Summary of Product Characteristics. Summary of Product Characteristics. 1. Name of the Medicinal Product

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1 1. Name f the Medicinal Prduct Tim-COMOD 0.1% eye drps Tim-COMOD 0.25% eye drps Tim-COMOD 0.5% eye drps 2. Qualitative and Quantitative Cmpsitin Active substance: Tim-COMOD 0.1% eye drps: 1 ml f eye drps cntains: Timll maleate Equivalent t 1.0 mg timll Tim-COMOD 0.25% eye drps: 1 ml f eye drps cntains: Timll maleate Equivalent t 2.5 mg timll Tim-COMOD 0.5% eye drps: 1 ml f eye drps cntains: Timll maleate Equivalent t 5.0 mg timll 1.37 mg 3.42 mg 6.84 mg Fr a full list f excipients see sectin Pharmaceutical Frm Eye drps. 4. Clinical Particulars 4.1 Therapeutic Indicatins Fr the therapy f elevated intracular pressure (cular hypertensin) chrnic pen-angle glaucma aphakic glaucma cngenital glaucma, if ther therapeutic regimens are nt sufficient.

2 4.2 Pslgy and Methd f Administratin Nrmally, therapy begins with 1 drp f 0.1 % timll eye drps twice daily. If required, the dse can be increased t 1 drp f 0.25 % r 0.5 % timll eye drps twice daily. Fr cular use. As general rule, cntact f the bttle tip with eye r skin surface shuld be avided when applying eye drps. 4.3 Cntraindicatins brnchial hyperreactivity existing r frmerly diagnsed brnchial asthma chrnic bstructive pulmnary diseases sinus bradycardia secnd and third degree atri-ventricular blck vert cardiac failure cardigenic shck hypersensitivity t the active substance r any ther ingredient f this prduct severe allergic rhinitis nutritinal disrders invlving the crnea 4.4 Special Warnings and Precautins fr Use Cntact lenses shuld be remved frm the eye befre applying the eye drps and reinserted again 15 minutes after applicatin. 4.5 Interactins with Other Medicinal Prducts and Other Frms f Interactin the cncmitant applicatin f adrenaline-cntaining eye drps may cause mydriasis. timll s pharmaclgic actin f reducing intracular pressure is enhanced by adrenaline- r pilcarpine-cntaining eye drps. the cncmitant systemic use f beta-blckers may lead t a mutual increase in each drug s pharmaclgic activity; intracular pressure reductin by timll will be enhanced as well as systemic beta-blcking activity n the cardivascular system. hyptensin and bradycardia may be ptentiated by the cncmitant use f timll with ral calcium antagnist, digitalis, catechlamine-releasers r beta-blckers. Nte: If cncmitant treatment with ther eye medicines is necessary, a perid f 15 minutes shuld elapse between the applicatin f the different prducts.

3 4.6 Pregnancy and Lactatin N well-cntrlled studies with Tim-COMOD eye drps in pregnant and breast-feeding wmen exist. Therefre, the expected benefit has t be balanced precisely against the pssible risks. When Tim-COMOD eye drps is applied t the mther shrtly befre delivery, bradycardia, hypglycemia and respiratry depressin in the nenate may ccur; there are reprts abut β-blckage in nenates with ther β-blckers. Nenates therefre shuld be bserved carefully fr several days after delivery. Lactatin: After cular administratin, timll is secreted int breast milk and may accumulate t higher cncentratins than in the mther s plasma. Althugh the amunt f active ingredient thus received in breast milk is prbably f n risk fr the newbrn, the child shuld be carefully bserved fr symptms f β-blckade. Premature and nrmal brn infants: In single cases, apnea was reprted in newbrns, pssibly related t the immaturity f these patients. Because f the pssibility f central-nervus effects, the use is nt recmmended in premature infants and nenates. In sme cases, the use f timll eye drps in nenates and infants led t cnsiderably higher timll-plasma levels than in adults. Therefre, infants shuld be exactly chsen fr timll therapy and, amngst thers after starting therapy be carefully bserved in view f symptms fr a systemic β-blckade. 4.7 Effects n Ability t Drive and Use Machines This medicinal prduct may cause blurred visin and impair reactin capability after applicatin even with prper use. Thus, it may influence the ability t drive, use machines r wrk withut secure hld. This is especially relevant in cmbinatin with alchl. 4.8 Undesirable Effects The assessment f undesirable effects fllws the fllwing frequencies: Very cmmn: ( 1/10) Cmmn: ( 1/100 - < 1/10) Uncmmn: ( 1/1,000 - < 1/100) Rare: ( 1/10,000 - < 1/1,000) Very rare: (< 1/10,000) Unknwn: Incidence nt assessable basing n the available data. Eyes: Irritatins f the eyes, such as cnjunctivitis, blepharitis, keratitis, as well as impaired visin, diplpia, ptsis and sensatin f dryness f the eyes.

4 Systemic side-effects: Cardivascular system: Bradycardia, arrhythmia, hyptensin, syncpes, atriventricular blck, cerebrvascular insult, cerebral ischemia, heart failure, palpitatins, cardiac arrest. Respiratry system: Brnchspasms (especially in patients with existing brnch-spastic diseases), respiratry insufficiency, dyspnea. Skin: Hypersensitivities, such as lcal r general exanthems, urticaria and alpecia. Other side-effects: Headache, weakness, vmiting, giddiness, depressin. Advice: Like in every treatment f glaucma, the intracular pressure as well as the crnea shuld be examined regularly. 4.9 Overdse Symptms f intxicatin: Overdse may lead t severe hyptensin, cardiac insufficiency, cardigenic shck, bradycardia up t cardiac arrest. In additin, respiratry disturbances, brnchial spasms, vmiting, cnfusin, and generalised cramping may ccur. Treatment f intxicatin: In additin t general measures, vital functins have t be checked and crrected, if necessary, under intensive care cnditins. The fllwing antidtes are suitable: Atrpine: mg as intravenus blus injectin Glucagn: Initially 1-10 mg intravenusly, afterwards mg per hur as infusin Beta-sympathmimetic drugs, based n bdy weight and efficacy: Dbutamine, isprenaline, rciprerialine, r epinephrine (adrenaline). Pace-maker therapy may be indicated in therapy-resistant bradycardia. Beta-2-sympathmimetic drugs (as aersl r, in case f insufficient activity, as injectin) r aminphylline, intravenusly, can be given in case f brnchial spasm. In case f cnvulsin, slw intravenus applicatin f diazepam is recmmended.

5 5. Pharmaclgical Prperties 5.1 Pharmacdynamic Prperties Pharmactherapeutic grup: Ophthalmics/Antiglaucmatsa/Beta-receptr blcking agents ATC-Cde: S01ED01 Timll is a nn-selective beta-receptr blcker withut intrinsic sympathmimetic activity r lcal anesthetic (membrane-stabilising) prperties. It inhibits β 1 -receptrs, which are lcalised abve all in the heart muscle, as well as β 2 -receptrs. The stimulating effect f catechlamines n the heart is reduced by timll. In cnsequence, the neural transmissin in the A-V nde is decelerated and the systlic discharge is dwncasted. The inhibitin f β-receptrs in the brnchi and brnchiles leads t an increase f the airway resistance because f a prepnderence f the parasymathicus. Effect n the eye Timll eye drps reduce bth elevated and nrmal intracular pressure. The accurate mechanism f actin f timll by decreasing the intracular pressure is nt knwn by nw. A flurmetric study and tngraphic investigatins suggest that its effect is based n a decrease in prductin f aqueus humr. In sme studies a better utflw f aqueus humr culd be bserved. The nset f pharmaclgic effect is generally rapid, beginning abut 20 minutes after lcal applicatin t the eye. The maximal reductin f intracular pressure is reached after ne t tw hurs and a significant decrease in intracular pressure lasts up t 24 hurs under the influence f 0.25% r 0.5% timll eye drps. As with ther agents which lwer intracular pressure, lng-term use f timll leads t tachyphylaxis in sme patients. Hwever, in a lng-term clinical trial, in which 164 patients treated with timll were studied ver 3 years, after intracular pressures remained stable at their lwered levels. In cntrast t mitics, timll reduces the intracular pressure withut effecting accmmdatin r pupil size. This is especially advantageus fr cataract patients. If the patient s therapeutic regimen is changed frm mitics t timll, a crrectin f refractin may be necessary after the mitic activity subsides. 5.2 Pharmackinetic Prperties Aqueus humur levels: In rabbits, aqueus humur levels f 461 ng/100 mg at maximum were measured 60 minutes after the applicatin f ne drp f timll 1,0%. In men, aqueus humur levels f timll 1 and 2 hurs after applicatin f 2 drps f timll 0,5% amunted 150 ng/100 mg. After 7 hurs the level decreased dwn t 10 ng/100 mg.

6 Ocular tissue levels: One drp f a 0.25 % slutin f 14 C-marked timll was applied t a rabbit eye. The maximum radiactivity was detected after minutes in varius cular tissues. In crnea, nictitating membrane, iris and ciliary bdy, radiactivities crrespnding t between 1 and 10 mg timll per 100 mg f tissue were measured. Systemic resrptin: Experiments shwed that timll is absrbed systemically after lcal applicatin t the eye. In a clinical trial, timll, which is secreted mainly by the kidneys alng with its metablites, was detected in the urine in all patients and healthy subjects. Plasma cncentratins: Plasma cncentratins f timll after lcal applicatin f the recmmended clinical dsages are frequently nt detectable (< 2 ng/ml) after either ne-time usage r cntinuus use fr 2 weeks. The maximal plasma cncentratin measured frm a dsage f 2 drps twice daily was 9.6 ng/ml. It ccurred 30 t 90 hurs after the nset f usage. In sme cases, the use f timll-cntaining eye drps in newbrns and small children leads t a higher plasma cncentratin than in adults. A three week ld infant, wh was treated with a 0.25 % timll-cntaining eye drp slutin at a dsage f ne drp twice daily, was fund t have a timll plasma cncentratin f 34 ng/ml. 5.3 Preclinical Safety Data Acute txicity: - See sectin 4.9 Overdse - Chrnic txicity / Subchrnic txicity: In studies n rabbits fr ne year and dgs fr ne t tw years, tpically administered timll maleate caused n side-effects n the eye. Even the lng-term ral administratin f high dses f timll maleate t dgs and rats did nt result in side-effects except fr bradycardia and an increase in the weight f several rgans, in particular, the heart, kidney and liver. Mutagenic and cancergenic prperties: Detailed data n mutagenicity are nt available; all currently available studies are negative. Tumrigenic ptential: During a tw year study n rats, in which timll maleate was rally administered at very high dses (300 times higher than the maximal recmmended dsage f I mg/kg/day fr humans), a statistically significant (p<0.05) increase in the rate f phechrmcytma f the adrenal gland ccurred in male rats. In rats administered with 25 t 100 times the maximal recmmended dse fr humans these types f changes did nt ccur. In a study n mice, in which timll was rally administered ver their entire life-span, a statistically significant (p<0.05) increase in the rate f benign and malignant lung tumrs as well as benign uterine plyps (in female mice) ccurred with dsages f 500 mg/kg/day. The increases did nt ccur, hwever, with dsages f 5 r 50 mg/kg/day.

7 Mammary adencarcinma rates als increased in the mice receiving very high dses f timll maleate (500 mg/kg/day). This may be related t an increase in the serum prlactin cncentratin, which was bserved t be increased in the mice receiving 500 mg/kg/day but nt in thse receiving 5 r 50 mg/kg/day. An increase in the rate f mammary adencarcinma in rdents is seen after administratin f several substances knwn t raise serum prlactin cncentratins. In adult wman, the ral ingestin f 60 mg f timll maleate, which is the maximum recmmended ral dse fr humans, des nt raise serum prlactin levels in a clinically significant manner. Female mice receiving 500 mg/kg/die shwed a statistically significant increase in neplasms. Reprductin txicity: Reprductin- und fertility-studies in rats shwed that the fertility f male and female rats was nt adversely effected by dses f timll up t 150 times greater than the maximum recmmended dsage fr humans. Experiments investigating the teratgenicity f rally ingested timll maleate in mice and rabbits shwed n evidence f fetal malfrmatins at dsages f up t 50 mg/kg/day. Ossificatin was smetimes delayed, but this had n bservable effect n pstnatal develpment. Dsages f 1000 mg/kg/day in mice (1000 times the maximal recmmended dse fr humans) resulted in maternal txicity as well as in increased rates f fetal resrptin. Rabbits receiving 100 mg/kg/day shwed similar increased resrptin rates but n signs f maternal txicity. 6. Pharmaceutical Particulars 6.1 List f Excipients Sdium dihydrgen phsphate dihydrate, sdium hydrgen phsphate ddecahydrate, water fr injectins. Tim-COMOD 0.1%/0.25%/0.5% des nt cntain any preservatives. 6.2 Incmpatibilities Nt applicable. 6.3 Shelf life 3 years. Tim-COMOD 0.1%/0.25%/0.5% can be used up t 12 weeks after first use. Tim-COMOD 0.1%/0.25%/0.5% shuld nt be used beynd the expiry date (imprinted n flding cartn and label).

8 6.4 Special Precautins fr Strage D nt stre abve 25 C. 6.5 Nature and Cntents f Cntainers Multiple dse cntainer with gas-free pump-system, bth f plyethylen. The fllwing pack sizes are available: Tim-COMOD 0.1%: Flding cartn with 1 bttle f 10 ml. Tim-COMOD 0.25%/0.5%: Flding cartn with 1 r 2 bttles f 10 ml. 6.6 Instructin fr Use/Handling N special requirements. 7. Name r Style and Permanent Address r Registered Place f Business f the Marketing Authrisatin Hlder URSAPHARM Arzneimittel GmbH & C. KG Industriestraße 35 D Saarbrücken Telephne: Germany - (0) Telefax: Scientific Affairs Germany - (0) Administratin/Sales Germany - (0) Marketing Authrisatin Number N.N. 9. Date f Apprval N.N. 10. Date f revisin f the text June Legal status On prescriptin nly.