Fosaprepitant (Fosaprepitantum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Antiemetic drugs

Included in the formulation
  • Emend® I / O
    lyophilizate d / infusion 
    Merck Sharp and Doum B.V.     Netherlands
    • АТХ:

    A.04.A.D   Other antiemetic drugs

    Pharmacodynamics:
    Antiemetic means. The active metabolite of fosaprepitant is aprepitant selective high affinity receptor antagonist of neurokinin 1 (NK1) receptor substance P. The selectivity of binding of aprepitant to NK1 receptors is at least 3000 times higher than with other enzymes, transport proteins, ion channels and receptors, including dopamine and serotonin receptors that are targets existing drugs to prevent nausea and vomiting during chemotherapy.
    Pre-clinical studies have shown that NK1 receptor antagonists prevent vomiting caused by chemotherapeutic drugs such as cisplatin, due to the central mechanism of action. According to the data obtained in studies with positron emission tomography (PET), aprepitant penetrates into the brain and binds to NK1 receptors in the brain. The central effect of aprepitant has a long duration, and it inhibits both acute and delayed phases of vomiting caused by cisplatin, and also increases the antiemetic activity of antagonists of 5-HT3 receptors (eg, ondansetron) and glucocorticosteroids (dexamethasone).
    In a randomized, double-blind, placebo-controlled study of the QTc interval, a single administration of fosapreptant at a dose of 200 mg did not affect the QTc interval value.
    With a single intravenous injection of fosapreptant 150 mg in healthy volunteers, the binding of NK1 receptors in the brain was 100% after 24 hours, at least 97% at 48 hours and 75% at 120 hours. The proportion of bound NK1 receptors correlated with the concentration of aprepitant in the plasma.
    Pharmacokinetics:

    After a single intravenous 20-minute infusion of 150 mg of fosaprepitant to healthy volunteers, the mean AUC0-∞ of aprepitant is 35 μg × h / ml and the average maximum concentration of aprepitant is 4.01 μg / ml.

    The binding of aprepitant to plasma proteins is more than 95%. The geometric mean of the apparent volume of distribution in the equilibrium state in humans is approximately 66 liters. Research data positron emission tomography showed that aprepitant penetrates the blood-brain barrier.

    Fosaprepitant is rapidly metabolized to aprepitant (with intravenous administration within 30 minutes after the end of infusion). The conversion of fosaprepitant into aprepitant can occur in a variety of tissues.

    Aprepitant undergoes active metabolism. In the human plasma, seven metabolites of aprepitant have been identified, which have a weak activity. The metabolism of aprepitant occurs to a greater extent by oxidation of the morpholine ring and its side chains. In vitro studies using human liver microsomes show that aprepitant is metabolized predominantly by CYP3A4, slightly - with the participation of CYP1A2 and CYP2C19, and CYP2D6, CYP2C9 and CYP2E1 do not participate in its metabolism.

    All metabolites that were detected in urine, feces and plasma after intravenous administration of 100 mg of [14C] -phosaprepitant were also determined after administration of [14C] -aprepitant by mouth.

    After a single intravenous injection of 100 mg of [14C] -phosaprepitant to healthy volunteers, 57% of radioactivity was detected in urine and 45% in feces.

    Aprepitant is excreted mainly in the form of metabolites, unchanged aprepitant not excreted by the kidneys. The final half-life of aprepitant is approximately 9 to 13 hours.

    Indications:To prevent acute and delayed nausea and vomiting caused by high or moderately emeticantitumourth chemotherapy (in combination with other antiemetics).
    ICD-10

    XVIII.R10-R19.R11   Nausea and vomiting

    Contraindications:Hepatic insufficiency is severe (more than 9 points on the Child-Pugh scale); simultaneous application with pimozide, terfenadine, astemizole and cisapride; pregnancy; childhood; hypersensitivity to fosaprepitantu, aprepitantu
    Carefully:Caution should be used in patients who are simultaneously receiving medication drugs, which are metabolized mainly with the participation of the CYP3A4 isoenzyme. Simultaneous administration with warfarin can lead to a clinically significant decrease in the international normalized relationship. In patients receiving long-term therapy with warfarin, the value of the international normalized ratio should be carefully monitored for 2 weeks with each cycle of chemotherapy and especially 7-10 days after the start of the 3-day schedule.
    Pregnancy and lactation:
    Use during pregnancy is contraindicated.
    It is not known whether fosaprepitant with breast milk. The issue of stopping breastfeeding or stopping the use of fosaprepitant should be addressed in the light of the need for treatment for the mother.
    Dosing and Administration:

    Enter intravenously in the form of infusion lasting from 20 to 30 minutes on the 1st day of chemotherapy approximately 30 minutes before the chemotherapy.

    Single dose is 150 mg.

    Apply according to a special scheme in combination with corticosteroids and agonists of serotonin 5-HT3 receptors.

    Side effects:
    Fosaprepitant is metabolized to aprepitant, therefore, when using fosaprepitant, the same adverse reactions are possible as for aprepitant.
    From the side hematopoiesis system: anemia, febrile neutropenia.
    Mental disorders: anxiety; euphoria, disorientation.
    From the side nervous system: dizziness, drowsiness; cognitive impairment, inhibition, perversion of taste.
    From the side sense organs: conjunctivitis, tinnitus.
    From the side of cardio-vascular system: heart palpitations, paroxysmal sensations of heat (hot flashes), increased blood pressure; rarely - bradycardia, thrombophlebitis (mainly, thrombophlebitis at the injection site).
    From the side respiratory system: hiccough; sore throat, sneezing, cough, postnasal swelling syndrome, throat irritation.
    From the side digestive system: dyspepsia, decreased appetite, increased ALT activity; eructation, nausea, gastroesophageal reflux, vomiting, abdominal pain, dry mouth, flatulence, increased activity of ACT, alkaline phosphatase; hard stool, perforated duodenal ulcer, neutropenic colitis, stomatitis, bloating.
    From the side skin and subcutaneous tissues: rash, acne, erythema; photosensitivity, excessive sweating, seborrhea, increased skin fat, itchy rash, Stevens-Johnson syndrome.
    From the side musculoskeletal system: muscle spasms, muscle weakness.
    From the side urinary system: dysuria; pollakiuria, an increase in diuresis, the presence of erythrocytes in the urine, polydipsia, edema.
    Infectious and parasitic diseases: candidiasis, staphylococcal infection.
    From the side metabolism: hyponatremia, weight loss, glucosuria.
    Allergic reactions: hypersensitivity reactions, including hives, erythema, dyspnea, anaphylactic reactions.
    Local reactions: erythema, itching, pain at the injection site; Sealing at the injection site.
    Other: fatigue; weakness, discomfort; a feeling of discomfort in the chest, gait disturbance, a decrease in the number of neutrophils.A single dose of 40 mg to prevent postoperative nausea and vomiting in patients (not receiving chemotherapy) after general anesthesia, ALT activity, upper abdominal pain, atypical intestinal noise, dysarthria, dyspnoea, hypoesthesia, insomnia, miosis, nausea, sensitivity disorders, discomfort in the intestine, decreased visual acuity, wheezing - wheezing). When used in doses of more than 150 mg, 1 case of constipation and 1 case of partial intestinal obstruction were observed.
    Overdose:

    Symptoms: The available data on the use of aprepitant in high doses without chemotherapy (once to 600 mg or 375 mg daily for 42 days) indicate good tolerability of the drug. One patient who received 1,440 mg of aprepitant had drowsiness and a headache.

    Treatment: The medication should be discontinued and the patient's condition monitored. If necessary, conduct symptomatic therapy. In connection with the antiemetic effect of aprepitant drugs that cause vomiting, most likely will not be effective. Antidote to the drug is unknown.Hemodialysis is not effective.

    Interaction:

    Due to the fact that fosaprepitant rapidly metabolized in aprepitant (a weak or moderate inhibitor of the isoenzyme CYP3A4), it should be used with caution in patients who are simultaneously receiving medications that are metabolized mainly with the participation of CYP3A4; some chemotherapeutic drugs are metabolized with the participation of the CYP3A4 isoenzyme. A weak inhibitory effect of fosaprepitant at a dose of 150 mg per isozyme CYP3A4 can lead to an increase in the concentrations of these concomitantly ingested drugs.

    Fosaprepitant should not be used concomitantly with pimozide, terfenadine, astemizole or cisapride. Inhibition of CYP3A4 under the influence of aprepitant may lead to an increase in the concentration of these drugs in plasma and to potentially serious or life-threatening reactions.

    It was found that aprepitant induces the metabolism of S (-) warfarin and tolbutamide, which are metabolized by CYP2C9. The simultaneous use of fosapreptant with these or other drugs that are also metabolized with the participation of the CYP2C9 isoenzyme (eg, phenytoin) can lead to a decrease in plasma concentrations of these drugs.

    Fosaprepitan is incompatible with solutions containing divalent cations (for example, Ca, Mg), including Hartmann's solution and Ringer's solution with lactate.

    The simultaneous use of fosaprepitant with drugs that are strong inducers of CYP3A4 can lead to a decrease in plasma concentration and a decrease in efficacy.

    The effectiveness of hormonal contraceptives during the period of application and within 28 days after the end of fosaprepitant intake can be reduced.

    In clinical studies after the administration of aprepitant, chemotherapeutic drugs were prescribed internally, the metabolism of which mainly or partially occurs with the participation of the CYP3A4 isoenzyme: etoposide, vinorelbine, docetaxel, ifosfamide, cyclophosphamide, irinotecan and paclitaxel. Doses of these drugs were not adjusted taking into account the potential drug interaction. Post-registration studies have documented cases of neurotoxicity, as a possible side effect of ifosfamide, used concomitantly with aprepitant.

    Dexamethasone. The standard dose of dexamethasone (when administered orally) in conjunction with fosaprepitanom 150 mg (intravenously in the 1 stday) should be reduced by approximately 50% to achieve dexamethasone exposure similar to that when administered without fosaprepitant 150 mg intravenously on the 1st day.

    Special instructions:

    Do not resume infusion of phosphaepitrate in patients who have experienced allergic reactions of immediate type.

    When using fosaprepitant in combination with other antiemetic drugs, follow the instructions for using these drugs.

    Impact on the ability to drive vehicles and manage mechanisms.

    However, some of the side effects associated with the use of aprepitant may affect the ability to drive vehicles and perform other activities that require increased concentration and speed of psychomotor reactions.

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