Tobravisc 3.0 mg / ml eye drops, solution

1. Name Of The Medicinal Product

TOBRAVISC, 3.0 mg/ml eye drops, solution

2. Qualitative And Quantitative Composition

1 ml solution contains 3 mg tobramycin.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Eye drops, solution.

Clear, colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of superficial bacterial infections of the eye, such as conjunctivitis, caused by tobramycin susceptible/suspected susceptible bacteria.

4.2 Posology And Method Of Administration

The dose is one drop of TOBRAVISC eye drops into the conjunctival sac two times daily (morning and evening) for 7±1 days. If severe disease: on the first day, four instillations while awake. Thereafter instil one drop in each eye twice a day, while awake, until completion of the 7±1 days-total treatment period.

To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas, or other surfaces with the dropper tip of the bottle. Keep the bottle tightly closed when not in use.

In case of concomitant therapy with other topical ocular medicines, an interval of 5-10 minutes should be allowed between successive applications.

Use in elderly

No dosage adjustment in elderly patients is necessary.

Use in children and adolescents

TOBRAVISC eye drops may be used in paediatric patients (1 year of age and older) at the same dose as in adults. However, limited information is available in paediatric patients.

Use in hepatic and renal impairment

Ocular application of tobramycin gives very little systemic exposure. In case of concomitantly administered systemic treatment with aminoglycoside antibiotics, care should be taken to monitor the total serum concentration in order to ensure that an appropriate therapeutic level is maintained.

4.3 Contraindications

Hypersensitivity to tobramycin, any other aminoglycosides, or any of the excipients

4.4 Special Warnings And Precautions For Use

• For topical ophthalmic use only. Not for injection or ingestion.

• Sensitivity to topically administered aminoglycosides may occur in some patients.

• Cross-hypersensitivity to other aminoglycosides can occur, and the possibility that patients who become sensitized to topical ocular tobramycin may also be sensitive to other topical and/or systemic aminoglycosides should be considered.

• Serious adverse reactions including neurotoxicity, ototoxicity and nephrotoxicity have occurred in patients receiving systemic tobramycin therapy. Although these effects have not been reported following topical ocular use of tobramycin, caution is advised when used concomitantly with aminoglycosides.

• As with other antibiotic preparations, prolonged use of TOBRAVISC may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.

• Contact lens wear is not recommended during treatment of an ocular infection. Therefore, patients should be advised not to wear contact lenses during treatment with the product.

• Additionally, this product contains benzododecinium bromide which may cause irritation and is known to discolour soft contact lenses. Avoid contact with soft contact lenses. Patients must be instructed to remove contact lenses prior to application of TOBRAVISC and wait 15 minutes after instillation of the dose before reinsertion.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

Topical corticosteroids, when used in combination with tobramycin 3 mg/ml, may mask the clinical signs of bacterial, fungal, or viral infections and may suppress hypersensitivity reactions.

4.6 Pregnancy And Lactation

Pregnancy

High systemic doses of tobramycin, well above those encountered with topical ocular use, have been associated with nephrotoxicity and ototoxicity. Tobramycin crosses the placenta into the foetal circulation and amniotic fluid.A study of orally and parenterally administered aminoglycosides (including tobramycin) to pregnant women demonstrated no detectable risk to the foetus. Systemic exposure following ocular administration is expected to be low. However, TOBRAVISC eye drops should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus. See section 5.3 concerning studies in pregnant animals.

Breast-feeding mothers

In systemic treatment, tobramycin passes over to human milk in such amounts that there is a risk of affecting the child. When instilled topically, systemic exposure is low, the risk is judged to be low when using TOBRAVISC eye drops. The benefits of treating the mother must be weighed up against the possible risk to the infant.

4.7 Effects On Ability To Drive And Use Machines

As with any eye drop, temporary blurred vision or other visual disturbacnces may effect the ability to drive or use machines. If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machinery.

4.8 Undesirable Effects

The most frequent adverse reactions related to TOBRAVISC are symptoms of localized ocular toxicity and hypersensitivity including eyelid pruritus and oedema, ocular hyperaemia, eye pruritus, and increased lacrimation.

The following adverse reactions are classified according to the following convention: very common (

System Organ Classification	MedDRA Preferred Term (v. 11.1)
Eye disorders	Common: eye allergy, eye pruritus, eyelids pruritus, eyelid oedema, ocular hyperaemia, increased lacrimation   Uncommon: erythema of eyelid, eye discharge, eyelid disorder, conjunctival oedema, ocular discomfort   Not known: eye irritation, keratitis, eye pain, foreign body sensation in eyes, vision blurred
Skin and Subcutaneous Tissue Disorders	Not known: rash, urticaria, erythema

Description of selected adverse events

• Sensitivity to topically administered aminoglycosides may occur in some patients (See Section 4.4 special warnings and precautions for use).

4.9 Overdose

Due to the characteristics of this preparation, no toxic effects are to be expected with the ophthalmic use of the product, nor in the event of accidental ingestion of the contents of one bottle or tube.

Clinically apparent signs and symptoms of an overdose of TOBRAVISC (punctate keratitis, erythema, increased lacrimation, oedema, and lid itching) may be similar to adverse reaction effects seen in some patients.

A topical overdose of TOBRAVISC may be flushed from the eye(s) with lukewarm water.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: ophthalmologicals; anti-infectives

ATC code: S01A A12

Mode of Action

The preparation contains tobramycin, a rapidily bactericidal aminoglycoside antibiotic. It exerts its primary effect on bacterial cells by inhibiting polypeptide assembly and synthesis on the ribosome.

Mechanism of resistance

Resistance to tobramycin occurs by several different mechanisms including (1) alterations of the ribosomal subunit within the bacterial cell; (2) interference with the transport of tobramycin into the cell, and (3) inactivation of tobramycin by an array of adenylylating, phosphorylating, and acetylating enzymes. Genetic information for production of inactivating enzymes may be carried on the bacterial chromosome or on plasmids. Cross resistance to other aminoglycosides may occur.

Breakpoints

The breakpoints and the in vitro spectrum as mentioned below are based on systemic use. These breakpoints might not be applicable on topical ocular use of the medicinal product as higher concentrations are obtained locally and the local physical/chemical circumstances can influence the activity of the product on the site of administration. In accordance with EUCAST, the following breakpoints are defined for tobramycin:

•Enterobacteriaceae S

•Pseudomonas spp. S

•Acinetobacter spp. S

•Staphylococcus spp. S

• Not species-related S

The information listed below gives only an approximate guidance on probabilities whether microorganisms will be susceptible to tobramycin in TOBRAVISC. Bacterial species that have been recovered from external ocular infections of the eye such as observed in conjunctivitis are presented here.

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of tobramycin in at least some types of infections is questionable.

COMMONLY SUSCEPTIBLE SPECIES

Aerobic Gram-positive microorganisms

Bacillus megaterium

Bacillus pumilus

Corynebacterium accolens

Corynebacterium bovis

Corynebacterium macginleyi

Corynebacterium pseudodiphtheriticum

Kocuria kristinae

Staphylococcus aureus (methicillin susceptible – MSSA)

Staphylococcus haemolyticus (methicillin susceptible - MSSH)

Aerobic Gram-negative microorganisms

Acinetobacter junii

Acinetobacter ursingii

Citrobacter koseri

Escherichia coli

Klebsiella oxytoca

Klebsiella pneumoniae

Moraxella catarrhalis

Moraxella oslonensis

Morganella morganii

Neisseria perflava

Proteus mirabilis

Pseudomonas aeruginosa

Serratia liquifaciens

SPECIES FOR WHICH ACQUIRED RESISTANCE MIGHT BE A PROBLEM

Acinetobacter baumanii

Bacillus cereus

Bacillus thuringiensis

Kocuria rhizophila

Staphylococcus epidermidis

Staphylococcus haemolyticus (methicillin resistant –MRSH)

Staphylococcus, other coagulase-negative spp.

Serratia marcescens

INHERENTLY RESISTANT ORGANISMS

Aerobic Gram-positive microorganisms

Enterococcus faecalis

Staphylococcus aureus (methicillin resistant – MRSA)

Streptococcus mitis

Streptococcus pneumoniae

Streptococcus pyogenes

Streptococcus sanguis

Aerobic Gram-negative microorganisms

Chryseobacterium indologenes

Haemophilus influenzae

Stenotrophomonas maltophilia

Anaerobic Bacteria

Propionibacterium acnes

5.2 Pharmacokinetic Properties

Tobramycin is poorly absorbed across the cornea and conjunctiva and minimal amounts are absorbed into the eye after topical administration of tobramycin.

5.3 Preclinical Safety Data

Tobramycin is very poorly absorbed from the gastrointestinal tract. High, parenterally administered doses of tobramycin have been reported to cause renal toxicity in rats and dogs, and ototoxicity in cats.

Systemic administration of high doses of tobramycin to pregnant rodents (30-100 mg/kg/day) during organogenesis was reported to result in renal toxicity and otoxicity in foetuses. Other studies performed in rats and rabbits with tobramycin at doses up to 100 mg/kg/day parenterally (> 400-times the maximum clinical dose) revealed no evidence of impaired fertility or harm to the foetus.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Xanthan gum

Benzododecinium bromide (BDAB)

Mannitol

Trometamol

Boric acid

Polysorbate 80

Sulphuric acid and/or sodium hydroxide (to adjust pH)

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

Discard four weeks after first opening.

6.4 Special Precautions For Storage

No special precautions for storage.

6.5 Nature And Contents Of Container

TOBRAVISC eye drops is supplied in 5 ml opaque low-density polyethylene bottles with polypropylene screw caps (DROPTAINER).

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Alcon Laboratories (UK) Ltd

Pentagon Park

Boundary Way

Hemel Hempstead

HP2 7UD

United Kingdom

8. Marketing Authorisation Number(S)

PL 00649/0172

9. Date Of First Authorisation/Renewal Of The Authorisation

14^th July 2005

10. Date Of Revision Of The Text

22/10/2009

Timoptol Unit Dose 0.25% and 0.5% w / v Eye Drops Solution

1. Name Of The Medicinal Product

TIMOPTOL® Unit Dose 0.25% w/v Eye Drops Solution

TIMOPTOL® Unit Dose 0.5% w/v Eye Drops Solution

2. Qualitative And Quantitative Composition

'Timoptol' Unit Dose 0.25% w/v Eye Drops Solution contains timolol maleate equivalent to 0.25% w/v solution of timolol without preservative.

'Timoptol' Unit Dose 0.5% w/v Eye Drops Solution contains timolol maleate equivalent to 0.5% w/v solution of timolol without preservative.

3. Pharmaceutical Form

Eye drops solution.

Clear, colourless to light yellow, sterile eye drops.

4. Clinical Particulars

4.1 Therapeutic Indications

'Timoptol' Eye Drops Solution is a beta-adrenoreceptor blocking agent used topically in the reduction of elevated intra-ocular pressure in various conditions including the following: patients with ocular hypertension; patients with chronic open-angle glaucoma including aphakic patients; some patients with secondary glaucoma.

4.2 Posology And Method Of Administration

Recommended therapy is one drop 0.25% solution in the affected eye twice a day.

If clinical response is not adequate, dosage may be changed to one drop 0.5% solution in each affected eye twice a day. If needed, 'Timoptol' may be used with other agent(s) for lowering intra-ocular pressure. The use of two topical beta-adrenergic blocking agents is not recommended (see 4.4 'Special warnings and precautions for use').

Intra-ocular pressure should be reassessed approximately four weeks after starting treatment because response to 'Timoptol' may take a few weeks to stabilise.

Provided that the intra-ocular pressure is maintained at satisfactory levels, many patients can than be placed on once-a-day therapy.

Transfer from other agents

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

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

'Timoptol' Unit dose: The Unit-dose Dispenser of 'Timoptol' is free from preservative and should be used for patients who may be sensitive to the preservative benzalkonium chloride, or when use of a preservative-free topical medication is advisable.

'Timoptol' Unit-dose is a sterile solution. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be maintained after the individual unit is opened, the remaining contents should be discarded immediately after administration.

Paediatric use: is not currently recommended.

Use in the elderly: there has been wide experience with the use of timolol maleate in elderly patients. The dosage recommendations given above reflect the clinical data derived from this experience.

4.3 Contraindications

Bronchial asthma, history of bronchial asthma or severe chronic obstructive pulmonary disease; sinus bradycardia, second- and third-degree AV block, overt cardiac failure, cardiogenic shock; and hypersensitivity to this product or other beta-blocking agents.

4.4 Special Warnings And Precautions For Use

Like other topically applied ophthalmic drugs, 'Timoptol' may be absorbed systemically and adverse reactions seen with oral beta-blockers may occur.

Cardiac failure should be adequately controlled before beginning therapy with 'Timoptol'. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked.

Respiratory and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death associated with cardiac failure have been reported.

The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be exaggerated when 'Timoptol' is given to patients already receiving a systemic beta-blocking agent. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not recommended.

There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenoreceptor blocking drugs. The reported incidence is small and in most cases the symptoms have cleared when treatment was withdrawn. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. Cessation of therapy involving beta-blockade should be gradual.

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.

'Timoptol' has been generally well tolerated in glaucoma patients wearing conventional hard contact lenses. 'Timoptol' has not been studied in patients wearing lenses made with material other than polymethylmethacrylate (PMMA), which is used to make hard contact lenses.

The Unit-dose Dispenser of 'Timoptol' is free from preservative and should, therefore, be discarded after single use to one or both eyes.

In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic. 'Timoptol' has little or no effect on the pupil. When 'Timoptol' is used to reduce elevated intra-ocular pressure in angle-closure glaucoma it should be used with a miotic and not alone.

Patients should be advised that if they develop an intercurrent ocular condition (e.g. trauma, ocular surgery or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container (see 6.6 'Special precautions for disposal and other handling')

There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.

Risk from anaphylactic reaction: 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, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine (adrenaline) used to treat anaphylactic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Although 'Timoptol' alone has little or no effect on pupil size, mydriasis has occasionally been reported when 'Timoptol' is given with epinephrine (adrenaline).

Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g.quinidine, SSRIs) and timolol.

Oral β-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.

'Timoptol' may potentially add to the effects of oral calcium antagonists, rauwolfia alkaloids or beta-blockers, to induce hypotension and/or marked bradycardia.

Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Oral calcium antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function.

The potential exists for hypotension, AV conduction disturbances and left ventricular failure to occur in patients receiving a beta-blocking agent when an oral calcium entry blocker is added to the treatment regimen. The nature of any cardiovascular adverse effect tends to depend on the type of calcium blocker used. Dihydropyridine derivatives, such as nifedipine, may lead to hypotension, whereas verapamil or diltiazem have a greater propensity to lead to AV conduction disturbances or left ventricular failure when used with a beta-blocker.

Intravenous calcium channel blockers should be used with caution in patients receiving beta-adrenergic blocking agents.

The concomitant use of beta-adrenergic blocking agents and digitalis with either diltiazem or verapamil may have additive effects in prolonging AV conduction time.

4.6 Pregnancy And Lactation

Use in pregnancy: 'Timoptol' has not been studied in human pregnancy. The use of 'Timoptol' requires that the anticipated benefit be weighed against possible hazards.

Breast-feeding mothers: Timolol is detectable in human milk. A decision for breast-feeding mothers, either to stop taking 'Timoptol' or stop nursing, should be based on the importance of the drug to the mother.

4.7 Effects On Ability To Drive And Use Machines

Possible side effects such as dizziness and visual disturbances may affect some patients' ability to drive or operate machinery.

4.8 Undesirable Effects

Side effects

'Timoptol' is usually well tolerated. The following adverse reactions have been reported with ocular administration of this or other timolol maleate formulations, either in clinical trials or since the drug has been marketed. Additional side effects have been reported in clinical experiences with systemic timolol maleate, and may be considered potential effects of ophthalmic timolol maleate:

Special senses:

ocular: signs and symptoms of ocular irritation, including burning and stinging, conjunctivitis, blepharitis, keratitis, dry eyes, and decreased corneal sensitivity. Tinnitus, visual disturbances, including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis and choroidal detachment following filtration surgery (see 4.4 'Special warnings and precautions for use').

Cardiovascular:

ocular: bradycardia, arrhythmia, hypotension, syncope, heart block, cerebrovascular accident, cerebral ischaemia, congestive heart failure, palpitation, cardiac arrest, oedema, claudication, Raynaud's phenomenon, cold hands and feet.

systemic: AV block (second- or third-degree), sino-atrial block, pulmonary oedema, worsening of arterial insufficiency, worsening of angina pectoris, vasodilation.

Respiratory:

ocular: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnoea, cough.

systemic: rales

Body as a whole:

ocular: headache, asthenia, fatigue, chest pain.

systemic: extremity pain, decreased exercise tolerance.

Integumentary:

ocular: alopecia, psoriasiform rash or exacerbation of psoriasis.

systemic: pruritus, sweating, exfoliative dermatitis.

Hypersensitivity:

ocular: signs and symptoms of allergic reactions including anaphylaxis, angioedema, urticaria, localised and generalised rash.

Nervous system/psychiatric:

ocular: dizziness, depression, insomnia, nightmares, memory loss, increase in signs and symptoms of myasthenia gravis, paraesthesia.

systemic: vertigo, local weakness, diminished concentration, increased dreaming.

Digestive:

ocular: nausea, diarrhoea, dyspepsia, dry mouth.

systemic: vomiting.

Urogenital:

ocular: decreased libido, Peyronie's disease.

systemic: impotence, micturition difficulties.

Immunologic:

ocular: systemic lupus erythematosus.

Endocrine:

systemic: hyperglycaemia, hypoglycaemia.

Musculoskeletal:

systemic: arthralgia.

Haematologic:

systemic: non-thrombocytopenic purpura.

4.9 Overdose

There have been reports of inadvertent overdosage with 'Timoptol' 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 4.8 'Undesirable effects').

If overdosage occurs, the following measures should be considered:

1. Gastric lavage, if ingested. Studies have shown that timolol does not dialyse readily.

2. Symptomatic bradycardia: atropine sulphate, 0.25 to 2 mg intravenously, should be used to induce vagal blockade. If bradycardia persists, intravenous isoprenaline hydrochloride should be administered cautiously. In refractory cases, the use of a cardiac pacemaker may be considered.

3. Hypotension: a sympathomimetic pressor agent such as dopamine, dobutamine or noradrenaline should be used. In refractory cases, the use of glucagon has been reported to be useful.

4. Bronchospasm: isoprenaline hydrochloride should be used. Additional therapy with aminophylline may be considered.

5. Acute cardiac failure: conventional therapy with digitalis, diuretics, and oxygen should be instituted immediately. In refractory cases, the use of intravenous aminophylline is suggested. This may be followed, if necessary, by glucagon, which has been reported useful.

6. Heart block (second- or third-degree): isoprenaline hydrochloride or a pacemaker should be used.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Unlike miotics, 'Timoptol' reduces IOP with little or no effect on accommodation or pupil size. In patients with cataracts, the inability to see around lenticular opacities when the pupil is constricted is avoided. When changing patients from miotics to 'Timoptol' a refraction might be necessary when the effects of the miotic have passed.

Diminished response after prolonged therapy with 'Timoptol' has been reported in some patients.

5.2 Pharmacokinetic Properties

The onset of reduction in intra-ocular pressure can be detected within one-half hour after a single dose. The maximum effect occurs in one or two hours; significant lowering of IOP can be maintained for as long as 24 hours with a single dose.

5.3 Preclinical Safety Data

No adverse ocular effects were observed in rabbits and dogs administered 'Timoptol' topically in studies lasting one and two years, respectively. The oral LD₅₀ of the drug is 1,190 and 900 mg/kg in female mice and female rats, respectively.

Carcinogenesis, mutagenesis, impairment of fertility

In a two-year oral study of timolol maleate in rats there was a statistically significant (p

In a lifetime oral study in mice, there were statistically significant (p

The increased occurrence of mammary adenocarcinoma was associated with elevations in serum prolactin which occurred in female mice administered timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents which elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in man. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate, the maximum recommended human oral dosage, there were no clinically meaningful changes in serum prolactin.

Timolol maleate was devoid of mutagenic potential when evaluated in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/ml). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant (p

Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at doses up to 150 times the maximum recommended human oral dose.

6. Pharmaceutical Particulars

6.1 List Of Excipients

'Timoptol' Unit Dose Eye Drops Solution contains the following inactive ingredients:

Disodium phosphate dodecahydrate

(may be replaced by equivalent amounts of the dihydrate or anhydrous form)

Sodium dihydrogen phosphate dihydrate

(may be replaced by equivalent amounts of the monohydrate)

Sodium hydroxide

Water for injection

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 Years

'Timoptol' Unit Dose Eye Drops Solution should be used immediately after opening and any remaining contents should be discarded immediately after administration.

6.4 Special Precautions For Storage

Do not store above 25°C and keep in outer carton.

6.5 Nature And Contents Of Container

Both the 0.25% and the 0.5% w/v solutions are presented in:

Unit-dose Dispensers, available in cartons of 30 unit doses.

6.6 Special Precautions For Disposal And Other Handling

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.

7. Marketing Authorisation Holder

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK

8. Marketing Authorisation Number(S)

0.25% w/v Eye Drops Solution, PL0025/0210

0.5% w/v Eye Drops Solution, PL0025/0211

9. Date Of First Authorisation/Renewal Of The Authorisation

Granted: 17 March 1992

Last renewed: 21 March 2002

10. Date Of Revision Of The Text

February 2008

LEGAL CATEGORY

POM.

® denotes registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

© Merck Sharp & Dohme Limited 2008 All rights reserved.

SPC.TOTUD.06.UK.2347 F.T. 080608

TIOPEX timolol 1 mg / g, eye gel in single-dose container

1. Name Of The Medicinal Product

TIOPEX 1 mg/g, eye gel in single-dose container

2. Qualitative And Quantitative Composition

1 g of gel contains 1 mg of timolol as timolol maleate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Eye gel in single-dose container.

Opalescent, colourless to slightly yellow gel.

4. Clinical Particulars

4.1 Therapeutic Indications

Reduction of the elevated intraocular pressure in patients with:

- ocular hypertension,

- chronic open angle glaucoma.

4.2 Posology And Method Of Administration

Ocular use.

Adults

The recommended dosage regimen is 1 drop of TIOPEX 1 mg/g in the affected eye (or eyes), once a day, in the morning.

Elderly:

There has been wide experience with the use of timolol eye drops in elderly patients. The dosage recommendations given above reflect the clinical data derived from this experience.

Children and adolescents

There is no experience in children and adolescents. This eye gel is therefore not recommended in such patients.

If the ophthalmologist considers it necessary, TIOPEX 1 mg/g may be combined with one or more other anti-glaucoma treatments (local and/or systemic route of administration).

However, the combination of two beta-blocker eye drops is not recommended (see section 4.4.).

The other eye drops should be administered at least 15 minutes before TIOPEX 1 mg/g. The eye gel should be the last medication instilled.

Nonetheless, response to TIOPEX 1 mg/g may take several weeks to stabilise intraocular pressure, therefore the monitoring of the treatment should include intraocular pressure assessment after a treatment period of approximately four weeks.

Method of administration

Timolol eye gel should be instilled into the conjunctival sac.

A single-dose contains enough gel to treat both eyes.

For single use only.

Patients should be instructed:

• to avoid contact between the dropper tip and the eye or eyelids,

• to use the eye gel immediately after first opening the single-dose container and to discard the single-dose after use.

When using nasolacrimal occlusion or closing the eyelids for 3 minutes, the systemic absorption may be reduced. This may result in a decrease in systemic side effects and in an increase in local activity.

Replacement of a previous treatment:

When TIOPEX 1 mg/g is used to replace another anti-glaucoma eye drops, this eye drops should be discontinued after a full day of therapy, and TIOPEX 1 mg/g should be started the next day at the dosage of one drop in the affected eye (or eyes) once a day, in the morning.

If TIOPEX 1 mg/g is replacing a combination of anti-glaucoma treatments, only one drug should be withdrawn at a time.

If the anti-glaucoma drug being replaced is not a beta-blocker eye drops, it should be continued and one drop of TIOPEX 1 mg/g should be instilled in the affected eye (or eyes), once a day. The following day, stop taking the previous drug completely.

When TIOPEX 1 mg/g is used to replace miotic eye drops, testing of refraction may prove necessary when the effects of the miotics have disappeared.

Medical prescription should be combined with the monitoring of intraocular pressure, particularly when the treatment is initiated.

4.3 Contraindications

The contra-indications of beta-blockers administered by the general route should be borne in mind, although systemic beta-blocker effects are only rarely observed following ocular instillation:

- hypersensitivity to timolol maleate, to other beta-blockers or to any component of the drug product,

- asthma, chronic obstructive lung disease, history of asthma, bronchial hyperreactivity and severe allergic rhinitis,

- cardiac insufficiency unsatisfactorily controlled by the treatment,

- cardiogenic shock,

- second and third degree atrioventricular blocks in the absence of a pacemaker,

- Prinzmetal's angina,

- sinus disease (including sinoatrial block),

- bradycardia (< 45 to 50 beats per minute),

- Raynaud's disease and peripheral circulatory disturbances,

- untreated pheochromocytoma,

- hypotension,

- corneal dystrophies,

- combination with floctafenine (see section 4.5.),

- combination with sultopride (see section 4.5.).

4.4 Special Warnings And Precautions For Use

Ocular

As with any glaucoma treatment, regular examination of the intraocular pressure and cornea is recommended.

The use of two beta-blocker eye drops is not recommended (see section 4.2).

If TIOPEX 1 mg/g is administered to reduce intraocular pressure in patients with closed-angle glaucoma, a miotic should be used in combination.

In such patients, the immediate objective of the treatment is to reopen the angle, which requires the use of a miotic agent in order to obtain pupil constriction, since timolol maleate has little or no effect on the pupil.

Choroidal detachment accompanying ocular hypotonia, has been reported after surgical treatment of glaucoma, with administration of anti-glaucoma drugs which reduce aqueous humour secretions (timolol, acetazolamide).

Patients wearing contact lenses

There is a risk of intolerance to contact lenses due to a beta-blocker induced reduction in lacrimal secretion.

Timolol eye gel has not been studied in patients using contact lenses, and therefore the wearing of contact lenses should be avoided while using of TIOPEX 1 mg/g.

General anaesthesia

In patients undergoing elective surgery, gradual withdrawal of ocular beta-adrenergic receptor blocking agents should be discussed.

General

The warnings and precautions for use of beta-blockers administered by the general route should be borne in mind, although systemic beta-blocker effects are only rarely observed following ocular instillation.

This drug should not generally be used in combination with certain calcium antagonists (bepridil, verapamil, diltiazem) (see section 4.5.).

Concomitant treatment with systemic beta-blockers should be exercised with cautions.

Sportsmen: Sportsmen should be warned that this drug contains an active substance, which may induce a positive analytical result in anti-doping controls.

Discontinuation of therapy

Beta-blocker therapy by general route should never be withdrawn abruptly, particularly in patients suffering from angina: sudden discontinuation may give rise to severe arrhythmia, myocardial infarction or sudden death.

The dose should be reduced gradually i.e. over a period of one or two weeks.

Cardiovascular diseases

The dosage should be reduced if the rate falls below 50-55 beats per minute at rest, and if the patient presents bradycardia-related symptoms.

Given the negative dromotrope effect of beta-blockers, such agents should be administered with caution to patients presenting first-degree atrioventricular block, if the patient presents sick sinus syndrome or low blood pressure.

Cardiac failure should be ruled out before starting treatment. Patients with a history of severe cardiac disease should be monitored for early signs of possible cardiac failure.

Beta-blockers may increase the risk of rebound hypertension.

Metabolic disease

It should be used with caution in patients with metabolic acidosis.

Treated pheochromocytoma

These patients should not receive β-blocking agents without concomitant α-adrenoceptor blocking therapy.

Elderly patients, impaired renal and/or hepatic function

When such agents are administered orally in such high-risk subjects, a dosage adjustment is often necessary.

Diabetic patients

Patients should be advised to increase self-monitoring of their glucose status during the early phase of treatment.

The signs of incipient hypoglycemia may be masked, particularly tachycardia, palpitations and sweating.

Psoriasis

Beta-blockers have been reported to aggravate psoriasis and its use in this condition therefore deserves careful consideration.

Allergic reactions

In patients at risk of severe anaphylactic reactions of whatever origin, particularly with iodine-containing contrast products, anaesthesia or floctafenine (see section 4.5) or during desensitisation, beta-blockers may aggravate the reaction and make it resistant to treatment with adrenalin at usual dosages.

General anaesthesia

Beta-blockers reduce sympathetic reflex activity. Continuing treatment with a systemic beta-blocker reduces the risk of arrhythmia, myocardial ischaemia and peroperative hypertensive attacks. The anaesthetist should be informed that the patient is receiving beta-blocker therapy.

If it is deemed necessary to discontinue treatment, a 48-hour period of withdrawal is considered sufficient to allow catecholamine sensitivity to reappear.

In certain cases, systemic beta-blocker treatment cannot be interrupted:

• in patients with coronary insufficiency it is preferable to continue treatment until surgery, given the risks associated with sudden discontinuation of beta-blockers;

• in an emergency, or if discontinuation is impossible, the patient should be protected from vagal predominance by sufficient premedication with atropine, which should be repeated as required.

Anaesthesia should be with agents, which cause as little myocardial depression as possible, and blood losses should be compensated for.

Thyrotoxicosis

Beta-blockers are likely to mask certain signs of thyrotoxicosis, particularly cardiovascular.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

1) Eye drops

Ophthalmological monitoring is necessary in the event of concomitant treatment with eye drops containing adrenaline (risk of mydriasis).

2) Other drugs

Although the quantity of beta-blockers, which passes into the systemic circulation is low after ocular instillation, the risk of drug interactions is still present.

It is therefore advisable to keep in mind the interactions observed with beta-blockers given by general route.

Combinations which are contraindicated

+ Floctafenine

In the event of shock or hypotension caused by floctafenine, beta-blockers attenuate compensatory cardiovascular mechanisms.

+ Sultopride

Increased risk of ventricular arrhythmia, particularly torsades de pointes.

Combinations which are not recommended

+ Bepridil

Automatism disorders (excessive bradycardia, sinus arrest), sinoatrial and atrioventricular conduction disorders and increased risk of ventricular rhythm disorders (torsades de pointes) as well as cardiac failure.

This combination should only take place under close clinical and ECG monitoring, particularly in elderly subjects or in those beginning treatment.

+ Diltiazem

Automatism disorders (excessive bradycardia, sinus arrest) sinoatrial and atrioventricular conduction disorders and cardiac failure.

This combination should only take place under close clinical and ECG monitoring, particularly in elderly subjects or those starting treatment.

+ Verapamil

Automatism disorders (excessive bradycardia, sinus arrest) sinoatrial and atrioventricular conduction disorders and cardiac failure (synergy of effects).

This combination should only take place under close clinical and ECG monitoring, particularly in elderly subjects or those starting treatment.

Combinations requiring precautions for use

+ Amiodarone

Contractility, automatism and conduction disorders (suppression of compensatory sympathetic mechanisms).

Clinical and ECG monitoring is recommended.

+ Volatile halogenated anaesthetic agents

Reduction in compensatory cardiovascular mechanisms by beta-blockers. Betaadrenergic inhibition may be counteracted during surgery by beta-mimetics.

As a general rule, do not discontinue beta-blocker therapy, and in any event, avoid a sudden discontinuation. The anaesthetist should be advised of this treatment.

+ Potentiation of the systemic beta-blocking effects of eye gel and an increase in plasma levels of the beta-blocker have been reported when beta-blocker eye gels are combined with quinidine, probably due to the inhibition of the beta-blocker metabolism by quinidine (described for timolol).

+ Baclofen

Enhancement of hypotension risk, notably orthostatic.

Blood pressure monitoring and, if necessary, dosage adjustment of the antihypertensive.

+ Central anti-hypertensives

Significant increase in arterial pressure if treatment with a central anti-hypertensive is suddenly discontinued.

Avoid sudden withdrawal of treatment with a central anti-hypertensive. Clinical monitoring.

+ Insulin, oral hypoglycaemic agents

All beta-blockers may mask certain symptoms of hypoglycaemia: palpitations and tachycardia.

Warn the patient and, particularly at the beginning of treatment, self-monitoring of glycaemia by the patient should be increased.

+ Lidocaine

With lidocaine used intravenously: increase in plasmatic concentrations of lidocaine with a possibility of adverse neurological and cardiac side effects (reduction in hepatic clearance of lidocaine).

Clinical and ECG monitoring and possibly testing of the plasmatic concentrations of lidocaine during the combined therapy and after the beta-blocker has been withdrawn.

Adaptation if necessary of dosage regimen of lidocaine.

+ Drugs which may cause torsades de pointes (except sultopride)

Enhanced risk of ventricular arrhythmia, particularly torsades de pointes.

Clinical and ECG monitoring is recommended.

+ Propafenone

Contractility, automatism and conduction disorders (suppression of compensatory sympathetic mechanisms).

Clinical and ECG monitoring is recommended.

Combinations to be taken into account

+ Alpha-blockers intended for urological use; Anti-hypertensive alphablockers

Enhancement of hypotensive effect. Increased risk of orthostatic hypotension.

+ Amifostine

Enhancement of hypotension risk, notably orthostatic.

+ Imipraminic antidepressants; Neuroleptic

Enhancement of hypotension risk, notably orthostatic.

+ Non-steroidal anti-inflammatory drugs

Reduction in the antihypertensive effect (inhibition of vasodilator prostaglandins by NSAIDs and of water and salt retention by pyrazole NSAIDs).

+ Other bradycardial drugs

Risk of excessive bradycardia (additive effects).

+ Dihydropyridines

Hypotension, cardiac failure in patients with latent or uncontrolled cardiac insufficiency (additional negative inotropic effects). Moreover, the beta-blocker can minimise the sympathetic reflex reaction, which comes into play in the event of excessive haemodynamic repercussion.

+ Dipyridamole

With dipyridamole IV: enhancement of the anti-hypertensive effect.

+ Pilocarpine

Risk of excessive bradycardia (additive bradycardial effects).

4.6 Pregnancy And Lactation

The systemic passage of beta-blockers with ocular administration is less than with oral administration, but nevertheless exists.

Pregnancy

Studies in animals have not revealed any teratogenic effect.

Clinically, to date, no teratogenic effect has been reported, and the results of controlled prospective studies performed with some beta-blockers have not shown any malformations at birth.

Beta-blockers reduce placentary flow, and consequently, foetal death or premature delivery may occur.

In neonates born to treated mothers, beta-blockers activity persists for several days after birth and may cause bradycardia, respiratory distress and hypoglycaemia, but in general this is of no clinical consequence.

However, as a result of depressed sympathetic compensatory mechanisms, cardiac failure, requiring intensive care, may occur , with careful avoidance of intravenous fluids (risk of acute pulmonary oedema).

Therefore, this drug may be used during pregnancy if necessary. If treatment is continued until delivery, close monitoring of the neonate (for heart rate and hypoglycaemia during the first 3 to 5 days after birth) is recommended.

Breast-feeding

Timolol is excreted in human milk.

An occurrence of hypoglycaemia and bradycardia with poorly protein-bound betablockers has been described. Therefore, for safety mesure, it is preferable to avoid breast-feeding when treatment is necessary.

4.7 Effects On Ability To Drive And Use Machines

TIOPEX 1 mg/g has minor influence on the ability to drive and use machines.

No studies on the effect of this medicinal product on the ability to drive have been conducted. While driving vehicles or operating different machines, it should be taken into account that occasionally visual disturbances may occur including refractive changes, diplopia, ptosis, frequent episodes of mild and transient blurred vision and occasional episodes of dizziness or fatigue.

4.8 Undesirable Effects

Like other topically applied ophthalmic drugs, timolol gel may be absorbed systemically. Adverse reactions seen with oral beta-blockers may occur.

Immune system disorders:

Systemic lupus erythematosus.

Signs and symptoms of allergic reactions including anaphylaxis, angio-oedema, urticaria, erythematous rash.

Metabolism and nutrition disorders:

Hypoglycaemia.

Nervous system and psychiatric disorders:

Headache, dizziness, increase in signs and symptoms of myasthenia gravis.

Depression, insomnia, nightmares, libido decreased, impotence.

Eye disorders:

Signs and symptoms of eye irritation, including mild burning or stinging sensation at the beginning of treatment, conjunctival hyperaemia, conjunctivitis, blepharitis, keratitis, decreased corneal sensitivity, and dry eyes.

Visual disturbances including blurred vision, refractive changes (due to withdrawal of miotic therapy in some cases), ptosis, diplopia, choroidal detachment (following filtration surgery).

Cardiac and vascular disorders:

Syncope, palpitations, arrhythmia, bradycardia, hypotension, cardiac insufficiency, atrioventricular block, slowing in atrioventricular conduction or intensification of an existing atrioventricular block, claudication, Raynaud's phenomenon, cold extremities.

Respiratory, thoracic, and mediastinal disorders:

Dyspnea, cough, bronchospasm (predominantly in patients with pre-existing obstructive lung disease).

Gastrointestinal disorders:

Dyspepsia, dry mouth, nausea, vomiting, diarrhea, gastralgia.

Skin and subcutaneous tissue disorders:

Alopecia.

Various skin symptoms, including urticaria, hypersensitivity reaction, angio-oedema (angioneurotic oedema), erythematous skin rash, rash psoriasiform or exacerbation of psoriasis (see section 4.4.).

General disorders and administration site conditions:

Fatigue, asthenia, chest pain.

Biologically:

Rare cases of antinuclear antibodies have been observed, only exceptionally accompanied by clinical symptoms such as lupus syndrome, which regress at treatment discontinuation.

4.9 Overdose

Although systemic absorption of beta-blockers after ocular instillation is low, the possible risk of overdosing should be borne in mind. The symptoms and management of overdose are similar to that of beta-blockers administered by the systemic route.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group : ANTIGLAUCOMA PREPARATIONS AND MIOTICS; Beta-blocking agents

ATC code: S01ED01

General:

Timolol can be characterised by three pharmacological properties:

- non-cardioselective beta-blockade,

- partial agonist potential [moderate intrinsic sympathomimetic activity (ISA)],

- non-significant membrane stabilising effect (local anaesthetic or quinidine-like).

Ocular:

- timolol maleate eye gel reduces intra-ocular pressure, whether or not this is associated with glaucoma;

- an effect is seen around 20 minutes following instillation, reaches a maximum in 1 to 2 hours and is still present after 24 hours;

- there is no effect on pupil diameter or visual acuity.

5.2 Pharmacokinetic Properties

The pharmacokinetic data arising from a comparative trial carried out on patients, suggests negligible systemic exposure, not greater than that obtained with a 0.1% timolol eye gel containing a preservative, used as a comparator in this study.

Plasmatic concentrations remain outside the quantification threshold (QL = 0.8 ng/ml) for both eye gels.

A similar level of systemic tolerance can therefore be anticipated for the two eye gels.

5.3 Preclinical Safety Data

None of the mutagenesis studies carried out in vivo and in vitro on timolol have produced any evidence of mutagenic potential. Cancerogenic potential in timolol has been shown in animals, at exposure levels much higher than those observed in clinical practice during treatment with TIOPEX 1 mg/g.

Reprotoxicity studies have not shown any teratogenic effect in mice, rats and rabbits.

In rats, a delay in ossification was observed at levels of exposure much higher than those observed in clinical practice during treatment with TIOPEX 1 mg/g. No effects on fertility were observed in rats.

In rabbits, a single or repeated instillation of TIOPEX 1 mg/g for 28 days did not cause any local or systemic intolerance, nor local anaesthetic effect.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sorbitol,

Polyvinyl alcohol,

Carbomer 974 P,

Sodium acetate trihydrate,

Lysine monohydrate,

Water for injections.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

30 months.

After opening of the single-dose container: use immediately and discard the singledose container after use.

After opening of the sachet: use the single-dose containers within 1 month.

6.4 Special Precautions For Storage

Keep the single-dose containers in the sachet and the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

10 single-dose containers (PEBD) containing 0.4 g of gel are packed in sachet (paper/aluminium), box of 3 or 9 sachets.

A pack size contains 30 (3x10) or 90 (9x10) single-dose containers.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Laboratoires THEA

12 Rue Louis Blériot

63017 Clermont-Ferrand Cedex 2

FRANCE

8. Marketing Authorisation Number(S)

PL 20162/0010

9. Date Of First Authorisation/Renewal Of The Authorisation

16/04/2010

10. Date Of Revision Of The Text

14/10/2010

Thymoglobuline 25 mg powder for solution for infusion

Thymoglobuline
25 mg, powder for solution for infusion

Rabbit anti-human thymocyte immunoglobulin

Read all of this leaflet carefully before you are given this medicine.

• Keep this leaflet. You may need to read it again.


• This medicine will be given to you by a doctor or nurse in hospital.


• If you have any further questions, please ask your doctor or nurse.


• If any of the side effects get serious or if you notice any side effects not listed in this leaflet, please tell your doctor.

In this leaflet:

• 1. What Thymoglobuline is and what it is used for


• 2. Before you are given Thymoglobuline


• 3. How Thymoglobuline is given


• 4. Possible side effects


• 5. How to store Thymoglobuline


• 6. Further information

What Thymoglobuline Is And What It Is Used For

Thymoglobuline belongs to a group of medicines called immunosuppressants (anti-rejection medicines). These medicines can help prevent the rejection of transplanted organs. They can also be used to treat other unwanted immune reactions.

Thymoglobuline is made by injecting human thymus cells into rabbits. It contains immunoglobulins (antibodies) which attach to and destroy some of the cells of your immune system in your body. These cells play a role in the rejection of transplanted organs or carry out other unwanted immune reactions.

Kidney and Heart Transplantation

Thymoglobuline is used in patients who have had a kidney or heart transplant, to prevent the rejection of a kidney or a heart transplant. It is also used to treat the rejection of a kidney transplant in patients who are resistant to treatment with corticosteroids. Thymoglobuline is a type of drug known as an immunosuppressant (anti-rejection drug) and is usually used in combination with other immunosuppressants. When a patient receives an organ, the body’s natural defence system will try to get rid of it (reject it). Thymoglobuline modifies the body’s defence mechanism and helps it accept the transplanted organ.

Before You Are Given Thymoglobuline

You should not be given Thymoglobuline

• if you are allergic (hypersensitive) to anti-human thymocyte globulin, rabbits , or any of the other ingredients of Thymoglobuline (see Section 6).


• if you have a severe infection because Thymoglobuline decreases your body’s ability to fight infections.

Take special care with Thymoglobuline

Tell your doctor if:

• you have ever had an allergic reaction to animals or other medicines. Your doctor will monitor you closely and stop treatment if there are any signs of an allergic reaction to Thymoglobuline.


• you have any blood disorders, such as lower than normal platelets in your blood (thrombocytopenia) or lower than normal white cells in your blood (leucopenia).The dose you will be given will depend on the number of white blood cells or platelets in your blood which will be checked before, during and after treatment.

Human blood components are used in the manufacturing process for Thymoglobuline. When medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. These include careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, and the testing of each donation and pools of plasma for signs of virus/infections. Also during manufacturer of Thymoglobuline, steps have been included during processing of the blood that can inactivate or remove the viruses. Despite these measures, when medicinal products prepared from human blood components are administered, the possibility of passing on infection cannot be totally excluded.

This also applies to any unknown or emerging viruses or other types of infections.

The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus and for the non-enveloped Hepatitis A and parvovirus B19 viruses.

Taking other medicines

Please tell your doctor if you are taking, or have recently taken any other medicines, including medicines taken without a prescription. It is especially important if you are taking:

• any other anti-rejection medicine (immunosuppressants), such as azathioprine or corticosteroids. This is because, if the body’s defense system is reduced too much, severe infections may occur. It may also increase the risk of developing cancer in the future.

Vaccinations

Do not have any vaccination during or soon after treatment with Thymoglobuline without first discussing it with your doctor as it may cause side effects or may not work because your immune system cannot respond to it.

Using Thymoglobuline with food and drink

It is unlikely that eating and drinking will affect your medicine.

Pregnancy and breast-feeding

Please tell your doctor if you are or think that you may be pregnant. This is because Thymoglobuline should not be given to pregnant women unless it is absolutely necessary as the effects are unkown.

Do not breastfeed while you are being given Thymoglobuline. This is because it may get into your breast milk and may affect the baby.

Driving and using machines

Do not drive or operate with machinery while being treated with Thymoglobuline

How Thymoglobuline Is Given

Your medicine will be given to you by a doctor or nurse in a hospital. Thymoglobuline is given through a plastic tube (catheter) directly into your blood stream (intravenous infusion) over a period of at least 6 hours. The first dose may be given over a longer period of time.

The dose you will be given will depend on your weight (unless you are obese when it will depend on your ideal weight), which medical problem you are being treated for, and if you are being given any other medicines at the same time.

To prevent kidney rejection:

Between 1 and 1.5 mg of Thymoglobuline for every kilogram of weight every day for 3 to 9 days.

To prevent heart rejection:

Between 1 and 2.5 mg of Thymoglobuline for every kilogram of weight for 3 to 5 days.

To treat kidney rejection in patients resistant to corticosteroids:

1.5 mg of Thymoglobuline for every kilogram of weight every day for 7 to 14 days.

There are no data in children for rejection of kidney tranplantation.

Your doctor or nurse will check you regularly while you receive your first dose because this is when you are more likely to get side effects. They will check for rashes, check your pulse, blood pressure and breathing. From time to time your doctor may also want you to have a blood test to monitor your blood cell count. If your white blood cell count is low, your doctor may also administer medicines to prevent or treat infections; if your platelet counts are low, your doctor may give you a platelet transfusion.

The dose of Thymoglobuline may be changed by your doctor if you have any side effects.

Other medicines your doctor may give you

Your doctor may give you some other medicines before, or at the same time as Thymoglobuline. These medicines are used to prevent, or treat possible side effects and could include:

• Antipyretics (like paracetamol) to reduce fever


• Corticosteroids (e.g. hydrocortisone) to prevent organ rejection and prevent side effects


• Antihistamines (e.g. cetirizine) to prevent an allergic response


• Heparin to reduce the risk of blood clots

If you are given more Thymoglobuline than you should have

It is unlikely you will be given more Thymoglobuline than you should, as you will be closely checked by your doctor or nurse during your treatment. If this does happen you may get a lower than normal platelet cell count (thrombocytopenia) or lower than normal white cell count (leucopenia). This can cause fever, chills, sore throat, mouth ulcers and bleeding or bruising more easily than normal.

Possible Side Effects

Like all medicines, Thymoglobuline can cause side effects, although not everybody gets them. Some side effects, such as fever, rash and headache, and others affecting your pulse rate, blood pressure and breathing, as well as some allergic reactions, are more likely to occur with your first or second dose of Thymoglobuline than with later doses.

Tell your doctor immediately if you notice:

• A raised itchy rash


• Difficulty in breathing


• Stomach pain


• Swelling of the face, tongue or throat

Sometimes, receiving a Thymoglobuline infusion may cause the following additional side effects. You should tell your doctor as soon as possible if you have any of the following:

• Difficulty breathing, wheezing or coughing


• Feeling or being sick


• Dizzy or feeling faint


• Tiredness


• Joint pain


• Headache


• Bleeding or bruising more easily than normal


• Irregular or fast heartbeat


• Symptoms of infection such as fever, chills, sore throat, mouth ulcers

The side effects listed below were recorded during a clinical study. This does not necessarily mean that all were caused by Thymoglobuline.

Very common (more than 1 in 10 patients) side effects include:

• Low white blood cell count; low platelet count


• Fever


• Infection

Common (up to 1 in 10 patients) include:

• Diarrhoea, difficulty swallowing, nausea, vomiting


• Shivering


• Serum sickness, which is an illness caused by antibodies against Thymoglobuline causing rash, itching, joint pains, kidney problems and swollen lymph nodes and which develops within 6-21 days. Serum sickness is usually mild and goes away without treatment or with a short course of corticosteroids


• Muscle pain


• Growths (including cancerous and non-cancerous)


• Shortness of breath


• Itchiness, rash


• Low blood pressure

These side effects may be mild and go away on treatment with other medicines. They may also be reduced by changing the dose of Thymoglobuline or increasing the period of time over which it is given.

Sometimes the effects of Thymoglobuline may not occur until months after it is used. These delayed effects may include an increased risk of infections and of certain types of cancer.

If you are receiving Thymoglobuline with other medicines which suppress your immune system, you may be more susceptible to infections.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

How To Store Thymoglobuline

Your medicine will be stored in a hospital by a doctor or nurse, out of the sight and reach of children.

The unopened vials of Thymoglobuline will be stored in a refrigerator (2 – 8 °C).

The doctor or nurse will check that the product has not passed its expiry date before preparation.

Further Information

Thymoglobuline is a prescription only medicine (POM)

What Thymoglobuline contains

The active substance is: 25 mg of rabbit anti-human thymocyte immunoglobulin.

The other ingredients are: mannitol, glycine, sodium chloride (salt). Thymoglobuline may also contain residues of polysorbate, from the manufacturing process.

What Thymoglobuline looks like and contents of the pack

Thymoglobuline is supplied in a glass vial containing a white powder. Before it is used it is mixed with 5 millilitres (ml) of sterile water to make a liquid. Each millilitre (ml) contains 5 mg of rabbit anti-human thymocyte immunoglobulin. This liquid is then mixed with a sodium chloride or glucose solution so that it can be given slowly (infused) into your bloodstream through a plastic tube (catheter) in a large vein.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation Holder is:

Genzyme Europe B.V.

Gooimeer 10

1411 DD Naarden

The Netherlands

Tel:+31 35 699 1200

Fax:+31 35 699 1444

The product is manufactured by:

Genzyme Polyclonals S.A.S.

1541 avenue Marcel Merieux

69280 Marcy l’Etoile

France

Tel:+33 4 37 28 16 00

Fax:+33 4 37 28 16 79

Local representative:

UK and Ireland

Genzyme Therapeutics Ltd

4620 Kingsgate

Cascade Way

Oxford Business Park South

Oxford

OX4 2SU

United Kingdom

Tel:+44 1865 405 200

Fax:+44 1865 774 172

Marketing Authorisation numbers:

UK: PL 12375/0021

Ireland: PA 611/3/1

Malta: MA 596/00201

For any information about Thymoglobuline, please contact the local representative or Marketing Authorisation Holder.

This leaflet was last approved in 11/2009

Testosterone Implant 100mg (Organon Laboratories Ltd)

1. Name Of The Medicinal Product

Testosterone Implant 100MG

2. Qualitative And Quantitative Composition

Testosterone implant containing 100mg testosterone.

3. Pharmaceutical Form

Implant for subcutaneous use.

4. Clinical Particulars

4.1 Therapeutic Indications

In the male: testosterone replacement therapy in primary or secondary hypogonadal disorders, for example:

- after castration,

- eunuchoidism,

- hypopituitarism,

- endocrine impotence,

- male climacteric symptoms such as decreased libido and decreased mental and physical activity.

Moreover, testosterone therapy may be indicated in osteoporosis in the male due to androgen deficiency.

In the female as an adjunct to estrogen replacement therapy in postmenopausal women to alleviate symptoms, such as decreased libido and/or loss of energy.

4.2 Posology And Method Of Administration

Posology

- In males:

100-600 mg depending on individual requirements. A dosage of 600 mg (6 x 100 mg) usually maintains plasma testosterone levels within the normal physiological range for 4-5 months.

- In females:

50-100 mg as an adjunct to Estradiol implants.

Method of implantation

Testosterone implants should be inserted subcutaneously into an area where there is relatively little movement or blood supply, such as the lower abdominal wall or the buttock. Insertion is made under local anaesthesia using a trocar and a cannula. The wound is closed either with an adhesive dressing or a fine suture. The implants must be placed subcutaneously to facilitate removal if necessary. Full aseptic "no touch" technique should be adopted.

4.3 Contraindications

- Known or suspected prostatic carcinoma or breast carcinoma in the male

- Pregnancy

- Breast-feeding

4.4 Special Warnings And Precautions For Use

- Androgens should be used with caution in women to avoid unacceptable and irreversible virilization. Female patients should therefore be counselled to report any deepening or hoarsening of the voice without delay.

- Androgens should be used with caution in prepubertal boys to avoid premature epiphyseal closure or precocious sexual development. Skeletal maturation should be monitored regularly.

- Due to the long-lasting action and the difficulty of removal, Testosterone implants should be used with extra caution. Therefore, it may be advisable to establish the beneficial effect and tolerance for androgen therapy by prior treatment with a shorter-acting testosterone preparation. This applies in particular to (pre)pubertal boys, women and elderly men.

- Patients with latent or overt cardiac failure, renal or hepatic dysfunction, hypertension, epilepsy or migraine (or a history of these conditions) should be kept under close medical supervision, since aggravation of recurrence may occasionally be induced.

- If androgen-associated adverse reactions occur the implant should be removed if possible.

- The use of steroids may influence the results of certain laboratory tests, (see Section 4.5).

Physicians should consider monitoring patients receiving Testosterone Implants, before implantation and at regular intervals thereafter, for the following parameters:

- testosterone, to confirm hypogonadism

- digital rectal examination (DRE) of the prostate and PSA to exclude benign prostate hyperplasia or a sub-clinical prostate cancer. Androgens may accelerate the progression of subclinical prostatic cancer and benign prostatic hyperplasia.

Testosterone implants should be used with caution in cancer patients at risk of hypercalcaemia (and associated hypercalcuria), due to bone metastases. Regular monitoring of serum calcium concentrations is recommended in these patients.

Rarely benign and malignant liver tumours have been reported in patients receiving oral testosterone replacement therapy with 17 α–alkylated testosterone derivatives, however, this has not been observed with testosterone implants.

Androgens should not be used to enhance ability in sports as it carries serious health risks.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Enzyme-inducing drugs may influence plasma testosterone levels.

Testosterone and derivatives have been reported to increase the activity of oral anti-coagulants. Patients receiving oral anti-coagulants require close monitoring, especially at the beginning or end of androgen therapy. Increased monitoring of the prothrombin time, and INR determinations, are recommended.

The concurrent administration of testosterone with ACTH or corticosteroids may enhance oedema formation; thus these active substances should be administered cautiously, particularly in patients with cardiac or hepatic disease or in patients predisposed to oedema.

Laboratory Test Interactions: Androgens may decrease levels of thyroxine binding globulin resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

Anti-diabetics: the hypoglycaemic effect is possibly enhanced due to improved insulin sensitivity.

4.6 Pregnancy And Lactation

Testosterone implants are contraindicated during pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

As far as known Testosterone implants have no effects on alertness and concentration.

4.8 Undesirable Effects

The following adverse reactions have been associated with androgen therapy:

- in general: water and sodium retention, hypercalcaemia;

- in women: symptoms of virilization, such as voice changes (deepening, hoarsening) and hirsutism;

- in prepubertal boys: precocious sexual development, increased frequency of erections, phallic enlargement and premature epiphyseal closure;

- in men: priapism and other signs of excessive sexual stimulation, oligospermia and decreased ejaculatory volume;

- extrusions occur in approximately 5% of the patients, depending upon the clinician's skill and experience. Most extrusions involve the loss of only a single implant and do not require specific treatment or replacement of implants;

- mild bleeding at the implantation site may occur occasionally within 2-3 hours after implantation and haematoma may occur within a few days after implantation;

- infection at the implantation site occurs rarely.

4.9 Overdose

The acute toxicity of testosterone is low. Priapism in men and undesired deepening of the voice in women are symptoms of chronic overdosage. In this case the implant(s) should be removed.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Testosterone is a naturally-occurring hormone formed in the interstitial cells of the testes under the control of the anterior lobe of the pituitary gland which controls the development and maintenance of the male sex organs and male secondary sex characteristics. Testosterone also produces systemic effects, such as increasing the retention of nitrogen, calcium, sodium, potassium, chloride and phosphate leading to an increase in skeletal weight, water retention and an increase in the growth of bone.

5.2 Pharmacokinetic Properties

Testosterone implants, when inserted subcutaneously release testosterone into the bloodstream at a relatively even rate supplying near physiological plasma testosterone levels.

Surface area of the implants is the most important factor influencing the rate of absorption. In general the absorption rate estimated by removal of implants at intervals and weighing appears to be appreciably more rapid than when the rate is assessed upon the clinical requirement. In addition to clinical evidence individual variation in the rate of absorption of implants must be taken into account.

The average daily absorption of testosterone has been estimated at 0.5mg for a 100mg implant with an approximate duration of 30 weeks.

5.3 Preclinical Safety Data

No particulars.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Testosterone implants are moulded pellets of pure testosterone (BP) without excipients.

6.2 Incompatibilities

No relevant incompatibilities are known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

Store in the original package.

6.5 Nature And Contents Of Container

Each sterile implant is supplied singly in a sealed glass tube, positioned between plugs of non-absorbent wool.

6.6 Special Precautions For Disposal And Other Handling

See "Posology and method of administration".

Administrative Data

7. Marketing Authorisation Holder

Organon Laboratories Limited, Cambridge Science Park, Milton Road, Cambridge, CB4 0FL

8. Marketing Authorisation Number(S)

PL 0065/5083R

9. Date Of First Authorisation/Renewal Of The Authorisation

04/10/2005

10. Date Of Revision Of The Text

04/10/2005

Ref: UStest100v2.3