Emend capsule set 125mg N1 + 80mg N2
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Active ingredients
Aprepitant
Release form
Capsules
Composition
Additional packaging: Capsules 1 caps. Supplement 80 mg2 pcs. - blisters (1). Capsules 1 caps. Suppressant 125 mg
Pharmacological effect
An antiemetic drug, a selective high affinity antagonist of neurokinin-1 (NK1) receptors of substance R. The selectivity of binding of aprepitant to NK1 receptors is at least 3000 times higher than for other enzymes, carriers of ion channels and receptor sites, including dopamine and serotonin receptors, which are targets of currently existing drugs used to treat nausea and vomiting associated with chemotherapy. In preclinical studies, it was shown that NK1 receptor antagonists prevent give the development of vomiting caused by chemotherapeutic drugs (for example, cisplatin) due to the central mechanism of action. The prepatant penetrates into the brain and binds to brain NK1 receptors. Possessing a long-lasting central effect, aprepitant inhibits both the acute and delayed phases of vomiting caused by cisplatin, and also enhances the antiemetic effect of ondansetron and dexamethasone.
Pharmacokinetics
Absorption After oral administration, Cmax in the blood plasma is reached in approximately 4 hours. The absolute bioavailability is on average 60-65%. Taking the capsule simultaneously with a meal does not have a clinical significant effect on the bioavailability of aprepitant. Aprepitant pharmacokinetics in the range of clinical doses is nonlinear. After ingestion of drug Emend in a dose of 125 mg per day and then at a dose of 80 mg / day in the 2nd and the 3rd day AUC for 24 hours was approximately 19.5 μg × h / ml on day 1 and 20.1 μg × h / ml on day 3. Cmax was 1.5 mcg / ml and 1.4 mcg / ml on the 1st and 3rd days, respectively, and was reached approximately 4 hours after taking the drug. The distribution of plasma protein binding is more than 95%. Vd in equilibrium is approximately 66 liters. Experimental studies have shown that aprepitant penetrates the placental barrier in rats and BBB in rats and ferrets. In humans, aprepitant penetrates BBB. MetabolismApprepitant is extensively metabolized in the liver through oxidation in the morpholine ring and its side chains are mainly under the action of CYP3A4 and only a small part of the drug is metabolized with the participation of CYP1A2 and CYP2C19 (CYP2D6,CYP2C9 or CYP2E1 are not involved in the metabolism of aprepitant). Injection The apparent T1 / 2 is approximately 9 to 13 h. The preprepant is eliminated mainly as metabolites through the intestines (86%) and kidneys (5%). up to 84 ml / min. Pharmacokinetics in special clinical situations The pharmacokinetics of the Emend drug in children and adolescents under the age of 18 years have not been studied. In patients aged 65 and older after ingestion of the drug Emend in a single dose of 125 mg on day 1 and then at a dose of 80 mg / day in the 2nd and the 5th day of the AUC for 24 hours was 21% more on the 1st day and 36% more on the 5th day than in people younger than 65 years. At the same time, Cmax 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 in a dose of 125 mg on day 1 and then in a dose of 80 mg / day in 2nd and the 3rd day AUC for 24 hours was 11% less on day 1 and 36% less on day 3 than in healthy volunteers who received the same doses 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. In patients with severe renal failure, the AUC for total aprepitant (both bound and non-protein bound) was reduced by 21%, and Cmax 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 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 ingestion of the drug Emend AUC0-24 and Cmax of the drug in women were 9% and 17% higher, respectively, than in men.T1 / 2 aprepitant in women was 25% less than in men, and there were no significant differences in the achievement of Cmax between women and men. These differences in pharmacokinetic parameters have no clinical significance. The dose correction of the drug Emend depending on the race is not required. The body mass index does not affect the pharmacokinetics of aprepitant.
Indications
- to prevent acute and delayed nausea and vomiting caused by high or moderately methogenic anticancer drugs (in combination with other antiemetic drugs).
Contraindications
- severe liver failure (> 9 points on the Child-Pugh scale); - simultaneous use with pimozide, terfenadine, astemizole and cisapride; - hypersensitivity to the components of the drug.
Precautionary measures
Emend should be used with caution 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's drug in 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 during 1 month after taking the last dose of Emend, alternative and backup methods of contraception should be used.
Use during pregnancy and lactation
Adequate and strictly controlled clinical studies of the safety of the drug during pregnancy were not conducted, therefore, 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.
Dosage and administration
The drug is taken orally regardless of food intake. Emend is prescribed for 3 days in combination with GCS and serotonin 5-HT3 receptor antagonists. Before starting treatment, you should familiarize yourself with the instructions for use of the antagonist of serotonin 5-HT3 receptors, administered simultaneously with Emend.The recommended dose of Emend in the three-day regimen is 125 mg 1 hour before taking chemotherapeutic drugs on day 1 and 80 mg 1 time / day in the morning on the 2nd and 3rd day. 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. Patients with severe renal insufficiency (CC <30 ml / min), as well as in patients with end-stage renal failure, are on hemodialysis, dose adjustment is not required. Dose adjustment based on gender, age, race or body mass index is not required.
Side effects
On the part of the hematopoietic system: infrequently - anemia, febrile neutropenia. On the side of metabolism and nutrition: often - loss of appetite; rarely - polydipsia. Psychiatric disorders: infrequently - anxiety; seldom - disorientation, euphoria. From the nervous system: infrequently - dizziness, drowsiness; rarely - cognitive impairment, lethargy, taste perversion. From the senses: rarely - conjunctivitis, tinnitus. From the cardiovascular system: infrequently - rapid heartbeat, hot flashes (hot flashes); rarely - bradycardia, cardiovascular disorders. From the respiratory system: often - hiccups; rarely - sore throat, sneezing, cough, post-nasal syndrome, pharyngeal irritation. On 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 side of the skin and subcutaneous fat: rarely - 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 on the part of laboratory parameters: often - increased activity of ALT; infrequently - increased AST activity, increased activity of alkaline phosphatase; rarely - an increase in diuresis, the presence of red blood cells in the urine, hyponatremia, weight loss, glucosuria,neutropenia. General disorders: often - fatigue; infrequently - asthenia, malaise; rarely, edema, discomfort in the chest, gait disturbance. The side effect profile of patients receiving high-emittogenic and moderate emethogenic chemotherapy during repeated courses (the maximum number of courses - 6) with aprepitant was comparable to that during the 1st cycle chemotherapy. In another study of the use of aprepitant for the prevention of nausea and vomiting induced by chemotherapy, a message was received about serious side effects - Stevens-Johnson syndrome, toxic and dermal necrolysis (Lyell's syndrome). Post-registration research data Due to the fact that reports came from volunteers from populations with an uncertain number, it is impossible to reliably determine the expected frequency or causal relationship with the drug. From the side of the skin and skin appendages: itching, rash, rash, rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome). For the immune system: hypersensitivity reactions, including anaphylactic reactions.
Overdose
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's therapy should be stopped and the patient’s condition should be monitored. If necessary, conduct symptomatic therapy. Due to 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.
Interaction with other drugs
Aprepitant is a substrate, a moderate inhibitor and inducer of the CYP3A4 isoenzyme, as well as an inducer of the CYP2C9 isoenzyme. When administered simultaneously, the aprepitant may increase the plasma concentration of drugs whose metabolism occurs with the participation of the CYP3A4 isoenzyme. Emend should not be used simultaneously with pimozide, terfenadine, astemizole, cisapride, ergot alkaloid derivatives.Inhibition of the CYP3A4 isoenzyme under the influence of aprepitant can lead to an increase in plasma concentrations of these drugs and to potentially serious and life-threatening reactions. The preprepant induces the metabolism of warfarin and tolbutamide. The simultaneous administration of the drug 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 concentration in plasma. No effect of the drug Emend on the AUC R (+) - or S (-) - warfarin was noted, however, 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 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 starting Emend's drug in a 3-day regimen, during each cycle of chemotherapy. Emend reduces AUC of tolbutamide which is the axial substrate of the CYP2C9 isoenzyme, by 23% on the 4th day, by 28% on the 8th day, and by 15% on the 15th day. In this case, tolbutamide in a single dose of 500 mg was administered before the start of the 3-day regimen of drug Emend on the 4th, 8th and 15th days. Interaction of the drug Emend with drugs that are substrates of the P-glycoprotein transporter is unlikely (no interaction Emend with digoxin). Aprepitant does not cause clinically significant changes in the pharmacokinetics of antagonists of serotonin 5HT3 receptors — ondansetron, granisetron, and hydrodolasetron (the active metabolite of dolasetron). At the same time taking the drug Emend and GCS, an increase in dexamethasone AUC (when taken orally) was noted by a factor of 2.2, an increase in deuxamethasone AUC (when taken orally) 2.2 times, methyl predate. - 1.3 times and methylprednisolone taken 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 IV and 50% when administered orally. When using the drug Emend together with chemotherapy drugs, the metabolism of which mainly or partially occurs with the participation of the isoenzyme CYP3A4 (etoposide, vinorelbine, docetaxel and paclitaxel) 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 were cases of neurotoxicity that could be considered as a possible side effect of ifosfamide, used in conjunction with an aprepitant. The effect of Emend on the pharmacokinetics of docetaxel was not detected. The effectiveness of hormonal contraceptives during the reception period and within 28 days after the end of Emend can be reduced. (during treatment with drug Emend and within 1 month after taking the last dose of drug Emend should use alternative or reserve methods of contraception). With simultaneous oral administration of midazolam and the drug 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 performed with the participation of CYP3A4 isoenzyme (alprazolam, triazolam), should be taken into account when co-administering these drugs with Emend. Simultaneous administration of Emend with the drugs that inhibit the activity of CYP3A4 isoenzyme may cause an increase in plasma aprepitant concentration. Therefore, it is necessary to carefully prescribe Emend 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, posaconazole, clarithromycin, telithromycin and protease inhibitors) does not cause clinically significant changes in the concentration of aprepitant in the blood plasma. inducers of CYP3A4 isoenzyme (for example, with rifampicin, phenytoin, carbamazepine, phenobarbital), can lead to a decrease in the concentration of aprepitant in plasma and, mayor manner Emend reduce the effectiveness of the drug. Also, simultaneous use of aprepitant with preparations of Hypericum perforatum is not recommended. In patients with mild and moderate arterial hypertension, taking aprepitant pills 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 led to an increase in AUC of aprepitant by 2 times and a simultaneous increase in AUC of diltiazem by 1.7 times.These pharmacokinetic effects did not lead to clinically significant changes on 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 pills in a dose comparable to 85 mg or 170 mg of the drug in capsules, and paroxetine in a dose of 20 mg 1 time / day resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% for both aprepitant and paroxetine.
special instructions
Inhibition of CYP3A4 with 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 Emend in children have not been established. Effect on driving ability of motor transport and control mechanisms. Studies on the effect of Emend drug on the ability to drive vehicles or work with mechanisms have not been carried out. s However, the side effects profile of the drug, which may affect the ability of patients to control the mechanisms, should be considered. Patients may have different reactions to Emend.