Panama - English - Ministerio de Salud (Dirección Nacional de Farmacia Y Drogas)

ipsen pharma - triptorelina (pamoato) - triptorelina (pamoato)....11.25 mg / manitol....0.016 g / agua para inyecciÓn....2.000 g

Panama - English - Ministerio de Salud (Dirección Nacional de Farmacia Y Drogas)

ipsen pharma - triptorelina (acetato) - triptorelina (acetato)....3.75 mg / manitol....0.016 g / agua para inyecciÓn....2.0 g

Ireland - English - HPRA (Health Products Regulatory Authority)

syn vet-pharma ireland limited - gonadorelin acetate - solution for injection - 50.0 microgram(s)/millilitre - gonadorelin

Ireland - English - HPRA (Health Products Regulatory Authority)

syn vet-pharma ireland limited - progesterone - vaginal delivery system - 1.0 gram(s) - progesterone

Ireland - English - HPRA (Health Products Regulatory Authority)

syn vet-pharma ireland limited - gonadotrophin, equine serum, for veterinary use - lyophilisate and solvent for solution for injection - 200 international unit(s)/millilitre - serum gonadotrophin

European Union - English - EMA (European Medicines Agency)

tmc pharma (eu) limited - fosdenopterin hydrobromide dihydrate - metal metabolism, inborn errors - other alimentary tract and metabolism products, - nulibry is indicated for the treatment of patients with molybdenum cofactor deficiency (mocd) type a.

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

aquabounty technologies, inc. - atlantic salmon transgenic whole (opafp-ghc2 rdna construct inserted into .alpha.-locus in the eo-1.alpha. lineage) (unii: ec8tzl340i) (atlantic salmon transgenic whole (opafp-ghc2 rdna construct inserted into .alpha.-locus in the eo-1.alpha. lineage)atlantic salmon transgenic whole (opafp-ghc2 rdna construct inserted into .alpha.-locus in the eo-1.alpha. lineage) - unii:ec8tzl340i) - atlantic salmon transgenic whole (opafp-ghc2 rdna construct inserted into .alpha.-locus in the eo-1.alpha. lineage)atlantic salmon transgenic whole (opafp-ghc2 rdna construct inserted into .alpha.-locus in the eo-1.alpha. lineage) 1 [amb'a'1'u] in 1 [amb'a'1'u] - 1. product definition 1.1 identity a single copy of the -form of the opafp-ghc2 recombinant dna construct at the -locus in the eo-1 lineage of triploid, hemizygous, all-female atlantic salmon (salmo salar) known as aquadvantage salmon. 1.2 claim significantly more aquadvantage salmon grow to at least 100 g within 2700°c-days than their comparators. 1.3 limitations aquadvantage salmon are produced as eyed-eggs and grown-out only in physically-contained, freshwater culture facilities specified in an fda-approved application. 2. product use 2.1 initial receipt remove the exterior cardboard packaging from the shipping container, then clean and disinfect the outside of the interior plastic crate before bringing it into the culture facility. open the plastic crate in an area that is designated for egg receipt, and remove the eggs for disinfection as described in §2.2. dispose of all packaging and the empty egg trays according to local regulations. 2.2 handling & disinfection important:this product was disinfected prior to packaging for shipment. if egg hatch has initiated during transit, do not subject to further disinfection as described below. open the plastic crate and determine the temperature of the eggs in the top and bottom trays. if the egg temperature is greater than that of the receiving water by 2°c, slowly equilbrate the eggs to the receiving temperature by pouring receiving water gently over the eggs until the difference is less than 2°c disinfect the eggs in accordance with local regulations; following disinfection, rinse the eggs gently but thoroughly in running water at the receiving temperature before placing them in incubators. 2.3 incubation & hatch in a vertically-stacked heath type incubator system, stock no more than 10,000 eggs in a single tray, preferably in a single layer. adjust water flow to ~10 l/min and maintain egg-incubation temperature at ~6-8°c.* clean the individual trays, removing dead eggs, a minimum of twice per week. following hatch, use a substrate when alevin become more active, typically at ~20% yolk sac absorption. * eggs may be incubated at water temperatures lower than the range stated for the purpose of delaying hatch. 2.4 first-feeding & initial culture before yolk sac absorption is complete, transfer the alevin to tanks appropriate for 1st-feeding and gradually increase water temperature to a maximum of ~15-16°c. when the yolk sac is fully absorbed, increase water flow rate to ~20 l/min. aquadvantage salmon grow very rapidly at this life stage. for maximum growth performance: it is recommended to use freshwater flow-through, rather than recirculation, until they are feeding well; increase the number of hours of light to 24 hours in a period of 5 7 days; and, feed to satiety at least once per hour using a manual and automated feeding system and appropriate pellet size, which will change several times during the first 2-3 months. if capabilities do not allow for optimum conditions, feed fry to satiety a minimum of six times, and preferably once per hour, during operational day-length. in either scenario, flushexcess feed from tanks once a day. observe fry carefully during this period for any change in behavior, which could indicate a deterioration of culture conditions that might lead to unnecessary mortality. it is recommended to grade these fish as needed; taking into account the accelerated growth of these fish. 2.5 grow-out & processing transfer fry to larger tanks for grow-out at a body weight consistent with established practices. to optimize growth performance, maintain dissolved oxygen content at a minimum value of 7 mg/l and stocking density at a value less than the maximum sustainable under local culture conditions. feed fish to satiety a minimum of twice per day according to manufacturers guidelines using a high-fat commercial diet of appropriate pellet-size; automatic feeders are recommended. important:you must euthanizeaquadvantage salmon before they leave the grow-out facility for processing. 3. conditions of use rear only in contained, freshwater culture facilities specified in an fda-approved application. do not grow aquadvantage salmon in net pens or release them into the environment. dispose of dead or morbid fish in a manner consistent with local regulations. 4. growth performance in a controlled study conducted for 2700°c-days after first-feeding, aquadvantage salmon and diploid comparators achieved average body weights of 261.0 g and 73.6 g, respectively; the proportion of individual aquadvantage salmon with a body weight greater than 100 g was 98.6% compared to 4.9% for the comparators. these differences in average body weight and proportion of fish weighing more than 100 g at 2700°c-days were significant (p < 0.0001). growth performance at 2700°c-days salmon 5. animal safety in a controlled study, some juvenile aquadvantage salmon exhibited changes in gross morphology similar in number and severity to those observed in diploid comparator salmon; these changes most often affected the operculum and gill structure, jaw, or fins. the degree of change from a perfectly-formed fish was ranked as none, slight, moderate, or severe; the vast majority of these malformations were regarded as slight. no remarkable differences were observed in the morphology of internal body structures or relative organ weights. gross morphologic change in juveniles aquadvantage salmon comparator diploid salmon (n) (%) (n) (%) none 150 89.8 156 83.4 slight 12 7.2 31 16.6 moderate 4 2.4 severe 1 0.6 totals 167 100.0 187 100.0 based on a sampling and assessment of three batches of pre-smolt (~20-60 g) fish from the 2010 and 2012 year classes of aquadvantage salmon, the following types and rates of gross morphologic irregularities were observed: % spinal % jaw % operculum % other moderate irregularities 0 - 4.3 0.1 – 1.4 0 - 5.6 0 - 2.5 severe irregularities1 0 - 0.4 1 severe irregularities are those which could have a significant impact on viability or render the fish unfit for commercial sale. based on data collected on the 2008-2012 year classes of aquadvantage salmon, the following tables present reported typical ranges for mortality and morbidity, respectively, on a monthly basis for different life-stages. mortality observed in aquadvantage salmon by life-stage on a monthly basis1 life stage approximate time period post first feeding in months range of % mortality on a monthly basis eggs and yolk-sac fry 2.2 to 5.1 fry from first feeding to 5 g size ~1 to 2 1.0 to 9.8 pre-smolt ~3 to 5 0.1 to 4.0 juveniles ~6 to 11 0.1 to 1.8 late juveniles to adults ~12 to 24 0.2 to 5.2 1 non-representative high values due to one-time events or atypical conditions have been excluded. morbidity observed in aquadvantage salmon by life-stage on a monthly basis1 life stage approximate time period post first feeding in months range of % morbidity on a monthly basis eggs and yolk-sac fry fry from first feeding to 5 g size ~1 to 2 0 to 0.4 pre-smolt ~3 to 5 0 to 3.2 juveniles ~6 to 11 0 to 2.2 late juveniles to adults ~12 to 24 0 to 3.4 1 observations made on fish that were eventually discarded, which included moribund fish with actual or presumptive disease conditions, those with gross morphological irregularities, and fish of inappropriate size. document and report substantial increases in morbidity, mortality, or incidence of gross morphologic change in aquadvantage salmon as soon as possible to customer support at aquabounty technologies. manufactured, packaged & distributed by aquabounty canada, inc., a wholly-owned subsidiary of aquabounty technologies, inc. approved by fda under nada # 141-454. for more information, contact: customer support 877-824-8544 aquabounty technologies, inc. www.aquabounty.com 233 ayer road ste 4 harvard, ma 01451 usa 1. definición de producto 1.1 identidad una sola copia de la forma-a de unidad compuesta de adn recombinante opafp-ghc2 en el locus-a de la línea eo-1a del salmón atlántico (salmo salar), triploide, hemicigoto y 100% hembra, conocido como salmón aquadvantage. 1.2. aseveración la proporción de salmones aquadvantage que llega a alcanzar 100 gramos o más a los 2700°c-día, es significativamente mayor que los salmones atlánticos comparables. 1.3. restricciones el salmón aquadvantage es producido como ova con ojo y criado únicamente en sistemas cerrados de agua dulce especificados en una solicitud aprobada por el u.s. fda. 2. uso del producto 2.1. recepción inicial remueva el empaque exterior de cartón del contenedor de envío. luego limpie y desinfecte el exterior del contenedor de plástico antes de ingresarlo a la instalación de cultivo. abra el contenedor de plástico en un área designada para la recepción de ovas y remueva las ovas para realizar la desinfección descrita en el punto 2.2. disponga todo el material de empaque y bandejas de ovas vacías acorde a las regulaciones locales. 2.2 manejo y desinfección importante: este producto fue desinfectado previo a su empaque para transporte. si el proceso de eclosión se ha iniciado durante el tránsito, no proceda con la desinfección descrita más abajo. abra la caja de plástico y mida la temperatura de las ovas tanto en la bandeja superior como inferior. si la temperatura de las ovas es 2°c que la temperatura de recepción del agua, iguale lentamente las ovas a la temperatura de recepción, vertiendo suavemente el agua de recepción sobre las ovas hasta que esta diferencia sea menor a 2°c. desinfecte las ovas de acuerdo a las regulaciones locales. después de la desinfección, proceda a lavar las ovas suave pero minuciosamente con agua corriendo a la temperatura de recepción antes de colocarlas en las incubadoras. 2.3 incubación y eclosión considerando un sistema de incubación vertical, coloque no más de 10.000 ovas por bandeja, preferentemente en una capa. ajuste el flujo de agua a ~10 l/min y mantenga la temperatura de a ~6-8°c.* limpie las bandejas individuales, removiendo las ovas muertas, al menos 2 veces por semana. a continuación de la eclosión, use sustratos cuando los alevines estén más activos, típicamente cuando hayan absorbido el ~20% del saco vitelino. * las ovas pueden ser incubadas a temperaturas menores a las indicadas con el propósito de retardar la eclosión. 2.4. primera alimentación y cultivo inicial antes de que el saco vitelino se haya absorbido completamente, transfiera los alevines a tanques apropiados para primera alimentación y gradualmente incremente la temperatura hasta un máximo de ~15-16°c. cuando el saco vitelino este completamente absorbido, incremente el flujo de agua a ~20 l/min. el salmon aquadvantage crece en forma muy rápida en esta etapa de vida. para un máximo crecimiento: es recommendable utilice agua dulce con flujo abierto, en vez de recirculación, hasta que estos estén alimentándose adecuadamente. incremente el numero de horas de luz hasta alcanzar un ciclo de 24 horas luz continua en un periodo de 5 7 dias desde primera alimentracion. alimente a los peces a mano o utilizando un sistema de alimentacion automatico, alimente a saciedad utilizando el adecuando tamaño de pellet, el cual cambiará varias veces durante los 2-3 primeros meses. si las capacidades no permiten óptimas condiciones, alimente los alevines a saciedad un mínimo de 6 veces por día, preferentemente cada hora, durante la jornada diaria de trabajo. bajo cualquier escenario, descargue de los tanques el exceso de alimento al menos una vez al día. durante este periodo, observe los alevines cuidadosamente de tal manera de detectar cambios de comportamiento que pudieran indicar deterioros en las condiciones de cultivo que pueden conllevar mortalidades innecesarias. se recomienda graduar acorde a necesidad teniendo en cuenta el crecimiento acelerado de estos peces. 2.5. engorda y proceso transfiera los alevines a tanques más grandes para su engorde, acorde a prácticas establecidas. para optimizar el crecimiento mantenga el nivel de oxígeno disuelto en un valor mínimo de 7 mg/l y densidades de cultivo menores a las condiciones máximas de cultivo local sustentable. alimente a los peces a saciedad, mínimo dos veces al día acorde a las recomendaciones de los proveedores de alimento, usando dietas altas en lípidos, tamaños de pellets adecuados y sistemas de alimentación automáticos. importante: los salmones aquadvantage deben ser sacrificados antes de salir de las instalaciones de cultivo para ser procesados. 3. condiciones de uso sólo para ser cultivados en sistemas de agua dulce, especificados en una solicitud aprobada por el u.s. fda. no cultive los salmones aquadvantage en redes - jaulas ni los libere al medio ambiente. disponga los peces muertos o moribundos acorde a las regulaciones locales. 4. crecimiento en un estudio bajo condiciones controladas desarrollado por 2700°c-día después de primera alimentación, los salmones aquadvantage y los diploides comparables, obtuvieron un peso de 261.0 g. y 73.6 g. respectivamente. además, la proporción de individuos aquadvantage con un peso superior a 100 g fue de 98.6% en comparación con 4.9% de sus similares no transgénicos. estas diferencias en promedio de peso y proporción de peces con pesos mayores a 100 g a los 2700°c-día son estadísticamente significativas (p < 0.0001). crecimiento a los 2700°c-día salmón aquadvantage salmón diploide comparable número de peces 369 306 peso promedio (g)  ± es 261.0 ± 3.3 72.6 ± 1.0 rango de peso 16.9 - 426.3 11.0 - 118.0 peces >100 g (%) 364 (98.6) 15 (4.9) 5. seguridad animal en un estudio controlado, algunos juveniles de salmón aquadvantage presentaron cambios morfológicos similares en número y severidad a los observados en salmones diploides no transgénicos: estos cambios en la mayoría de los casos afectaron a los opérculos, branquias, mandíbula o aletas. el grado de cambio morfológico puede variar entre no existente, ligero, moderado o severo. en el caso de los salmones aquadvantage es considerado como leve. no se observaron diferencias marcadas en la morfología interna o peso relativo de órganos. cambios morfológicos generales en juveniles salmón aquadvantage salmón diploide comparable (n) (%) (n) (%) ninguno 150 89.8 156 83.4 leve 12 7.2 31 16.6 moderado 4 2.4 severo 1 0.6 totales 167 100.0 187 100.0 basado en muestreos y evaluaciones de tres grupos de peces pre-smolt (~20-60 g) de las generaciones de los anos 2010 y 2012 del salmón aquadvantage, se observaron los siguientes tipos y porcentajes de evidentes irregularidades morfológicas: % columna vertebral % mandibula % operculo % otros irregularidades moderadas 0 - 4.3 0.1 – 1.4 0 - 5.6 0 - 2.5 irregularidades severas1 0 - 0.4 1 irregularidades severas son aquellas que pueden tener un impacto significativo sobre la viabilidad o valor comercial de los peces. las siguientes tablas - basadas en los datos recogidos de las generaciones de los anos 2008-2012 del salmón aquadvantage -presentan los rangos típicos mensuales de mortalidad y morbididad observadas en las diferentes etapas de vida. mortalidad mensual, por etapa de vida, observada en el salmón aquadvantage 1 etapa de vida periodo de tiempo aproximado (en meses) despues de primera alimentacion rango  de mortalidad por mes (%) ovas y alevines de saco 2.2 - 5.1 alevines – desde primera alimentación hasta 5 g ~1 - 2 1.0 - 9.8 pre-smolt ~3 - 5 0.1 - 4.0 juveniles ~6 - 11 0.1 - 1.8 pre-adulto hasta adulto ~12 - 24 0.2 - 5.2 1 valores altos no-representativos resultando de eventos singulares o condiciones atipicas han sido excluidos.     morbididad mensual, por etapa de vida, observada en el salmón aquadvantage 1 etapa de vida periodo de tiempo aproximado (en meses) despues de primera alimentacion rango de mortalidad por mes (%) ovas y alevines de saco alevines – desde primera alimentación hasta 5 g ~1 - 2 0 – 0.4 pre-smolt ~3 - 5 0 – 3.2 juveniles ~6 -11 0 – 2.2 pre-adulto hasta adulto ~12 - 24 0 – 3.4 1  observaciones realizadas en peces que luego fueron eventualmente descartados, incluyendo peces moribundos con signos evidentes o presuntos de enfermedad, peces con reales irregularidades morfologicas y peces de un tamano inapropriado. registre y reporte incrementos sustanciales de morbilidad, mortalidad o incidencia de cambios morfológicos generales en los salmones aquadvantage tan pronto como sea posible a servicios al cliente de aquabounty technologies. producido, empacado y distribuido por aquabounty canadá, subsidiario de aquabounty technologies inc. aprobado por la fda bajo nada # 141-454. para mayor información contacte a: servicio al cliente 877-824-8544 aquabounty technologies, inc. www.aquabounty.com 233 ayer road ste 4 harvard, ma 01451 usa

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

viiv healthcare company - cabotegravir sodium (unii: 3l12pt535m) (cabotegravir - unii:hmh0132z1q) -       vocabria is indicated in combination with edurant (rilpivirine) tablets for short-term treatment of hiv-1 infection in adults and adolescents 12 years of age and older and weighing at least 35 kg who are virologically suppressed (hiv-1 rna <50 copies/ml) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine, for use as [see microbiology (12.4), clinical studies (14.1)] : vocabria is indicated in at-risk adults and adolescents weighing at least 35 kg for short-term pre-exposure prophylaxis (prep) to reduce the risk of sexually acquired hiv-1 infection. individuals must have a negative hiv-1 test prior to initiating vocabria for hiv-1 prep. vocabria may be used as [see dosage and administration (2.2), contraindications (4), warnings and precautions (5.1), clinical studies (14.2)] : treatment of hiv-1 infection vocabria is contraindicated in patients: prior to initiation of vocabria, note that use of cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) with rifabutin is contraindicated. since vocabria is taken in combination with edurant tablets, the prescribing information for edurant should be consulted for additional contraindications. hiv-1 pre-exposure prophylaxis vocabria is contraindicated in individuals: pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to vocabria during pregnancy. healthcare providers are encouraged to register patients by calling the antiretroviral pregnancy registry (apr) at 1-800-258-4263. risk summary there are insufficient human data on the use of vocabria during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. while there are insufficient human data to assess the risk of neural tube defects (ntds) with exposure to vocabria during pregnancy, ntds were associated with dolutegravir, another integrase inhibitor. discuss the benefit-risk of using vocabria with individuals of childbearing potential or during pregnancy. the apr has been established to monitor for birth defects following prenatal exposure to antiretrovirals. the rate of miscarriage is not reported in the apr. the background risk for major birth defects and miscarriage for the indicated population is unknown. the background rate for major birth defects in a united states (u.s.) reference population of the metropolitan atlanta congenital defects program (macdp) is 2.7%. the estimated background rate of miscarriage in clinically recognized pregnancies in the u.s. general population is 15% to 20%. the apr uses the macdp as the u.s. reference population for birth defects in the general population. the macdp evaluates mothers and infants from a limited geographic area and does not include outcomes for births that occurred at <20 weeks’ gestation. in animal reproduction studies with oral cabotegravir, a delay in the onset of parturition and increased stillbirths and neonatal deaths were observed in a rat pre- and postnatal development study at >28 times the exposure at the recommended human dose (rhd). no evidence of adverse developmental outcomes was observed with oral cabotegravir in rats or rabbits (>28 times or similar to the exposure at the rhd, respectively) given during organogenesis (see data) . data human data: data from a birth outcome surveillance study in botswana showed that dolutegravir, another integrase inhibitor, was associated with increased risk of ntds when administered at the time of conception and in early pregnancy. data from clinical trials are insufficient to address this risk with cabotegravir. animal data: cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from 15 days before cohabitation, during cohabitation, and from gestation days 0 to 17. there were no effects on fetal viability when fetuses were delivered by caesarean, although a minor decrease in fetal body weight was observed at 1,000 mg/kg/day (>28 times the exposure in humans at the rhd). no drug-related fetal toxicities were observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the rhd), and no drug-related fetal malformations were observed at any dose. cabotegravir was administered orally to pregnant rabbits at 0, 30, 500, or 2,000 mg/kg/day from gestation days 7 to 19. no drug-related fetal toxicities were observed at 2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the rhd). in a rat pre- and postnatal development study, cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from gestation day 6 to lactation day 21. a delay in the onset of parturition and increases in the number of stillbirths and neonatal deaths by lactation day 4 were observed at 1,000 mg/kg/day (>28 times the exposure in humans at the rhd); there were no alterations to growth and development of surviving offspring. in a cross-fostering study, similar incidences of stillbirths and early postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were nursed from birth by control mothers. there was no effect on neonatal survival of control pups nursed from birth by cabotegravir-treated mothers. a lower dose of 5 mg/kg/day (13 times the exposure at the rhd) was not associated with delayed parturition or neonatal mortality in rats. studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in fetal tissue. risk summary there are no data on the presence of cabotegravir in human milk, the effects on the breastfed infant, or the effects on milk production. cabotegravir is present in animal milk (see data) . when a drug is present in animal milk, it is likely that the drug will be present in human milk. potential risks of breastfeeding include: (1) hiv‑1 transmission (in hiv-1–negative infants), (2) developing viral resistance (in hiv-1–positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults. in hiv-1–uninfected mothers, the developmental and health benefits of breastfeeding and the mother’s clinical need for vocabria for hiv-1 prep should be considered along with any potential adverse reactions on the breastfed child from vocabria and the risk of hiv-1 acquisition due to nonadherence and subsequent mother to child transmission. mothers should not breastfeed if acute hiv-1 infection is suspected because of the risk of hiv-1 transmission to the infant. data animal lactation studies with cabotegravir have not been conducted. however, cabotegravir was detected in the plasma of nursing pups on lactation day 10 in the rat pre- and postnatal development study. treatment of hiv-1 infection the safety and effectiveness of vocabria have been established in adolescents aged 12 to younger than 18 years and weighing at least 35 kg, which is supported by the following: mocha trial the safety, tolerability, and pharmacokinetics of oral and injectable cabotegravir and oral and injectable rilpivirine are being assessed in an ongoing phase 1/2 multicenter, open-label, non-comparative study, mocha (impaact 2017). data are available from the week 16 interim analysis from mocha. the primary objective at week 16 was to confirm the use of the adult dose, through the evaluation of safety and pharmacokinetics, for oral and injectable cabotegravir and injectable rilpivirine in 23 hiv-1–infected virologically suppressed adolescents (aged 12 to younger than 18 years and weighing at least 35 kg) receiving background antiretroviral therapy. a total of 8 hiv-1–infected pediatric participants 12 years of age and older and weighing at least 35 kg and receiving background antiretroviral therapy received oral cabotegravir. the safety of vocabria in adolescents is expected to be similar to adults, as there was no clinically significant difference in drug exposure [see adverse reactions (6.1), clinical pharmacology (12.3)] . please refer to the cabenuva prescribing information for additional information. the safety, efficacy, and pharmacokinetics of vocabria have not been established in pediatric patients younger than 12 years of age or weighing <35 kg. hiv-1 pre-exposure prophylaxis the safety and effectiveness of vocabria for hiv-1 prep in at-risk adolescents weighing at least 35 kg is supported by data from 2 adequate and well-controlled trials of vocabria for hiv-1 prep in adults with additional safety and pharmacokinetic data from studies in hiv-1–infected adults who were administered cabenuva and in hiv-1–infected pediatric subjects who were administered separate components of cabenuva in addition to their current antiretroviral therapy [see dosage and administration (2.2), adverse reactions (6.1), clinical pharmacology (12.3), clinical studies (14.2)] . apretude for hiv-1 prep is being evaluated in 2 open-label multicenter clinical trials in adolescent individuals. fifty-nine adolescents have been enrolled. of these, 54 adolescent participants received one or more injections after receiving vocabria. in adolescents receiving vocabria and apretude for hiv-1 prep, the safety data were comparable to the safety data reported in adults receiving apretude for hiv-1 prep. while using apretude, hiv-1 testing should be conducted prior to initiating apretude (with or without an oral lead-in with oral cabotegravir) and prior to each injection of apretude. adolescents may benefit from more frequent visits and counseling to support adherence to the dosing schedule [see dosage and administration (2.2), warnings and precautions (5.1)]. the safety, efficacy, and pharmacokinetics of vocabria in pediatric participants younger than 12 years of age or weighing <35 kg have not been established. clinical trials of vocabria did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. in general, caution should be exercised in administration of vocabria in elderly patients, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy [see clinical pharmacology (12.3)] . no dosage adjustment of vocabria is necessary for patients with mild to moderate (creatinine clearance equal to 30 ml/min to <90 ml/min) or severe renal impairment (creatinine clearance <30 ml/min) [see clinical pharmacology (12.3)] . the effect of end-stage renal disease (creatinine clearance <15 ml/min) on the pharmacokinetics of cabotegravir is unknown. as cabotegravir is >99% protein bound, dialysis is not expected to alter exposures of cabotegravir. since vocabria is taken in combination with edurant for the treatment of hiv-1 infection, the prescribing information for edurant should be consulted for additional recommendations in patients with severe impairment or end-stage renal disease. no dosage adjustment of vocabria is necessary for patients with mild or moderate hepatic impairment (child-pugh a or b). the effect of severe hepatic impairment (child-pugh c) on the pharmacokinetics of cabotegravir is unknown [see clinical pharmacology (12.3)] .

Australia - English - Department of Health (Therapeutic Goods Administration)

gilead sciences pty ltd - tenofovir disoproxil fumarate; rilpivirine hydrochloride; emtricitabine -

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

viiv healthcare company - cabotegravir (unii: hmh0132z1q) (cabotegravir - unii:hmh0132z1q) - cabenuva is indicated as a complete regimen for the treatment of hiv-1 infection in adults and adolescents 12 years of age and older and weighing at least 35 kg to replace the current antiretroviral regimen in those who are virologically suppressed (hiv-1 rna <50 copies/ml) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine [see microbiology (12.4), clinical studies (14.1)] . cabenuva is contraindicated in patients: pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to cabenuva during pregnancy. healthcare providers are encouraged to register patients by calling the antiretroviral pregnancy registry (apr) at 1-800-258-4263. risk summary there are insufficient human data on the use of cabenuva during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. while there are insufficient human data to assess the risk of neural tube defects (ntds) with exposure to cabenuva during pregnancy, ntds were associated with dolutegravir, another integrase inhibitor. discuss the benefit-risk of using cabenuva with individuals of childbearing potential or during pregnancy. cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of cabenuva; therefore, consideration should be given to the potential for fetal exposure during pregnancy [see warnings and precautions (5.6), drug interactions (7.2)] . cabotegravir use in pregnant individuals has not been evaluated. available data from the apr show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in a united states (u.s.) reference population of the metropolitan atlanta congenital defects program (macdp) (see data) . the rate of miscarriage is not reported in the apr. the background risk for major birth defects and miscarriage for the indicated population is unknown. the background rate for major birth defects in a u.s. reference population of the macdp is 2.7%. the estimated background rate of miscarriage in clinically recognized pregnancies in the u.s. general population is 15% to 20%. the apr uses the macdp as the u.s. reference population for birth defects in the general population. the macdp evaluates mothers and infants from a limited geographic area and does not include outcomes for births that occurred at <20 weeks’ gestation. in animal reproduction studies with oral cabotegravir, a delay in the onset of parturition and increased stillbirths and neonatal deaths were observed in a rat pre- and postnatal development study at >28 times the exposure at the recommended human dose (rhd). no evidence of adverse developmental outcomes was observed with oral cabotegravir in rats or rabbits (>28 times or similar to the exposure at the rhd, respectively) given during organogenesis (see data) . no adverse developmental outcomes were observed when rilpivirine was administered orally at exposures 15 (rats) and 70 (rabbits) times the exposure in humans at the rhd (see data) . clinical considerations lower exposures with oral rilpivirine were observed during pregnancy. viral load should be monitored closely if the patient remains on cabenuva during pregnancy. cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of cabenuva; therefore, consideration should be given to the potential for fetal exposure during pregnancy [see warnings and precautions (5.6)] . data human data: cabotegravir: data from a birth outcome surveillance study in botswana showed that dolutegravir, another integrase inhibitor, was associated with increased risk of ntds when administered at the time of conception and in early pregnancy. data from clinical trials are insufficient to address this risk with cabotegravir.             rilpivirine: based on prospective reports to the apr of over 580 exposures to oral rilpivirine-containing regimens during the first trimester of pregnancy and over 200 during second/third trimester of pregnancy, the prevalence of birth defects in live births was 1.5% (95% ci: 0.7% to 2.9%) and 1.5% (95% ci: 0.3% to 4.2%) following first and second/third trimester exposures, respectively, compared with the background birth defect rate of 2.7% in the u.s. reference population of the macdp. in a clinical trial, total oral rilpivirine exposures were generally lower during pregnancy compared with the postpartum period. refer to the prescribing information for edurant (rilpivirine) for additional information on rilpivirine. animal data: cabotegravir: cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from 15 days before cohabitation, during cohabitation, and from gestation days 0 to 17. there were no effects on fetal viability when fetuses were delivered by caesarean, although a minor decrease in fetal body weight was observed at 1,000 mg/kg/day (>28 times the exposure in humans at the rhd). no drug-related fetal toxicities were observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the rhd), and no drug-related fetal malformations were observed at any dose. cabotegravir was administered orally to pregnant rabbits at 0, 30, 500, or 2,000 mg/kg/day from gestation days 7 to 19. no drug-related fetal toxicities were observed at 2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the rhd). in a rat pre- and postnatal development study, cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from gestation day 6 to lactation day 21. a delay in the onset of parturition and increases in the number of stillbirths and neonatal deaths by lactation day 4 were observed at 1,000 mg/kg/day (>28 times the exposure in humans at the rhd); there were no alterations to growth and development of surviving offspring. in a cross-fostering study, similar incidences of stillbirths and early postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were nursed from birth by control mothers. there was no effect on neonatal survival of control pups nursed from birth by cabotegravir-treated mothers. a lower dose of 5 mg/kg/day (13 times the exposure at the rhd) was not associated with delayed parturition or neonatal mortality in rats. studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in fetal tissue.             rilpivirine: rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on gestation days 6 through 17 and 6 through 19, respectively). no significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times the exposure in humans at the rhd. in a pre- and postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day through lactation. no adverse effects were noted in the offspring at maternal exposures up to 63 times the exposure in humans at the rhd. risk summary based on limited data after oral administration, rilpivirine is present in human breast milk. the data do not allow determination of the amount of rilpivirine that is transferred to milk. there are no data on the presence of cabotegravir in human milk. cabotegravir is present in animal milk (see data). when a drug is present in animal milk, it is likely that the drug will be present in human milk. it is not known if the components of cabenuva affect human milk production or have effects on the breastfed infant. residual exposures in human milk of cabotegravir (if present) and rilpivirine may remain for 12 months or longer after the last injections have been administered [see warnings and precautions (5.6)] . potential risks of breastfeeding include: (1) hiv‑1 transmission (in hiv-1–negative infants), (2) developing viral resistance (in hiv-1–positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults. data cabotegravir: animal lactation studies with cabotegravir have not been conducted. however, cabotegravir was detected in the plasma of nursing pups on lactation day 10 in the rat pre- and postnatal development study. the safety and effectiveness of cabenuva have been established in adolescents aged 12 to younger than 18 years and weighing at least 35 kg, which is supported by the following: mocha trial the safety, tolerability, and pharmacokinetics of oral and injectable cabotegravir and oral and injectable rilpivirine are being assessed in an ongoing phase 1/2 multicenter, open-label, non-comparative study, mocha (impaact 2017). data are available from the week 16 interim analysis from mocha. the primary objective at week 16 was to confirm the use of the adult dose, through the evaluation of safety and pharmacokinetics, for oral and injectable cabotegravir and injectable rilpivirine in hiv-1–infected virologically suppressed adolescents. twenty-three hiv-1–infected and virologically suppressed adolescents aged 12 to younger than 18 years and weighing at least 35 kg were assigned to 1 of 2 cohorts, 1c or 1r, based on their background antiretroviral regimen. in cohort 1c, participants (n = 8) received one 30-mg cabotegravir tablet daily for 1 month, followed by monthly cabotegravir injections (month 1: 600-mg injection, months 2 and 3: 400-mg injection) for an additional 3 months, while continuing background antiretroviral therapy. in cohort 1r, participants received one 25-mg rilpivirine tablet (n = 15) daily for 1 month, followed by monthly rilpivirine injections (n = 13) (month 1: 900-mg injection, months 2 and 3: 600-mg injection) for an additional 3 months, while continuing background antiretroviral therapy. at baseline, in cohort 1c, the median age of participants was 14.5 years; the median weight was 57.2 kg (range: 43.0, 73.5); 25% were female; 100% were non-white; and no participant had a cd4+ cell count <350 cells per mm3 . at baseline, median cd4+ cell count was 725 cells per mm3 (range: 629 to 924). in cohort 1r, the median age of participants was 17 years; the median weight was 63.0 kg (range: 44.1, 98.5); 53% were female; 73% were non-white; and no participant had a cd4+ cell count <350 cells per mm3 . at baseline, median cd4+ cell count was 827 cells per mm3 (range: 439 to 1,509). the safety of cabenuva in adolescents is expected to be similar to adults, as there was no clinically significant difference in drug exposure for the components of cabenuva [see adverse reactions (6.1)] . the efficacy of cabenuva in adolescents is extrapolated from adults with support from pharmacokinetic analyses showing similar drug exposure [see clinical pharmacology (12.3)] . the safety, efficacy, and pharmacokinetics of cabenuva have not been established in pediatric patients younger than 12 years of age or weighing <35 kg. clinical trials of cabenuva did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. in general, caution should be exercised in administration of cabenuva in elderly patients, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy [see clinical pharmacology (12.3)] . based on studies with oral cabotegravir and population pharmacokinetic analyses of oral rilpivirine, no dosage adjustment of cabenuva is necessary for patients with mild (creatinine clearance ≥60 to <90 ml/min) or moderate renal impairment (creatinine clearance ≥30 to <60 ml/min). in patients with severe renal impairment (creatinine clearance 15 to <30 ml/min) or end-stage renal disease (creatinine clearance <15 ml/min), increased monitoring for adverse effects is recommended [see clinical pharmacology (12.3)] . in patients with end-stage renal disease not on dialysis, effects on the pharmacokinetics of cabotegravir or rilpivirine are unknown. as cabotegravir and rilpivirine are >99% protein bound, dialysis is not expected to alter exposures of cabotegravir or rilpivirine. based on separate studies with oral cabotegravir and oral rilpivirine, no dosage adjustment of cabenuva is necessary for patients with mild or moderate hepatic impairment (child-pugh a or b). the effect of severe hepatic impairment (child-pugh c) on the pharmacokinetics of cabotegravir or rilpivirine is unknown [see clinical pharmacology (12.3)] . overview: a complete dose of cabenuva requires two injections: 400 mg (2 ml) of cabotegravir and 600 mg (2 ml) of rilpivirine. cabotegravir and rilpivirine are suspensions that do not need further dilution or reconstitution. the preparation steps for both medicines are the same. carefully follow these instructions when preparing the suspension for injection to avoid leakage. cabotegravir and rilpivirine are for gluteal intramuscular use only. each injection must be administered to separate gluteal intramuscular sites (on opposite sides or at least 2 cm apart). note: the ventrogluteal site is recommended. the administration order is not important. storage information store in refrigerator at 2°c to 8°c (36°f to 46°f). do not freeze. prior to administration: your pack contains: consider the patient’s build and use medical judgment to select an appropriate injection needle length. you will also need: preparation: 4. inspect suspension. figure d 8. lift off the packaging. figure h 11. press the plunger. figure k injection: injections must be administered to a gluteal site. see figure o . select from the following areas for the injection: use the z-track injection technique to minimize medicine leakage from the injection site. figure w after injection: repeat for 2nd medicine. questions and answers manufactured for: viiv healthcare durham, nc 27701 trademarks are owned by or licensed to the viiv healthcare group of companies. ©2023 viiv healthcare group of companies or its licensor. cbn:5ifu2 this instructions for use has been approved by the u.s. food and drug administration.                          revised: 12/2023 overview: a complete dose of cabenuva requires two injections: 600 mg (3 ml) of cabotegravir and 900 mg (3 ml) of rilpivirine. cabotegravir and rilpivirine are suspensions that do not need further dilution or reconstitution. the preparation steps for both medicines are the same. carefully follow these instructions when preparing the suspension for injection to avoid leakage. cabotegravir and rilpivirine are for gluteal intramuscular use only. each injection must be administered to separate gluteal intramuscular sites (on opposite sides or at least 2 cm apart). note: the ventrogluteal site is recommended. the administration order is not important. storage information store in refrigerator at 2°c to 8°c (36°f to 46°f). do not freeze. prior to administration: your pack contains: consider the patient’s build and use medical judgment to select an appropriate injection needle length. you will also need: preparation: 4. inspect suspension. figure d 8. lift off the packaging. figure h 11. press the plunger. figure k figure l figure n injection: injections must be administered to a gluteal site. see figure o. select from the following areas for the injection: use the z-track injection technique to minimize medicine leakage from the injection site. figure w after injection: repeat for 2nd medicine. questions and answers manufactured for: viiv healthcare durham, nc 27701 trademarks are owned by or licensed to the viiv healthcare group of companies. ©2023 viiv healthcare group of companies or its licensor. cbn:6ifu3 this instructions for use has been approved by the u.s. food and drug administration.                          revised: 12/2023