The European Agency for the Evaluation of Medicinal Products Veterinary Medicines and Information Technology EMEA/MRL/726/00-FINAL March 2000 COMMITTEE FOR VETERINARY MEDICINAL PRODUCTS SPECTINOMYCIN (cattle, pigs and poultry) SUMMARY REPORT (3) 1. Spectinomycin is an aminocyclitol antibiotic produced by Streptomyces spectabilis.Itexertsits bacteriostatic effect by binding to the 30S subunit of bacterial ribosomes and inhibiting the translation of protein synthesis. Spectinomycin is indicated for use via the oral and parenteral routes, often in conjunction with lincomycin, in the treatment of a variety of enteric, respiratory and other infections of cattle, sheep, pigs and poultry. In veterinary medicine spectinomycin is used as hydrocloride and sulphate salts. In cattle including lactating cows, products are given by intramuscular injection at a dosage of 30 mg/kg bw/day or subcutaneous injection at 15 mg/kg bw/day, in both cases for 5 consecutive days. In pigs, spectinomycin is administered in the diet at 22 mg/kg feed for 21 consecutive days or as an intramuscular injection of 11 mg/kg bw. In chickens, spectinomycin is administered orally in drinking water and feed at doses equivalent to 100 mg/kg bw/day for 3 to 7 days. Spectinomycin is currently entered into Annex III of Council Regulation (EEC) No 2377/90 in accordance with the following tables: Pharmacologically Marker residue Animal MRLs Target Other provisions active substance(s) species tissues Spectinomycin Spectinomycin Bovine, 300 µg/kg Muscle Provisional MRLs porcine, 500 µg/kg Fat expire on poultry 2000 µg/kg Liver 01.07.2000 5000 µg/kg Kidney Bovine 200 µg/kg Milk Pharmacologically Marker residue Animal MRLs Target Other provisions active substance(s) Species tissues Spectinomycin Spectinomycin Ovine 300 µg/kg Muscle Provisional MRLs 500 µg/kg Fat expire on 2000 µg/kg Liver 01.01.2002. 5000 µg/kg Kidney Not for use in Chicken 200 µg/kg Eggs animals producing milk for human consumption. Further data were provided to support the establishment of final MRLs for spectinomycin in respect of cattle, pigs and poultry. 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Switchboard (44-20-7) 418 8400 Fax (44-20-7) 418 8447 E-mail: [email protected] http://www.eudra.org/emea.html EMEA 2000 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged 2. Pharmacokinetic data indicate that absorption is poor via the oral route in humans and in animals, but rapid and extensive after intramuscular injection. After oral administration of 100 and 500 mg/kg bw to dogs, mean peak serum concentrations were around 22 µg/ml and 80 µg/ml, respectively. Spectinomycin is not extensively bound to proteins either in serum or in milk. Plasma elimination half lives range from 1 to 3 hours in various species (sheep, cattle, dogs and humans) when administered via the oral, intramuscular and intravenous routes. Following an intramuscular dose of 2 g or 4 g, the Cmax values in humans were approximately 103 mg/l, 1 hour after treatment and 160 mg/l, 2 hours after treatment, respectively. The half-life of plasma elimination ranged from 1.2 to 2.8 hours. After parenteral administration, spectinomycin is rapidly and extensively excreted in the urine. In humans, 70 to 100% of the administered dose is excreted unchanged in the urine within 48 hours after treatment. After oral administration, excretion is primarily in the faeces. The data available suggest that spectinomycin is not extensively metabolised in animals or in humans. In some studies in cattle, the metabolite dihydrospectinomycin, which has 10% of the microbiological activity of spectinomycin, was foundinliver. 3. Spectinomycin has low acute toxicity in mice, rats and dogs when administered by various routes. The acute oral and subcutaneous LD50 values were greater than 5000 mg/kg bw in rats. No signs of toxicity were observed in dogs given single doses of up to 270 mg/kg bw. 4. In numerous repeated dose studies where spectinomycin was administered by injection (intramuscular, intravenous, subcutaneous) the only significant findings were injection site reactions. Spectinomycin is irritant on intramuscular injection. Groups of TUC/SPD rats were given daily oral gavage doses of a 1:1 mixture of spectinomycin:lincomycin for 90 days. The most notable finding was a change in the consistency of the faeces. There were some minor changes in clinical chemistry parameters in the groups administered 300 and 1000 mg/kg bw/day but these did not correlate with any pathological changes. The NOEL was 100 mg/kg bw/day spectinomycin:lincomycin, equivalent to 50 mg spectinomycin/kg bw/day. Groups of Beagle dogs were given daily oral doses of 0, 100, 250, 500, 750 or 1000 mg spectinomycin/kg bw/day, in gelatin capsules, for 28 days. The only observed effect was an increase in soft faeces at the top dose level. The NOEL was 750 mg/kg bw/day. In another study, groups of Beagle dogs were given daily oral doses of 0, 100, 300 or 1000 mg/kg bw/day of a 1:1 mixture of spectinomycin:lincomycin, in gelatin capsules, for 90 days. Intermittent diarrhoea and soft faeces were the only significant findings. The NOEL was 100 mg/kg bw/day spectinomycin:lincomycin, equivalent to 50 mg spectinomycin/kg bw/day. 5. In a 3-generation reproduction study in Sprague-Dawley rats, doses equivalent to 0, 100, 200 or 400 mg/kg bw/day were administered in the diet. There were no adverse effects on reproductive parameters up to the highest dose administered. Hepatocellular changes, notably clumped basophilic material in the cytoplasm and hepatocellular swelling was noted in some animals in the F1b generation. The NOEL was 100 mg/kg bw/day. 6. Developmental toxicity was examined in mice, rats and rabbits. There was no evidence of teratogenicity or foetotoxicity in two studies in which pregnant ICR mice were treated intraperitoneally from days 7 to 12 of gestation, using dose levels of 0, 400 or 1600 mg/kg bw/day. There was no evidence of teratogenicity or foetotoxicity after oral administration of 0, 100 or 300 mg/kg bw/day to pregnant TUC/SPD rats or following oral administration of 0, 100, 300, 1000 or 3000 mg/kg bw/day to pregnant Sprague-Dawley rats from days 6 to 15 of gestation. The substance was not teratogenic in further studies in rats using intraperitoneal administration (0, 400 or 1600 mg/kg bw/day) or subcutaneous administration (0, 100, 300 mg/kg bw/day). In rabbits, litter size and weight were reduced following subcutaneous administration of 150 and 300 mg/kg bw/day from days 8 to 18 of gestation, but there was no evidence of teratogenicity. The substance was not teratogenic in two further studies in rabbits using intramuscular administration (0, 100 and 300 mg/kg bw/day and 0 and 100 mg/kg bw/day). 2/8 EMEA 2000 7. Spectinomycin was not mutagenic in a range of well conducted in vivo and in vitro tests. These included in vitro assays for gene mutation in Salmonella typhimurium TA98a, TA98, TA100, TA102, TA1535, TA1537 and TA1538 and in Chinese Hamster Ovary cell lines CHO-K1-BH4 (HPRT locus) and AS52 (XGPT locus). Negative results were also obtained in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes and in an in vitro chromosomal aberration assay in human lymphocytes. In an in vivo bone marrow micronucleus test groups of Sprague-Dawley rats were given intraperitoneal doses of 750, 1500 or 3000 mg spectinomycin/kg bw, as 2 half doses, 24 hours apart and killed 30 or 48 hours after the first dose. CD-1 mice were given intraperitoneal doses of up to 2500 mg/kg bw and killed 24, 48 or 72 hours later. The incidence of micronucleated polychromatic erythrocytes was not increased in either study. 8. No carcinogenicity studies were carried out. Such studies were not considered necessary due to the negative results in the mutagenicity assays, the absence of structurally-alerting features and the lack of pre-neoplastic lesions in the repeated dose toxicity studies. 9. Groups of cats were given daily intramuscular injections of 0, 30, 60 or 120 mg/kg bw/day for 75 to 90 days. Tests for cochlear function were carried out twice weekly. No abnormalities were found and there was no evidence of reduced eighth nerve function. In another study, tests for cochlear and vestibular function indicated no signs of ototoxicity in 15 healthy male volunteers given daily intramuscular injections of 8 mg spectinomycin/day, (equivalent to 130 mg/kg bw/day) for 21 days. 10. Spectinomycin is used in human medicine for the treatment of gonorrhoea. It is normally administered by intramuscular injection to adults at a dose of 2 g or 4 g or to children at a dose of 40 mg/kg bw. The most common adverse reactions were reported to be soreness at the injection site, urticaria, dizziness, nausea, chills and fever. Anaphylaxis was reported to be rare. Spectinomycin did not cross react with penicillins in human clinical trials. 11. The repeated dose toxicity studies conducted on spectinomycin were performed using the substance alone or in combination with lincomycin. The lowest NOEL identified using spectinomycin alone was 100 mg/kg bw in a rat dietary reproduction study. In combination with lincomycin, the lowest NOEL was 50 mg spectinomycin/kg bw in 90-day studies in rats and dogs. A conservative toxicological ADI of 0.25 mg/kg bw can be established, using a safety factor of 200 to account for the combined use of the substances. 12. The potential for adverse effects on the human gut flora was studied in vitro in a wide range of organisms including both animal and human pathogens.