natgillin/translations-raw huggingface dataset:
Rifampicin Rifampicin er en potent CYP3A4- inducer og har vist sig at forårsage en reduktion i amprenavir AUC med 82%, hvilket kan føre til manglende virologisk effekt og resistensudvikling.
Rifampicin Rifampicin is a strong CYP3A4 inducer and has been shown to cause an 82% decrease in amprenavir AUC, which can result in virological failure and resistance development.
29 • Andre kombinationer
• Other combinations
Baseret på data opnået i disse studier og fordi ritonavir ikke forventes at have nogen signifikant indvirkning på farmakokinetikken for NRTI’ erne, forventes den samtidige administration af fosamprenavir og ritonavir med disse lægemidler ikke at ændre virkningen af disse.
Based on data derived from these studies and because ritonavir is not expected to have a significant impact on the pharmacokinetics of NRTIs, the co-administration of fosamprenavir and ritonavir with these medicinal products is not expected to significantly alter the exposure of the co-administered active substances.
Der forventes ingen signifikant interaktion med didanosin enterokapsel.
No significant interaction is expected with didanosine gastro-resistent capsule
Der kan ikke gives doseringsanbefalinger for samtidig administration af fosamprenavir og ritonavir med tenofovir.
30 Tenofovir: no recommendations can be drawn at this stage on the co-administration of fosamprenavir with ritonavir with tenofovir.
Der er ikke foretaget interaktionsstudier af fosamprenavir og ritonavir i kombination med protease - hæmmerne indinavir, saquinavir, nelfinavir og atazanavir.
No interaction studies have been undertaken between fosamprenavir with ritonavir and the following protease inhibitors: indinavir, saquinavir, nelfinavir and atazanavir.
Antibiotika/ svampemidler
Antibiotics / Antifungals
Samtidig administration kan resultere i en moderat stigning i koncentrationen af clarithromycin hos disse patienter.
Clarithromycin: a reduction in the clarithromycin dose should be considered when co-administered with Telzir with ritonavir in patients with renal impairment as moderate increases in clarithromycin concentrations are expected when coadministered with Telzir with ritonavir.
Cmax, AUC og Cmin for
Ketoconazole / Itraconazole: co-administration of fosamprenavir 700 mg with ritonavir 100 mg twice daily and ketoconazole 200 mg once daily increased plasma ketoconazole Cmax by 25% and increased AUC(0-τ) to values 2.69-fold those observed on administration of ketoconazole 200 mg once daily without concurrent fosamprenavir with ritonavir.
30 amprenavir var uforandret.
The Cmax, AUC and Cmin of amprenavir were unchanged.
Sammenlignet med administration af rifabutin alene (300 mg en gang daglig) giver administration af nedsat dosis rifabutin (150 mg hver anden dag) samtidig med administration af fosamprenavir 700 mg 2 gange daglig og ritonavir 100 mg 2 gange daglig uændret plasma rifabutin AUC (0- 48) og nedsat Cmax med 14%.
Rifabutin: compared to rifabutin administered alone (300 mg once daily), plasma rifabutin AUC (0- 48) was unchanged and Cmax was decreased 14% following co-administration of reduced doses of rifabutin (150 mg every other day) with fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily.
Når en enkelt 1400 mg dosis af fosamprenavir blev administreret sammen med en enkelt 30 ml dosis af antacidsuspension (equivalent med 3, 6 gram aluminiumhydroxid og 1, 8 gram magnesiumhydroxid) blev AUC og Cmax for amprenavir nedsat med henholdsvis 18% og 35%, mens Cmin (C12h) var uændret.
The AUC and Cmax of amprenavir were decreased by 18% and 35% respectively, whilst the Cmin (C12h) was comparable, when a single 1400 mg dose of fosamprenavir was co-administered with a single 30 ml
Lægemidler hvis plasmaniveauer kan blive forøget når disse administreres i kombination med Telzir
Medicinal products whose plasma levels may be increased when co-administered with Telzir
Større påvirkning kan forventes når
Fluticasone propionate (interaction with ritonavir): in a clinical study where ritonavir 100 mg capsules bid were co-administered with 50 µg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, the fluticasone propionate plasma levels increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% confidence interval 82-89%).
31 fluticasonpropionat inhaleres.
Greater effects may be expected when fluticasone propionate is inhaled.
Hvis behandling med HMG- CoA- reduktasehæmmere er indiceret, anbefales behandling med pravastatin eller fluvastatin, fordi deres metabolisme ikke afhænger af CYP3A4 og der forventes ikke interaktioner med proteasehæmmere.
HMG-CoA reductase inhibitors: if treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended because their metabolism is not dependent on CYP3A4 and interactions are not expected with protease inhibitors.
Da en øget koncentration af HMG- CoA- reduktasehæmmere kan forårsage myopati, herunder rhabdomyolyse, kan samtidig administration af Telzir og ritonavir ikke anbefales.
Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of lovastatin or simvastatin with Telzir with ritonavir is not
Når atorvastatin administreres sammen med Telzir og ritonavir, bør doser større end 200 mg/ dag anvendes med omhyggelig observation for tegn på toksicitet af atorvastatin.
When used with Telzir with ritonavir, doses of atorvastatin no greater than 20 mg/ day should be administered, with careful monitoring for atorvastatin toxicity.
Hvis Telzir/ ritonavir gives i kombination med parenteral midazolam, skal det gøres på en intensivafdeling eller under tilsvarende forhold, som sikrer tæt klinisk monitorering og tilgængelig medicinsk behandling i tilfælde af, at der skulle opstå respiratorisk depression og/ eller forlænget sedation.
If Telzir/ ritonavir is co-administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/ or prolonged sedation.
Samtidig administration af fosamprenavir 700 mg 2 gange daglig + ritonavir 100 mg 2 gange daglig med et oralt præventionsmiddel indeholdende ethinyl estradiol (EE) 0, 035 mg/ norethisteron (NE) 0, 5 mg en gang daglig nedsatte plasma EE AUC( 0- τ) og Cmax med henholdsvis 37% og 28% og nedsatte plasma NE AUC( 0- τ), Cmax og Cτ med henholdsvis 34%, 38% og 26%.
Co-administration of fosamprenavir 700 mg twice daily + ritonavir 100 mg twice daily with an oral contraceptive containing ethinyl estradiol (EE) 0.035 mg/ norethisterone (NE) 0.5 mg once daily decreased plasma EE AUC(0- τ) and Cmax by 37% and 28%, respectively, and decreased plasma NE AUC(0-τ), Cmax, and Cτ by 34%, 38%, and 26%, respectively.
Paroxetin:
33 Paroxetine:
Der er fundet materiale relateret til amprenavir i rottemælk, men det vides ikke, om amprenavir udskilles i modermælk.
Lactation Amprenavir-related material was found in rat milk, but it is not known whether amprenavir is excreted in human milk.
Rotteunger der før og efter fødslen har været eksponeret for amprenavir og fosamprenavir blev der obseveret tegn på udvikingsrelateret toksicitet (se pkt.
Rat pups exposed pre and post-natally to amprenavir and fosamprenavir showed developmental toxicity (see section 5.3).
33 Sikkerheden ved fosamprenavir er undersøgt hos 755 voksne i fase II og III kontrollerede kliniske afprøvninger.
The safety of fosamprenavir has been studied in 755 adult patients in Phase II and III controlled clinical trials.
I APV30002 (n = 322) med behandlingsnaive patienter blev fosamprenavir (1400 mg) administreret 1 gang daglig sammen med ritonavir (200 mg) som del af et tripel- regime indeholdende abacavir og lamivudin.
APV30002 (n = 322) in antiretroviral naïve patients, fosamprenavir (1400 mg) given once daily in combination with ritonavir (200 mg) as part of a triple regimen including abacavir and lamivudine.
I APV30003, med patienter tidligere behandlet med proteasehæmmere, blev fosamprenavir administreret sammen med en lav dosis ritonavir enten 1 gang daglig (1400 mg / 200 mg) (n = 106) eller 2 gange daglig (700 mg / 100 mg) (n = 106) i kombination med to aktive reverse transkriptasehæmmere (RTI’ er).
APV30003 in protease inhibitor experienced patients, fosamprenavir given in combination with low dose ritonavir either once daily (1400 mg / 200 mg) (n = 106) or twice daily (700 mg / 100 mg) (n = 106) in combination with two active reverse transcriptase inhibitors (RTIs).
Bivirkninger vises nedenfor iht.
34 Adverse reactions are listed by MedDRA system organ class and absolute frequency.
MedDRA- systemorganklasser og absolut frekvens.
Frequencies. are defined as:
34 hvor patienterne fik behandling med fosamprenavir/ ritonavir 1 gang daglig sammenlignet med APV29005 (39%), hvor patienterne fik fosamprenavir/ ritonavir 2 gange daglig.
Drug-related adverse events were more common in APV20003 (55%) where subjects received once daily fosamprenavir / ritonavir when compared to APV29005 (39%) where subjects received twice daily fosamprenavir / ritonavir.
Alvorlige og livstruende hudreaktioner, herunder Stevens- Johnson syndrom, er sjældne.
Severe or life-threatening cases of rash, including Stevens-Johnson syndrome are rare.
Forhøjet ALAT (almindelig), ASAT (almindelig), serumlipase (almindelig) og triglycerider (meget al - mindelig).
35 Clinical chemistry abnormalities: clinical chemistry abnormalities (Grade 3 or 4) potentially related to treatment with fosamprenavir with ritonavir and reported in greater than or equal to 1% of adult patients, included: increased ALT (common), AST (common), serum lipase (common) and triglycerides (very common).
Samtidig administration af ritonavir og fosamprenavir øger plasma- AUC for amprenavir ca.
Co-administration of ritonavir with fosamprenavir increase plasma amprenavir AUC by approximately 2-fold and plasma C τ, ss by 4- to 6-fold, compared to values obtained when fosamprenavir is administered alone.
2 gange og plasma- Cτ, ss 4 til 6 gange, sammenlignet med registrerede værdier, når fosamprenavir administreres alene.
Administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice
Administration af 700 mg fosamprenavir 2 gange daglig i kombination med 100 mg ritoavir 2 gange daglig resulterer i plasmakoncentrationer af amprenavir med proteinjusterede gennemsnitlige ratioer for Cmin/ IC50 og Cmin/ IC95 på henholdsvis 21, 7 (interval 1, 19- 240) og 3, 21 (interval 0, 26- 30, 0) (data fra studie APV30003 af patienter, der tidligere er behandlet med antiretrovirale midler).
36 daily results in plasma amprenavir concentrations (data from study APV30003 in antiretroviral experienced patients) which results in protein adjusted median ratios of Cmin/ IC50 and Cmin/ IC95 of 21.7 (range 1.19-240) and 3.21 (range 0.26-30.0), respectively.
a) ART- naive eller PI- naive patienter
b) ART-naïve or PI-naïve patients
36 Blandt de 59 involverede PI- naive patienter viste genotypeanalyser af isolater fra 13 ud af 14 pædiatriske patienter med virologisk svigt resistensmønstre, som var magen til dem observeret hos voksne.
Genotypic analysis of isolates from 13 of 14 paediatric patients exhibiting virological failure among the 59 PI-naïve patients enrolled, demonstrated resistance patterns similar to those observed in adults.
Følgende mutationer blev påvist hos de patienter, der fik virologsik svigt i løbet af 96 uger:
37 In the studies of PI-experienced patients, APV30003 and its extension, APV30005 (fosamprenavir 700 mg / ritonavir 100 mg twice daily: n=107), the following mutations emerged in patients experiencing virological failure through 96 weeks:
Baseret på data fra 25 antiviral- naive patienter, der er blevet behandlet med et svigtende fosamprenavirregime (hvoraf én udviste resistens over for lopinavir og saquinavir ved baseline og en anden over for tipranavir), frembringer resistensmønstret, som er forbundet med amprenavir, begrænset krydsresistens over for atazanavir/ ritonavir (tre ud af 25 isolater), darunavir/ ritonavir (fire ud af 25 isolater),
Based on data from twenty-five antiretroviral naïve patients failing a fosamprenavir containing regimen (one of whom showed Baseline resistance to lopinavir and saquinavir and another to tipranavir) the resistance pathways associated with amprenavir produce limited cross-resistance to atazanavir/ ritonavir (three of 25 isolates), darunavir/ ritonavir (four of 25 isolates), indinavir/ ritonavir (one of 25 isolates), lopinavir/ ritonavir (three of 24 isolates, saquinavir (three of 24 isolates) and tipranavir/ ritonavir (four of 24 isolates).
Omvendt bevarer amprenavir aktivitet mod nogle isolater med resistens over for andre PI’ er.
Conversely amprenavir retains activity against some isolates with resistance to other PIs and this retained activity would depend on the number and type of protease resistance mutations present in the isolates.
Den kliniske erfaring med fosamprenavir boosted med ritonavir er hovedsageligt baseret på tre åbne studier.
38 Clinical experience with fosamprenavir boosted with ritonavir is mainly based on three open label studies.
Over 48 uger viste behand - lingen effekt sammenlignelig med nelfinavir (1250 mg) administreret 2 gange daglig i kombination med abacavir og lamivudin (300 og 150 mg 2 gange daglig).
In antiretroviral naïve patients in APV30002, fosamprenavir (1400 mg) given once daily in combination with low dose ritonavir (200 mg) as part of a triple regimen including abacavir (300 mg twice daily) and lamivudine (150 mg twice daily) showed similar efficacy over 48 weeks compared to nelfinavir (1250 mg) given twice daily in combination with abacavir plus lamivudine (300 and 150 mg twice daily).
Der blev vist ligeværdighed mellem fosamprenavir i kombination med ritonavir og nelfinavir baseret på den del af patienterne som opnåede HIV- 1 RNA niveauer i plasma større end 400 kopier/ ml ved uge 48 (primære end- point).
Non-inferiority was demonstrated between fosamprenavir with ritonavir and nelfinavir based on the proportions of patients achieving plasma HIV-1 RNA levels < 400 copies/ ml at 48 weeks (primary endpoint).
Median plasma HIV- 1 RNA var ved uge 48 faldet med 3. 1 log10 kopier/ ml og 3, 0 log10 kopier/ ml for henholdsvis armen med fosamprenavir i kombination med ritonavir og armen med nelfinavir.
The median plasma HIV-1 RNA had decreased by 3.1 log10 copies/ ml and 3.0 log10 copies/ ml at Week 48 in the fosamprenavir with ritonavir and nelfinavir arms respectively.
Medianstigningen over baseline ved uge 48 var på henholdsvis +203 og +207 celler/ mm3.
CD4+ cell counts increased in both the fosamprenavir with ritonavir and nelfinavir groups, with median increases above baseline being similar in magnitude at Week 48 (+203 and +207 cells/ mm3, respectively).
Disse data viser, at fosamprenavir i kombination med ritonavir (henholdsvis 1400 og 200 mg OD) 1 gang daglig hos antiretroviralnaive patienter har samme virkning som nelfinavir administreret 2 gange daglig.
The data presented above demonstrates that the once daily regimen of fosamprenavir with ritonavir (1400/ 200 mg OD) in antiretroviral naïve patients showed similar efficacy compared to nelfinavir given twice daily.
Ikke- inferioritet blev demonstreret mellem fosamprenavir sammen med ritonavir og lopinavir/ ritonavir baseret på den andel af patienter, der opnåede plasma HIV- 1 RNA niveauer < 400 kopier/ ml ved 48
Non-inferiority was demonstrated between fosamprenavir co-administered with ritonavir and lopinavir / ritonavir based on the proportions of patients achieving plasma HIV-1 RNA levels < 400 copies/ ml at 48 weeks (primary endpoint).
Medianforøgelsen i CD4- celletal var 176 celler/ mm3 i fosamprenavir med ritonavir armen og 191 celler/ mm3 i lopinavir/ ritonavir armen ved uge 48.
Median increase in CD4 cell count was 176 cells/ mm3 in the fosamprenavir with ritonavir arm and 191 cells/ mm3 in the lopinavir / ritonavir arm respectively by Week 48.
I et randomiseret åbent studie (APV30003) med proteasehæmmer- experienced patienter, som havde virologisk svigt (< 2 PI’ er) viste kombinationen med fosamprenavir og ritonavir (700/ 100 mg 2 gange daglig eller 1400/ 200 mg 1 gang daglig) ikke non- inferioritet over for lopinavir/ ritonavir med hensyn til viral suppression målt ved det gennemsnitlige areal under kurven minus baseline (AAUCMB) for plasma HIV- 1 RNA over 48 uger (det primære end- point).
39 In a randomised open-label study (APV30003) in protease inhibitor experienced patients with virological failure (less than or equal to two PIs) the fosamprenavir with ritonavir (700 / 100 mg twice daily or 1400 / 200 mg once daily) did not demonstrate non-inferiority to lopinavir / ritonavir with regard to viral suppression as measured by the average area under the curve minus baseline (AAUCMB) for plasma HIV-1 RNA over 48 weeks (the primary end point).
Varigheden (median) af sidste behandling med proteasehæmmere var 149 uger for patienter, som fik fosamprenavir og ritonavir 2 gange daglig (49% havde tidligere fået ≥ 2 PI’ er), og 130 uger for patienter, som fik lopi - navir/ ritonavir (40% havde tidligere fået ≥ 2 PI’ er).
The median durations of prior exposure to protease inhibitors were 149 weeks for patients receiving fosamprenavir with ritonavir twice daily (49% received ≥ 2 prior PIs) and 130 weeks for patients receiving lopinavir/ ritonavir (40% received ≥ 2 prior PIs).
39 Den gennemsnitlige ændring i AAUCMB (Log10 kopier/ ml) i ITT( E) populationen (observeret analyse) ved uge 48 er beskrevet i tabellen nedenfor:
The mean AAUCMBs (log10 c/ ml) in the ITT (E) population (Observed analysis) at 48 weeks are described in the table below:
/ ml > 10. 000 – 100. 000
copies/ ml > 10.000 – 100,000
0, 244 (- 0, 047; 0, 536)
(-0.047, 0.536)
For patienter med højt viralt indhold ved baseline (> 100. 000 kopier/ ml) havde 7/ 14 (50%) af de patienter som fik lopinavir/ ritonavir og 6/ 19 (32%) af de patienter som fik fosamprenavir i kombination med ritonavir plasmakoncentrationer af HIV- 1 RNA < 400 kopier/ ml.
40 In patients with high viral load at baseline (> 100,000 copies/ ml) 7/ 14 (50%) patients in the lopinavir / ritonavir group and 6/ 19 (32%) patients in the fosamprenavir with ritonavir group had plasma HIV-1 RNA < 400 copies/ ml.
Dette blev målt via den mediane ændring fra baseline i CD4- celletal (fosamprenavir og ritonavir 2 gange daglig:
The fosamprenavir with ritonavir twice daily regimen and the lopinavir / ritonavir twice daily regimen showed similar immunological improvements through 48 weeks of treatment as measured by median change from baseline in CD4+ cell count (fosamprenavir with ritonavir twice daily:
81 celler / mm3; lopinavir / ritonavir 2 gange daglig:
81 cells/ mm3: lopinavir / ritonavir twice daily:
40 APV29005 involverer 25 patienter mellem 6 og 11 år (hvoraf de fleste behandles med 18 mg fosamprenavir/ kg og 3 mg ritonavir/ kg 2 gange daglig eller voksendoseringen) og 29 patienter mellem 12 og 18 år (hvoraf de fleste behandles med voksendoseringen).
APV29005 enrolled 25 patients aged 6 to 11 (the majority of whom were treated with fosamprenavir / ritonavir 18/ 3 mg/ kg twice daily or the adult tablet regimen) and 29 patients aged 12 to 18 (the majority of whom were treated with the adult tablet regimen).
Samlet set indgik patienterne i studiet med en median HIV- 1- RNA log10 på 4, 6 kopier/ ml (hvoraf 33% havde > 100. 000 kopier/ ml ved baseline) og et median CD4+- celletal på 18% (hvoraf 37% havde CD4+ - celletal på < 15% ved baseline).
Overall, patients enrolled with a median 4.6 HIV-1 RNA log10 copies/ ml (33% of whom had > 100,000 copies/ ml at baseline) and a median% CD4+ cell of 18% (39% of whom had% CD4+ of < 15% at baseline).
4. 2).
Therefore for adult patients the Telzir oral suspension should be taken without food and on an empty stomach (see section 4.2).
2 timer efter administrationen.
41 After single dose administration of fosamprenavir, amprenavir peak plasma concentrations are observed approximately 2 hours after administration.
Administration af fosamprenavir oral suspension sammen med et meget fedtholdigt måltid (967 kcal, 67 gram fedt, 33 gram protein, 58 gram kulhydrat) reducerede plasma amprenavir AUC( 0- ∞) med 28% og Cmax med 46% og forsinkede Tmax med 0, 72 timer.
Administration of the fosamprenavir oral suspension formulation with a high fat meal (967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) reduced plasma amprenavir AUC(0- ∞) by 28% and Cmax by 46% and delayed Tmax by 0.72 hours.
Børn og unge bør tage fosamprenavir oral suspension sammen
In children and adolescents the fosamprenavir oral suspension should be taken with food.
4. 2).
The dose recommendations for this population therefore take into account the observed food effect (see section 4.2).
Elimination
42 Elimination
Ca.
The primary route of elimination of amprenavir is via hepatic metabolism with less than 1% excreted unchanged in the urine and no detectable amprenavir in faeces.
Disse personer blev sammenlignet med personer med normal leverfunktion, der fik 700 mg fosamprenavir og 100 mg ritonavir to gange daglig.
In subjects with mild hepatic impairment (Child-Pugh score of 5-6), the dosage regimen of fosamprenavir 700 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily
Hos personerne med let nedsat leverfunktion sås en let forhøjet plasma- Cmax for amprenavir (17%), en let forhøjet plasma- AUC( 0- 12) for amprenavir (22%), tilsvarende totale plasma- C12 - værdier for amprenavir og cirka 117% højere plasma- C12- værdier for ubundet amprenavir.
43 provided slightly higher plasma amprenavir Cmax (17%), slightly higher plasma amprenavir AUC(0-12) (22%), similar plasma total amprenavir C12 values and approximately 117% higher plasma unbound amprenavir C12 values compared to subjects with normal hepatic function receiving the standard fosamprenavir / ritonavir 700 mg / 100 mg twice daily regimen.
De totale plasma- C12- værdier for amprenavir forventes at være 35% lavere og cirka 88% højere plasma- C12- værdier for ubundet amprenavir.
In subjects with moderate hepatic impairment (Child-Pugh score of 7-9), a reduced dose of fosamprenavir 450 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily is predicted to deliver similar plasma amprenavir Cmax and AUC(0-12), but approximately 35% lower plasma total amprenavir C12 values and approximately 88% higher plasma unbound amprenavir C12 values than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg / 100 mg twice daily regimen.
Hos kaniner var den systemiske eksponering af den højeste dosis kun 0, 3 gange den dosis for human eksponering ved maksimum klinisk dosis og derfor er den udviklingsrelaterede toksicitet af fosamprenavir ikke klarlagt.
In rabbits, systemic exposure at the high dose level was only 0.3 times human exposure at the maximum clinical dose and thus the development toxicity of fosamprenavir has not been fully determined.
Relevansen af de hepatocellulære fund hos gnavere er ukendt for mennesker.
The relevance of the hepatocellular findings in the rodents for humans is uncertain;
Der er dog ingen kliniske studier eller postmarketingsdata, der tyder på, at disse hepatocellulære fund har klinisk betydning.
44 however, there is no evidence from clinical trials or marketed use to suggest that these findings are of clinical significance.
Hos hanrotter sås en højere forekomst af interstitiel celle- hyperplasi ved eksponeringsniveauer 0, 5 gange større end den humane, og i hunrotter sås en stigning i uterin endometrial adenocarcinomaer ved eksponeringsniveauer 1, 1 gange større end den humane.
In rats only there was an increase in interstitial cell hyperplasia in males at exposure levels equivalent to 0.5-fold those in humans, and an increase in uterine endometrial adenocarcinoma in females at an exposure level equivalent to 1.1-fold those in humans.