natgillin/translations-raw huggingface dataset:
Sikkerhed og effekt hos børn og unge under 18 år er ikke fastlagt.
Safety and efficacy in children and adolescents below the age of 18 years have not been established.
5. 1 og 5. 2).
Therefore posaconazole is not recommended for use in patients below 18 years of age (see sections 5.1 and 5.2).
4. 5).
Co-administration with ergot alkaloids (see section 4.5).
4. 4 and 4. 5).
Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes (see sections 4.4 and 4.5).
4. 5).
Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin (see section 4.5).
3 Overfølsomhed:
Hypersensitivity:
Der bør udøves forsigtighed, når Noxafil ordineres til patienter, som er overfølsomme over for andre azoler.
Caution should be used when prescribing Noxafil to patients with hypersensitivity to other azoles.
Levertoksicitet:
Hepatic toxicity:
Der har været set hepatiske reaktioner (f. eks. milde til moderate forhøjelser af ALT, AST, alkalisk phosphatase og total bilirubin og/ eller klinisk hepatitis) under behandling med posaconazol.
Hepatic reactions (e. g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin and/ or clinical hepatitis) have been reported during treatment with posaconazole.
Monitorering af leverfunktion:
Monitoring of hepatic function:
QTc- forlængelse:
QTc prolongation:
Nogle azoler har været forbundet med forlængelse af QTc- intervallet.
Some azoles have been associated with prolongation of the QTc interval.
4. 3 og 4. 5).
Noxafil must not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong the QTc interval (see sections 4.3 and 4.5).
4. 3).
Noxafil should be administered with caution to patients with pro-arrhythmic conditions such as: • Congenital or acquired QTc prolongation • Cardiomyopathy, especially in the presence of cardiac failure • Sinus bradycardia • Existing symptomatic arrhythmias • Concomitant use with medicinal products known to prolong the QTc interval (other than those mentioned in section 4.3).
Elektrolytforstyrrelser, især dem som er forbundet med kalium -, magnesium - eller calciumniveauer, bør monitoreres og korrigeres efter behov før og under behandling med posaconazol.
Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.
4. 5).
Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances during treatment with other medicinal products that are metabolised by CYP3A4 (see section 4.5).
4. 5).
Concomitant use with posaconazole should be avoided unless the benefit to the patient outweighs the risk (see section 4.5).
Rifamycin antibakterielle midler (rifampicin, rifabutin), visse antiepileptika (phenytoin, carbamazepin, phenobarbital, primidon), efavirenz og cimetidin:
Rifamycin antibacterials (rifampicin, rifabutin), certain anticonvulsants (phenytoin, carbamazepine, phenobarbital, primidone), efavirenz and cimetidine:
4. 5).
Posaconazole concentrations may be significantly lowered in combination; therefore, concomitant use with posaconazole should be avoided unless the benefit to the patient outweighs the risk (see section 4.5).
1, 75 g glucose per 5 ml suspension.
This medicinal product contains approximately 1.75 g of glucose per 5 ml of suspension.
Patienter med glucose- galactose malabsorption bør ikke tage denne medicin.
Patients with glucose-galactose malabsorption should not take this medicine.
Posaconazol metaboliseres via UDP glucuronidering (fase 2 enzymer) og er et substrat for p - glycoprotein (P- gp) efflux in vitro.
Posaconazole is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for p- glycoprotein (P-gp) efflux in vitro.
Hæmmere (f. eks. verapamil, ciclosporin, chinidin, chlarithromycin, erythromycin og andre) eller induktorer (f. eks. rifampicin, rifabutin, visse antiepileptika og andre) af disse eliminationsveje kan således henholdsvis forhøje eller nedsætte posaconazolplasmakoncentrationer.
Therefore, inhibitors (e. g. verapamil, ciclosporin, quinidine, clarithromycin, erythromycin, etc.) or inducers (e. g. rifampicin, rifabutin, certain anticonvulsants, etc.) of these clearance pathways may increase or decrease posaconazole plasma concentrations, respectively.
Rifabutin (300 mg 1 gang dagligt) nedsatte Cmax (maksimal plasmakoncentration) og AUC (arealet under plasmakoncentrationstidskurven) af posaconazol til henholdsvis 57% og 51%.
4 Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole to 57% and 51%, respectively.
Samtidig administration af posaconazol og rifabutin og lignende induktorer (f. eks. rifampicin) bør undgås,
Concomitant use of posaconazole and rifabutin and similar inducers (e. g. rifampicin) should be avoided unless the benefit to the patient outweighs the risk.
Efavirenz (400 mg en gang daglig) nedsatte Cmax og AUC på posaconazol med henholdsvis 45% og 50%.
Efavirenz (400 mg once a day) decreased the Cmax and AUC of posaconazole by 45% and 50%, respectively.
Phenytoin (200 mg 1 gang dagligt) nedsatte Cmax og AUC af posaconazol med henholdsvis 41% og 50%.
Phenytoin (200 mg once a day) decreased the Cmax and AUC of posaconazole by 41% and 50%, respectively.
Samtidig administration af posaconazol og phenytoin og lignende induktorer (f. eks. carbamazepin, phenobarbital, primidon) bør undgås, medmindre fordelen for patienten opvejer risikoen.
Concomitant use of posaconazole and phenytoin and similar inducers (e. g. carbamazepine, phenobarbital, primidone) should be avoided unless the benefit to the patient outweighs the risk.
H2- receptor antagonister og protonpumpehæmmere:
H2 receptor antagonists and proton pump inhibitors:
Posaconazolplasmakoncentrationer (Cmax og AUC) reduceredes med 39%, da posaconazol blev administreret samtidig med cimetidin (400 mg 2 gange dagligt) på grund af reduceret absorption, som muligvis var sekundær til reduktion af mavesyreproduktionen.
Posaconazole plasma concentrations (Cmax and AUC) were reduced by 39% when posaconazole was administered with cimetidine (400 mg twice a day) due to reduced absorption possibly secondary to a decrease in gastric acid production.
Det er ikke undersøgt om andre H2- receptor antagonister (f. eks. famotidin, ranitidin) og protonpumpehæmmere (f. eks. omeprazol), som undertrykker mavesyreproduktionen i flere timer, indvirker på plasmakoncentrationen af posaconazol, men en reduktion af biotilgængeligheden kan forekomme, så samtidig administration bør om muligt undgås.
The effect of other H2 receptor antagonists (e. g. famotidine, ranitidine) and proton pump inhibitors (e. g. omeprazole) that may suppress gastric acidity for several hours on plasma levels of posaconazole has not been studied but a reduction in bioavailability may occur so that co- administration should be avoided if possible.
Virkning af posaconazol på andre lægemidler Posaconazol er en potent hæmmer af CYP3A4.
Posaconazole is a potent inhibitor of CYP3A4.
Hvis posaconazol anvendes sammen med CYP3A4 substrater, som indgives oralt, og for hvilke en stigning i plasmakoncentrationerne kan være forbundet med uacceptable bivirkninger, bør plasmakoncentrationerne af CYP3A4 substrat og/ eller bivirkninger følges nøje, og dosis justeres efter behov.
If posaconazole is used concomitantly with CYP3A4 substrates that are administered orally, and for which an increase in plasma concentrations may be associated with unacceptable adverse events, plasma concentrations of the CYP3A4 substrate and/ or adverse events should be closely monitored and the dose adjusted as needed.
5. 2).
The effect of co- administration with posaconazole on plasma levels of CYP3A4 substrates may also be variable within a patient, unless posaconazole is administered in a strictly standardised way with food, given the large food effect on posaconazole exposure (see section 5.2).
Terfenadin, astemizol, cisaprid, pimozid, halofantrin og chinidin (CYP3A4 substrater):
Terfenadine, astemizole, cisapride, pimozide, halofantrine and quinidine (CYP3A4 substrates):
Samtidig administration af posaconazol og terfenadin, astemizol, cisaprid, pimozid, halofantrin eller chinidin er kontraindiceret.
Co-administration of posaconazole and terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine is contraindicated.
4. 3).
Co-administration may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes (see section 4.3).
Sekalealkaloider:
Ergot alkaloids:
4. 3).
Co-administration of posaconazole and ergot alkaloids is contraindicated (see section 4.3).
HMG- CoA reduktasehæmmere metaboliseres via CYP3A4 (f. eks. simvastatin, lovastatin og atorvastatin):
HMG-CoA reductase inhibitors metabolised through CYP3A4 (e. g. simvastatin, lovastatin, and atorvastatin):
Posaconazol kan øge plasmaniveauerne af HMG- CoA reduktasehæmmere, som metaboliseres af CYP3A4, betydeligt.
Posaconazole may substantially increase plasma levels of HMG-CoA reductase inhibitors that are metabolised by CYP3A4.
4. 3).
5 should be discontinued during treatment with posaconazole as increased levels have been associated with rhabdomyolysis (see section 4.3).
Vincaalkaloider:
Vinca alkaloids:
Posaconazol kan øge plasmakoncentrationen af vincaalkaloider (f. eks. vincristin og vinblastin), hvilket kan føre til neurotoksicitet.
Posaconazole may increase the plasma concentration of vinca alkaloids (e. g. vincristine and vinblastine), which may lead to neurotoxicity.
5 vincaalkaloider bør derfor undgås, medmindre fordelen for patienten opvejer risikoen.
Therefore, concomitant use of posaconazole and vinca alkaloids should be avoided unless the benefit to the patient outweighs the risk.
Posaconazol øgede Cmax og AUC af rifabutin med henholdsvis 31% og 72%.
Posaconazole increased the Cmax and AUC of rifabutin by 31% and 72%, respectively.
Hvis disse lægemidler administreres samtidigt, anbefales omhyggelig monitorering af fuldt blodbillede og bivirkninger relateret til forhøjede rifabutinniveauer (f. eks. uveitis).
If these medicinal products are co-administered, careful monitoring of full blood counts and adverse events related to increased rifabutin levels (e. g. uveitis) is recommended.
Ciclosporin:
Ciclosporin:
Posaconazol 200 mg en gang dagligt øgede ciclosporinkoncentrationerne hos hjertetransplanterede patienter på stabil dosis af ciclosporin, hvilket medførte behov for dosisnedsættelser.
In heart transplant patients on stable doses of ciclosporin, posaconazole 200 mg once daily increased ciclosporin concentrations requiring dose reductions.
Når behandling med posaconazol initieres hos patienter, der allerede modtager ciclosporin, bør ciclosporin dosis nedsættes (f. eks. til omkring tre fjerdedele af den aktuelle dosis).
When initiating treatment with posaconazole in patients already receiving ciclosporin, the dose of ciclosporin should be reduced (e. g. to about three quarters of the current dose).
Posaconazol øgede Cmax og AUC af tacrolimus (0, 05 mg/ kg kropsvægt som enkeltdosis) med henholdsvis 121% og 358%.
Posaconazole increased Cmax and AUC of tacrolimus (0.05 mg/ kg body weight single dose) by 121% and 358%, respectively.
I kliniske effektundersøgelser rapporteredes klinisk signifikante interaktioner, som resulterede i hospitalsindlæggelse og/ eller afbrydelse af behandling med posaconazol.
Clinically significant interactions resulting in hospitalisation and/ or posaconazole discontinuation were reported in clinical efficacy studies.
Når behandling med posaconazol initieres hos patienter, der allerede får tacrolimus, bør dosis af tacrolimus nedsættes (f. eks. til ca. en tredjedel af den aktuelle dosis).
When initiating posaconazole treatment in patients already receiving tacrolimus, the dose of tacrolimus should be reduced (e. g. to about one third of the current dose).
Gentagen administration af oralt posaconazol (400 mg to gange daglig i 16 dage) øgede Cmax og AUC af sirolimus (2 mg enkelt dosis) med henholdsvist et gennemsnit på 6, 7 gange og 8, 9 gange (interval 3, 1 til 17, 5 gange) hos raske forsøgspersoner.
Repeat dose administration of oral posaconazole (400 mg twice daily for 16 days) increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 6.7-fold and 8.9-fold (range 3.1 to 17.5-fold), respectively, in healthy subjects.
Sirolimusdosis justeres i overensstemmelse hermed.
Sirolimus concentrations should be measured upon initiation, during co-administration, and at discontinuation of posaconazole treatment, with sirolimus doses adjusted accordingly.
Som resultat heraf må dalkoncentrationer af sirolimus, der ligger inden for det sædvanlige terapeutiske indeks, resultere i sub- terapeutiske niveauer.
As a result, sirolimus trough concentrations that fall within the usual therapeutic range may result in sub-therapeutic levels.
HIV- Proteasehæmmere:
HIV Protease Inhibitors:
Da HIV- proteasehæmmere er CYP3A4- substrater forventes det, at posaconazol vil øge plasmaniveauer af disse antiretrovirale midler.
As HIV protease inhibitors are CYP3A4 substrates, it is expected that posaconazole will increase plasma levels of these antiretroviral agents.
Efter samtidig indtagelse af oralt posaconazol (400 mg to gange daglig) med atazanavir (300 mg en gang daglig) i 7 dage hos raske forsøgspersoner øgedes Cmax og AUC for atazanavir med et gennmsnit på henholdsvis 2, 6 gange og 3, 7 gange (interval 1, 2 til 26 gange).
Following co-administration of oral posaconazole (400 mg twice daily) with atazanavir (300 mg once daily) for 7 days in healthy subjects Cmax and AUC of atazanavir increased by an average of 2.6-fold and 3.7-fold (range 1.2 to 26- fold), respectively.
Efter samtidig indtagelse af oralt posaconazol (400 mg to gange daglig) med atazanavir og ritonavir (300/ 100 mg en gang daglig) i 7 dage hos raske forsøgspersoner øgedes Cmax og AUC for atazanavir med et gennemsnit på henholdsvis 1, 5 gange og 2, 5 gange (interval 0, 9 til 4, 1 gange).
Following co-administration of oral posaconazole (400 mg twice daily) with atazanavir and ritonavir (300/ 100 mg once daily) for 7 days in healthy subjects Cmax and AUC of atazanavir increased by an average of 1.5-fold and 2.5-fold (range 0.9 to 4.1-fold), respectively.
Der anbefales hyppig monitorering for bivirkninger og toksicitet relateret til antiretrovirale midler, der er CYP3A4 substrater under samtidig indtagelse med posaconazol.
6 to antiretroviral agents that are substrates of CYP3A4 is recommended during co-administration with posaconazole.
Midazolam og andre benzodiazepiner som metaboliseres af CYP3A4:
Midazolam and other benzodiazepines metabolised by CYP3A4:
I et studie med raske frivillige øgede posaconazol (200 mg en gang daglig i 10 dage) eksponeringen (AUC) af IV midazolam
In a study in healthy volunteers posaconazole (200 mg once daily for 10 days) increased the exposure (AUC) of IV midazolam (0.05 mg/ kg) by 83%.
I et andet studie med raske frivillige øgede gentagen administration af oralt posaconazol (200 mg to gange daglig i 7 dage) Cmax og AUC af IV midazolam (0, 4 mg enkelt dosis) med et gennemsnit på henholdsvis 1, 3 og 4, 6 gange (interval 1, 7 til 6, 4 gange); Posaconazol 400 mg to gange daglig i 7 dage øgede IV midazolam Cmax og AUC med henholdsvis 1, 6 og 6, 2 gange (interval 1, 6 til 7, 6 gange).
In another study in healthy volunteers, repeat dose administration of oral posaconazole (200 mg twice daily for 7 days) increased the Cmax and AUC of IV midazolam (0.4 mg single dose) by an average of 1.3- and 4.6-fold (range 1.7 to 6.4-fold), respectively; Posaconazole 400 mg twice daily for 7 days increased the IV midazolam Cmax and AUC by 1.6 and 6.2-fold (range 1.6 to 7.6-fold), respectively.
Begge doser af posaconazol øgede Cmax og AUC af oralt midazolam (2 mg enkelt oral dosis) med henholdsvis 2, 2 og 4, 5 gange.
Both doses of posaconazole increased Cmax and AUC of oral midazolam (2 mg single oral dose) by 2.2 and 4.5-fold, respectively.
Oralt posaconazol (200 mg eller 400 mg) forlængede ydermere middelterminalhalveringstiden af midazolam fra omkring 3- 4 timer til 8- 10 timer under samtidig indtagelse.
In addition, oral posaconazole (200 mg or 400 mg) prolonged the mean terminal half-life of midazolam from approximately 3-4 hours to 8- 10 hours during co-administration.
Som følge af risikoen for forlænget sedering, anbefales det at dosisjustering bør overvejes, når posaconazol gives samtidig med ethvert benzodiazepin, der metaboliseres af CYP3A4 (f. eks. midazolam, triazolam, alprazolam).
Due to the risk of prolonged sedation it is recommended that dose adjustments should be considered when posaconazole is administered concomitantly with any benzodiazepine that is metabolised by CYP3A4 (e. g. midazolam, triazolam, alprazolam).
Calciumantagonister metaboliseret via CYP3A4 (f. eks. diltiazem, verapamil, nifedipin, nisoldipin):
Calcium channel blockers metabolised through CYP3A4 (e. g. diltiazem, verapamil, nifedipine, nisoldipine):
Der anbefales hyppig monitorering for bivirkninger og toksicitet relateret til calciumantagonister ved administration sammen med posaconazol.
Frequent monitoring for adverse events and toxicity related to calcium channel blockers is recommended during co-administration with posaconazole.
Sulfonylureas:
Sulfonylureas:
Glucosekoncentrationerne faldt hos nogle raske forsøgspersoner, da glipizid administreredes samtidig med posaconazol.
Glucose concentrations decreased in some healthy volunteers when glipizide was co- administered with posaconazole.
5. 3).
Posaconazole is excreted into the milk of lactating rats (see section 5.3).
Sikkerheden af posaconazol er vurderet hos > 2. 400 patienter og frivillige raske forsøgspersoner i kliniske studier og på baggrund af post- marketing erfaring.
The safety of posaconazole has been assessed in > 2,400 patients and healthy volunteers enrolled in clinical trials and from post-marketing experience.
7 Tabel 2.
7 Blood and lymphatic system disorders Common:
neutropeni thrombocytopeni, leukopeni, anæmi, eosinofili, lymfadenopati
neutropenia thrombocytopenia, leukopenia, anaemia, eosinophilia, lymphadenopathy
hæmolytisk uræmisk syndrom, thrombotisk thrombocytopenisk purpura, pancytopeni, koagulopati, blødning
haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, pancytopenia, coagulopathy, haemorrhage
Øjensygdomme Usædvanlig:
Uncommon:
Langt QT syndrom§, unormalt elektrokardiogram§, palpitationer
long QT syndrome§, electrocardiogram abnormal§, palpitations
torsade de pointes, pludselig død, ventrikulær takykardi, kardio- respiratorisk stop, nedsat hjertefunktion, myokardieinfarkt
torsade de pointes, sudden death, ventricular tachycardia, cardio-respiratory arrest, cardiac failure, myocardial infarction
pulmonal hypertension, interstitiel pneumoni, pneumonitis
Respiratory, thoracic and mediastinal disorders Rare: pulmonary hypertension, interstitial pneumonia, pneumonitis Gastrointestinal disorders Common:
opkastning, kvalme, abdominal smerte, diarre, dyspepsi, mundtørhed, flatulens
vomiting, nausea, abdominal pain, diarrhoea, dyspepsia, dry mouth, flatulence
pancreatitis blødning i mave/ tarm, ileus
pancreatitis gastrointestinal haemorrhage, ileus
forhøjet leverfunktionstests (øget ALT, øget AST, øget bilirubin, øget alkalisk fosfatase, øget GGT)
liver function tests raised (ALT increased, AST increased, bilirubin increased, alkaline phosphatase increased, GGT increased)
Usædvanlig:
Rare:
hepatocellulær ødelæggelse‫, ٭ ‬hepatitis, gulsot, hepatomegali
hepatocellular damage*, hepatitis, jaundice, hepatomegaly hepatic failure, hepatitis cholestatic, cholestasis,
8
8 hepatosplenomegaly, liver tenderness, asterixis
Sygdomme i hud og subkutane væv
Skin and subcutaneous tissue disorders Common:
Sygdomme i bevægeapparatet og bindevæv
rash mouth ulceration, alopecia Stevens Johnson syndrome, vesicular rash
udslæt mundsår, alopeci Stevens Johnson- syndrom, vesikulært udslæt
Musculoskeletal and connective tissue disorders
Lidelser i det reproduktive system og brystsygdomme Usædvanlig:
Reproductive system and breast disorders Uncommon:
4. 4.
Uncommon: § See section 4.4.
4. 4).
hepatic injury with fatal outcome has been reported (see section 4.4).
Under kliniske undersøgelser havde patienter, som fik posaconazol i doser op til 1. 600 mg/ dag, ikke oplevet andre bivirkninger end dem, der blev observeret hos patienter på lavere doser.
During clinical trials, patients who received posaconazole doses up to 1,600 mg/ day experienced no different adverse reactions from those reported with patients at the lower doses.
Uforsætlig overdosering sås hos en patient, som tog 1. 200 mg to gange dagligt i 3 dage.
Accidental overdose was noted in one patient who took 1,200 mg twice a day for 3 days.
Antimykotika til systemisk anvendelse – triazolderivater ATC- kode:
Antimycotics for systemic use-triazole derivatives, ATC code:
Virkningsmekanisme Posaconazol hæmmer enzymet lanosterol 14α- demetylase (CYP51), som katalyserer et essentielt trin i ergosterol biosyntesen.
Mechanism of action Posaconazole inhibits the enzyme lanosterol 14α -demethylase (CYP51), which catalyses an essential step in ergosterol biosynthesis.
Mikrobiologi Posaconazol har in vitro vist effekt over for følgende mikroorganismer:
9 Microbiology Posaconazole has been shown in vitro to be active against the following microorganisms:
Aspergillus arter (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), Candida arter (Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis), Coccidioides immitis, Fonsecaea pedrosoi, og arter af Fusarium, Rhizomucor, Mucor og Rhizopus.
Aspergillus species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), Candida species (Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis), Coccidioides immitis, Fonsecaea pedrosoi, and species of Fusarium, Rhizomucor, Mucor, and Rhizopus.
Resistens 9 Kliniske isolater med nedsat følsomhed over for posaconazol er set.
Resistance Clinical isolates with decreased susceptibility to posaconazole have been identified.
Der foreligger imidlertid endnu ikke klinisk bevis for at kombinationsbehandling vil føre til øget effekt.
Combination with other antifungal agents The use of combination antifungal therapies should not decrease the efficacy of either posaconazole or the other therapies; however, there is currently no clinical evidence that combination therapy will provide an added benefit.
Farmakokinetiske / Farmakodynamiske relationer:
Pharmacokinetic / Pharmacodynamic relationships:
Der er fundet korrelation imellem den totale eksponering af lægemiddel divideret med MIC (AUC/ MIC) og den kliniske effekt.
A correlation between total medicinal product exposure divided by MIC (AUC/ MIC) and clinical outcome was observed.
4. 2 og 5. 2 doseringsvejledning og virkning af føde på absorption).
It is particularly important to try to ensure that maximal plasma levels are achieved in patients infected with Aspergillus (see sections 4.2 and 5.2 on recommended dose regimens and the effects of food on absorption).