DEXTROROTATORY CLOPROSTENOL + LECIRELIN

Twin-action fertility Receptor DEXTROROTATORY CLOPROSTENOL LECIRELIN

Receptor

The female genital system shows considerable receptor selectivity Hypothalamic GnRH exerts a fundamental action on the control of fertility as it induces secretion of FSH and of LH and therefore only recognises prostaglandins with a dextrorotatory from the pituitary gland. Levorotatory conformation. Endogenous PgF2α molecules, in fact, are DEXTROROTATORY Cloprostenol The act in their turn on the ovary, where they stimulate the development and maturation of the dextrorotatory. ISOMER follicle (FSH) and subsequent ovulation and transformation into a corpus luteum (LH). On the one hand is favoured shows a high affinity for the the onset of signs of normal and easily identifiable estrus; on the other hand are also ensured optimal conditions for Dalmazin is a medicinal product based on dextrorotatory specific receptors the establishment of pregnancy. present on the ovaries cloprostenol, the only active form of cloprostenol. and uterus LEVOROTATORY ISOMER it does not bind to the specific Dalmarelin is a medicinal product based on lecirelin, a synthetic nonapeptide analogue of natural GnRH. receptors, causing a lack Thanks to the special structural properties of lecirelin, Dalmarelin shows a greater affinity for the hypophyseal causing a displacement of the dextrorotatory isomer and a GnRH receptors, producing a massive release of LH and FSH. lack of activity Selective affinity for the PgF2α receptors Optimal stimulation of LH

COMPETITION CURVE Comparative evaluation of 3 GnRH analogues3

Re et al. evaluated the affinity 120 PgF2α 12 heifers were subjected to treatment with different GnRH analogues: of PgF2α, d-cloprostenol and d-cloprostenolo 100 dl-cloprostenolo dl-cloprostenol for the natural • 100 µg/animal prostaglandin receptors present in 80 • lecirelin 25 µg/animal equivalent to 1 ml of Dalmarelin the bovine myometrium and corpus bond (%) Specific PgF2α The receptor affinity • lecirelin 50 µg/animal equivalent to 2 ml of Dalmarelin luteum. 60 of d-cloprostenol is • 10 µg/animal In vitro results showed that in cattle identical to that of the endogenous PgF2α d-cloprostenol had a receptor binding 40 affinity 150 times greater than that During the study, the follicular dynamics and the plasma concentrations of LH and progesterone were evaluated. of dl-cloprostenol for corpus luteum 20 and a 10 times greater affinity for 0 myometrium receptors. 11 10 9 8 7 6 5 4 POTENT AND PROLONGED 20 -Log of the concentration of the active substances 10 ACTION Gonadorelin 18 Lecirelin 25 Maximum luteolytic activity Lecirelin induces an LH peak around 16 Lecirelin 50 3 times that of gonadorelin and Buserelin entirely comparable to that induced 14 2 21 The following study compared the 3 Dalmazin by buserelin . (ng/ml) LH concentration 12 luteolytic activity of dextrorotatory 18 Levorotatory cloprostenol cloprostenol (Dalmazin) and the Moreover, the plasma 10 15 levorotatory isomer in heifers at the concentrations of LH following 12th day of the cycle. 8 12 administration of lecirelin, are Following administration of The selectivity of d-cloprostenol for PgF2α receptors allows a rapid maintained at levels above base 6 Dalmazin, a rapid collapse in 9 luteolytic action. On the other hand values for almost double the period blood levels of progesterone (ng/ml) levels Mean blood progesterone the formulation containing the 4 6 levorotatory isomer does not (6 hours versus 3.5 hours) compared is noted, which instead remain 3 induce a luteolytic action to gonadorelin . 2 constants, owing to the persistence 3 of the corpus luteum, after the 0 0 administration of levorotatory 1 2 3 4 5 6 0 1 2 3 4 5 6 7 cloprostenol. Days following treatment Time (h)

1) Re, Badino, Novelli, Vallisneri and Girardi; Specific binding of dl cloprostenol and d cloprostenol to PGF2a receptors in bovine corpus luteum and myometrial cell membranes. Journal of Veterinary Pharmacology 3) Picard-Hagen N., Lhermie G., Florentin S., Frein P., Merle D., Gayrard V., Effect of gonadorelin, lecirelin and buserelin on LH surge ovulation and progesterone in cattle, Theriogenology 84(2): 177-183, 2015. and Therapeutics, 17(6): 455 - 458, 1994.

2) Data on file. LUTEOLYTIC ACTIVITY (Dalmazin 2 ml/animal) UTEROTONIC ACTIVITY (Dalmazin 2 ml/animal)

INDUCTION OF ESTRUS INDUCTION OF PARTURITION Corpus luteum detection 48 h 60 h 72 h 96 h Administer Dalmazin after the 270th day of pregnancy. Calving occurs, on average, within 30-60 hours after treatment. Heat A.I.

DELAYED UTERINE INVOLUTION Standard dose (n=5) 20 5 Double dose (n=5) Administer Dalmazin and, if considered advisable, perform one or two subsequent treatments at 24 hour intervals. 19 G: P<0,1 G: P<0,05 D: P<0,05 18 D: P<0,05 4 G*D: P<0,05 G*D: P<0,05 Diameter of the corpus 17 luteum (CL) and blood 16 3 levels of progesterone 15 The reduction in the diameter 14 2 (P4) following the diameter luteum Corpus of the corpus luteum and the 13 (ng/ml) P4 concentration decrease in blood levels of administration of 12 1 EXPULSION OF A MUMMIFIED FOETUS 0.15 and 0.30 mg of 11 progesterone emphasises the high luteolytic activity of Dalmazin in Dalmazin in cattle with 10 0 the presence of a sensitive Expulsion of the foetus takes place, on average, within 3-4 days after administration of Dalmazin. corpus luteum at 132 0 1 2 3 4 0 1 2 3 4 corpus luteum Days after treatment with Dalmazin hours4 Days after treatment with Dalmazin

TREATMENT OF OVARIAN DYSFUNCTION (PERSISTENT CORPUS LUTEUM AND LUTEINIC CYSTS) ENDOMETRITIS AND PYOMETRA TREATMENT 72 h 96 h -14 days 0 days 72 h 96 h

A.I. A.I.

SYNCHRONISATION OF ESTRUS -14 days 0 days 48 h 60 h 72 h 96 h 20-26 days 34-40 days Parturition postpartum postpartum Heat A.I. d-cloprostenol d-cloprostenol

The reproductive parameters st 1 dose 63.51% of the subjects with endometritis d-cloprostenol HEALTY treated with d-cloprostenol returned to levels comparable Pregnant animals (%) 79,5 76,4 to those of the healthy Percentage of induction of heat in treated cows control animals Days open 110,9 110,6 The administration with Dalmazin (0.15 mg/animal IM), repeated of Dalmazin induced after 14 days for a maximum of three treatments Voluntary waiting period 76,5 74,4 in case of non-manifestation of heat5 estrus in approximately 80% Conception Rate (%) 39 36 of the treated subjects % conception at the 1st service 40 36 3rd dose 12.16% 2nd dose 24.32% Comparison of various fertility indices between the 34th and the 40th day postpartum between a healthy CONTROL group and a TREATED group consisting of subjects with INTERRUPTION OF PREGNANCY (Dalmazin 2 ml/animal) endometritis of differing severity which received 2 administrations of d-cloprostenol (0.15 mg/animal IM) 14 days apart Administer in the first half of pregnancy PARTURITION

4) Valldecabres-Torres et al., Effects of d-cloprostenol dose and corpus luteum age on ovulation, luteal function, and morphology in nonlactating dairy cows with early corpora lutea, Journal of Dairy Science, 6) Falkenberg U., Heuwieser W., Untersuchungen zum Zeitpunkt der Prostaglandin F2a - Applikation bei der Behandlung der chronischen Endometritis des Rindes, Dtsch. Tier. Wschr., 112, 252-256, 2005. 95(8): 4389 - 4395, 2012.

5) Perez-Marin et al., Reproductive efficacy obtained with a programme based on the repeated administration of d-cloprostenol during the postpartum in dairy cows VIIIth International Congress of Bovine Medicine - ANEMBRE 2002. Prostaglandin +

TREATMENT OF FOLLICULAR CYSTS 4 ml/animal equivalent to 100 µg lecirelin/kg b.w. LATEST SCIENTIFIC WORKS

In various studies the use of Prostaglandin and Dalmarelin have 80 % In cows with ovarian cysts, 75% of subjects treated Dalmarelin been used as part of the ovulation synchronisation programmes, with single administration of Dalmarelin (4 ml/animal group in combination with each other or with other active substances. Control group intramuscularly) showed, at the subsequent echographic 60% control after a week, a recovery of cycling activity with OVSYNCH regression of the cystic structure and appearance of the Kaçar et al. 200810 7 corpus luteum . 40% after 0 days 7 days 9 days 16 h Percentage of recovery of cycling activit of recovery Percentage

20% D-cloprostenol + Vit. E + β-carotene inj 0% Animals showing a recovery of cycling activity D-cloprostenol 2 ml/animal IM INSEMINATION Dalmarelin 2 ml/animal IM Vit. E + β-carotene 7 ml/100 kg IM Injection of 2 ml/animal of Dalmarelin by the epidural Estrus route in cows with follicular cysts induced the appearance n° 60 Pregnancy Rate of the characteristic signs of estrus within 15 ± 3 days of + 18% COSYNCH administration in 75% of the animals compared to 57% in n° 60 11 10 8 Kaçar et al. 2014 Kaçar et al. 2008 the group treated with the same dosage intramuscularly . after + 17% 0 days 7 days 56h 0 days 7 days 9 days

D-cloprostenol D-cloprostenol + Vit. E + β-carotene inj

INSEMINATION D-cloprostenol 2 ml/animal IM INSEMINATION Percentage of increase in the detection of heat and the pregnancy rate in subjects D-cloprostenol 2 ml/animal IM treated with Dalmarelin by the epidural route compared to the intramuscular route Dalmarelin 2 ml/animal IM Dalmarelin 2 ml/animal IM Vit. E + β-carotene 7 ml/100 kg IM INDUCTION OF OVULATION AT THE TIME OF INSEMINATION IN CASES OF SHORT, SILENT OR PROLONGED HEATS 2 ml/animal equivalent to 50 µg lecirelin/kg b.w. DOUBLESYNCH Use of D-cloprostenol and Dalmarelin in the context of a protocol of “Doublesynch” in primipara cows in anestrus improved The administration of Dalmarelin (50 µg of lecirelin) in 80% the Pregnancy Rate by 43% compared to the Ovsynch group. Dalmarelin cows and heifers at the time of insemination produced a 70% Control Öztürk et al. 201012 conception rate at the first service of 50% compared to 44% 100% 60% in the negative control group. Doublesynch Ovsynch 50% 0 days 2 days 9 days 11 days 12 days 80%

This parameter was considerably higher in pluripara cows 40% 9 (67% in the treated group versus 49% in the control group) . 60% 30% D-cloprostenol D-cloprostenol

20% 40%

10% 20% 0% INSEMINATION Conception Rate (%) Conception Rate (%) D-cloprostenol 2 ml/animal IM at the first service at the first service 0% of pluripara cows Dalmarelin 2 ml/animal IM Pregnancy Rate (%)

7) A.M. Silva et al., Treatment of ovarian cysts in cattle with lecireline , Proceedings of the 26th Annual Meeting of the Brazilian Embryo Technology Society (SBTE), August 30th to September 2nd, 2012, 10) Kaçar et al., Ineklerde ß-karoten + E Vitamini Uygulamasiyla Kombine Edilen Ovsynch ve Cosynch Senkronizasyon Programlarinin Gebelik Orani Üzerine Etkisi, Kafkas Üniv Vet Fak Derg, 14(1): 45-50, 2008. Foz de Iguacu, PR, Brazil. Abstracts. 12) Kaçar et al., The Effects on Follicular Dynamics Caused by Changing the Application Time of PGF2α and GnRh in the Cosynch Protocol Administered in Montofon Cows with Estrus Stimulated by 8) Rizzo A. et al., Epidural vs intramuscular administration of lecirelin, a GnRH analogue, for the resolution of follicular cysts in dairy cows, Anim. Reprod. Sci., 126(1-2): 19 - 22, 2011. Presynchronization, Kafkas Univ Vet Fak Derg, 20(6): 951-956, 2014. 13) Öztürk et al., Is Doublesynch protocol a new alternative for timed artificial insemination in anestrous dairy cows, Theriogenology, 73(5): 568 - 576, 2010. 9) Martin R., Schmausser M., Seidl S., Schmauder S., Mansfeld R. Untersuchungen zum Einsatz von Lecirelin zur Verbesserung des Besamungserfolges, Praktische Tierarzt, 86(12): 914 - 918, 2005. WITHDRAWAL PERIODS Meat and offal: 0 days Milk: 0 hours LECIRELIN PACKS

10 ml vial VETERINARIANS F044/E/g1 FOR 20 ml vial

1 NAME OF THE VETERINARY MEDICINAL PRODUCT DALMARELIN, 25 micrograms/ml, solution for injection for cattle and rabbits. 2 QUALITATIVE AND QUANTITATIVE COMPOSITION 1 ml contains: Active substance: Lecirelin acetate equivalent to lecirelin 25 micrograms. Excipients: Benzyl alcohol (E1519) 20 mg. For a full list of exciients, see section 6.1. 3 PHARMACEUTICAL FORM Solution for injection. Clear colourless solution. 4 CLINICAL PARTICULARS 4.1 Target Species Cattle (cow) and rabbits. 4.2 Indications for use, specifying the target species Cattle: - Treatment of follicular ovarian cysts. - Cycle induction in early post-partum cows from day 14 post-partum. - Induction of ovulation at the time of insemination in cases of short, silent heat or prolonged heat. - Induction of ovulation in cycling cows in association with artificial insemination to optimise the time of ovulation. - Induction and synchronisation of oestrus and ovulation in combination with prostaglandin F2α (PGF2α) or PGF2α analogue, with or without progesterone, as part of fixed time artificial insemination (FTAI) protocols. Rabbits: - Induction of ovulation. - Conception rate enhancement. 4.3 Contraindications None. 4.4 Special warnings for each target species The product should be administered to cows with normal ovaries at least 14 days after calving due to the absence of receptivity of the hypophysis before that time. The product should be administered at least 35 days post-partum for the induction of ovulation in association with artificial insemination (with or without FTAI protocols). The OvSynch procedure may not be as efficacious in heifers as in cows. 4.5 Special precautions for use Special precautions for use in animals Animals in poor condition, whether from illness, inadequate nutrition, or other factors, may respond poorly to treatment. Special precautions to be taken by the person administering the veterinary medicinal product to animals Women of childbearing age should administer Dalmarelin with caution since lecirelin has been shown to be foetotoxic in rats. In case of accidental self-injection, seek medical advice. GnRH-analogues may be absorbed through intact skin. In case of dermal contact wash the exposed area immediately with soap and water. 4.6 Adverse reactions (frequency and seriousness) None observed. 4.7 Use during pregnancy, lactation or lay The use of Dalmarelin is not recommended during pregnancy. Dalmarelin can be used during lactation. 4.8 Interaction with other medicinal products and other forms of interaction None known. 4.9 Amounts to be administered and administration route Administer by the intramuscular route. The closures should not be punctured more than 25 times. The posology varies according to the indications and the animal species, as follows. Cattle: - Treatment of follicular ovarian cysts:4 ml of the product (100 µg of lecirelin). - Cycle induction in early post-partum cows from day 14 post-partum: 2 ml of the product (50 µg of lecirelin). - Induction of ovulation at the time of insemination in cases of short, silent heat or prolonged heat: 2 ml of the product (50 µg of lecirelin). - Induction of ovulation in cycling cows in association with artificial insemination to optimise the time of ovulation: 2 ml of the product (50 µg of lecirelin). After oestrus detection, the product should be administered at the time of the artificial insemination (AI) or up to 8 hours beforehand. No more than 20 hours should elapse between onset of observable oestrus and AI. - Induction and synchronisation of oestrus and ovulation in combination with prostaglandin F2α (PGF2α) or PGF2α analogue, with or without progesterone, as part of fixed time artificial insemination (FTAI) protocols: 2 ml of the product (50 µg of lecirelin). On the basis of results of clinical studies and scientific literature, lecirelin can be used in combination with prostaglandin F2α (PGF2α)/PGF2α analogue, with or without progesterone, in protocols of induction and synchronization of ovulation (e.g. OvSynch) with fixed time artificial insemination (AI) in cattle. The OvSynch (i.e. GnRH/prostaglandin/GnRH) protocol for breeding dairy cows at a pre-planned time without the need for specific heat detection is summarised below: Day 0 2 ml of the product (50 µg of lecirelin); Day 7 PGF2α/PGF2α analogue at luteolytic dose Day 9 2 ml of the product (50 µg of lecirelin). AI 16 - 20 hours after the second lecirelin injection, or at observed oestrus if sooner. The OvSynch protocol combined with progesterone supplementation for breeding dairy cows at a pre-planned time without the need for specific heat detection is summarised below: Day 0 Insert progesterone releasing intravaginal device Administer 2 ml of the product (50 µg of lecirelin); Day 7 Remove device. Administer PGF2α/PGF2α analogue at luteolytic dose; Day 9 2 ml of the product (50 µg of lecirelin). AI 16 - 20 hours after the second lecirelin injection, or at observed oestrus if sooner. Other protocols may be equally relevant in a given herd. Judgement on the protocol to be used should be made by the veterinarian responsible, on the basis of the characteristics of the individual herd. Rabbits: - Induction of ovulation: 0.2 ml. - Conception rate enhancement: 0.3 ml. Treatment may be administered 24 h postpartum. Mating or insemination must take place immediately after administration. 4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary. No adverse reactions were recorded in cattle with up to 3 times the recommended dose and in rabbits with up to 2 times the recommended dose. 4.11 Withdrawal period(s) Meat and offal: Zero days. Milk: Zero hours. 5 PHARMACOLOGICAL or IMMUNOLOGICAL PROPERTIES Pharmacotherapeutic group: -releasing hormones ATC Vet Code: QHO1CA92. 5.1 Pharmacodynamic properties Lecirelin is a synthetic analogue of gonadotropin releasing hormone (GnRH). It differs by substitution of D-tertiary leucine for glycine at position 6 and replacement of glycine by ethyl amide at position 10. Consequently, it is a nonapeptide. Due to structural differences between lecirelin and natural GnRH, the lecirelin molecule shows greater persistence at the site of the specific hypophyseal receptors. The physiological action of the gonadotropins results from stimulating the maturation of the follicle, inducing ovulation and the appearance of corpora lutea in the ovary. 5.2 Pharmacokinetic particulars Lecirelin, administered by the intramuscular route, is rapidly absorbed. Plasma elimination occurs rapidly, whilst the hormonal action persists for several hours, because of greater persistence in binding to the receptor site. However, pharmacokinetics is species and dose dependent. GnRH-analogues accumulate primarily in the liver, kidney and hypophysis whereupon they are metabolised enzymatically, producing compounds devoid of pharmacological activity, which are subsequently excreted in the urine. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Benzyl alcohol (E1519) - Glacial acetic acid (E 260) - Disodium phosphate dodecahydrate (E339ii) - Sodium chloride - Water for injections. 6.2 Major incompatibilities In the absence of compatibility studies, this veterinary medicinal product must not be mixed with other veterinary medicinal products. 6.3 Shelf-life Shelf life of the veterinary medicinal product as packaged for sale: 2 years. Shelf life after first opening the immediate packaging: 28 days. 6.4 Special precautions for storage. Do not store above 25 °C. 6.5 Nature and composition of immediate packaging 4-, 10- or 20-ml type I or type II neutral colourless glass vials, closed with a type I rubber stopper and an aluminium overseal, in a cardboard box. 100 ml High Density Polyethylene (HDPE) container closed with a type I rubber stiopper and an aluminium overseal, in a cardboard box. Package sizes: - 1 X 4-ml vial of product per box; - 10 X 4-ml vials of product per box; - 1 X 10-ml vial of product per box; - 5 X 10-ml vials of product per box; - 1 X 20-ml vial of product per box; - 1 X 100 ml collapsible container. Not all pack sizes may be marketed. 6.6 Special precautions for the disposal of unused veterinary medicinal products or waste materials derived from the use of such products Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal product should be disposed of in accordance with local requirements. 7 MARKETING AUTHORISATION HOLDER FATRO S.p.A. Via Emilia, 285 - 40064 Ozzano Emilia Bologna Italy. 8 MARKETING AUTHORISATION NUMBER(S) VPA 10836/002/001. 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 19th March 2004 Date of last renewal: 30th August 2008. 10 DATE OF REVISION OF THE TEXT April 2018.

WITHDRAWAL PERIODS Meat and offal:Cattle: 0 days Swine: 1 day DEXTROROTATORY CLOPROSTENOL Milk: 0 hours PACKS 20 ml vial 60x2 ml vials

Summary of Product Characteristics 1 NAME OF THE VETERINARY MEDICINAL PRODUCT Dalmazin 75 micrograms/ml solution for injection for cows and sows. 2 QUALITATIVE AND QUANTITATIVE COMPOSITION 1 ml contains: Active ingredient d-cloprostenol 75 μg. Excipients Chlorocresol 1.000 mg. For a full list of excipients, see section 6.1. 3 PHARMACEUTICAL FORM Solution for injection. Clear, colourless solution with no visible particles. 4 CLINICAL PARTICULARS 4.1 Target Species Cattle (cows) and Pigs (sows and gilts). 4.2 Indications for use, specifying the target species Cows: - Indications for reproduction: Synchronization or induction of oestrus. Induction of parturition after day 270 of gestation. - Therapeutic indications: Ovarian dysfunction (persistent corpus luteum, luteal cyst), endometritis/pyometra, delayed uterine involution, induction of abortion in the first half of pregnancy and expulsion of mummified foetuses. Sows: Indications for reproduction: Induction of parturition. 4.3 Contraindications Do not use in pregnant females, unless it is desirable to induce parturition or induction of abortion. Do not use in sows which are expected to have a distocic parturition due to abnormal position of the foetus, mechanical obstruction, etc. Do not use in animals suffering cardiovascular or respiratory diseases. Do not use in animals with spastic diseases of the respiratory or gastrointestinal tract. 4.4 Special warnings for each target species None. 4.5 Special precautions for use Special precautions for use in animals As with parenteral administration of any substance, basic antiseptic rules should be observed. The injection site must be thoroughly cleaned and disinfected in order to reduce the risk of infection with anaerobic bacteria. Induction of labour before the 111th day of gestation may cause mortality in piglets and an increase in the number of sows that require manual assistance. Do not administer by intravenous route. Special precautions to be taken by the person administering the veterinary medricinal product to animals Prostaglandins of the F2 type can be absorbed through the skin and may cause bronchospasm or miscarriage. Care should be taken when handling the product to avoid self-injection or skin contact. Women of child-bearing age, asthmatics and people with bronchial or other respiratory problems, should avoid contact with, or wear disposable plastic gloves when administering the product. Accidental spillage on the skin should be washed off immediately with soap and water. In case of accidental self injection seek medical advice and show the label to the physician. Should shortness of breath result from accidental inhalation or injection, seek urgent medical advice and show the doctor this warning. Do no eat, drink or smoke while handling the product. 4.6 Adverse reactions (frequency and seriousness) Occurrence of anaerobic infection is likely if anaerobic bacteria penetrate the tissue of the injection site. This applies especially to intramuscular injection and in particular to cows. Typical local reactions due to anaerobic infection are swelling and crepitus at the injection site. When used in cows for induction of parturition and dependent on the time of treatment relative to the date of conception, the incidence of retained placenta may be increased. Behavioural changes seen after treatment for induction of farrowing are similar to those changes associated with natural farrowing and usually cease within one hour. 4.7 Use during pregnancy, lactation or lay Do not use in gestating animals unless it is desirable to induce parturition or therapeutic induction of abortion. 4.8 Interaction with other medicinal products and other forms of interaction Do not administer the treatment together with non-steroidal anti-inflammatory drugs since they inhibit endogenous prostaglandin synthesis. The activity of other oxytocic agents can be increased after the administration of cloprostenol. 4.9 Amounts to be administered and administration route COWS: Administer 2 ml of DALMAZIN, equivalent to 150 micrograms of d-cloprostenol/animal by intramuscular route. Repeat after 11 days for the synchronisation of oestrus. The dose of 2 ml equivalent to 150 micrograms of d-cloprostenol/animal by intramuscular route can be repeated for the induction of oestrus and for the treatment of ovarian dysfunction, endometritis/pyometra delayed uterine involution. In particular: - Induction of oestrus (also in cows showing weak or silent heat): administer DALMAZIN after having established the presence of a corpus luteum (6-18th day of the cycle); heat usually appears within 48-60 hours. Proceed, therefore, with insemination 72-96 hours after injection. If oestrus is not evident, administration of the product needs to be repeated 11 days after the first injection. - Synchronisation of oestrus: administer DALMAZIN twice, with an interval of 11 days between each dose. Proceed therefore with two artificial inseminations at intervals of 72 and 96 hours from the second injection. - Induction of parturition: administer DALMAZIN after 270 days of pregnancy. Birth usually results within 30-60 hours of treatment. - Mummified foetus: expulsion of the foetus is observed within 3-4 days after administration of DALMAZIN. - Induction of abortion: administer DALMAZIN in the first half of pregnancy. - Ovarian dysfunction (persistent corpus luteum, luteal cysts): administer DALMAZIN, then proceed to inseminate at the first oestrus after injection. If oestrus is not evident, conduct a further gynaecological examination, and repeat the injection 11 days after the first administration. Insemination must always be carried out 72-96 hours after injection. - Endometritis, pyometra: administer DALMAZIN. If necessary repeat the treatment after 10-11 days. - Delayed uterine involution: administer DALMAZIN and, if considered necessary, carry out one or two successive treatments at 24 hour intervals. SOWS: Administer 1 ml of DALMAZIN, equivalent to 75 micrograms of d-cloprostenol/animal, by intramuscular route, not earlier than 112 days of pregnancy. Repeat after 6 hours. Alternatively, 20 hours after the initial dose of DALMAZIN, a myometrial stimulant (oxytocin or carazolol) may be administered. Following the protocol of the double administration, approximately 70-80% of the animals will give birth during the interval between 20 and 30 hours after the first administration. As with every prostaglandin-based product, injection in contaminated skin areas is to be avoided in order to reduce the risk of infection with anaerobic bacteria. The injection site must be thoroughly cleaned and disinfected before administration. 4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary. At 10 times the therapeutic dose, no adverse reactions were reported. In general, a large overdose could result in the following symptoms: increased pulse and breathing rate, bronchoconstriction, increased body temperature, increased amounts of loose faeces and urine, salivation and vomiting. As no specific antidote has been identified, in the case of overdose, symptomatic therapy is advisable. An overdose will not accelerate corpus luteum regression. 4.11 Withdrawal Period(s) Meat and offal: cattle Zero days. swine 1 day. Milk: Zero hours. 5 PHARMACOLOGICAL or IMMUNOLOGICAL PROPERTIES Pharmacotherapeutic group: prostaglandins ATC Vet Code: QG02AD90. 5.1 Pharmacodynamic properties DALMAZIN is a sterile aqueous solution containing 75 micrograms/ml of dextrorotatory cloprostenol, a synthetic analogue of the prostaglandin F2. d-cloprostenol, the dextrorotatory enantiomer, constitutes the biologically active component of the racemic cloprostenol molecule and results in an approximate 3.5-fold increase in activity. Administered in the luteal phase of the oestrus cycle, d-cloprostenol induces functional and morphological regression of the corpus luteum (luteolysis) resulting in a sharp fall in progesterone levels. The increased release of the follicle stimulating hormone (FSH), induces the follicular maturation followed by signs of oestrus and by ovulation. 5.2 Pharmacokinetic properties Pharmacokinetic studies demonstrate a rapid absorption of d-cloprostenol. The peak blood level is reached a few minutes following intramuscular administration, as well as a rapid diffusion to the ovaries and uterus, the organs in which the maximum concentration is reached 10-20 minutes after administration. Following intramuscular administration of 150 micrograms of d-cloprostenol in the cow, the peak plasma level (Cmax) of 1.4 micrograms/l is reached after approximately 90 minutes, while the elimination half life (t½) is in the order of 1 hour 37 minutes. In sows, a Cmax of approximately 2 micrograms/l is observed between 30 and 80 minutes following administration of 75 micrograms d-cloprostenol, with an elimination half life in the order of 3 hours 10 minutes. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Chlorocresol - ethanol - sodium hydroxide - anhydrous citric acid - water for injections. 6.2 Incompatibilities None known. 6.3 Shelf-life Shelf life of the veterinary medicinal product as packaged for sale: 3 years. Shelf life after first opening the immediate packaging: 28 days. 6.4 Special precautions for storage Do not store above 25°C. 6.5 Nature and composition of immediate packaging 2 ml, 10 ml, 20 ml vials in glass type I or type II, closed with a chlorobutyl rubber stopper with an aluminium overseal. Package sizes: one 2 ml vial of product per box + syringe; fifteen 2 ml vials of product per box; sixty 2 ml vials of product per box; one 10 ml vial of product per box; ten 10 ml vials of product per box; one 20 ml vial of product per box; five 20ml vials of product per box. Not all pack sizes may be marketed. 6.6 Special precautions for the disposal of unused veterinary medicinal products or waste materials. Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal product should be disposed of in accordance with local requirements. 7 MARKETING AUTHORISATION HOLDER FATRO S.p.A. Via Emilia, 285 Ozzano Emilia Bologna Italy. 8 MARKETING AUTHORISATION NUMBER(S) VPA: 10836/001/001. 9 DATE OF THE FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 28th June 2010. 10 DATE OF REVISION OF THE TEXT _____.

FATRO Veterinary Pharmaceutical Industry Duggan Veterinary Supplies Ltd. 40064 Ozzano Emilia (BO) - ITALY Holycross, Thurles, Co. Tipperary - E41A093, Ireland Tel. +39 051 6512711 - Fax +39 051 6512728 Tel. +353 (0)504 43169 - Fax +353 (0)504 43147 www.fatro.com - e-mail: [email protected] www.dugganvet.ie - e-mail: [email protected]