SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET
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SUMMARY OF PRODUCT CHARACTERISTICS
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1. NAME OF THE MEDICINAL PRODUCT
Taptiqom 15 micrograms/ml + 5 mg/ml eye drops, solution in single-dose container.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml solution contains: tafluprost 15 micrograms and timolol (as maleate) 5 mg.
One single-dose container (0.3 ml) of eye drops, solution, contains 4.5 micrograms of tafluprost and 1.5 mg of timolol. One drop (about 30 µl) contains about 0.45 micrograms of tafluprost and 0.15 mg of timolol.
Excipient with known effect: One ml of eye drops solution contains 1.3 mg phosphates and one drop contains approximately 0.04 mg phosphates.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Eye drops, solution in single-dose container (eye drops).
A clear, colourless solution with a pH of 6.0-6.7 and an osmolality of 290-370 mOsm/kg.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Reduction of intraocular pressure (IOP) in adult patients with open angle glaucoma or ocular hypertension who are insufficiently responsive to topical monotherapy with beta-blockers or prostaglandin analogues and require a combination therapy, and who would benefit from preservative free eye drops.
4.2 Posology and method of administration
Posology
Recommended therapy is one eye drop in the conjunctival sac of the affected eye(s) once daily. If one dose is missed, treatment should continue with the next dose as planned. The dose should not exceed one drop in the affected eye(s) daily. Taptiqom is a preservative free sterile solution packaged in a single-dose container. For single use only, one container is sufficient to treat both eyes. Any unused solution should be discarded immediately after use.
Paediatric population The safety and efficacy of Taptiqom in children and adolescents below the age of 18 years have not been established. No data are available. Taptiqom is not recommended for use in children and adolescents below the age of 18 years.
Use in elderly No dosage alteration in elderly patients is necessary.
Use in renal/hepatic impairment Tafluprost and timolol eye drops have not been studied in patients with renal/hepatic impairment and Taptiqom should therefore be used with caution in such patients.
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Method of administration
Ocular use To reduce the risk of darkening of the eyelid skin the patients should wipe off any excess solution from the skin.
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 of local activity.
If more than one topical ophthalmic medicinal product is being used, each one should be administered at least 5 minutes apart.
Contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes.
Patients should be instructed to avoid allowing the container to come into contact with the eye or surrounding structures as this could cause injury to the eye (see instructions for use).
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.
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 .
Reactive airway disease including bronchial asthma, or a history of bronchial asthma, severe chronic obstructive pulmonary disease.
Sinus bradycardia, sick sinus syndrome, including sino-atrial block, second or third degree atrioventricular block not controlled with pace-maker. Overt cardiac failure, cardiogenic shock.
4.4 Special warnings and precautions for use
Systemic effects: Like other topically applied ophthalmic agents, tafluprost and timolol are absorbed systemically. Due to the beta-adrenergic component timolol, the same types of cardiovascular, pulmonary and other adverse reactions as seen with systemic beta-adrenergic blocking agents may occur. Incidence of systemic adverse reactions after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2.
Cardiac disorders: In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension, therapy with beta-blockers should be critically assessed and the therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of adverse reactions. Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.
Vascular disorders: Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.
Respiratory disorders:
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Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers. Taptiqom should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.
Hypoglycemia/diabetes: Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.
Beta-blockers may also mask the signs of hyperthyroidism. Abrupt withdrawal of beta-blocker therapy may precipitate a worsening of symptoms.
Corneal diseases: Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
Other beta-blocking agents: The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated when timolol (a component of Taptiqom) is given to the patients already receiving a systemic beta-blocking agent. The response of these patients should be closely observed. The use of two topical -adrenergic blocking agents is not recommended.
Angle-closure glaucoma: In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic. Timolol has little or no effect on the pupil. When timolol is used to reduce elevated intraocular pressure in angle-closure glaucoma it should be used with a miotic and not alone.
Anaphylactic reactions: 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 repeated challenge with such allergens and unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.
Choroidal detachment: Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.
Surgical anaesthesia: Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.
Before treatment is initiated, patients should be informed of the possibility of eyelash growth, darkening of the eyelid skin and increased iris pigmentation which are related to tafluprost therapy. Some of these changes may be permanent, and may lead to differences in appearance between the eyes when only one eye is treated.
The change in iris pigmentation occurs slowly and may not be noticeable for several months. The change in eye colour has predominantly been seen in patients with mixed coloured irises, e.g. blue-brown, grey-brown, yellow-brown and green-brown. The risk of lifelong heterochromia between the eyes in unilateral cases is obvious.
There is a potential for hair growth to occur in areas where tafluprost solution comes repeatedly in contact with the skin surface.
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There is no experience with tafluprost in neovascular, angle-closure, narrow-angle or congenital glaucoma. There is only limited experience with tafluprost in aphakic patients and in pigmentary or pseudoexfoliative glaucoma.
Caution is recommended when using tafluprost in aphakic patients, pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema or iritis/uveitis.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
There is a potential for additive effects resulting in hypotension and/or marked bradycardia when ophthalmic beta blockers solution is administered concomitantly with oral calcium channel blockers, beta- adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine. Oral -adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.
Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol. Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.
4.6 Fertility, pregnancy and lactation
Pregnancy There are no or limited amount of data from the use of Taptiqom in pregnant women.
Women of childbearing potential have to use effective contraception during Taptiqom treatment.
Taptiqom should not be used during pregnancy unless clearly necessary (in case no other treatment options are available).
Tafluprost: There are no adequate data for the use of tafluprost in pregnant women. Tafluprost can have harmful pharmacologic effects on pregnancy and/or the fetus/newborn child. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Timolol: There are no adequate data for the use of timolol in pregnant women. Timolol should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. 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 Taptiqom is administered until delivery, the neonate should be carefully monitored during the first days of life.
Breast-feeding Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce the systemic absorption, see 4.2. It is unknown whether tafluprost and/or its metabolites are excreted in human milk. Available toxicological data in animals have shown excretion of tafluprost and/or its metabolites in milk (for details see section 5.3). However, at therapeutic doses of tafluprost in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms in the infant.
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As a precautionary measure lactation is not recommended if treatment with Taptiqom is required.
Fertility There are no data on the effects of Taptiqom on human fertility.
4.7 Effects on ability to drive and use machines
No studies on the effects of Taptiqom on the ability to drive and use machines have been performed. If adverse reactions such as transient blurred vision occurs at instillation, the patient should not drive or operate machinery until the patient feels well and has clear vision.
4.8 Undesirable effects
In clinical studies, over 484 patients have been treated with Taptiqom. The most frequently reported treatment-related adverse event was conjunctival/ocular hyperaemia. It occurred in approximately 7% of the patients participating in the clinical studies in Europe, was mild in most cases, and was associated with discontinuation of treatment in 1.2% of patients.
The adverse reactions reported in the clinical studies using Taptiqom were limited to those earlier reported for either of the single active substances tafluprost or timolol. No new adverse reactions specific for Taptiqom were observed in the clinical studies. The majority of adverse reactions reported were ocular, mild or moderate in severity and none were serious.
Like other topically applied ophthalmic agents, tafluprost and timolol are absorbed systemically. 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. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers.
The following adverse reactions have been reported with Taptiqom during clinical trials (within each frequency grouping, adverse reactions are presented in order of decreasing frequency). The frequency of possible adverse reactions listed below is defined using the following convention:
Very common ≥1/10 Common ≥1/100 to <1/10 Uncommon ≥1/1,000 to <1/100 Rare ≥1/10,000 to <1/1,000 Very rare <1/10,000 Not known Frequency cannot be estimated from the available data
Taptiqom (Tafluprost/timolol combination) System Organ Class Frequency Adverse Reactions
Nervous system disorders Uncommon Headache.
Eye disorders Common Conjunctival/ocular hyperaemia, eye pruritus, eye pain, change of eyelashes (increased length, thickness and number of lashes), eyelash discolouration, eye irritation, foreign body sensation in eyes, blurred vision, photophobia.
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Uncommon Abnormal sensation in eye, dry eye, ocular discomfort, conjunctivitis, erythema of eyelid, eye allergy, eyelid oedema, superficial punctate keratitis, lacrimation increased, anterior chamber inflammation, asthenopia, blepharitis.
Additional adverse reactions that have been seen with either of the active substances (tafluprost or timolol), and may potentially occur also with Taptiqom are listed below:
Tafluprost System Organ Class Adverse Reactions
Eye disorders Reduced visual acuity, increased iris pigmentation , blepharal pigmentation, conjunctival oedema, eye discharge, anterior chamber cell, anterior chamber flare, allergic conjunctivitis, conjunctival pigmentation, conjunctival follicles, deepening of eye lid sulcus, iritis/uveitis, macular oedema/cystoid macular oedema.
Skin and subcutaneous tissue Hypertrichosis of eyelid. disorders
Respiratory disorders Exacerbation of asthma, dyspnea.
Timolol System Organ Class Adverse Reactions
Immune system disorders Signs and symptoms of allergic reactions including angioedema, urticaria, localized and generalized rash, anaphylaxis, pruritus.
Metabolism and nutrition Hypoglycaemia. disorders
Psychiatric disorders Depression, insomnia, nightmares, memory loss, nervousness, hallucination.
Nervous system disorders Dizziness, syncope, paraesthesia, increase in signs and symptoms of myasthenia gravis, cerebrovascular accident, cerebral ischaemia.
Eye disorders Keratitis, decreased corneal sensitivity, visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases), ptosis, diplopia, choroidal detachment following filtration surgery (see Special warning and precautions for use 4.4), tearing, corneal erosion.
Ear and labyrinth disorders Tinnitus.
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Cardiac disorders Bradycardia, chest pain, palpitation, oedema, arrhythmia, congestive heart failure, cardiac arrest, heart block, atrioventricular block, cardiac failure.
Vascular disorders Hypotension, claudication, Raynaud’s phenomenon, cold hands and feet.
Respiratory, thoracic, and Dyspnoea, bronchospasm (predominantly in patients with pre-existing mediastinal disorders bronchospastic disease), respiratory failure, cough.
Gastrointestinal disorders Nausea, dyspepsia, diarrhoea, dry mouth, dysgeusia, abdominal pain, vomiting.
Skin and subcutaneous tissue Alopecia, psoriasiform rash or exacerbation of psoriasis, skin rash. disorders
Musculoskeletal and connective Systemic lupus erythematosus, myalgia, arthropathy. tissue disorders
Reproductive system and breast Peyronie’s disease, decreased libido, sexual dysfunction. disorders
General disorders and Asthenia/fatigue, thirst. administration site conditions
Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.
Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V*.
4.9 Overdose
A topical overdose with tafluprost is not likely to occur or to be associated with toxicity.
There have been reports of inadvertent overdosage with timolol 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 (see also section 4.8).
If overdose with Taptiqom occurs, treatment should be symptomatic and supportive. Timolol does not dialyse readily.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiglaucoma preparations and miotics, beta blocking agents, ATC code: S01ED51
Mechanism of action
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Taptiqom is a fixed combination of two active substances tafluprost and timolol. These two active substances lower intraocular pressure (IOP) by complementary mechanisms of action and the combined effect results in additional IOP reduction compared to either compound alone.
Tafluprost is a fluorinated analogue of prostaglandin F2α. Tafluprost acid, the biologically active metabolite of tafluprost, is a highly potent and selective agonist of the human prostanoid FP receptor. Pharmacodynamic studies in monkeys indicate that tafluprost reduces intraocular pressure by increasing the uveoscleral outflow of aqueous humour.
Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. The precise mechanism of action of timolol maleate in lowering intraocular 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.
Clinical efficacy In a 6-month study (n=400) in patients with open-angle glaucoma or ocular hypertension and mean untreated IOPs between 24-26 mmHg, the IOP lowering effect of Taptiqom (once daily in the morning) was compared to concomitant administration of 0.0015% tafluprost (once daily in the morning) and 0.5% timolol (twice daily). Taptiqom was non-inferior to the effect of concomitantly used 0.0015% tafluprost and 0.5% timolol at all time points and visits with the generally used non-inferiority margin of 1.5 mmHg. The mean diurnal IOP decrease from baseline was 8 mmHg in both arms at the primary endpoint of 6 months (decreases ranging between 7 to 9 mmHg in both arms at the different time points during the day over the study visits).
Another 6-month study (n=564) compared Taptiqom with the respective monotherapies in patients with open-angle glaucoma or ocular hypertension and mean untreated IOPs between 26-27 mmHg. Patients insufficiently controlled either with 0.0015% tafluprost (IOP 20 mmHg or greater on treatment) or 0.5% timolol (IOP 22 mmHg or greater on treatment) were randomized to be treated with Taptiqom or the same monotherapy. The mean diurnal IOP reduction of Taptiqom was statistically superior to that of tafluprost given once daily in the morning or timolol given twice daily, at visits 6 weeks, 3 months (primary efficacy endpoint) and 6 months. The mean diurnal IOP decrease from baseline of Taptiqom at 3 months was 9 mmHg, in comparison to 7 mmHg observed for both monotherapies. IOP decreases with Taptiqom at the different time points during the day over the visits ranged between 8 to 9 mmHg in the tafluprost monotherapy comparison group and between 7 to 9 mmHg in the timolol monotherapy comparison group.
Combined data from Taptiqom patients with high baseline IOP of 26 mmHg (mean diurnal) or above in these two pivotal studies (n=168) showed that the mean diurnal reduction in the IOP was 10 mmHg at the primary end point (3 or 6 months) ranging between 9 and 12 mmHg at the different time points during the day.
The European Medicines Agency has waived the obligation to submit the results of studies with Taptiqom in all subsets of the paediatric population (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption Plasma concentrations of tafluprost acid and timolol were investigated in healthy volunteers after single and repeated ocular dosing for eight days of Taptiqom (once daily), 0.0015% tafluprost (once daily) and 0.5% timolol (twice daily). Tafluprost acid plasma concentrations peaked at 10 minutes after dosing and declined below the lower limit of detection (10 pg/ml) before 30 minutes after Taptiqom dosing. Accumulation of tafluprost acid was negligible and the tafluprost acid mean AUC0-last (monotherapy: 4.45±2.57 pg·h/ml; Taptiqom: 3.60±3.70 pg·h/ml) and the mean Cmax (monotherapy: 23.9±11.8 pg/ml; Taptiqom: 18.7±11.9 pg/ml) were both slightly lower with Taptiqom as compared to tafluprost monotherapy on Day 8. Timolol plasma concentrations peaked at median Tmax values of 15 and 37.5 minutes after Taptiqom dosing on Days 1 and 8, respectively. The Day 8 timolol mean AUC0-last (monotherapy: 5750±2440 pg·h/ml; Taptiqom:4560±2980 pg·h/ml) and the mean Cmax (monotherapy: 1100 ± 550 pg/ml; Taptiqom: 840 ± 520 pg/ml ) were both somewhat lower with Taptiqom compared to timolol monotherapy. The lower plasma
Taptiqom-sd-qrd-en-common-proposed-December-2020 10 timolol exposure with Taptiqom appears to be due to once-daily dosing for Taptiqom versus twice daily dosing with timolol monotherapy.
Tafluprost and timolol are absorbed through the cornea. In rabbits, corneal penetration of tafluprost from Taptiqom was similar to that of tafluprost monopreparation after a single instillation while the penetration of timolol was slightly less from the Taptiqom compared to timolol monopreparation. For tafluprost acid, AUC4h was 7.5 ng·h/ml following administration of Taptiqom and 7.7 ng·h/ml following administration of tafluprost monopreparation. For timolol, AUC4h was 585 ng·h/ml and 737 ng·h/ml following administration of Taptiqom and timolol monopreparation, respectively. Tmax for tafluprost acid was 60 minutes for both Taptiqom and tafluprost monopreparation, while for timolol Tmax was 60 min for Taptiqom and 30 min for timolol monopreparation.
Distribution
Tafluprost In monkeys, there was no specific distribution of radiolabelled tafluprost in the iris-ciliary body or choroid including retinal pigment epithelium, which suggested low affinity for melanin pigment. In a whole body autoradiography study in rats, the highest concentration of radioactivity was observed in the cornea followed by the eyelids, sclera and the iris. Outside the eye radioactivity was distributed to the lacrimal apparatus, palate, oesophagus and gastrointestinal tract, kidney, liver, gall bladder and urinary bladder. The binding of tafluprost acid to human serum albumin in vitro was 99% at 500 ng/ml tafluprost acid.
Timolol The peak level of timolol-related radioactivity in the aqueous humor was reached after 30 minutes following a single application of 3H-radiolabelled timolol (0.5% solution: 20 µl/eye) to both eyes in rabbits. Timolol is eliminated from the aqueous humor much faster than from the pigmented tissues iris and ciliary body.
Biotransformation
Tafluprost The principal metabolic pathway of tafluprost in human, which was tested in vitro, is the hydrolysis to the pharmacologically active metabolite, tafluprost acid, which is further metabolized by glucuronidation or beta-oxidation. Products of beta-oxidation, 1,2-dinor and 1,2,3,4-tetranor tafluprost acids, which are pharmacologically inactive, may be glucuronidated or hydroxylated. Cytochrome P450 (CYP) enzyme system is not involved in the metabolism of tafluprost acid. Based on the study in rabbit corneal tissue and with purified enzymes, the main esterase responsible for the ester hydrolysis to tafluprost acid is carboxyl esterase. Butylcholine esterase but not acetylcholine esterase may also contribute to the hydrolysis.
Timolol Timolol is metabolized in the liver primarily by CYP2D6 enzyme into inactive metabolites, which are excreted primarily through the kidneys.
Elimination
Tafluprost Following once daily administration of 3H-tafluprost (0.005% ophthalmic solution; 5 μl/eye) for 21 days to both eyes in rats, approximately 87% of the total radioactive dose was recovered in the excreta. Percent of the total dose excreted in urine was approximately 27-38% and approximately 44-58% of the dose was excreted in the feces.
Timolol Apparent elimination half-life from the human plasma is about 4 hours. Timolol is extensively metabolised in the liver and the metabolites are excreted in the urine in addition to 20% unchanged timolol following oral administration.
5.3 Preclinical safety data
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Taptiqom Non-clinical data reveal no special hazard for humans based on repeated dose toxicity study and ocular pharmacokinetic studies. The ocular and systemic safety profile of the individual components is well established.
Tafluprost Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, systemic repeated dose toxicity, genotoxicity and carcinogenic potential. As with other PGF2 agonists, repeated dose topical ocular administration of tafluprost to monkeys produced irreversible effects on iris pigmentation and reversible enlargement of the palpebral fissure.
Increased contraction of rat and rabbit uteri in vitro was observed at tafluprost acid concentrations that exceeded 4 to 40 times, respectively, the maximum plasma concentrations of tafluprost acid in humans. Uterotonic activity of tafluprost has not been tested in human uterus preparations.
Reproduction toxicity studies were performed in the rat and rabbit with intravenous administration. In rats, no adverse effects on fertility or early embryonic development were observed at systemic exposure over 12,000 times the maximum clinical exposure based on Cmax or greater than 2,200 times based on AUC.
In conventional embryo-foetal development studies, tafluprost caused reductions in foetal body weights and increases in post-implantation losses. Tafluprost increased the incidence of skeletal abnormalities in rats as well as the incidence of skull, brain and spine malformations in rabbits. In the rabbit study, plasma levels of tafluprost and its metabolites were below the level of quantification.
In a pre- and postnatal development study in rats, increased mortality of newborns, decreased body weights and delayed pinna unfolding were observed in offspring at tafluprost doses greater than 20 times the clinical dose.
The experiments in rats with radiolabelled tafluprost showed that around 0.1% of the topically applied dose on eyes was transferred into milk. As the half-life of active metabolite (tafluprost acid) in plasma is very short (not detectable after 30 minutes in humans), most of the radioactivity probably represented metabolites with little, or no pharmacologic activity. Based on metabolism of tafluprost and natural prostaglandins, the oral bioavailability is expected to be very low.
Timolol Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Glycerol Disodium phosphate dodecahydrate Disodium edetate Polysorbate 80 Hydrochloric acid and/or sodium hydroxide for pH adjustment Water for injections.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
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3 years After first opening a foil pouch: 28 days.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C). After opening the foil pouch: Keep the single-dose containers in the original foil pouch in order to protect from light Do not store above 25°C Discard an opened single-dose container with any remaining solution immediately after use.
6.5 Nature and contents of container
Low-density polyethylene (LDPE) single-dose containers packed in a foil pouch made of a paper-coated, aluminum-polyethylene laminate. Each single-dose container has a fill volume of 0.3 ml and there are 10 containers in each foil pouch.
The following pack sizes are available: 30 x 0.3 ml single-dose containers and 90 x 0.3 ml single-dose containers.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
<[To be completed nationally]>
{Name and address} <{tel}> <{fax}> <{e-mail}>
8. MARKETING AUTHORISATION NUMBER(S)
<[To be completed nationally]>
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: {DD month YYYY}>
<[To be completed nationally]>
10. DATE OF REVISION OF THE TEXT
<{MM/YYYY}> <{DD/MM/YYYY}>
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<{DD month YYYY}>
<[To be completed nationally]>
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LABELLING
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PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON FOR 30 SINGLE-DOSE CONTAINERS AND CARTON FOR 90 SINGLE-DOSE CONTAINERS
1. NAME OF THE MEDICINAL PRODUCT
Taptiqom 15 micrograms/ml + 5 mg/ml eye drops, solution in single-dose container. tafluprost / timolol
2. STATEMENT OF ACTIVE SUBSTANCE(S)
1 ml solution contains: tafluprost 15 micrograms and timolol (as maleate) 5 mg,
3. LIST OF EXCIPIENTS glycerol, disodium phosphate dodecahydrate, disodium edetate, polysorbate 80, hydrochloric acid and/or sodium hydroxide, water for injections.
4. PHARMACEUTICAL FORM AND CONTENTS
Eye drops, solution in single-dose container 30 x 0.3 ml 90 x 0.3 ml
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Ocular use. Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
Exp: After opening the foil pouch: The single-dose containers can be used for 28 days
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9. SPECIAL STORAGE CONDITIONS
Store in a refrigerator. After opening the foil pouch: Keep the single-dose containers in the original foil pouch in order to protect from light Do not store above 25°C Discard an opened single-dose container with any remaining solution immediately after use.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
[To be completed nationally]
12. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
[To be completed nationally]
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE taptiqom
17. UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA
PC: {number} SN: {number} NN: {number}
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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
POUCH
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION
Taptiqom 15 micrograms/ml + 5 mg/ml eye drops, solution in single-dose container. tafluprost / timolol Ocular use
2. METHOD OF ADMINISTRATION
3. EXPIRY DATE
Exp: Opened: ______
4. BATCH NUMBER
Lot
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
10 x 0.3 ml
6. OTHER
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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
SINGLE-DOSE CONTAINER
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION
Taptiqom eye drops
2. METHOD OF ADMINISTRATION
3. EXPIRY DATE
Exp: [embossed]
4. BATCH NUMBER
Lot [embossed]
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
0.3 ml
6. OTHER
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PACKAGE LEAFLET
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Package leaflet: Information for the patient
Taptiqom 15 micrograms/ml + 5 mg/ml Eye drops, solution in single-dose container
Tafluprost/Timolol
Read all of this leaflet carefully before you start using this medicine because it contains important information for you. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor, pharmacist or nurse. This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet 1. What Taptiqom is and what it is used for 2. What you need to know before you use Taptiqom 3. How to use Taptiqom 4. Possible side effects 5. How to store Taptiqom 6. Contents of the pack and other information
1. What Taptiqom is and what it is used for
What kind of medicine is it and how does it work? Taptiqom eye drops contain tafluprost and timolol. Tafluprost belongs to a group of medicines called prostaglandin analogues and timolol belongs to a group of medicines called beta blockers. Tafluprost and timolol work together and lower the pressure in the eye. Taptiqom is used when the pressure in the eye is too high.
What is your medicine for? Taptiqom is used to treat a type of glaucoma called open angle glaucoma and also a condition known as ocular hypertension in adults. Both of these conditions are linked with an increase in the pressure within your eye and eventually they may affect your eyesight.
2. What you need to know before you use Taptiqom
Do not use Taptiqom: if you are allergic to tafluprost, timolol, beta blockers or any of the other ingredients of this medicine (listed in section 6.) if you have now or have had in the past respiratory problems such as asthma, severe chronic obstructive bronchitis (severe lung disease which may cause wheeziness, difficulty in breathing and/or long-standing cough) if you have a slow heart beat, heart failure or disorders of the heart rhythm (irregular heart beats).
Warnings and precautions Talk to your doctor, pharmacist or nurse before using Taptiqom.
Before you use this medicine, tell your doctor if you have now or have had in the past:
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coronary heart disease (symptoms can include chest pain or tightness, breathlessness or choking), heart failure, low blood pressure disturbances of heart rate such as slow heart beat breathing problems, asthma or chronic obstructive pulmonary disease poor blood circulation disease (such as Raynaud’s disease or Raynaud’s syndrome) diabetes as timolol may mask signs and symptoms of low blood sugar overactivity of the thyroid gland as timolol may mask signs and symptoms of thyroid disease any allergies or anaphylactic reactions myasthenia gravis (a rare disease causing muscle weakness) other eye diseases; for example, disease of the cornea (the transparent tissue that covers the front of the eye) or a disease requiring eye surgery.
Tell your doctor if you have kidney problems liver problems.
Please note that Taptiqom may have the following effects and that some of them may be permanent: Taptiqom may increase the length, thickness, colour and/or number of your eyelashes and may cause unusual hair growth on your eyelids. Taptiqom may cause darkening of the colour of the skin around the eyes. Wipe off any excess solution from the skin. This will reduce the risk of skin darkening. Taptiqom may change the colour of your iris (the coloured part of your eye). If Taptiqom is used in one eye only, the colour of the treated eye may permanently become different from the colour of the other eye. Taptiqom may cause hair growth in areas where the solution comes repeatedly in contact with the skin surface.
Tell your doctor before you have an operation that you are using Taptiqom as timolol may change effects of some medicines used during anaesthesia.
Children and adolescents Taptiqom is not recommended for children and adolescents below 18 years due to a lack of data on safety and efficacy in this age group.
Other medicines and Taptiqom Tell your doctor or pharmacist if you are taking, have recently taken or might take other medicines. Taptiqom may affect or be affected by other medicines you are using. In particular, tell your doctor if you are using or intend to use: other eye drops for the treatment of glaucoma medicines to lower blood pressure heart medicine medicines to treat diabetes quinidine (used to treat heart conditions and some types of malaria) antidepressants known as fluoxetine and paroxetine.
If you use other medicines in the eye, leave at least 5 minutes between putting in Taptiqom and the other medication.
Contact lenses Remove contact lenses before putting in the drops and wait at least 15 minutes before putting the lenses back.
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Pregnancy, breast-feeding and fertility If you may become pregnant, you must use an effective method of birth control during Taptiqom therapy. Do not use Taptiqom if you are pregnant. You should not use Taptiqom if you are breast-feeding. Ask your doctor for advice.
Driving and using machines There are side effects associated with Taptiqom, such as blurred vision, which may affect your ability to drive and/or operate machinery. Do not drive or operate machinery until you feel well and your vision is clear.
Taptiqom contains phosphate buffers This medicine contains approximately 0.04 mg phosphates in each drop which is equivalent to 1.3 mg/ml. If you suffer from severe damage to the clear layer at the front of the eye (the cornea), phosphates may cause in very rare cases cloudy patches on the cornea due to calcium build-up during treatment.
3. How to use Taptiqom
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.
The recommended dose is 1 drop of Taptiqom in the eye or eyes, once daily. Do not instil more drops or use more often than as instructed by your doctor. This may make Taptiqom less effective. Only use Taptiqom in both eyes if your doctor told you to. Discard the opened container with any remaining contents immediately after use.
For use as eye drops only. Do not swallow.
Do not allow the single-dose container to touch the eye or areas around the eye. It could cause injury to your eye. It may also become contaminated with bacteria that can cause eye infections leading to serious damage of the eye, even loss of vision. To avoid possible contamination of the single dose container, keep the tip of the single dose container away from contact with any surface.
Instructions for use: When you start a new pouch: Do not use the single-dose containers if the pouch is broken. Open the pouch along the dashed line. Write down the date you opened the pouch in the space reserved for the date on the pouch. Every time you use Taptiqom:
1. Wash your hands.
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2. Take the strip of containers from the pouch. 3. Detach one single-dose container from the strip. 4. Put the remaining strip back in the pouch and fold the edge to close the pouch. 5. To open the container, twist off the tab. (Picture A) 6. Hold the container between your thumb and index finger. Note that the tip of the container must not show more than 5 mm above the edge of your index finger. (Picture B) 7. Tilt your head backwards or lie down. Place your hand on your forehead. Your index finger should be aligned with your eyebrow or resting on the bridge of the nose. Look up. Pull the lower eyelid downwards with the other hand. Do not allow any part of the container to touch your eye or any area around your eye. Gently squeeze the container to let one drop fall into the space between the lid and the eye. (Picture C) 8. Close your eye and press the inner corner of the eye with your finger for about two minutes. This helps prevent the eye drop from draining down the tear duct. (Picture D) 9. Wipe off any excess solution from the skin around the eye.
If a drop misses your eye, try again.
If your doctor has told you to use drops in both eyes, repeat steps 7 to 9 for your other eye. The contents of one single-dose container are sufficient for both eyes. Discard the opened container with any remaining contents immediately after use.
If you use other medicines in the eye, leave at least 5 minutes between putting in Taptiqom and the other medication.
If you use more Taptiqom than you should, you may feel dizzy or have headache, heart symptoms or breathing problems. If necessary, contact a doctor for advice.
If the medicine is accidentally swallowed, contact a doctor for advice.
If you forget to use Taptiqom, use a single drop as soon as you remember, and then go back to your regular routine. However, if it is nearly time for the next dose, skip the missed dose. Do not use a double dose to make up for a forgotten dose.
Do not stop using Taptiqom without asking your doctor. If you stop using Taptiqom, the pressure in the eye will increase again. This may cause a permanent injury to your eye. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them. Most side effects are not serious.
You can usually carry on using the drops, unless the effects are serious. If you are worried, talk to a doctor or pharmacist.
The following are known side effects of using Taptiqom:
Common side effects The following may affect up to 1 in 10 people: Eye disorders Itching of the eye. Irritation in the eye. Eye pain. Redness of the eye. Changes in the length, thickness and number of eyelashes. Foreign body sensation in the eye. Discolouration of eyelashes. Sensitivity to light. Blurred vision.
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Uncommon side effects The following may affect up to 1 in 100 people: Nervous system disorders Headache. Eye disorders Dry eye. Redness of the eyelids. Small spotlike areas of inflammation on the surface of the eye. Watery eyes. Puffy eyelids. Tired eyes. Inflammation of the eyelids. Inflammation inside the eye. Discomfort in the eye. Eye allergy. Inflammation of the eye. Abnormal sensation in the eye.
The following additional side effects have been seen with the medicines in Taptiqom (tafluprost and timolol) and therefore might occur when you use Taptiqom:
The following side effects have been seen with tafluprost: Eye disorders Reduction in the eye’s ability to see details. Change of colour of the iris (may be permanent). Change of colour of the skin around the eyes. Swelling of the eye’s surface membranes. Eye discharge. Pigmentation of the eye’s surface membranes. Follicles in the surface membranes of the eye. Sunken eye. Iritis/uveitis (inflammation of the coloured part of the eye). Macular oedema/Cystoid macular oedema (swelling of the retina within the eye leading to worsening vision). Skin disorders Unusual hair growth on eyelids. Effects on the respiratory system Worsening of asthma, shortness of breath.
The following side effects have been seen with timolol: Immune system disorders Allergic reactions, including swelling beneath the skin, hives, rash. Severe sudden life-threatening allergic reaction. Itching. Metabolism and nutrition disorders Low blood sugar. Psychiatric disorders Depression. Difficulty sleeping. Nightmares. Memory loss. Nervousness. Hallucination. Nervous system disorders Dizziness. Fainting. Unusual sensations (like pins and needles). Increases in signs and symptoms of myasthenia gravis (muscle disorder). Stroke. Reduced blood supply to the brain. Eye disorders Inflammation of the cornea. Decreased corneal sensitivity. Visual disturbances including refractive changes (sometimes due to withdrawal of miotic therapy). Drooping of the upper eyelid. Double vision. Blurred vision and detachment of the layer below the retina that contains blood-vessels following filtration surgery which may cause visual disturbances. Corneal erosion. Ear disorders Tinnitus (ringing in the ears). Heart disorders Slow heart rate. Chest pain. Palpitations. Oedema (fluid build up). Changes in the rhythm or speed of the heartbeat. Congestive heart failure (heart disease with shortness of breath and swelling of the feet and legs due to fluid build up). A type of heart rhythm disorder. Heart attack. Heart failure. Vascular disorders Low blood pressure. Limping. Raynaud’s phenomenon, cold hands and feet. Breathing disorders Constriction of the airways in the lungs (predominantly in patients with pre-existing disease). Difficulty breathing. Cough. Gastrointestinal disorders Nausea. Indigestion. Diarrhoea. Dry mouth. Taste disturbances. Abdominal pain. Vomiting. Skin disorders Hair loss. Skin rash with white silvery-coloured appearance (psoriasiform rash) or worsening of psoriasis. Skin rash.
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Muscle and skeletal disorders Muscle pain not caused by exercise. Joint pain. Reproductive system and breast disorders Peyronie’s disease (which may cause a curvature of the penis). Sexual dysfunction. Decreased libido. General disorders Muscle weakness/tiredness. Thirst.
Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V*. By reporting side effects you can help provide more information on the safety of this medicine.
5. How to store Taptiqom
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the single-dose container, pouch and the carton after ‘Exp’. The expiry date refers to the last day of that month.
Store the unopened foil pouches in a refrigerator (2°C - 8°C). Do not open the pouch until you are about to start using the eye drops as unused containers in an open pouch must be discarded 28 days after first opening the pouch.
After opening the foil pouch: Keep the single-dose containers in the original foil pouch in order to protect from light. Do not store above 25°C Discard unused single-dose containers after 28 days from date of first opening of the foil pouch Discard an opened single-dose container with any remaining solution immediately after use.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other information
What Taptiqom contains The active substances are tafluprost and timolol. 1 ml of solution contains 15 micrograms of tafluprost and 5 mg of timolol. The other ingredients are glycerol, disodium phosphate dodecahydrate, disodium edetate, polysorbate 80, hydrochloric acid and/or sodium hydroxide (to adjust pH), and water for injections.
What Taptiqom looks like and contents of the pack Taptiqom is a clear, colourless liquid (solution) supplied in single-dose plastic containers, each containing 0.3 ml of solution. Ten single-dose containers are provided in one pouch. Taptiqom is supplied in packs containing 30 or 90 single-dose containers. Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
[To be completed nationally]
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This medicinal product is authorised in the following Member States of the EEA under the name Taptiqom: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Latvia, Lithuania, Luxembourg, The Netherlands, Norway, Poland, Portugal, Slovakia, Slovenia, Spain, Sweden, United Kingdom
Loyada: Italy
This leaflet was last revised in <{MM/YYYY}> <{month YYYY}>.
<[To be completed nationally]>
Detailed information on this medicine is available on the web site of {name of MS/Agency}. [To be completed nationally]
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