogenic shock severe renal impairment (CrCl < 30ml/min) or hyperchloraemic acidosis The above are based on the components and are not unique to the combination.

4.4 Special warnings and precautions for use

Cardiovascular/respiratory reactions The active substances may be absorbed systemically. Timolol is a beta-blocker. Therefore, the same types of adverse reactions found with systemic administration of beta-blockers may occur with topical administration, including worsening of Prinzmetal's angina, worsening of severe peripheral and central circulatory disorders, and hypotension.


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Because of the timolol maleate component, cardiac failure should be adequately controlled before beginning therapy with dorzolamide/timolol. In patients with a history of severe cardiac disease, signs of cardiac failure should be watched for and pulse rates should be checked. Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and rarely death in association with cardiac failure, have been reported following administration of timolol maleate. Hepatic impairment Dorzolamide/timolol has not been studied in patients with hepatic impairment and therefore should be used with caution in such patients. Immunology and hypersensitivity The active substances may be absorbed systemically. Dorzolamide is a sulphonamide. Therefore the same types of adverse reactions found with systemic administration of sulphonamides may occur with topical administration, 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. Local ocular adverse effects, similar to those observed with dorzolamide hydrochloride eye drops, have been seen with dorzolamide/timolol. If such reactions occur, discontinuation of dorzolamide/timolol should be considered. While taking beta-blockers, 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 The following concomitant medication is not recommended: dorzolamide and oral carbonic anhydrase inhibitors topical beta-adrenergic blocking agents. 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 Therapy with beta-blockers may mask certain symptoms of hypoglycaemia in patients with diabetes mellitus or hypoglycaemia. Therapy with beta-blockers may mask certain symptoms of hyperthyroidism. Abrupt withdrawal of beta-blocker therapy may precipitate a worsening of symptoms. 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 dorzolamide/timolol, urolithiasis has been reported infrequently. Because dorzolamide/timolol 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 dorzolamide/timolol. Other The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide/timolol has not been studied in patients with acute angle-closure glaucoma. Corneal oedema and irreversible corneal decompensation have been reported in patients with pre-existing chronic corneal defects and/or a history of intra-ocular surgery while using dorzolamide. Topical dorzolamide should be used with caution in such patients. Choroidal detachment concomitant with ocular hypotony have been reported after filtration procedures with administration of aqueous suppressant therapies. 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


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years, no significant difference in mean intra-ocular pressure has been observed after initial stabilisation. Contact lens use Dorzolamide/timolol eye drops have not been studied in patients wearing contact lenses. Paediatric use See section 5.1.

4.5 Interaction with other medicinal products and other forms of interaction

Specific interaction studies have not been performed with dorzolamide/timolol. 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 or beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, 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., SSRIs) quinidine and timolol. The dorzolamide component of this medicinal product is a carbonic anhydrase inhibitor and although administered topically, is absorbed systemically. In clinical studies, dorzolamide hydrochloride ophthalmic solution was not associated with acid-base disturbances. However, these disturbances have been reported with oral carbonic anhydrase inhibitors and have in some instances, resulted in interactions (e.g., toxicity associated with high-dose salicylate therapy). Therefore, the potential for such interactions should be considered in patients receiving dorzolamide/timolol. Although dorzolamide/timolol alone has little or no effect on pupil size, mydriasis resulting from concomitant use of ophthalmic timolol maleate and 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. In clinical studies, dorzolamide/timolol was used concomitantly with the following systemic agents without evidence of adverse interactions: ACE-inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory drugs including aspirin, and hormones (e.g. oestrogen, insulin, thyroxine).

4.6 Pregnancy and lactation

Use during pregnancy Dorzolamide/timolol should not be used during pregnancy. Dorzolamide No adequate clinical data in exposed pregnancies are available. In rabbits, dorzolamide produced teratogenic effects at maternotoxic doses. Timolol Well controlled epidemiological studies with systemic beta blockers showed no evidence of teratogenic effects, but some pharmacological effects such as bradycardia were observed in fetuses or neonates. If dorzolamide/timolol is administered until delivery, the neonate should be carefully monitored during the first days of life. (see section 5.3) Use during lactation 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. Timolol does appear in human milk. If treatment with dorzolamide/timolol is required, breast feeding is not recommended.


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4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. Possible side effects such as blurred vision may affect some patients' ability to drive and/or operate machinery.

4.8 Undesirable effects

In clinical studies no adverse experiences specific to dorzolamide/timolol have been observed; adverse experiences have been limited to those that were reported previously with dorzolamide hydrochloride and/or timolol maleate. In general, common adverse experiences were mild and did not cause discontinuation. During clinical studies, 1,035 patients were treated with dorzolamide/timolol. Approximately 2.4% of all patients discontinued therapy with dorzolamide/timolol because of local ocular adverse reactions, approximately 1.2% of all patients discontinued because of local adverse reactions suggestive of allergy or hypersensitivity (such as lid inflammation and conjunctivitis). The following adverse reactions have been reported with dorzolamide/timolol or one of its components either during clinical trials or during post-marketing experience: [Very common: (≥1/10), common: (≥1/100 to <1/10), uncommon: (≥1/1000 to <1/100), and rare: (≥1/10,000 to <1/1000)] Blood and lymphatic system disorders Timolol maleate ophthalmic solution: Rare: systemic lupus erythematosus Nervous system and psychiatric disorders Dorzolamide hydrochloride ophthalmic solution: Common: headache* Rare: dizziness*, paresthesia* Timolol maleate ophthalmic solution: Common: headache* Uncommon: dizziness*, depression* Rare: insomnia*, nightmares*, memory loss, paraesthesia*, increase in signs and symptoms of myasthenia gravis, decreased libido*, cerebrovascular accident* Eye disorders Dorzolamide/timolol: Very common: burning and stinging Common: conjunctival injection, blurred vision, corneal erosion, ocular itching, tearing Dorzolamide hydrochloride ophthalmic solution: Common: eyelid inflammation*, eyelid irritation* Uncommon: iridocyclitis* Rare: irritation including redness*, pain*, eyelid crusting*, transient myopia (which resolved upon discontinuation of therapy), corneal oedema*, ocular hypotony*, choroidal detachment (following filtration surgery)* Timolol maleate ophthalmic solution: Common: signs and symptoms of ocular irritation including blepharitis*, keratitis*, decreased corneal sensitivity, and dry eyes* Uncommon: visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases)* Rare: ptosis, diplopia, choroidal detachment (following filtration surgery)* Ear and labyrinth disorders Timolol maleate ophthalmic solution: Rare: tinnitus* Cardiac and vascular disorders Timolol maleate ophthalmic solution: Uncommon: bradycardia*, syncope*


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Rare: hypotension*, chest pain*, palpitation*, oedema*, arrhythmia*, congestive heart failure*, heart block*, cardiac arrest*, cerebral ischaemia, claudication, Raynaud's phenomenon*, cold hands and feet* Respiratory, thoracic, and mediastinal disorders Dorzolamide/Timolol: Common: sinusitis Rare: shortness of breath, respiratory failure, rhinitis Dorzolamide hydrochloride ophthalmic solution: Rare: epistaxis* Timolol maleate ophthalmic solution: Uncommon: dyspnoea* Rare: bronchospasm (predominantly in patients with pre-existing bronchospastic disease)*, cough* Gastro-intestinal disorders Dorzolamide/timolol: Very common: taste perversion Dorzolamide hydrochloride ophthalmic solution: Common: nausea* Rare: throat irritation, dry mouth* Timolol maleate ophthalmic solution: Uncommon: nausea*, dyspepsia* Rare: diarrhoea, dry mouth* Skin and subcutaneous tissue disorders Dorzolamide/timolol: Rare: contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis Dorzolamide hydrochloride ophthalmic solution: Rare: rash* Timolol maleate ophthalmic solution: Rare: alopecia*, psoriasiform rash or exacerbation of psoriasis* Renal disorders Dorzolamide/timolol: Uncommon: urolithiasis Reproductive system and breast disorders Timolol maleate ophthalmic solution: Rare: Peyronie's disease* General disorders and administration site disorders Dorzolamide/timolol: Rare: signs and symptoms of systemic allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylaxis, rarely bronchospasm Dorzolamide hydrochloride ophthalmic solution: Common: asthenia/fatigue* Timolol maleate ophthalmic solution: Uncommon: asthenia/fatigue* *These adverse reactions were also observed with dorzolamide/timolol during post-marketing experience.


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Laboratory findings Dorzolamide/timolol was not associated with clinically meaningful electrolyte disturbances in clinical studies.

4.9 Overdose

No data are available in humans in regard to overdosage by accidental or deliberate ingestion of dorzolamide/timolol. 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. 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 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.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: S01E D51 (Antiglaucoma preparations and miotics - Beta-Blocking Agents) Mechanism of action Dorzolamide/timolol is comprised of two components: dorzolamide hydrochloride and timolol maleate. Each of these two components decreases elevated intra-ocular pressure by reducing aqueous humor secretion, but does so by a different mechanism of action. Dorzolamide hydrochloride is a potent inhibitor of human carbonic anhydrase II. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. The precise mechanism of action of timolol maleate in lowering intra-ocular pressure is not clearly established at this time, although a fluorescein study and tonography studies indicate that the predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed. The combined effect of these two agents results in additional intra-ocular pressure reduction compared to either component administered alone. Following topical administration, dorzolamide/timolol reduces elevated intra-ocular pressure, whether or not associated with glaucoma. Elevated intra-ocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. Dorzolamide/timolol reduces intra-ocular pressure without the common side effects of miotics such as night blindness, accommodative spasm and pupillary constriction. Pharmacodynamic effects Clinical effects Clinical studies of up to 15 months duration were conducted to compare the IOP-lowering effect of dorzolamide/timolol b.i.d. (dosed morning and bedtime) to individually- and concomitantly-administered 0.5% timolol and 2.0% dorzolamide in patients with glaucoma or ocular hypertension for whom concomitant therapy was considered appropriate in the trials. This included both untreated patients and patients inadequately controlled with timolol monotherapy. The majority of patients were treated with topical beta-blocker monotherapy prior to study enrollment. In an analysis of the combined studies, the IOP-lowering effect of dorzolamide/timolol b.i.d. was greater than that of monotherapy with either 2% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOP-lowering effect of dorzolamide/timolol b.i.d. was equivalent to that of concomitant therapy with dorzolamide b.i.d. and timolol b.i.d. The IOP-lowering effect of dorzolamide/timolol b.i.d. was demonstrated when measured


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at various time points throughout the day and this effect was maintained during long-term administration. Paediatric use A three month controlled study, with the primary objective of documenting the safety of 2% dorzolamide hydrochloride ophthalmic solution in children under the age of 6 years has been conducted. In this study, 30 patients under six and greater than or equal to two years of age whose IOP was not adequately controlled with monotherapy by dorzolamide or timolol received dorzolamide/timolol in an open label phase. Efficacy in those patients has not been established. In this small group of patients, twice daily administration of dorzolamide/timolol was generally well tolerated with 19 patients completing the treatment period and 11 patients discontinuing for surgery, a change in medication, or other reasons.

5.2 Pharmacokinetic properties

Dorzolamide hydrochloride Unlike oral carbonic anhydrase inhibitors, topical administration of dorzolamide hydrochloride allows for the substance to exert its effects directly in the eye at substantially lower doses and therefore with less systemic exposure. In clinical trials, this resulted in a reduction in IOP without the acid-base disturbances or alterations in electrolytes characteristic of oral carbonic anhydrase inhibitors. When topically applied, dorzolamide reaches the systemic circulation. To assess the potential for systemic carbonic anhydrase inhibition following topical administration, parent substance and metabolite concentrations in red blood cells (RBCs) and plasma and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates in RBCs during chronic dosing as a result of selective binding to CA-II while extremely low concentrations of free substance in plasma are maintained. The parent substance forms a single N-desethyl metabolite that inhibits CA-II less potently than the parent substance but also inhibits a less active isoenzyme (CA-I). The metabolite also accumulates in RBCs where it binds primarily to CA-I. Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in the urine; the metabolite is also excreted in urine. After dosing ends, dorzolamide washes out of RBCs non-linearly, resulting in a rapid decline of substance concentration initially, followed by a slower elimination phase with a half-life of about four months. When dorzolamide was given orally to simulate the maximum systemic exposure after long term topical ocular administration, steady state was reached within 13 weeks. At steady state, there was virtually no free substance or metabolite in plasma; CA inhibition in RBCs was less than that anticipated to be necessary for a pharmacological effect on renal function or respiration. Similar pharmacokinetic results were observed after chronic, topical administration of dorzolamide hydrochloride. However, some elderly patients with renal impairment (estimated CrCl 30-60ml/min) had higher metabolite concentrations in RBCs, but no meaningful differences in carbonic anhydrase inhibition and no clinically significant systemic side effects were directly attributable to this finding. Timolol maleate In a study of plasma substance concentration in six subjects, the systemic exposure to timolol was determined following twice daily topical administration of timolol maleate ophthalmic solution 0.5%. The mean peak plasma concentration following morning dosing was 0.46 ng/ml and following afternoon dosing was 0.35 ng/ml.

5.3 Preclinical safety data

The ocular and systemic safety profile of the individual components is well established. Dorzolamide In rabbits given maternotoxic doses of dorzolamide associated with metabolic acidosis, malformations of the vertebral bodies were observed. Timolol Animal studies have not shown a teratogenic effect. Furthermore, no adverse ocular effects were seen in animals treated topically with dorzolamide hydrochloride and timolol maleate ophthalmic solution or with concomitantly-administered dorzolamide hydrochloride and timolol maleate. In vitro and in vivo studies with each of the components did not reveal a mutagenic potential. Therefore, no significant risk for human safety is expected with therapeutic doses of dorzolamide/timolol.


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6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Hydroxyethyl cellulose, Mannitol Sodium citrate dihydrate Sodium hydroxide (to adjust pH) Water for injections

6.2 Incompatibilities

Not applicable. 6.3 Shelf life

2 years After first opening of the pouch: 15 days. Discard any unused single dose containers after that time. Discard the opened single dose container immediately after first use.

6.4 Special precautions for storage

Store below 25°C. Store in the original package in order to protect from light Do not refrigerate or freeze.

6.5 Nature and contents of container

0.5ml low density polyethylene single dose containers containing 0.2ml of solution. Five single-dose containers are packed in a foil pouch. Pack sizes: 5, 20, 30, 60 and 120 single dose containers Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. 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 the eye and subsequent loss of vision may result from using contaminated solutions. Usage instructions 1. Open the pouch which contains 5 individual single dose containers. 2. First wash your hands then break off one single dose container from the strip and twist open the top. 3. Tilt your head back and pull your lower eyelid down slightly to form a pocket between your eyelid and eye. 4. Instill one drop in the affected eye(s) as directed by your physician. Each single dose container contains enough solution for both eyes. 5. After instillation, discard the used single dose container even if there is solution remaining. 6. Store the remaining single dose containers in the pouch; the remaining single dose containers must be used within 15 days after opening of the pouch.

7 MARKETING AUTHORISATION HOLDER


8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/1239 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

02/12/2010


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10 DATE OF REVISION OF THE TEXT 02/12/2010


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Module 3


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Module 4

Labelling


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Module 5 Scientific discussion during initial procedure

I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Reference Member State (RMS) and Concerned Member States (CMSs) consider that the application for Dorzolamide/Timolol 20mg/ml + 5mg/ml, Preservative-free, Single Dose Eye Drops, Solution, in the treatment of elevated intra-ocular pressure (IOP) in patients with open-angle glaucoma or pseudo-exfoliative glaucoma when topical beta-blocker monotherapy is not sufficient, could be approved. This application was submitted under a decentralised procedure (DCP), according to Article 10.3 of Directive 2001/83 EC, as amended, as a hybrid application. The reference product to which this application refers is Cosopt® Preservative Free, Single Dose Eye Drops, (PL 00025/0689) licensed to Merck Sharp & Dohme B.V. on the 6th March 1998. The reference product has been authorised in the EEA for more than 10 years. With UK as the RMS in this Decentralised Procedure (UK/H/2364/001/DC), TEVA UK Limited applied for the Marketing Authorisation for Dorzolamide/Timolol 20mg/ml + 5mg/ml, Preservative-free, Single Dose Eye Drops, Solution in Austria, Bulgaria, Cyprus, Denmark, Estonia, Greece, Spain, Finland, France, Hungary, Italy, Lithuania, Latvia, The Netherlands, Poland, Portugal, Romania, Sweden, Slovenia, and Slovak Republic. Dorzolamide hydrochloride is a potent inhibitor of human carbonic anhydrase II. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. The precise mechanism of action of timolol maleate in lowering intra-ocular pressure is not clearly established at this time, although a fluorescein study and tonography studies indicate that the predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed. The combined effect of these two agents results in additional intra-ocular pressure reduction compared to either component administered alone. No new non-clinical or clinical studies were conducted, which is acceptable. Essential similarity with the originator product is based on comparative quality attributes of the products. The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. The RMS considers that the Pharmacovigilance System as described by the applicant fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. A suitable justification has been provided for non-submission of a Risk Management Plan.


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All member states agreed to grant a respective licence for the above product at the end of procedure (Day 210 – 15th September 2010). After a subsequent national phase, the UK granted a licence for this product on 2nd December 2010 (PL 00289/1239).


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II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Dorzolamide/Timolol 20 mg/ml + 5 mg/ml, Preservative-Free, Single Dose Eye Drops, Solution

Name(s) of the active substance(s) (USAN)

dorzolamide hydrochloride and timolol maleate

Pharmacotherapeutic classification (ATC code)

S01E D51 (Antiglaucoma preparations and miotics - Beta-Blocking Agents)

Pharmaceutical form and strength(s) 20 mg/ml + 5 mg/ml, Preservative-Free, Single Dose Eye Drops, Solution

Reference numbers for the Decentralised Procedure

UK/H/2364/001/DC

Reference Member State United Kingdom Concerned Member States

Austria, Bulgaria, Cyprus, Denmark, Estonia, Greece, Spain, Finland, France, Hungary, Italy, Lithuania, Latvia, The Netherlands, Poland, Portugal, Romania, Sweden, Slovenia, and Slovak Republic.

Marketing Authorisation Number(s) PL 00289/1239 Name and address of the authorisation holder



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III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS DRUG SUBSTANCE INN: Timolol Maleate Chemical Names: (2S)-1-[1,1-dimethylethyl)amino]-3-[[4-morpholin-4-yl)-1,2,5- thiadiazol-3-yl]oxy]propan-2-ol (Z)-butenedionate (1:1) salt. Structure:

Molecular formula: C17H28N4O7S Molecular weight: 432.5 All aspects of the manufacture and control of the active substance are covered by a European Directorate for the Quality of Medicines (EDQM) certificate of suitability. Dorzolamide hydrochloride Chemical Names: (4S-trans)-4-(Ethylamino)-5,6-dihydro-(6S)-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide, monohydrochloride salt Structure:

Molecular formula: C10H16N2O4S3-HCl Molecular weight: 324.44 Synthesis of the drug substance from the designated starting material has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents, and these are supported by relevant certificates of analysis. An appropriate specification is provided for the drug substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Certificates of Analysis for all working standards have been provided. Batch analysis data are provided and comply with the proposed specification. Satisfactory specifications and Certificates of Analysis have been provided for all packaging used to store the drug substance. Confirmation has been provided that the primary packaging complies with current guidelines concerning materials in contact with food.


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Appropriate stability data have been generated, supporting a suitable retest period when the drug substance is stored in the proposed packaging. DRUG PRODUCT Other Ingredients Other ingredients consist of the pharmaceutical excipients hydroxyethyl cellulose, mannitol, sodium citrate dihydrate, sodium hydroxide (to adjust pH) and water for injections All excipients comply with the European Pharmacopoeia monograph. Satisfactory Certificates of Analysis have been provided for these excipients. The above excipients do not contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of this product. Pharmaceutical Development The objective of the pharmaceutical development programme was to formulate a stable ophthalmic preparation containing dorzolamide hydrochloride and timolol maleate that is comparable in performance to the reference product Cosopt® Preservative Free, Single Dose Eye Drops, (Merck Sharp & Dohme B.V.). Suitable pharmaceutical development data have been provided for this application. Manufacture A description and flow-chart of the manufacturing method have been provided. In-process controls are satisfactory based on process validation data and controls on the finished products. Process validation has been carried out on batches of the product. The results are satisfactory.

Finished Product Specifications The finished product specification is satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specifications. Certificates of Analysis have been provided for any working standards used.

Container Closure System The finished product is supplied in 0.5ml low density polyethylene single dose containers containing 0.2ml of solution. Five single-dose containers are packed in a foil pouch. Specifications and Certificates of Analysis for the primary packaging material have been provided. These are satisfactory. All primary packaging is controlled to European Pharmacopoeia standards and complies with guidelines. Stability Finished product stability studies have been conducted in accordance with current guidelines and in the packaging proposed for marketing. Based on the results, a shelf-life of 2 years for unopened container and after first opening of the pouch 15 days has been set, with a storage condition of “Store below 25°C”, “Store in the original package in order to protect from light” and “Do not refrigerate or freeze”.


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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SPC, PIL and labelling are pharmaceutically satisfactory. User testing of the package leaflet has been accepted, based on a bridging report provided by the applicant making reference to the user-testing of the PIL for Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution (Multi dose). The parent PIL (Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution (Multi dose)) and the daughter PIL (Dorzolamide/Timolol 20mg/ml + 5mg/ml Eye Drops, Solution (Single dose)) are from the same therapeutic class and have similar indications. A critical analysis demonstrated that the key messages for safe and effective use for both leaflets were similar. The justification on the rationale for bridging is accepted. Marketing Authorisation Application (MAA) Forms The MAA form is pharmaceutically satisfactory. Expert Report A pharmaceutical expert report has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion There are no objections to the approval of this product from a pharmaceutical point of view. III.2 NON-CLINICAL ASPECTS PHARMACODYNAMICS, PHARMACOKINETICS, TOXICOLOGY The pharmacological, pharmacokinetic and toxicological properties of dorzolamide hydrochloride and timolol maleate are well-known. No new non-clinical data have been supplied with this application and none are required. The non-clinical expert report has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier. A suitable justification has been provided for non-submission of the environmental risk assessment. There are no objections to the approval of this product from a non-clinical point of view. III.3 CLINICAL ASPECTS Introduction This assessment report represents an evaluation of the key elements of the information provided by the company in the dossier. Clinical study reports Biowaiver No clinical studies have been conducted to support the application. Essential similarity with the originator product is based on the comparative quality attributes of the product. The applicant refers to clarification provided from the Co-ordination Group for Mutual Recognition and Decentralised Procedures - human (CMD (h)) [CMD (h) minutes from meeting held on 20 and 21 April 2009], this application is being made under Article 10.3 of Directive 2001/83/EC, which states that bioequivalence cannot be demonstrated through bioavailability studies for products for local use intended to act without systemic absorption -


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in this case – after ocular administration. As bioavailability studies are not required (per Article 10.3 of the directive) and do not form part of the development strategy for this product (due to the biowaver), the product is not designated a generic, but is rather a hybrid version of the reference product. Pharmacokinetics No new data have been submitted and none are required for this application.

Although ~73% of dorzolamide is lost through tear overflow, the remaining drug penetrates well into ocular tissues and fluids, thus achieving desirable clinical effects at much lower doses compared to oral dosing. When applied chronically to the eye, dorzolamide enters the systemic circulation and accumulates in the red blood cells. In clinical trials, this resulted in a reduction in Intraocular pressure (IOP) without significant systemic effect. CA inhibition in RBCs was ~12% after 12 months of regular use which is less than the enzyme inhibition required to affect the renal function or respiration. Metabolism of dorzolamide mainly involves CYP 2B1/2, 2E1 and 3A2. Timolol can be measured in aqueous humour up to 48 hours after administration. At steady-state, timolol is detected in human plasma for up to 12 hours after administration. Timolol metabolism is mediated primarily by CYP2D6. Although it has previously been shown in animal studies that carbonic anhydrase inhibitors such as acetazolamide and dorzolamide raise optic nerve oxygen tension (ONPO2), this effect has not been observed following systemic administration of timolol alone or given simultaneously with dorzolamide (Kiilgaard et al, 2004). Given the high systemic bioavailability of timolol when applied to the eyes, the potential adverse effects of systemic beta blockade, especially in the elderly and patients with cardiopulmonary disease can be significant. In this context, adequate demonstration of identical formulation to the reference product is crucial to ensure optimal ocular/systemic drug absorption ratio. Although the expert report has not provided additional PK data with regard to possible PK interactions of the 2 components of their product, nor commented on this aspect of PK, the applicant has presented physico-chemical data for their formulation which supports their claim that their product will behave the same way as the originators. Pharmacodynamics No new data have been submitted and none are required for this application.

Dorzolamide hydrochloride and timolol maleate decrease elevated intra ocular pressure by reducing aqueous humour secretion, but does so by different mechanisms of action and without direct pharmacodynamic interaction. Dorzolamide is a carbonic anhydrase inhibitor and is highly selective for CA-II. Inhibition of almost 100% of CA-II activity in the ciliary process is required for the desired therapeutic effect to take place. Timolol is a non-selective β-blocking agent and its IOP reducing effect may be exerted through down-regulation of adenylate cyclase via β2 adrenoceptor inhibition in the ciliary process. The IOP lowering effect of dorzolamide/timolol b.i.d. has been shown to be equivalent to that of concomitant therapy with dorzolamide b.i.d. and timolol b.i.d. when given separately, and this effect was maintained during long term administration.


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Clinical efficacy No new data have been submitted and none are required for this application.

Meta-analysis of the clinical efficacy data on the dorzolamide/timolol combination has shown that the IOP lowering effect of dorzolamide/timolol b.i.d. was greater than that of monotherapy with either 2% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOP lowering effect of dorzolamide/timolol b.i.d. was equivalent to that of concomitant therapy with dorzolamide b.i.d. and timolol b.i.d. The IOP lowering effect of dorzolamide/timolol b.i.d. was demonstrated when measured at various time points throughout the day and this effect was maintained during long term administration. Mean reductions in morning trough and peak IOPs from baseline were in the ranges 2.8-7.7 mm Hg (10.6-27.4%) after 2 weeks treatment and 4.4-9.0mm Hg (17.3-32.7%) after 3 months treatment. Compared with concomitant therapy with the individual components, the primary advantage of fixed combination dorzolamide/timolol is convenience. Clinical safety No adverse drug reactions specific to dorzolamide/timolol have been observed in clinical trials; ADRs have been limited to those that were reported previously with dorzolamide hydrochloride and/or timolol maleate. In general, common ADRs were mild and did not cause discontinuation. The most common ADRs with dorzolamide/timolol eye drop are headache, burning and stinging, conjunctival injection, blurred vision, corneal erosion, ocular itching, tearing, sinusitis, distorted taste, nausea and fatigue.

Dorzolamide hydrochloride and timolol maleate have an acceptable adverse events profile. No new safety data are supplied or required for this application. Dorzolamide hydrochloride and timolol maleate have a well-established side-effect profile and are generally well-tolerated. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and labelling The SmPC, PIL and labelling are medically satisfactory and consistent with those for the reference product. Clinical Expert Report The clinical expert report is written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. Marketing Authorisation Application (MAA) Forms The MAA form is medically satisfactory. Clinical Conclusion There are no objections to the approval of this product from a clinical point of view.


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IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Dorzolamide/Timolol 20 mg/ml + 5 mg/ml, Preservative-Free, Single Dose Eye Drops, Solution are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of this type. EFFICACY AND SAFETY No clinical studies have been conducted to support the application. Essential similarity with the originator product is based on the comparative quality attributes of the product. The applicant refers to clarification provided from the Co-ordination Group for Mutual Recognition and Decentralised Procedures - human (CMD (h)) [CMD (h) minutes from meeting held on 20 and 21 April 2009], this application is being made under Article 10.3 of Directive 2001/83/EC, which states that bioequivalence cannot be demonstrated through bioavailability studies for products for local use intended to act without systemic absorption - in this case – after ocular administration. As bioavailability studies are not required (per Article 10.3 of the directive) and do not form part of the development strategy for this product (due to the biowaver), the product is not designated a generic, but is rather a hybrid version of the reference product. No new safety data are supplied or required for this application. Dorzolamide hydrochloride and timolol maleate have a well-established side-effect profile and are generally well-tolerated. The SmPC, PIL and labelling are satisfactory. BENEFIT-RISK ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. The data supplied supports the claim that the applicant’s product and the innovator product are interchangeable. Extensive clinical experience with dorzolamide hydrochloride and timolol maleate is considered to demonstrate the therapeutic value of the product. The benefit-risk is, therefore, considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

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Public Assessment Report Decentralised Procedure Dorzolamide

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