Buy Emend capsules 125/80 mg 3 pcs
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Emend [Aprepitant]

Merck Sharp & Dohme
1436 Items
2019-09-19
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Clinical Pharmacology

Antiemetic drug, selective high affinity antagonist of neurokinin-1 receptors (NK1) substance R. Selectivity of binding aprepitant with NK1-receptors are at least 3000 times higher than for other enzymes, ion channel carriers and receptor sites, including dopamine and serotonin receptors, which are the targets of currently existing drugs used to treat nausea and vomiting associated with chemotherapy.

Preclinical studies have shown that NK antagonists1-receptors prevent the development of vomiting caused by chemotherapeutic drugs (for example, cisplatin) due to the central mechanism of action.

Aprepitant enters the brain and binds to the brain NK1receptors. Possessing a long central action, aprepitant inhibits both acute and delayed phases of vomiting caused by cisplatin, and also enhances the antiemetic effect of ondansetron and dexamethasone.

Pharmacokinetics

Suction

After ingestion Cmax in blood plasma is reached in approximately 4 hours. The absolute bioavailability averages about 60-65%. Taking a capsule simultaneously with a meal does not have a significant clinical effect on the bioavailability of aprepitant.

The pharmacokinetics of aprepitant in the range of clinical doses is nonlinear.

After ingestion of the drug Emend® at a dose of 125 mg on day 1 and then at a dose of 80 mg / day on the 2nd and 3rd days of AUC for 24 hours was approximately 19.5 μg × h / ml in 1– day and 20.1 μg × h / ml on the 3rd day. Cmax amounted to 1.5 mcg / ml and 1.4 mcg / ml in the 1st and 3rd days, respectively, and was reached approximately 4 hours after taking the drug.

Distribution

Plasma protein binding is more than 95%. Vd in equilibrium state is approximately 66 l.

Experimental studies have shown that aprepitant penetrates the placental barrier in rats and through BBB in rats and ferrets.

In humans, aprepitant penetrates the BBB.

Metabolism

Aprepitant undergoes intensive metabolism in the liver through oxidation in the morpholine ring and its side chains mainly under the action of CYP3A4 and only a small part of the drug is metabolized with CYP1A2 and CYP2C19 (CYP2D6, CYP2C9 or CYP2E1 is not involved in the metabolism of aprepitant).

Removal

Seeming t1/2 is approximately from 9 to 13 am

Aprepitant is excreted mainly as metabolites through the intestines (86%) and by the kidneys (5%).

The apparent plasma clearance of aprepitant is approximately 60 to 84 ml / min.

Pharmacokinetics in special clinical situations

The pharmacokinetics of drug Emend® in children and adolescents under the age of 18 years has not been studied.

In patients aged 65 years and older after ingestion of the drug Emend® in a single dose of 125 mg per day and then at a dose of 80 mg / day in the 2nd and 5th days of AUC for 24 h was 21% more on the 1st day and 36% more on the 5th day than in persons younger than 65 years. Cmax it was 10% higher on day 1 and 24% higher on day 5. These differences were not clinically significant.

In patients with mild hepatic insufficiency (5-6 points on the Child-Pugh scale) after ingestion of the drug Emend® at a dose of 125 mg on day 1 and then at a dose of 80 mg / day on the 2nd and 3rd days of AUC within 24 h was 11% less on day 1 and 36% less on day 3 than in healthy volunteers who received the same dose of the drug. In patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale), the AUC for 24 hours was 10% more on day 1 and 18% more on day 3 than in healthy volunteers who received same dose. These differences are not recognized as clinically significant.

Patients with severe renal failure (CK <30 ml="" min="" and="" end-stage="" patients="" with="" renal="" failure="" who="" need="" hemodialysis="" received="" emend="" once="" in="" a="" dose="" of="" 240="" mg="" severe="" the="" auc="" for="" total="" aprepitant="" both="" bound="" unbound="" to="" proteins="" was="" reduced="" by="" 21="" c="" sub="">max was reduced by 32% compared with healthy volunteers.In patients with end-stage renal disease on hemodialysis, the AUC for total aprepitant was 42% less, and Cmax by 32%. Due to a slight decrease in the binding of aprepitant to plasma proteins in patients with renal insufficiency, the AUC values ​​of the pharmacologically active unbound drug in these patients and in healthy individuals did not differ significantly. Hemodialysis performed 4 and 48 hours after taking the drug did not significantly affect the pharmacokinetics of aprepitant. In dialysate, less than 0.2% of the aprepitant dose was detected.

After a single dose of Emend® AUC0-24 and Cmax drug in women were 9% and 17%, respectively, higher than in men. T1/2 aprepitant in women was 25% less than in men, and significant differences in time to achieve Cmax between women and men not noted. These differences in pharmacokinetic parameters have no clinical significance. Dose adjustment of the drug Emend® depending on race is not required. The body mass index does not affect the pharmacokinetics of aprepitant.

Indications

For the prevention of acute and delayed nausea and vomiting caused by high or moderately methogenic anticancer drugs (in combination with other antiemetic drugs).

Composition

1 capsule contains:

Active substance: aprepitant 80 and 125 mg.

Excipients: hydroxypropylcellulose, sodium lauryl sulfate, sucrose, microcrystalline cellulose;

Capsule Composition: titanium dioxide, gelatin; 125 mg capsules also contain yellow iron oxide and red iron oxide.

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Emend [Aprepitant]

Dosage and Administration

The drug is taken orally, regardless of the meal.

Emend® is prescribed for 3 days in combination with GCS and serotonin antagonists 5-HT3-receptors.

Before starting treatment, you should read the instructions for use of a serotonin 5-HT antagonist.3 receptors, administered simultaneously with the drug Emend®. The recommended dose of Emend® with a three-day regimen is 125 mg 1 hour before taking chemotherapeutic drugs on the 1st day and 80 mg 1 time / day in the morning on the 2nd and 3rd days.

The tables show the regimen of medication, depending on the degree of emetogenicity of antitumor therapy.

High Effective Chemotherapy

A drug

Day 1

Day 2

Day 3

Day 4

Emend®

125 mg orally for 1 h before the start of chemotherapy

80 mg (in the morning)

80 mg (in the morning)

-

Dexamethasone

12 mg orally 30 minutes before the start of chemotherapy

8 mg orally (in the morning)

8 mg orally (in the morning)

8 mg orally (in the morning)

Serotonin 5-HT Antagonists3 receptors

see relevant instructions for medical use.

-

-

-

Mild chemotherapy

A drug

Day 1

Day 2

Day 3

Emend®

125 mg orally for 1 h before the start of chemotherapy

80 mg (in the morning)

80 mg (in the morning)

Dexamethasone

12 mg orally 30 minutes before the start of chemotherapy

-

-

Serotonin 5-HT Antagonists3 receptors

see relevant instructions for medical use.

-

-

In patients with mild or moderate liver failure (from 5 to 9 points on the Child-Pugh scale) dose adjustment is not required. Clinical data on the use of the drug in patients with severe liver failure (> 9 points on the Child-Pugh scale) are not available.

In patients with severe renal failure (CC <30 ml="" min="" as="" well="" in="" patients="" with="" end-stage="" renal="" disease="" who="" are="" on="" hemodialysis="" dose="" adjustment="" is="" not="" required="" p="">

Dose adjustment based on gender, age, race or body mass index is not required.

Adverse reactions

The safety of aprepitant was evaluated in approximately 6500 patients.

Prevention of nausea and vomiting caused by chemotherapy

High Effective Therapy

The clinical study involved 544 patients who received highly emethogenic therapy and aprepitant in the first cycle. 413 patients from this group continued therapy (the maximum number of chemotherapy courses was 6). The three-day regimen of the drug Emend® in combination with ondansetron and dexamethasone was well tolerated by patients. Most of the adverse reactions reported in clinical trials have been identified as mild to moderate.

The most frequent adverse reactions on the background of high-efficacy chemotherapy in patients who received aprepitant in combination with serotonin 5-HT3 receptor antagonists and dexamethasone (were observed with greater frequency than during therapy with serotonin 5-HT antagonists3receptors and dexamethasone): hiccups (4.6%), increased ALT activity (2.8%), dyspepsia (2.6%), constipation (2.4%), headache (2%), and decreased appetite ( 2%).

In an additional clinical study in 1169 patients who received various types of high-efficacy chemotherapy and regimens for the prevention of nausea and vomiting with the use of aprepitant and serotonin antagonists 5-HT3receptors and dexamethasone or serotonin 5-HT antagonists only3receptor and dexamethasone, the profile of adverse reactions was the same.

Mild Effective Therapy

In a clinical trial involving 868 patients, the most frequent adverse reaction against moderate emethogenic chemotherapy in patients who received aprepitant in combination with 5-HT antagonists3-receptors and dexamethasone (was observed with greater frequency than during therapy with 5-HT antagonists3 receptor and dexamethasone), was fatigue (1.4%).

In the combined analysis of high-emittogenic and moderate emethogenic chemotherapy in patients treated with aprepitant, the following side effects were observed with the use of the drug, and more often than with standard therapy:

  • often (≥1 / 100 to <1/10);
  • infrequently (from ≥1 / 1000 to <1/100);
  • rarely (from ≥1 / 10,000 to <1/1000).

Infectious and parasitic diseases: rarely - candidiasis, a staph infection.

From the hemopoietic system: infrequently - anemia, febrile neutropenia.

Metabolism and nutrition: often - loss of appetite; rarely polydipsia.

Mental Disorders: infrequently - anxiety; rarely - disorientation, euphoria.

From the nervous system: infrequently - dizziness, drowsiness; rarely - cognitive impairment, lethargy, taste perversion.

From the senses: rarely - conjunctivitis, tinnitus.

Since the cardiovascular system: infrequently - heart palpitations, hot flashes ("hot flashes"); rarely - bradycardia, cardiovascular disorders.

On the part of the respiratory system: often - hiccups; rarely - sore throat, sneezing, cough, post-nasal syndrome, pharyngeal irritation.

From the digestive system: often - dyspepsia; rarely — belching, nausea, gastroesophageal reflux, vomiting, abdominal pain, dry mouth, flatulence; rarely - solid feces, perforated duodenal ulcer, neutropenic colitis, stomatitis, bloating.

On the part of the skin and subcutaneous fat: infrequently - rash, acne; rarely - photosensitization, excessive sweating, seborrhea, increased oily skin, itchy rash.

From the musculoskeletal system: rarely, muscle spasms, muscle weakness.

From the urinary system: infrequently - dysuria; rarely - pollakiuria.

Changes from laboratory indicators: often - increased activity of ALT; infrequently - increased AST activity, increased alkaline phosphatase activity; rarely - an increase in diuresis, the presence of red blood cells in the urine, hyponatremia, weight loss, glycosuria, neutropenia.

Common disorders: often - fatigue; infrequently - asthenia, malaise; rarely - swelling, discomfort in the chest, gait disturbance.

The side effect profile of patients receiving highly emittogenic and moderate emethogenic chemotherapy during the repeated courses (the maximum number of courses was 6) using aprepitant was comparable to that during the 1st cycle of chemotherapy.

In another study of the use of aprepitant for the prevention of nausea and vomiting induced by chemotherapy, a report was received about serious side effects - Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

Post-registration data

Due to the fact that reports were received from volunteers from groups of the population with an undetermined number, it is impossible to reliably determine the expected frequency or causal relationship with taking the drug.

From the skin and skin appendages: itching, rash, urticaria, rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

On the part of the immune system: hypersensitivity reactions, including anaphylactic reactions.

With caution: Emend® should be used in patients simultaneously receiving medications that are metabolized mainly with the participation of the CYP3A4 isoenzyme. The simultaneous appointment of the drug Emend® with warfarin can lead to a clinically significant reduction in INR. In patients receiving long-term warfarin therapy, the INR value should be carefully monitored for 2 weeks with each cycle of chemotherapy and especially 7-10 days after starting Emend® on a 3-day regimen. The effectiveness of hormonal contraceptives may decrease during and within 28 days after treatment with Emend®. During treatment with Emend® and within 1 month after taking the last dose of Emend®, alternative and backup methods of contraception should be used.

Drug interactions

Aprepitant is a substrate, a moderate inhibitor and inducer of the isoenzyme CYP3A4, as well as an inducer of the isoenzyme CYP2C9.

With the simultaneous appointment of aprepitant can increase the plasma concentration of drugs, the metabolism of which occurs with the participation of the isoenzyme CYP3A4.Emend® should not be used simultaneously with pimozide, terfenadine, astemizole, cisapride, ergot alkaloid derivatives. Inhibition of CYP3A4 isoenzyme under the influence of aprepitant can lead to increased plasma concentrations of these drugs and to potentially serious and life-threatening reactions.

Aprepitant induces the metabolism of warfarin and tolbutamide. The simultaneous administration of Emend® with these or other drugs that are metabolized with the participation of the CYP2C9 isoenzyme (for example, phenytoin) can lead to a decrease in their plasma concentration. No effect of Emend® on AUC R (+) - or S (-) - warfarin was noted, but when used together, a decrease in the minimum concentration of S (-) - warfarin was observed, which was accompanied by a decrease in INR by 14% 5 days after the end of the drug Emend®.

In patients receiving warfarin therapy for a long time, the level of INR should be carefully monitored for 2 weeks, and especially for 7–10 days after the start of Emend® administration on a 3-day regimen, during each cycle of chemotherapy.

Emend® reduces the AUC of tolbutamide, a substrate of the CYP2C9 isoenzyme, by 23% on the 4th day, by 28% on the 8th day, and by 15% on the 15th day. At the same time, tolbutamide in a single dose of 500 mg was administered before the start of the 3-day regimen with Emend® on the 4th, 8th, and 15th days.

The interaction of the drug Emend® with drugs that are substrates of the P-glycoprotein transporter is unlikely (no interaction of the drug Emend®® with digoxin). Aprepitant does not cause clinically significant changes in the pharmacokinetics of serotonin 5HT antagonists3-receptors - ondansetron, granisetron and hydrodolasetron (the active metabolite of dolasetron).

With simultaneous administration of Emend® and GCS, there was an increase in AUC of dexamethasone (by ingestion) 2.2 times, methylprednisolone administered IV, 1.3 times, and methylprednisolone orally, 2.5 times. In this regard, to achieve the desired effect, the standard dose of dexamethasone, when taken orally, in combination with aprepitant, is reduced by 50%, methylprednisolone is reduced by approximately 25% when administered intravenously, and if administered orally, by 50%.

When using the drug Emend® together with chemotherapeutic drugs, the metabolism of which mainly or partially occurs with the participation of the CYP3A4 isoenzyme (etoposide, vinorelbine, docetaxel and paclitaxel), the doses of these drugs can not be adjusted. However, caution is advised when applying to patients receiving these drugs, and to provide additional monitoring. In post-registration studies, there have been cases of neurotoxicity, which can be considered as a possible side effect of ifosfamide, used in conjunction with aprepitant.

The effect of Emend® on the pharmacokinetics of docetaxel was not detected.

The effectiveness of hormonal contraceptives during the period of administration and within 28 days after the end of the administration of the drug Emend® can be reduced (during treatment with the drug Emend® and for 1 month after the last dose of the drug Emend®, alternative or reserve methods of contraception should be used).

With simultaneous oral administration of midazolam and Emend®, an increase in the AUC of midazolam was noted. A possible increase in plasma concentration of midazolam or other benzodiazepines, the metabolism of which is carried out with the participation of CYP3A4 isoenzyme (alprazolam, triazolam), should be taken into account when co-prescribing these drugs with Emend®.

Simultaneous administration of Emend® with drugs that inhibit the activity of CYP3A4 isoenzyme may lead to an increase in the concentration of aprepitant in the blood plasma. Therefore, it is necessary to prescribe Emend® with caution in combination with strong inhibitors of the CYP3A4 isoenzyme (for example, with ketoconazole).However, simultaneous administration of Emend® with moderate inhibitors of the CYP3A4 isoenzyme (for example, with diltiazem, itraconazole, voriconazole, posonazol, clarithromycin, telithromycin and protease inhibitors) does not cause clinically significant changes in the concentration of aprepitant in blood plasma.

Simultaneous administration of Emend® with drugs that are strong inducers of CYP3A4 isoenzyme (for example, with rifampicin, phenytoin, carbamazepine, phenobarbital) can lead to a decrease in plasma aprepitant concentration and, thus, to a decrease in the effectiveness of Emend®. Also, the simultaneous use of aprepitant with preparations of Hypericum perforatum is not recommended.

In patients with mild and moderate arterial hypertension, taking an aprepitant tablet containing a dose comparable to 230 mg of the drug in capsules in combination with diltiazem at a dose of 120 mg 3 times / day for 5 days resulted in a 2-fold increase in AUC of aprepitant and simultaneous increase AUC diltiazem 1.7 times. These pharmacokinetic effects did not lead to clinically significant changes in the ECG, heart rate or blood pressure compared with changes in these indicators when taking only diltiazem.

Simultaneous administration of aprepitant 1 time / day in the form of tablets at a dose comparable to 85 mg or 170 mg of the drug in capsules, and paroxetine at a dose of 20 mg 1 time / day resulted in a decrease in AUC by approximately 25% and Cmax approximately 20% for aprepitant and for paroxetine.

Pregnancy and Lactation

Adequate and strictly controlled clinical studies of the safety of the drug during pregnancy have not been conducted, so the use of the drug Emend® during pregnancy is not recommended.

It is not known whether aprepitant is excreted in human breast milk. If necessary, the use of the drug during lactation should decide on the termination of breastfeeding due to the risk of undesirable effects on the infant.

Special instructions

Inhibition of CYP3A4 by an aprepitant can lead to an increase in plasma concentrations of drugs that are metabolized mainly with the participation of the CYP3A4 isoenzyme (including some chemotherapeutic drugs).

Use in Pediatrics

Safety and efficacy of the drug Emend® in children have not been established.

Impact on the ability to drive vehicles and other mechanisms that require high concentration of attention

Studies on the effect of Emend® on the ability to drive or work with mechanisms have not been conducted. However, you should consider the profile of side effects of the drug, which may affect the ability of patients to control mechanisms. Patients may have different reactions to Emend®.

Overdosage

Symptoms: available data on the use of aprepitant in high doses without chemotherapy (once up to 600 mg or 375 mg daily for 42 days) indicate good tolerability of the drug. In 1 patient, who took 1440 mg of aprepitant, drowsiness and headache were observed.

Treatment: Emend® therapy should be stopped and the patient’s condition should be monitored. If necessary, carry out symptomatic therapy. In connection with the anti-emetic effect of aprepitant, drugs that induce vomiting are not likely to be effective. Antidote to the drug is unknown. Hemodialysis is not effective.

  • Brand name: Emend
  • Active ingredient: Aprepitant
  • Dosage form: Capsules
  • Manufacturer: Merck Sharp & Dohme
  • Country of Origin: USA

Studies and clinical trials of Aprepitant (Click to expand)

  1. HYPOLIPIDEMIC INFLUENCE OF A NEW ANTIOXIDATIVE DRUG-ELTACIN IN POSTINFARCTION CARDIOSCLEROSIS OLD PATIENTS
  2. Practical Asymmetric Synthesis of Aprepitant (I), a Potent Human NK-1 Receptor Antagonist, via a Stereoselective Lewis Acid Catalyzed trans Acetalization Reaction.
  3. Syntheses of Morpholine-2,3-diones and 2-Hydroxymorpholin-3-ones: Intermediates in the Synthesis of Aprepitant.
  4. Prevention of Nausea and Vomiting: Aprepitant, the First Therapeutically Active NK1 Receptor Antagonist
  5. ChemInform Abstract: A Convergent Approch to the Synthesis of Aprepitant: A Potent Human NK-1 Receptor Antagonist.
  6. ChemInform Abstract: Efficient Synthesis of (1R)-[3,5-Bis(trifluoromethyl)phenyl] Ethanol, a Key Intermediate for Aprepitant, an NK-1 Receptor Antagonist.
  7. Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting
  8. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting : Results from a randomized, double-blind, placebo-controlled trial in Latin America
  9. Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin : Analysis of combined data from two phase III randomized clinical trials
  10. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy
  11. Herrstedt J, Muss HB, Warr DG, et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy. Cancer. 2005;104:1548–55.
  12. Randomized, placebo-controlled, pilot study evaluating aprepitant single dose plus palonosetron and dexamethasone for the prevention of acute and delayed chemotherapy-induced nausea and vomiting
  13. [14C]Dimethyltitanocene and [14C]Methyl(methyltrimethylsilyl) titanocene–Reagents for the [14C]olefination of carbonyl compounds: synthesis of [14C]Aprepitant
  14. The syntheses of [14C] and [13C2,15N3]aprepitant
  15. Lack of effect of aprepitant (APR) on the pharmacokinetics (PK) and safety of palonosetron (PALO)
  16. Lack of effect of aprepitant on the pharmacokinetics of hydrodolasetron in CYP2D6 extensive and poor metabolizers
  17. Aprepitant has little inductive effect on CYP3A4 activity when coadministered with dexamethasone
  18. A Reduction in Chemoradiation Induced Nausea and Vomiting (CRINV) with Prophylactic Aprepitant/5HT-3/Dexamethasone Therapy during Upper Abdominal Chemoradiation
  19. Simultaneous determination of Aprepitant and two metabolites in human plasma by high-performance liquid chromatography with tandem mass spectrometric detection
  20. A sensitive and rapid liquid chromatography-tandem mass spectrometry method for the quantification of the novel neurokinin-1 receptor antagonist aprepitant in rhesus macaque plasma, and cerebral spinal fluid, and human plasma with application in translational NeuroAIDs research
  21. Syntheses of morpholine-2,3-diones and 2-hydroxymorpholin-3-ones: intermediates in the synthesis of aprepitant
  22. A convergent approach to the synthesis of aprepitant: a potent human NK-1 receptor antagonist
  23. Effects of the neurokinin1

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