Aprepitant

When ATH:
A04AD12

Characteristic.

Antiemetic. White or almost white solid, practically insoluble in water, hardly soluble in ethanol and isopropyl acetate and slightly soluble acetonitrile. Molecular weight 534,43.

Pharmacological action.
Antiemetic.

Application.

For prevention of acute and delayed nausea and vomiting, causes high- umerennoemetogennymi or anticancer drugs (in combination with other antiemetic agents).

Contraindications.

Hypersensitivity, severe liver failure (>9 points on the Child-Pugh); concurrent use with pimozide, terfenadine, astemizole, and cisapride (cm. "Interaction").

Restrictions apply.

Childhood (safety and efficacy of aprepitant has not been studied in children).

Pregnancy and breast-feeding.

Teratogenic effects. Research teratogenicity, conducted in rats using oral doses of up to 1000 mg / kg twice a day (плазменная AUC_{0–24 ч} - About 1,6 exposure in humans at the recommended dose) and in rabbits at oral doses of up to 25 mg / kg / day (плазменная AUC_{0–24 ч} - About 1,4 exposure in humans at the recommended dose) showed no impaired fertility or malformations in the fetus. Adequate and well-controlled clinical studies safety of pregnancy has not been, Therefore, the appointment during pregnancy is not recommended.

Category actions on the fetus by the FDA — B. (The study of reproduction in animals revealed no risk of adverse effects on the fetus, and adequate and well-controlled studies in pregnant women have not done.)

Aprepitant is excreted in the milk of rats. Unknown, whether aprepitant is allocated with breast milk in humans. If necessary, use during lactation should decide the issue of termination of breastfeeding due to the risk of unwanted effect of aprepitant on infant (potentsialyno carcinogenic, что показано в исследованиях у грызунов).

Side effects.

Two well-controlled clinical trials in patients, vysokoemetogennuyu receiving anticancer therapy, 544 of patients receiving aprepitant 1 cycle of chemotherapy. Aprepitant was administered in combination with ondansetron and dexamethasone. In most cases, side effects, identified during studies, It was mild to moderate. In the loop 1 Side effects were observed in approximately 69% patients, poluchavshih aprepitant, compared to 68% patients, are on standard therapy. The table below shows adverse effects, observed with a frequency of ≥3%.

Table

Side effects, marked during the treatment cycle vysokoemetogennoy 1 during clinical trials aprepitant

Besides, We note the following clinically significant side effects (the frequency of occurrence >0,5% and higher, than with standard therapy) regardless of the causal relationship with the reception of aprepitant:

Body as a Whole: increased sweating, swelling, tides, malaise, malignant tumor, pelvic pain, septic shock, upper respiratory tract infection.

Cardiovascular system: deep vein thrombosis, Hypertension / hypotension, myocardial infarction, pulmonary embolism, tachycardia, anemia, febrile neutropenia, thrombocytopenia.

Digestive system: acid reflux, swallowing disorder, dysgeusia, dyspepsia, dysphagia, flatulence, constipation, increased salivation, taste disturbance, increased appetite, increase in liver transaminases (GOLD, IS).

Nervous system and sense organs: peripheral neuropathy, sensory neuropathy, anxiety, disorientation, depression.

Respiratory system: nazalynaya secretion, pharyngitis, voice disorder, cough, dyspnoea, lower respiratory tract infections, non-small cell lung cancer, pneumonitis, respiratory insufficiency.

Other: kaliopenia, diabetes, weight loss, muscular weakness, myalgia, myalgia, alopecia, rash, dizurija, renal failure.

Besides, в отдельных случаях были отмечены следующие серьезные побочные реакции безотносительно причины их возникновения — брадикардия, disorientation, perforated duodenal ulcer.

Cooperation.

Aprepitant yavlyaetsya substratom, moderate inhibitor (dose-dependent) и индуктором изофермента CYP3A4, а также индуктором изофермента CYP2C9. With simultaneous use of aprepitant (in a dose of 40 mg or repeated doses) can significantly improve the clinical plasma concentrations PM, the metabolism which takes place with the participation of CYP3A4.

Aprepitant should not be used concurrently with pimozide, terfenadine, astemizole, and cisapride (cm. "Contra"), because the dose-dependent inhibition of CYP3A4 of cytochrome P450 under the influence of aprepitant could result in elevated concentrations of these drugs in the plasma and potentially serious and life-threatening reactions.

Aprepitant induces the metabolism of S(-)-warfarin and tolbutamide. Co-administration of aprepitant with these or other drugs, которые метаболизируются CYP2C9 (such as phenytoin), may reduce their concentration in plasma. There was no effect of aprepitant on the AUC R(+)- или S(-)-varfarina, However, a joint application was observed reduction in the minimum concentration of S(-)-varfarina, which was accompanied by a decrease in INR 14% through 5 days after receiving the aprepitant.

Interactions with drugs, is a substrate of P-glycoprotein transporter, unlikely (in a clinical study showed no interaction with digoxin). Aprepitant does not cause clinically significant changes in the pharmacokinetics of antagonizing 5-HT₃-рецепторов — ондансетрона, granisetron and gidrodolasetrona (aktivnogo metabolites DOLASETRON).

At the same time taking aprepitant and glucocorticoids was an increase in AUC of dexamethasone (ingestion) in 2,2 times, for methylprednisolone, input / in, - In 1,3 times and methylprednisolone, принимаемого внутрь — в 2,5 times. In this regard, to achieve the desired effect of a standard dose of dexamethasone when administered in combination with aprepitant reduced by 50%, methylprednisolone at / in a decrease of approximately 25%, при назначении внутрь — на 50%.

When using aprepitant together with chemotherapeutic agents, metabolism are mainly or partly takes place with the participation of CYP3A4 (etoposide, vynorelbyn, docetaxel and paclitaxel), doses of these drugs can not adjust. However, we recommend caution when using patients, receiving these drugs, and to provide additional monitoring. Effect of aprepitant on the pharmacokinetics of docetaxel have been identified.

The efficacy of oral contraceptives, containing ethinylestradiol / noretidron during reception and for 28 days after receiving the aprepitant may be reduced (during treatment with aprepitant and for 1 months after the last dose of aprepitant should be used alternative or back-up methods of contraception).

Simultaneous oral midazolam and an increase of aprepitant AUC of midazolam. Possible increase in plasma concentrations of midazolam or other benzodiazepines, the metabolism of which is carried out with the participation of CYP3A4 (alprazolam, triazolam), It should be taken into account while appointing these drugs.

The combined use of aprepitant with drugs, which inhibit CYP3A4 activity, It may lead to increased concentrations of dexamethasone in the plasma, therefore, caution should appoint aprepitant in combination with potent inhibitors of CYP3A4 (e.g. ketoconazole). However, concomitant use of aprepitant with moderate CYP3A4 inhibitors (eg diltiazem) It does not cause clinically significant changes in the concentration of dexamethasone in the plasma. Simultaneous administration of aprepitant with drugs, which are strong inducers of CYP3A4 (rifampin e.g.), may reduce the concentration of dexamethasone in the plasma and, thus, reduce its effectiveness.

In patients with mild to moderate hypertension reception 1 Table. aprepitant, dose containing, comparable 230 mg per capsule, in combination with a dose of diltiazem 120 mg 3 twice a day for 5 days resulted in an increase in AUC of aprepitant 2 times and the simultaneous increase in diltiazem AUC 1,7 times. These pharmacokinetic effects did not cause clinically significant changes in ECG, Heart rate or blood pressure compared to the changes in these indicators only when taking diltiazem.

Simultaneous administration of aprepitant 1 once daily in tablet form in doses, comparable 85 or 170 mg per capsule, paroxetine dose 20 mg 1 once a day resulted in a decrease in AUC of about 25% and C_max approximately 20% for aprepitant, and paroxetine.

Overdose.

Symptoms: the available data on the use of high doses of aprepitant without chemotherapy (once before 600 mg or 375 mg daily for 42 days) evidence of its good tolerability. In 1 patient, accepting 1440 mg aprepitant, observed drowsiness and headache.

Treatment: discontinuation of the drug, monitoring of the patient; if necessary - symptomatic therapy. In connection with antiemetic action aprepitant PM, induce vomiting, not likely to be effective. Antidote unknown. Hemodialysis is not effective.

Dosing and Administration.

Inside (regardless of the meal), during 3 days in combination with glucocorticoids and antagonists of serotonin 5-HT₃-receptors. The recommended dose: 125 mg for 1 hours prior to receiving chemotherapy drugs in 1st day 80 mg 1 once a day in the morning 2- and 3-j days. Supplementation depends on the degree of anti-tumor therapy emetogenicity.

Precautions.

C Caution should be used in patients, while receiving drugs, are metabolized mainly by the participation of CYP3A4 (incl. Some chemotherapy drugs), tk. Inhibition of CYP3A4 aprepitant could result in increased concentrations of these drugs in the blood plasma. Co-administration with warfarin may result in a clinically significant decrease in INR. Patients, receiving long-term warfarin therapy, should be carefully monitored for INR 2 weeks every cycle of chemotherapy, and particularly 7-10 days after the beginning of reception aprepitant 3-day scheme. The efficacy of hormonal contraceptives may be reduced during and for 28 days after treatment aprepitant. During treatment with aprepitant and for 1 months after the last dose you should use alternative methods of contraception and backup.

Patients with mild to moderate hepatic insufficiency (from 5 to 9 points on the Child-Pugh) dose adjustment is required. Patients with severe renal insufficiency (creatinine clearance <30 ml / min), as well as in patients with end-stage renal disease, hemodialysis, dose adjustment is required. Elderly patients (65 and older) dose adjustment is required. No dose adjustment based on gender or race is not required.