Posaconazole
When ATH:
J02AC04
Pharmacological action
Antifungal agent with a broad spectrum of antifungal activity. It inhibits the enzyme lanosterol14α-demethylase (SYR51), which catalyzes an important step ergosterol biosynthesis, main component of the cytoplasmic membrane of fungi.
It is active against yeast and mold pathogens fungal infections, including strains, resistant to fluconazole, vorikonazolu, itraconazole and amphotericin B.
Active against Candida species (FROM. albicans, FROM. glabrata, FROM. krusei, FROM. parapsilosis, FROM. Portugal), Aspergillus species (A. fumigatus, A. yellow, A. Terreus, A. nidulans, A. niger, A. justice, A. ochraceous), Absida spp., Cryptococcus neoformans, Merciless coccidioides, Fonsecaea pedrosoi, Histoplasma capsulatum, Pseudallescheria boydii, Alternaria spp., Exophiala spp., Fusarium spp, Ramichloridium spp., Rhizomucor spp., Mucor spp, Rhizopus spp.
In experiments in vitro studies also demonstrated activity in respect of posaconazole following microorganisms: genus Candida (FROM. of Dublin, FROM. bands, FROM. guilliermondiiText, FROM. Portugal, FROM. kefir. FROM. rough, FROM. tropicalis, FROM. zeylanoides, FROM. invisible, FROM. lipolytica, FROM. Norwegian, FROM. pseudotropicalis), Cryptococcus Lawrence, Kluyveromyces marxianus, Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia spp., Trichosporon spp., Aspergillus sydowii, Bjerkandera crackle, Blastomyces dermatitidis, Epidermophyton floccosum, P. brasiliensis, Pcedosporium apiospermum, Sporothrix schenckii, Wangiella dermatitidis, Absida spp., Apophysomyces spp, Bipolaris spp., Curvularia spp., Microsporum spp, Paecilomyces spp., Penicillium spp., Trichophyton spp. However, in clinical studies, the efficacy and safety of posaconazole in the treatment of infections, caused by these microorganisms, not investigated.
Under laboratory conditions, it was not possible to obtain strains of Candida albicans, resistant to posaconazole. Spontaneously mutated strains of Aspergillus fumigatus laboratory, showed a decrease in sensitivity to posaconazole, occurred at a frequency of 1×108 1×109. Clinical isolates of Candida albicans and Aspergillus fumigatus with reduced susceptibility to posaconazole rare. In these rare cases it is not established a distinct relationship between reduced susceptibility to posaconazole and clinical failure. There are cases of clinical efficacy of posaconazole in mycosis, caused by resistant to azole antifungal agents or amphotericin B, against which posaconazole was active in vitro. The criteria for clinical significance of in vitro susceptibility of any fungi to posaconazole is not installed.
Pharmacokinetics
Absorption
After oral administration, the duration of absorption of posaconazole is 3-5 no. Posaconazole different linear pharmacokinetics in single or multiple doses prior to admission 800 mg. At doses more 800 mg / increase the pharmacokinetic parameters there is no. Changing the pH of gastric contents will not affect the absorption of posaconazole. As compared with the fasted, Posaconazole AUC when taken with a low-fat diet or supplementation (14 g fat) increases about 2.6 times, and when taken with fatty foods (about 50 g fat) – in 4 times.
Division of the daily dose into two doses (by 400 mg) It leads to increased pharmacokinetic parameters for 184% compared to the single administration 800 mg.
Distribution
Posaconazole has a high Vd (1774 l), It is indicating a significant tissue distribution. Plasma protein binding (mostly to albumin) – more 98%. The equilibrium state is achieved after 7-10 day multiple dose.
Metabolism
Posaconazole does not constitute active circulating metabolites, unlikely, that its concentration altered by inhibitors of CYP450 isoenzymes. Of the circulating metabolites account for the bulk of glucuronide conjugates of posaconazole, and a small fraction of the metabolites, oxidation involving CYP450 isoenzymes.
Deduction
Posaconazole is slowly eliminated from the body, average T1 / 2 is 35 no (20-66 no), and the total clearance 32 l /. Write mainly through the intestine (77%), wherein 66% accounted for unmodified substance. Renal clearance is approximately 14% (the starting material is less than 0.2%). Excretion via the kidneys and intestines as metabolites is about 17% of the administered dose.
Pharmacokinetics in special clinical situations
After applying a daily dose of posaconazole 800 mg, divided into several times, plasma concentration in patients aged 8-17 years was comparable to the levels in patients aged 18-64 years (average, 776 ng / ml 817 ng / ml). Pharmacokinetic data for children under 8 years not available.
Older people have pointed to an increase in Cmax 26% and AUC of 29% compared to people aged 18-45 years. However, in clinical studies, the safety performance of posaconazole in young and elderly were similar. Therefore, dose adjustments depending on the age is required.
The pharmacokinetics of posaconazole is not dependent on sex.
There was a slight (on 16%) decrease in AUC and Cmax of posaconazole in patients Blacks compared to Caucasians. Dose adjustments depending on the race not required.
When a single application posaconazole renal insufficiency of mild to moderate severity did not affect the pharmacokinetics of the drug, therefore, dose adjustment in these patients is not required. In patients with severe renal insufficiency AUC of posaconazole vary greatly (coefficient of variation 96%) in comparison with other patients with renal insufficiency (coefficient of variation <40%). But, since the renal clearance is negligible posaconazole, unlikely, that severe renal impairment on the pharmacokinetics of the drug effect, therefore dose adjustment is required in this case.
In patients with hepatic insufficiency was an increase in T1 / 2 (26.6, 35.3 and 46.1 h for mild hepatic insufficiency, moderate and severe classification Child-Pugh respectively), compared to patients with normal liver function. Due to the limited pharmacokinetic data, recommendations for dose adjustment in patients with hepatic impairment have not been developed.
Testimony
Treatment of invasive fungal infections, * refractory to amphotericin B, itraconazole or fluconazole, or intolerance of these drugs: invasive candidiasis, esophageal candidiasis, invasive aspergillosis, zigomikoz (mukormikoz), kryptokokkoz, fuzarioz, xromomikoz, mycetoma, kokcidioidoz.
Orofaringealynogo treating candidiasis – first-line therapy in patients with severe disease or immunocompromised, which is not expected to effect substantial application of topical preparations.
Prevention of invasive fungal infections in lowered immunity and increased risk of such infections in hematological patients with prolonged neutropenia due to chemotherapy; transplant recipients hematopoietic stem cells, receiving high doses immunosulressorov.
* Refractivity considered progression of infection or lack of improvement of the patient after treatment for 7 days (when candidemia – during 3 days, candidiasis of the esophagus – during 14 days, with other forms of invasive candidiasis 7 days).
Dosage regimen
For the treatment of invasive fungal infections appoint 400 mg 2 Patients, which can not take the drug with food or food additives, It is encouraged to nominate for 200 mg 4 The duration of therapy depends on the severity of the underlying disease of the patient, immunodeficiency and the effectiveness of the treatment.
For the treatment of candidiasis orofaringealnsgo the first day of treatment prescribed 200 mg 1 time / (vvodnaya dose), then 100 mg 1 times / over the next 13 days.
For the treatment of oropharyngeal candidiasis, refractory to itrakonazopu and / or fluconazole appoint 400 mg 2 The duration of therapy depends on the severity of the underlying disease of the patient and the efficiency of the treatment.
Increasing the dose posaconazole over 800 mg / does not lead to more effective treatments.
For the prevention of invasive fungal infections appoint 200 mg 3 The duration of preventive treatment depends on the duration of neutropenia in hematological patients, or severity of immunosuppression in recipients of hematopoietic stem cell transplants. In patients with acute myeloid leukemia or myelodysplastic syndrome, prophylactic treatment should be started several days before the anticipated onset of neutropenia and continue for 7 days after the increase in the number of neutrophils to the level of more than 500 cells / mm.
If the kidney function dose adjustment is required.
The pharmacokinetic data on the use of posaconazole with abnormal liver function are limited, therefore recommendations for dose adjustment in these patients have not been developed. A small number of patients with impaired liver function, an increase in T1 / 2 of posaconazole.
The drug should be taken with food. Patients, which can not combine the drug with a normal diet, to improve absorption of posaconazole should take the drug at the same time taking liquid nutraceutical.
Side effect
Frequently – nausea (6%) and headache (6%).
The frequency of side effects: often (>1/100, <1/10), sometimes (>1/1000, <1/100), rarely (>1/10000, <1/1000).
From the hematopoietic system: often – neutropenia; sometimes – thrombocytopenia, leukopenia, anemia, eozinofilija, lymphadenopathy; rarely – hemolytic uremic syndrome, tromboticheskaya trombotsitopenicheskaya purpura, pancytopenia, bleeding (unspecified).
From the blood coagulation system: rarely – blood coagulation disorders (unspecified).
On the part of the endocrine system: rarely – adrenal insufficiency, reduction of gonadotropins.
From the central and peripheral nervous system: often – paresthesia, dizziness, drowsiness, headache; sometimes – convulsions, Neuropathy, gipesteziya, tremor; rarely – fainting, encephalopathy, perifericheskaya neuropathy, psychosis, depression.
From the senses: sometimes – blurred vision; rarely – diplopia, scotoma (visual field defects), hearing loss.
Cardio-vascular system: sometimes – lengthening the interval QTc / QT, ECG changes, palpitation, increase or decrease in blood pressure; rarely – type of ventricular arrhythmia “pirouette”, sudden death, ventricular tachycardia, cardiac arrest and respiratory, heart failure, myocardial infarction, cerebrovascular accident, pulmonary embolism, deep vein thrombosis (unspecified).
The respiratory system: rarely – pulmonary hypertension, interstitial pneumonia, pneumonitis.
From the digestive system: often – vomiting, nausea, abdominal pain, diarrhea, dyspepsia, flatulence, dry mouth, abdominal distention, anorexia, increased ALT, ACT, Alkaline phosphatase, GGT, increase of bilirubin in the blood; sometimes – pancreatitis, hepatocyte damage, ulceration of the mucous membrane of the mouth; rarely – gastrointestinal bleeding, bowel obstruction, hepatic failure, cholestatic hepatitis, cholestasis, hepatosplenomegaly, liver tenderness, asteriksis (liver tremor).
Dermatological reactions: often – skin rash; sometimes – alopecia; rarely – vesicular rash.
On the part of the musculoskeletal system: sometimes – backache.
From the urinary system: sometimes – acute renal failure, renal failure, elevation of serum creatinine; rarely – interstitial nephritis, renal tubular acidosis.
On the part of the reproductive system: sometimes – menstrual irregularities; rarely – breast tenderness.
Other: often – fever, asthenia, fatigue; sometimes – swelling, weakness, pain, chills, malaise; rarely – swelling of the tongue, swelling of the face.
Allergic reactions: sometimes – anaphylactic reactions; rarely – Stevens-Johnson syndrome, hypersensitivity reactions.
From the laboratory parameters: often – electrolyte imbalance; sometimes – giperglikemiâ.
Contraindications
The combined use of ergot alkaloids (due to the risk of increasing the concentration of ergot alkaloids in the blood and the development ergotism); concomitant use with CYP3A4 substrates – terfenadine, astemizolom, cizapridom, pimozidom, halofantrine or quinidine (due to the risk of increasing the concentration of active substances in the blood, subsequent QTc prolongation and, rarely, type of ventricular arrhythmias “pirouette”; Combined use of inhibitors of HMG-CoA reductase – simvastatin, lovastatin, atorvastatin (in connection with the risk of increasing concentrations of these drugs in the blood and rhabdomyolysis); hypersensitivity to posaconazole.
To use caution in case of hypersensitivity to other azole compounds history, with severe liver dysfunction, congenital or acquired QTc prolongation, when cardiomyopathy (especially in conjunction with heart failure), when sinus bradycardia, when diagnosed symptomatic arrhythmia, coadministration with drugs, prolonging the QTc interval (other than those listed above), due to increased risk of heart rhythm disorders.
Pregnancy and breast-feeding
Information on the safety of posaconazole during pregnancy and lactation is not enough. Use of the drug during pregnancy is possible only in case, when the intended benefits to the mother outweighs the potential risk to the fetus. If necessary, use during lactation should decide the issue of termination of breastfeeding.
In experimental animal studies revealed toxic effect of the drug on the fetus. Posaconazole is excreted in the milk of lactating rats.
Cautions
Treatment can begin, without waiting for the results of microbiological studies, but after receiving them should make adequate correction of antifungal therapy.
Information about cross-sensitivity between posaconazole and other azole antifungal compounds there, However, caution should be exercised in the appointment of posaconazole to patients with hypersensitivity to other azoles.
In clinical studies, it was recorded reports of changes in liver function (eg, Low to moderate increase in ALT, ACT, ALP and total bilirubin in serum) during treatment with posaconazole. These reactions are observed, mainly, in patients with severe underlying diseases (eg, hematological) and they were not grounds for termination of therapy. Improving indicators of liver function tests were reversible and ends after cessation of therapy, and in some cases there is a normalization of functional parameters to discontinuation of therapy.
Care should be taken when appointing posaconazole to patients with severe hepatic impairment. In such patients, the elongation T1 / 2 of posaconazole can exacerbate its action. Patients, who during therapy with posaconazole noted abnormal liver function according to laboratory studies, should be under the supervision of clinical development for the prevention of more serious damage to the liver. Monitoring should include laboratory monitoring of liver function (in particular, determination of ALT, ACT, ALP and total bilirubin in serum).
Electrolyte balance should be monitored, especially the potassium content, magnesium and calcium, and optionally, make appropriate correction before and during posaconazole therapy.
Data on the pharmacokinetics in patients with severe gastrointestinal dysfunction, which may lead to lower concentrations of posaconazole in the blood (eg, in severe diarrhea or vomiting), limited. Such patients should be carefully monitored for timely detection of possible activation of fungal infection.
Use in Pediatrics.
The efficacy and safety of posaconazole in children under the age of 13 years have not been established.
Effects on ability to drive vehicles and management mechanisms
Data on the impact of posaconazole on the ability to drive and there are no other mechanisms.
Overdose
Patients, received posaconazole doses up to 1600 mg /, revealed no additional adverse reactions compared to those, who received lower doses. Accidental overdose was noted in one patient, who took the drug for 1200 mg 2 during 3 days. Adverse reactions, associated with overdose, this patient was not observed.
Posaconazole is not displayed in hemodialysis.
Drug Interactions
Posaconazole metaboliziruetsя putem glюkuronirovaniя UDF (enzymatic reaction phase II) and the substrate for removing the p-glycoprotein in vitro. Thus, inhibitors (incl. verapamil, cyclosporine, quinidine, clarithromycin, erythromycin and others.) or inductors (incl. rifampicin, rifabutin, Some anticonvulsants.) This pathway may be increased or decreased, respectively, plasma concentrations of posaconazole.
Efavirenz (400 mg 1 time /) reduces Cmax and AUC of posaconazole on 45% and 50% respectively, and therefore should avoid joint use of these drugs.
Rifabutin (300 mg 1 time /) reduces Cmax and AUC of posaconazole on 57% and 51 % respectively. Posaconazole uvelichivaet Cmax and AUC of rifabutin 31 % and 72% respectively. Avoid joint use of posaconazole and rifabutin and similar inducers (eg, rifampicin), if the benefits of a joint application does not exceed its risks for the patient. In a joint application of these drugs is recommended to carefully monitor the blood count and the presence of side effects, related to the high concentration of rifabutin (eg, uveitis).
Phenytoin (200 mg 1 time /) reduces Cmax and AUC of posaconazole on 41 % and 50% respectively. Avoid joint use of posaconazole and phenytoin and similar inducers (eg, karʙamazepina, fenoʙarʙitala, prymydona), if the benefits of a joint application does not exceed its risks for the patient.
Perhaps the reduction in the Cmax and AUC of posaconazole on 39%, while the application of posaconazole with cimetidine (400 mg 2). This is due to a decrease in absorption, probably due to the decrease in gastric acidity. Effect of other H2 receptor antagonists or proton pump inhibitors, capable of reducing the acidity of gastric juice for a few hours, concentration in plasma posaconazole has not been studied, however, due to a possible decrease posaconazole bioavailability should be, possibly, Avoid combining it with these drugs.
Posaconazole is an inhibitor of CYP3A4, and, if the patient is already taking drugs, metabolized with the participation of isoenzyme, the posaconazole should be used only in the event, where the benefits of the combination therapy did not exceed the risk to the patient.
The introduction in the dose posaconazole 200 mg 1 time / increases the concentration of midazolam – the CYP3A4 substrate – on 83% after / in the. Use caution when coadministered drugs, and posaconazole, which are substrates of the CYP3A4 isoenzyme, input / in, This may require dose reduction last. Effect of substrate concentration on posaconazole CYP3A4 in plasma when administered orally is not known, but can be expected, that it will be much more pronounced, than with on / in a substrate. If posaconazole is used with oral CYP3A4 substrates, that at higher concentrations in plasma can cause serious adverse effects, it should carefully monitor their blood concentrations and monitor the possible development of adverse events, if necessary, reducing their dose.
Care should be taken while applying benzodiazepines, which are metabolized by the CYP3A4 isoenzyme.
The combined use of terfenadine, astemizola, cisapride, pimozida, halofantrine or quinidine is contraindicated with posaconazole, tk. may lead to increased concentrations of these drugs in plasma, followed QT prolongation and, rarely, type of ventricular arrhythmias “pirouette”.
Posaconazole may substantially increase the blood concentration of HMG-CoA reductase (eg, simvastatin, lovastatin and atorvastatin), which are metabolized by the CYP3A4 isoenzyme. During treatment with posaconazole receiving HMG-CoA reductase inhibitors should be discontinued, because increasing the concentration of these substances in the blood is associated with the development of rhabdomyolysis.
In a joint application with posaconazole it is often recommended to control the side effects and toxic reactions, associated with the action of calcium channel blockers (eg, diltiazem, verapamil, nifedipine, nisoldipine), and, if necessary, adjust the dose of these drugs,
Since HIV protease inhibitors are substrates of CYP3A4, can be expected, posaconazole which increases their concentration in the blood. In healthy volunteers the use of posaconazole (400 mg 2 during 7 days) increases Cmax and AUC of atazanavir (300 mg 1 time / within 7 days) on average 2.6 times and 3.7 fold, respectively. The use of posaconazole in healthy volunteers (400 mg 2 during 7 days) increases Cmax and AUC of atazanavir to a lesser extent when coadministered with ritonavir (300 mg and atazanavir 100 mg ritonavir 1 time / within 7 days) – on average 1.5 times and 2.5 fold, respectively. Patients, taking these drugs together with posaconazole, should be under close clinical observation to identify possible toxic reactions.
Non-nucleoside reverse transcriptase inhibitors are substrates isoenzyme SYRZA4. It can be expected, that posaconazole increases their concentration. Patients, taking these drugs together with posaconazole, should be under close clinical observation to identify possible toxic reactions.
Posaconazole may increase the blood concentration of ergot (ergotamine and dihydroergotamine), which can lead to poisoning – ergotism (concomitant use is contraindicated).
Posaconazole may increase the blood concentration of vinca alkaloids (eg, vincristine and vinblastine), which can cause neurotoxic reaction (Avoid sharing application). If necessary, the joint use of these drugs is recommended to adjust the dose of vinca alkaloid.
Patients, heart transplant and receiving a stable dose of cyclosporine, posaconazole increases the concentration of cyclosporine in the blood, which requires a reduction of dose. In studies on the clinical efficacy have been reported cases of serious side effects, caused an increase in the blood concentration of cyclosporin, including nephrotoxic reactions and one case of fatal leukoencephalopathy. It is recommended to monitor levels of cyclosporine in the blood before starting treatment with posaconazole, during treatment and after its termination, adaptïrwya, if necessary, dose cyclosporine.
Posaconazole increases Cmax and AUC of tacrolimus (single dose – 0.05 mg / kg body weight) on 121% and 358% respectively. In studies on the clinical efficacy have been reported cases of clinically significant drug interactions, require hospitalization and / or discontinuation of posaconazole. In the appointment of posaconazole to patients, receiving tacrolimus, dose of the latter should be reduced (eg, to 1/3 the current dose). After the start of the joint use of drugs and at the end of the use of posaconazole should carefully monitor the level of tacrolimus in the blood and, if necessary, adjust the dose.
In healthy volunteers the use of posaconazole (400 mg 2 during 16 days) increases Cmax and AUC of sirolimus (2 mg 1 time /) on average 6.7 times 8.9 times, respectively,.
When concomitant administration with sirolimus, the last dose should be reduced (eg, to 1/10 from the received dose). Thus it is often necessary to monitor the concentration of sirolimus in the blood. It is recommended to control the level of sirolimus in the blood before starting treatment with posaconazole, during treatment and after its termination, korrektiruя, if necessary, the dose of sirolimus.
Clinical studies have shown no clinically significant interaction between zidovudine, lamivudine, ritonavir and indinavir with posaconazole, in connection with the joint application of correction dosing regime is not required.
Known, that the introduction of azoles was associated with increased digoxin. Therefore, posaconazole may also increase the concentration of digoxin in the blood, in this connection, should control the level of co-administering with posaconazole and after combination therapy.
Some healthy volunteers in the combined use of posaconazole and glipizide decreased glucose. It is recommended to monitor blood glucose levels in diabetic patients, receiving sulfonylureas and posaconazole.
In the study of posaconazole combinations with amphotericin B or caspofungin in vitro and in vivo, there was little or no antagonism was detected antifungals, In some cases, there is an additive effect. The clinical significance of these findings is not defined.
