European Union - English - EMA (European Medicines Agency)

astrazeneca ab - selumetinib sulfate - neurofibromatosis 1 - antineoplastic agents - koselugo as monotherapy is indicated for the treatment of symptomatic, inoperable plexiform neurofibromas (pn) in paediatric patients with neurofibromatosis type 1 (nf1) aged 3 years and above

European Union - English - EMA (European Medicines Agency)

plusultra pharma gmbh - sirolimus - angiofibroma; tuberous sclerosis - hyftor is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis complex in adults and paediatric patients aged 6 years and older.

Nigeria - English - NAFDAC (National Agency for Food and Drugs Administration and Control)

vibunum opulus urtica dioca, hammamelis virginiana l. artium lappa, capsicum annum, kaolin

Israel - English - Ministry of Health

astrazeneca (israel) ltd - selumetinib as hyd-sulfate - hard capsule - selumetinib as hyd-sulfate 10 mg - selumetinib - koselugo is indicated for the treatment of pediatric patients 2 years of age and older withneurofibromatosis type 1 (nf1) who have symptomatic, inoperable plexiform neurofibromas (pn).

Israel - English - Ministry of Health

astrazeneca (israel) ltd - selumetinib as hyd-sulfate - hard capsule - selumetinib as hyd-sulfate 25 mg - selumetinib - koselugo is indicated for the treatment of pediatric patients 2 years of age and older withneurofibromatosis type 1 (nf1) who have symptomatic, inoperable plexiform neurofibromas (pn).

United Kingdom - English - VMD (Veterinary Medicines Directorate)

intervet uk ltd - rabbit fibroma virus -

United States - English - NLM (National Library of Medicine)

nobelpharma america, llc - sirolimus (unii: w36zg6ft64) (sirolimus - unii:w36zg6ft64) - hyftor is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients 6 years of age and older. hyftor is contraindicated in patients with a history of hypersensitivity to sirolimus or any other component of hyftor. reactions to sirolimus have included anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis [see warning and precautions (5.1)] . risk summary based on animal studies and mechanism of action, oral sirolimus can cause fetal harm when administered to a pregnant woman. hyftor is systemically absorbed after topical administration and may result in fetal exposure. the available data from case reports on hyftor use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. animal reproduction studies have not been conducted with hyftor. in an animal reproduction study, oral administration of 0.5 mg/kg/day sirolimus caused embryo-fetal lethality in pregnant rats when administered during the period of organogenesis (see data). the available data do not allow the calculation of relevant comparisons between the systemic exposure of sirolimus observed in animal studies to the systemic exposure that would be expected in humans after topical use of hyftor. the background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. data animal data in embryo-fetal development studies in rats, oral administration of sirolimus to pregnant rats during the period of organogenesis (gestation days 6 -15) induced embryo-fetal lethality at 0.5 mg/kg/day, reduced fetal body weight at 1.0 mg/kg/day and caused maternal toxicity at 2.0 mg/kg/day. no treatment related embryo-fetal developmental effects were observed at 0.1 mg/kg/day. in embryo-fetal development studies in rabbits, oral administration of sirolimus to pregnant rabbits during the period of organogenesis (gestation days 6 -18) induced maternal toxicity (decreased body weight) at 0.05 mg/kg/day, which was associated with embryo-fetal loss or early resorption. no treatment related developmental effects were observed at 0.025 mg/kg/day. in a pre- and postnatal development toxicity study, oral administration of sirolimus to pregnant rats during gestation and lactation (gestation day 6 through lactation day 20) increased the incidence of dead pups, resulting in reduced live litter size at 0.5 mg/kg/day. no treatment related developmental effects were observed at 0.1 mg/kg/day. sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg/day, the highest dose tested. risk summary there are no available data on the presence of sirolimus in human milk, the effects on the breastfed infant, or the effects on milk production. after oral administration, sirolimus was present in the milk of lactating rats. because of the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during treatment with hyftor. contraception based on animal studies with oral sirolimus, hyftor may cause fetal harm when administered to pregnant women. females of reproductive potential are recommended to avoid becoming pregnant and to use an effective contraceptive method. effective contraception should be initiated before hyftor therapy and used throughout treatment and for 12 weeks after the final dose of hyftor [see warnings and precautions (5.7), use in specific populations (8.1)] . infertility based on clinical findings and findings in animal studies, male and female fertility may be compromised by the treatment with sirolimus [see warnings and precautions (5.8), nonclinical toxicology (13.1)]. ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females with the use of oral sirolimus. azoospermia has been reported in males with the use of oral sirolimus and have been reversible upon discontinuation of sirolimus in most cases. the safety and effectiveness of hyftor have been established in pediatric patients aged 6 years and older for the topical treatment of facial angiofibroma associated with tuberous sclerosis. use of hyftor in this age group is supported by data from a randomized, vehicle-controlled, double-blind 12-week trial along with additional efficacy and long-term safety data from a 104-week open label safety trial. a total of 13 pediatric subjects aged 6 years to 17 years received hyftor in the phase 3 clinical trial along with 48 pediatric subjects aged 3 years to 17 years in the 104-week open label safety trial. adverse reactions occurred with similar frequency in adult and pediatric subjects [see adverse reaction (6.1), clinical studies (14)]. the safety and effectiveness of hyftor for this indication have not been established in pediatric patients less than 6 years of age. clinical studies of hyftor did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients.

United States - English - NLM (National Library of Medicine)

astrazeneca pharmaceuticals lp - selumetinib (unii: 6uh91i579u) (selumetinib - unii:6uh91i579u) - koselugo is indicated for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (nf1) who have symptomatic, inoperable plexiform neurofibromas (pn). none. risk summary based on findings from animal studies and its mechanism of action [see clinical pharmacology (12.1)] , koselugo can cause fetal harm when administered to a pregnant woman. there are no available data on the use of koselugo in pregnant women to evaluate drug-associated risk. in animal reproduction studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryofetal survival at exposures approximately > 5 times the human exposure at the clinical dose of 25 mg/m2 twice daily (see data ). advise pregnant women of the potential risk to the fetus. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. data animal data in embryo-fetal development studies in mice at doses > 2.5 mg/kg twice daily (~5-times the human exposure based on area under the curve [auc] at the clinical dose of 25 mg/m2 twice daily), selumetinib caused increases in post-implantation loss, a reduction in mean fetal and litter weights, and an increased occurrence of open eye and cleft palate, but did not induce significant maternal toxicity. administration of selumetinib to pregnant mice from gestation day 6 through lactation day 20 resulted in reduced pup body weights and fewer pups met the pupil constriction criterion on day 21 post-partum. the incidence of malformations (e.g., prematurely open eye(s) and cleft palate) was increased even at the lowest dose of 0.5 mg/kg twice daily (maternal maximal concentration [cmax ] of ~0.6 times the human cmax at the clinical dose of 25 mg/m2 twice daily). risk summary there are no data on the presence of selumetinib or its active metabolite in human milk or their effects on the breastfed child or milk production. selumetinib and its active metabolite were present in the milk of lactating mice (see data ). due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with koselugo and for 1 week after the last dose. data animal data selumetinib and its active metabolite were present in milk from mice dosed with selumetinib throughout gestation and lactation, with a mean plasma/milk ratio of 1.5 in lactating dams dosed at 5 mg/kg twice daily. administration of selumetinib to dams during gestation and early lactation was associated with adverse events in pups, including reduced growth rates and incidence of malformations [see use in specific populations (8.1)]. koselugo can cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1)] . pregnancy testing verify the pregnancy status of females of reproductive potential prior to initiating koselugo [see use in specific populations (8.1)] . contraception females advise females of reproductive potential to use effective contraception during treatment and for 1 week after the last dose. males advise male patients with female partners of reproductive potential to use effective contraception during treatment with koselugo and for 1 week after the last dose. the safety and effectiveness have been established in pediatric patients 2 years of age and older with nf1 who have inoperable pn and the information on this use is discussed throughout the labeling. the safety and effectiveness of koselugo have not been established in pediatric patients younger than 2 years of age. animal toxicity data in 3-month general toxicology studies, male rats receiving selumetinib at doses ≥ 10 mg/kg daily (~60-times the human exposure based on auc at the clinical dose of 25 mg/m2 twice daily) showed growth plate dysplasia. clinical studies did not include patients 65 years of age and older. no dose adjustment is recommended in patients with renal impairment or those with end stage renal disease [see clinical pharmacology (12.3)]. selumetinib exposures increased in patients with moderate or severe hepatic impairment [see clinical pharmacology (12.3)] . reduce the dose of koselugo for patients with moderate hepatic impairment (child-pugh b). a recommended dosage of koselugo for use in patients with severe hepatic impairment (child-pugh c) has not been established [see dosage and administration (2.3)] .

United States - English - NLM (National Library of Medicine)

recombinetics, inc. - sus scrofa g.(nc_010454.4)43530892c>t + 43530890_43530889insagctt in ossabaw miniature swine (unii: fy9nu6d8jd) (sus scrofa g.(nc_010454.4)43530892c>t + 43530890_43530889insagctt in ossabaw miniature swine - unii:fy9nu6d8jd) - limitations: this is a model of progressive disease. some of the disease symptoms associated with neurofibromatosis type i disease in humans take time to develop, and like the human disease, are variable in presentation from animal to animal. product use: model animals and/or materials derived from these animals are intended for purchase only under license agreement with recombinetics, inc., and solely for use in connection with the specific licensed biomedical research. conditions of use: this model animal and any products derived from it are for biomedical research purposes only and not for use in humans. this is an investigational animal. edible products of investigational animals are not to be used for food unless authorization has been granted by the u.s. food and drug administration or by the u.s. department of agriculture.

United States - English - NLM (National Library of Medicine)

recombinetics, inc. - sus scrofa (g.(nc_010454.4)43530860g>t + 43530872c>t + 43530892c>t + 43530899t>c) one copy in ossabaw breed miniature swine (unii: j64839n3eh) (sus scrofa (g.(nc_010454.4)43530860g>t + 43530872c>t + 43530892c>t + 43530899t>c) one copy in ossabaw breed miniature swine - unii:j64839n3eh) - limitations: this is a model of progressive disease. some of the disease symptoms associated with neurofibromatosis type i disease in humans take time to develop, and like the human disease, are variable in presentation from animal to animal. product use: model animals and/or materials derived from these animals are intended for purchase only under license agreement with recombinetics, inc., and solely for use in connection with the specific licensed biomedical research. conditions of use: this model animal and any products derived from it are for biomedical research purposes only and not for use in humans. this is an investigational animal. edible products of investigational animals are not to be used for food unless authorization has been granted by the u.s. food and drug administration or by the u.s. department of agriculture.