Malaysia - English - NPRA (National Pharmaceutical Regulatory Agency, Bahagian Regulatori Farmasi Negara)

pt. sari sihat (m) sdn. bhd. - zingiberis rhizoma/ginger oleoresin; zingiberis aromaticae rhizoma; rhizoma zingiberis purpurei; retrofacti fructus; gallae rhizoma; curcumae rhizoma; curcumae domestica rhizoma; corrigents/korigentia; coriandri fructus; colae semen -

Malaysia - English - NPRA (National Pharmaceutical Regulatory Agency, Bahagian Regulatori Farmasi Negara)

pt. sari sihat (m) sdn. bhd. - zingiberis rhizoma; zingiber aromatica; retrofracti fructus; piperis nigri fructus/lada ekor; parkiae semen; myristicae semen; languatis rhizoma; glycyrrhizae radix; foenigraeci semen; curcumae rhizoma; coptici fructus; anisi fructus; alyxiae cortex -

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

lundbeck pharmaceuticals llc - vigabatrin (unii: gr120krt6k) (vigabatrin - unii:gr120krt6k) - vigabatrin 50 mg in 1 ml - sabril is indicated as adjunctive therapy for adults and pediatric patients 2 years of age and older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss [see warnings and precautions (5.1)] . sabril is not indicated as a first line agent for complex partial seizures. sabril is indicated as monotherapy for pediatric patients with infantile spasms 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss [see warnings and precautions (5.1) ]. none. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to aeds, including sabril, during pregnancy. encourage women who are taking sabril during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry. this can be done by calling the toll-free number 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/ . this must be done by the patient herself. risk summary there are no adequate data on the developmental risk associated with the use of sabril in pregnant women. limited available data from case reports and cohort studies pertaining to sabril use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. however, based on animal data, sabril use in pregnant women may result in fetal harm. when administered to pregnant animals, vigabatrin produced developmental toxicity, including an increase in fetal malformations and offspring neurobehavioral and neurohistopathological effects, at clinically relevant doses. in addition, developmental neurotoxicity was observed in rats treated with vigabatrin during a period of postnatal development corresponding to the third trimester of human pregnancy (see data) . in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown. data animal data administration of vigabatrin (oral doses of 50 to 200 mg/kg/day) to pregnant rabbits throughout the period of organogenesis was associated with an increased incidence of malformations (cleft palate) and embryofetal death; these findings were observed in two separate studies. the no-effect dose for adverse effects on embryofetal development in rabbits (100 mg/kg/day) is approximately 1/2 the maximum recommended human dose (mrhd) of 3 g/day on a body surface area (mg/m2 ) basis. in rats, oral administration of vigabatrin (50, 100, or 150 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. the no-effect dose for adverse effects on embryo-fetal development in rats (50 mg/kg/day) is approximately 1/5 the mrhd on a mg/m2 basis. oral administration of vigabatrin (50, 100, 150 mg/kg/day) to rats from the latter part of pregnancy through weaning produced long-term neurohistopathological (hippocampal vacuolation) and neurobehavioral (convulsions) abnormalities in the offspring. a no-effect dose for developmental neurotoxicity in rats was not established; the low-effect dose (50 mg/kg/day) is approximately 1/5 the mrhd on a mg/m2 basis. in a published study, vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to a mutant mouse strain on a single day during organogenesis (day 7, 8, 9, 10, 11, or 12). an increase in fetal malformations (including cleft palate) was observed at both doses. oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. the early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. the no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg/day) was associated with plasma vigabatrin exposures (auc) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg. risk summary vigabatrin is excreted in human milk. the effects of sabril on the breastfed infant and on milk production are unknown. because of the potential for serious adverse reactions from vigabatrin in nursing infants, breastfeeding is not recommended. if exposing a breastfed infant to sabril, observe for any potential adverse effects [see warnings and precautions (5.1, 5.3, 5.4, 5.8)] . the safety and effectiveness of sabril as adjunctive treatment of refractory complex partial seizures in pediatric patients 2 to 16 years of age have been established and is supported by three double-blind, placebo-controlled studies in patients 3 to 16 years of age, adequate and well-controlled studies in adult patients, pharmacokinetic data from patients 2 years of age and older, and additional safety information in patients 2 years of age [see clinical pharmacology (12.3) and clinical studies (14.1)]. the dosing recommendation in this population varies according to age group and is weight-based [see dosage and administration (2.2)]. adverse reactions in this pediatric population are similar to those observed in the adult population [see adverse reactions (6.1)] . the safety and effectiveness of sabril as monotherapy for pediatric patients with infantile spasms (1 month to 2 years of age) have been established [see dosage and administration (2.3) and clinical studies (14.2)] . safety and effectiveness as adjunctive treatment of refractory complex partial seizures in pediatric patients below the age of 2 and as monotherapy for the treatment of infantile spasms in pediatric patients below the age of 1 month have not been established. duration of therapy for infantile spasms was evaluated in a post hoc analysis of a canadian pediatric epilepsy network (cpen) study of developmental outcomes in infantile spasms patients. this analysis suggests that a total duration of 6 months of vigabatrin therapy is adequate for the treatment of infantile spasms. however, prescribers must use their clinical judgment as to the most appropriate duration of use [see clinical studies (14.2)].   abnormal mri signal changes and intramyelinic edema (ime) in infants and young children being treated with sabril have been observed [see warnings and precautions (5.3, 5.4)] . juvenile animal toxicity data oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain gray matter vacuolation, decreased myelination, and retinal dysplasia) abnormalities. the no-effect dose for developmental neurotoxicity in juvenile rats (the lowest dose tested) was associated with plasma vigabatrin exposures (auc) substantially less than those measured in pediatric patients at recommended doses. in dogs, oral administration of vigabatrin (30 or 100 mg/kg/day) during selected periods of juvenile development (postnatal days 22-112) produced neurohistopathological abnormalities (brain gray matter vacuolation). neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. a no-effect dose for neurohistopathology was not established in juvenile dogs; the lowest effect dose (30 mg/kg/day) was associated with plasma vigabatrin exposures lower than those measured in pediatric patients at recommended doses [see warnings and precautions (5.4)]. clinical studies of vigabatrin did not include sufficient numbers of patients aged 65 and over to determine whether they responded differently from younger patients. vigabatrin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. oral administration of a single dose of 1.5 g of vigabatrin  to elderly (≥65 years) patients with reduced creatinine clearance (<50 ml/min) was associated with moderate to severe sedation and confusion in 4 of 5 patients, lasting up to 5 days. the renal clearance of vigabatrin was 36% lower in healthy elderly subjects (≥65 years) than in young healthy males. adjustment of dose or frequency of administration should be considered. such patients may respond to a lower maintenance dose [see dosage and administration (2.4) and clinical pharmacology (12.3 )] . other reported clinical experience has not identified differences in responses between the elderly and younger patients. dose adjustment, including initiating treatment with a lower dose, is necessary in pediatric patients 2 years of age and older and adults with mild (creatinine clearance >50 to 80 ml/min), moderate (creatinine clearance >30 to 50 ml/min) and severe (creatinine clearance >10 to 30 ml/min) renal impairment [see dosage and administration (2.4) and clinical pharmacology (12.3)] . vigabatrin is not a controlled substance. vigabatrin did not produce adverse events or overt behaviors associated with abuse when administered to humans or animals. it is not possible to predict the extent to which a cns active drug will be misused, diverted, and/or abused once marketed. consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of vigabatrin (e.g., incrementation of dose, drug-seeking behavior). following chronic administration of vigabatrin to animals, there were no apparent withdrawal signs upon drug discontinuation.  however, as with all aeds, vigabatrin should be withdrawn gradually to minimize increased seizure frequency [see warnings and precautions (5.6)] .

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

lundbeck pharmaceuticals llc - vigabatrin (unii: gr120krt6k) (vigabatrin - unii:gr120krt6k) - vigabatrin 500 mg - sabril is indicated as adjunctive therapy for adults and pediatric patients 2 years of age and older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss [see warnings and precautions (5.1)] . sabril is not indicated as a first line agent for complex partial seizures. sabril is indicated as monotherapy for pediatric patients with infantile spasms 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss [see warnings and precautions (5.1) ]. none. pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to aeds, including sabril, during pregnancy. encourage women who are taking sabril during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry. this can be done by calling the toll-free number 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/ . this must be done by the patient herself. risk summary there are no adequate data on the developmental risk associated with the use of sabril in pregnant women. limited available data from case reports and cohort studies pertaining to sabril use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. however, based on animal data, sabril use in pregnant women may result in fetal harm. when administered to pregnant animals, vigabatrin produced developmental toxicity, including an increase in fetal malformations and offspring neurobehavioral and neurohistopathological effects, at clinically relevant doses. in addition, developmental neurotoxicity was observed in rats treated with vigabatrin during a period of postnatal development corresponding to the third trimester of human pregnancy (see data) . in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. the background risk of major birth defects and miscarriage for the indicated population is unknown. data animal data administration of vigabatrin (oral doses of 50 to 200 mg/kg/day) to pregnant rabbits throughout the period of organogenesis was associated with an increased incidence of malformations (cleft palate) and embryofetal death; these findings were observed in two separate studies. the no-effect dose for adverse effects on embryofetal development in rabbits (100 mg/kg/day) is approximately 1/2 the maximum recommended human dose (mrhd) of 3 g/day on a body surface area (mg/m2 ) basis. in rats, oral administration of vigabatrin (50, 100, or 150 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. the no-effect dose for adverse effects on embryo-fetal development in rats (50 mg/kg/day) is approximately 1/5 the mrhd on a mg/m2 basis. oral administration of vigabatrin (50, 100, 150 mg/kg/day) to rats from the latter part of pregnancy through weaning produced long-term neurohistopathological (hippocampal vacuolation) and neurobehavioral (convulsions) abnormalities in the offspring. a no-effect dose for developmental neurotoxicity in rats was not established; the low-effect dose (50 mg/kg/day) is approximately 1/5 the mrhd on a mg/m2 basis. in a published study, vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to a mutant mouse strain on a single day during organogenesis (day 7, 8, 9, 10, 11, or 12). an increase in fetal malformations (including cleft palate) was observed at both doses. oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. the early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. the no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg/day) was associated with plasma vigabatrin exposures (auc) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg. risk summary vigabatrin is excreted in human milk. the effects of sabril on the breastfed infant and on milk production are unknown. because of the potential for serious adverse reactions from vigabatrin in nursing infants, breastfeeding is not recommended. if exposing a breastfed infant to sabril, observe for any potential adverse effects [see warnings and precautions (5.1, 5.3, 5.4, 5.8)] . the safety and effectiveness of sabril as adjunctive treatment of refractory complex partial seizures in pediatric patients 2 to 16 years of age have been established and is supported by three double-blind, placebo-controlled studies in patients 3 to 16 years of age, adequate and well-controlled studies in adult patients, pharmacokinetic data from patients 2 years of age and older, and additional safety information in patients 2 years of age [see clinical pharmacology (12.3) and clinical studies (14.1)]. the dosing recommendation in this population varies according to age group and is weight-based [see dosage and administration (2.2)]. adverse reactions in this pediatric population are similar to those observed in the adult population [see adverse reactions (6.1)] . the safety and effectiveness of sabril as monotherapy for pediatric patients with infantile spasms (1 month to 2 years of age) have been established [see dosage and administration (2.3) and clinical studies (14.2)] . safety and effectiveness as adjunctive treatment of refractory complex partial seizures in pediatric patients below the age of 2 and as monotherapy for the treatment of infantile spasms in pediatric patients below the age of 1 month have not been established. duration of therapy for infantile spasms was evaluated in a post hoc analysis of a canadian pediatric epilepsy network (cpen) study of developmental outcomes in infantile spasms patients. this analysis suggests that a total duration of 6 months of vigabatrin therapy is adequate for the treatment of infantile spasms. however, prescribers must use their clinical judgment as to the most appropriate duration of use [see clinical studies (14.2)].   abnormal mri signal changes and intramyelinic edema (ime) in infants and young children being treated with sabril have been observed [see warnings and precautions (5.3, 5.4)] . juvenile animal toxicity data oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain gray matter vacuolation, decreased myelination, and retinal dysplasia) abnormalities. the no-effect dose for developmental neurotoxicity in juvenile rats (the lowest dose tested) was associated with plasma vigabatrin exposures (auc) substantially less than those measured in pediatric patients at recommended doses. in dogs, oral administration of vigabatrin (30 or 100 mg/kg/day) during selected periods of juvenile development (postnatal days 22-112) produced neurohistopathological abnormalities (brain gray matter vacuolation). neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. a no-effect dose for neurohistopathology was not established in juvenile dogs; the lowest effect dose (30 mg/kg/day) was associated with plasma vigabatrin exposures lower than those measured in pediatric patients at recommended doses [see warnings and precautions (5.4)]. clinical studies of vigabatrin did not include sufficient numbers of patients aged 65 and over to determine whether they responded differently from younger patients. vigabatrin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. oral administration of a single dose of 1.5 g of vigabatrin  to elderly (≥65 years) patients with reduced creatinine clearance (<50 ml/min) was associated with moderate to severe sedation and confusion in 4 of 5 patients, lasting up to 5 days. the renal clearance of vigabatrin was 36% lower in healthy elderly subjects (≥65 years) than in young healthy males. adjustment of dose or frequency of administration should be considered. such patients may respond to a lower maintenance dose [see dosage and administration (2.4) and clinical pharmacology (12.3 )] . other reported clinical experience has not identified differences in responses between the elderly and younger patients. dose adjustment, including initiating treatment with a lower dose, is necessary in pediatric patients 2 years of age and older and adults with mild (creatinine clearance >50 to 80 ml/min), moderate (creatinine clearance >30 to 50 ml/min) and severe (creatinine clearance >10 to 30 ml/min) renal impairment [see dosage and administration (2.4) and clinical pharmacology (12.3)] . vigabatrin is not a controlled substance. vigabatrin did not produce adverse events or overt behaviors associated with abuse when administered to humans or animals. it is not possible to predict the extent to which a cns active drug will be misused, diverted, and/or abused once marketed. consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of vigabatrin (e.g., incrementation of dose, drug-seeking behavior). following chronic administration of vigabatrin to animals, there were no apparent withdrawal signs upon drug discontinuation.  however, as with all aeds, vigabatrin should be withdrawn gradually to minimize increased seizure frequency [see warnings and precautions (5.6)] .

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

viiv healthcare pty ltd - cabotegravir, quantity: 30 mg (equivalent: cabotegravir sodium, qty mg) - tablet, film coated - excipient ingredients: titanium dioxide; magnesium stearate; hypromellose; lactose monohydrate; microcrystalline cellulose; sodium starch glycollate type a; macrogol 3350 - vocabria tablets are indicated in combination with rilpivirine tablets for the short-term treatment of human immunodeficiency virus type 1 (hiv-1) infection in adults who are virologically suppressed (hiv-1 rna <50 copies/ml) and have no known or suspected resistance to either cabotegravir or rilpivirine (see sections 4.2 dose and method of administration and 5.1 pharmacodynamic properties, clinical trials) for: ? oral lead in to assess tolerability of cabotegravir prior to administration of cabotegravir prolonged-release suspension for injection plus rilpivirine prolonged-release suspension for injection. ? oral therapy for adults who will miss planned dosing with cabotegravir prolonged-release suspension for injection.

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

sanofi-aventis australia pty ltd - vigabatrin, quantity: 500 mg - tablet, uncoated - excipient ingredients: sodium starch glycollate; hypromellose; microcrystalline cellulose; macrogol 8000; magnesium stearate; titanium dioxide; povidone - vigabatrin should be used under the general direction of a specialist practitioner who is experienced in the treatment of epilepsy for the treatment of refractory epilepsy which is not satisfactorily controlled by other antiepileptic drugs. it should be used, initially, as add on therapy.

European Union - English - EMA (European Medicines Agency)

viiv healthcare b.v. - cabotegavir sodium, cabotegravir - hiv infections - antivirals for systemic use - vocabria tablets are indicated in combination with rilpivirine tablets for the short-term treatment of human immunodeficiency virus type 1 (hiv-1) infection in adults who are virologically suppressed (hiv-1 rna

Israel - English - Ministry of Health

glaxo smith kline (israel) ltd - cabotegravir - prolonged release suspension for injection - cabotegravir 200 mg / 1 ml - vocabria injection is indicated, in combination with rilpivirine injection, for the treatment of human immunodeficiency virus type 1 (hiv-1) infection in adults who are virologically suppressed (hiv-1 rna <50 copies/ml) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the nnrti and ini class

Israel - English - Ministry of Health

glaxo smith kline (israel) ltd - cabotegravir as sodium - film coated tablets - cabotegravir as sodium 30 mg - vocabria tablets are indicated in combination with rilpivirine tablets for the short-term treatment of human immunodeficiency virus type 1 (hiv-1) infection in adults who are virologically suppressed (hiv-1 rna <50 copies/ml) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the nnrti and ini class for: • oral lead in to assess tolerability of vocabria and rilpivirine prior to administration of long acting cabotegravir injection plus long acting rilpivirine injection. • oral therapy for adults who will miss planned dosing with cabotegravir injection plus rilpivirine injection.

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)] .