Actions of Em Ex in details
Pharmacology: Em Ex is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1, 5-HT1A, 5-HT1B/C, 5-HT2; for α1-, α2-, β-adrenoreceptors; for dopamine-D2, or for histamine-H1; benzodiazepine; picrotoxin or opioid receptors. Radioligand binding studies have demonstrated that Em Ex has negligible affinity for other receptor types including 5-HT and dopamine D2 binding sites.
Serotonin receptors of the 5-HT3type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger, the area postrema. During chemotherapy-induced vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT3 receptors. This evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, Em Ex blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli eg, cisplatin. In the ferret animal model, a single Em Ex injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5-30 seconds.
In most human studies, Em Ex has had little effect on blood pressure, heart rate or ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in other studies.
Em Ex is effective orally prophylactically in abolishing the retching and vomiting evoked by cytotoxic chemotherapy and radiotherapy.
Em Ex injection exhibited no effect oro-cecal transit time in normal volunteers given a single IV infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral doses slowed colonic transit in normal volunteers.
Pharmacokinetics: Tablet: Following oral administration, Em Ex is rapidly and completely absorbed, though oral bioavailability is reduced to about 60% as a result of first-pass metabolism.
Oral bioavailability is generally not influenced by food.
Em Ex is extensively distributed in the body (volume of distribution: 200 L), and that about 65% of the drug in plasma is protein bound. The pharmacokinetics of Em Ex exhibits considerable interindividual variation, and the elimination half-life is reported to be around 3-4 hrs in healthy subjects but about 9-12 hrs in cancer patients. It is metabolised in the liver, primarily by 7-hydroxylation, with <20% of a dose recovered unchanged in urine, whilst that of metabolites amount to about 47% of a dose. The remainder is excreted in faeces as metabolites.
Em Ex demonstrates a clinical dose-response curve between the doses 0.25-1 mg when administered twice daily. It shows no marked deviations from linear pharmacokinetics at oral doses up to 2.5-fold or the recommended clinical dose.
The plasma concentration of Em Ex is not clearly correlated with antiemetic efficacy. Clinical benefit may be conferred even when Em Ex is not detectable in plasma.
Vial: In adult cancer patients undergoing chemotherapy and in volunteers, infusion of a single 40-mcg/kg dose of Em Ex injection produced the following pharmacokinetic data:.
There was high inter- and intrasubject variability noted in these studies. No difference in mean AUC was found between males and females, although males had a higher Cmax generally.
Em Ex is extensively distributed in the body (volume of distribution: 200 L), and that about 65% of the drug in plasma is protein bound. The pharmacokinetics of Em Ex exhibits considerable interindividual variation, and the elimination half-life is reported to be around 3-4 hrs in healthy subjects but about 9-12 hrs in cancer patients. Em Ex metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. Animal studies suggest that some of the metabolites may also have 5-HT3 receptor antagonist activity.
Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately 12% of the administered dose is eliminated unchanged in the urine in 48 hrs. The remainder of the dose is excreted as metabolites, 49% in the urine and 34% in the feces.
In vitro liver microsomal studies show that Em Ex's major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily.
Plasma protein-binding is approximately 65% and Em Ex distributes freely between plasma and red blood cells.
Elderly: The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a single 40-mcg/kg IV dose of Em Ex injection, were generally similar to those in younger healthy volunteers; mean values were lower for clearance and longer for half-life in the elderly.
Children: A pharmacokinetic study in pediatric cancer patients (2-16 years), given a single 40-mcg/kg IV dose of Em Ex injection, showed that volume of distribution and total clearance increased with age. No relationship with age was observed for peak plasma concentration or terminal phase plasma half-life. When volume of distribution and total clearance are adjusted for body weight, the pharmacokinetics of Em Ex is similar in paediatric and adult cancer patients.
Renal Impairment: Total clearance of Em Ex was not affected in patients with severe renal failure who received a single 40-mcg/kg IV dose of Em Ex injection.
Hepatic Impairment: A pharmacokinetic study in patients with hepatic impairment due to neoplastic liver involvement showed that total clearance was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters noted in patients and the good tolerance of doses well above the recommended 10 mcg/kg dose, dosage adjustment in patients with possible hepatic functional impairment is not necessary.
Clinical Trials: Em Ex injection has been shown to prevent nausea and vomiting associated with single-day and repeat cycle cancer chemotherapy.
Single-Day Chemotherapy: Cisplatin-Based Chemotherapy: In a double-blind, placebo-controlled study in 28 cancer patients, Em Ex injection, administered as a single IV infusion of 40 mcg/kg, was significantly more effective than placebo in preventing nausea and vomiting by cisplatin chemotherapy.
Em Ex injection was also evaluated in randomized dose response study of cancer patients receiving cisplatin ≥75 mg/m2. Additional chemotherapeutic agents included anthracyclines, carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydrazine, nitrogen mustard analogs, podophyllotoxin derivatives, pyrimidine analogs and vinca alkaloids. Em Ex injection doses of 10 and 40 mcg/kg were superior to 2 mcg/kg in preventing cisplatin-induced nausea and vomiting, but 40 mcg/kg was not significantly superior to 10 mcg/kg.
Em Ex injection (Em Ex hydrochloride was also evaluated in a double-blind, randomized dose response study of 353 patients stratified for high (≥80-120 mg/m2) or low (50-79 mg/m2) cisplatin dose. Response rate of patients for both cisplatin strata are given in Table 4.
For both the low and high cisplatin strata, the 10, 20 and 40 mcg/kg doses were more effective than the 5 mcg/kg dose in preventing nausea and vomiting within 24 hrs of chemotherapy administration. The 10 mcg/kg dose was at least as effective as the higher doses.
Moderately Emetogenic Chemotherapy: Em Ex injection, 40 mcg/kg, was compared with the combination of chlorpromazine (50-200 mg/24 hrs) and dexamethasone (12 mg) in patients treated with moderately emetogenic chemotherapy, including primarily carboplatin >300 mg/m2, cisplatin 20-50 mg/m2 and cyclophosphamide >600 mg/m2. Em Ex injection was superior to the chlorpromazine regimen in preventing nausea and vomiting.
In other studies of moderately emetogenic chemotherapy, no significant difference in efficacy was found between Em Ex doses of 40 mcg/kg and 160 mcg/kg doses.
Repeat-Cycle Chemotherapy: In an uncontrolled trial, 512 cancer patients received Em Ex injection, 40 mcg/kg, prophylactically for 2 cycles of chemotherapy, 224 patients received it for at least 4 cycles and 108 patients received it for at least 6 cycles. Em Ex injection efficacy remained relatively constant over the 1st 6 repeat-cycles, with complete response rates (no vomiting and no moderate or severe nausea in 24 hrs) of 60-69%. No patients were studied for >15 cycles.
Pediatric Studies: A randomized double-blind study evaluated the 24-hr response of 80 pediatric cancer patients (2-16 years) to Em Ex injection 10, 20 or 40 mcg/kg. Patients were treated with cisplatin ≥60 mg/m2, cytarabine ≥3 g/m2, cyclophosphamide ≥1 g/m2 or nitrogen mustard ≥6 mg/m2.
A 2nd pediatric study compared Em Ex injection 20 mcg/kg to chlorpromazine plus dexamethasone in 88 patients treated with ifosfamide ≥3 g/m2/day for 2 or 3 days. Em Ex injection was administered on each day of ifosfamide treatment. At 24 hrs, 225 of Em Ex injection patients achieved complete response (no vomiting and no moderate or severe nausea in 24 hrs) compared with 10% on the chlorpromazine regimen. The median number of vomiting episodes with Em Ex injection was 1.5; with chlorpromazine it was 7.
How should I take Em Ex?
Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.
Em Ex is usually taken only on the day of treatment with chemotherapy or radiation.
Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.
Your doctor may want you to take only one dose, up to 1 hour before chemotherapy or radiation.
For patients undergoing chemotherapy, a second dose of Em Ex is sometimes given 12 hours after the first dose. Follow your doctor's dosing instructions very carefully.
Em Ex is not likely to be useful if you keep taking it during times when you are not receiving chemotherapy or radiation treatment.
Do not share this medicine with another person.
Store at room temperature away from moisture, heat, and light.
Store the liquid medicine in an upright position. Keep the bottle tightly closed when not in use.
Em Ex administration
Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.
Em Ex is usually started up to 1 hour before chemotherapy. Follow your doctor's instructions.
Measure the liquid form of Em Ex with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.
Store Em Ex at room temperature away from moisture and heat.
Em Ex pharmacology
Em Ex is a selective 5-hydroxytryptamine antagonist) antiemetics. Total body irradiation consisted of 11 fractions of 120 cGy administered over 4 days, with three fractions on each of the first 3 days, and two fractions on the fourth day. Em Ex (Em Ex) Tablets were given one hour before the first radiation fraction of each day.
Twenty-two percent (22%) of patients treated with Em Ex (Em Ex) Tablets did not experience vomiting or receive rescue antiemetics over the entire 4-day dosing period, compared to 0% of patients in the historical negative control group (P < 0.01).
In addition, patients who received Em Ex (Em Ex) Tablets also experienced significantly fewer emetic episodes during the first day of radiation and over the 4-day treatment period, compared to patients in the historical negative control group. The median time to the first emetic episode was 36 hours for patients who received Em Ex (Em Ex) Tablets.
Fractionated Abdominal Radiation
The efficacy of Em Ex (Em Ex) Tablets, 2 mg daily, was evaluated in a double-blind, placebo-controlled randomized trial of 260 patients. Em Ex (Em Ex) Tablets were given 1 hour before radiation, composed of up to 20 daily fractions of 180 to 300 cGy each. The exceptions were patients with seminoma or those receiving whole abdomen irradiation who initially received 150 cGy per fraction. Radiation was administered to the upper abdomen with a field size of at least 100 cm².
The proportion of patients without emesis and those without nausea for Em Ex (Em Ex) Tablets, compared to placebo, was statistically significant (P < 0.0001) at 24 hours after radiation, irrespective of the radiation dose. Em Ex (Em Ex) was superior to placebo in patients receiving up to 10 daily fractions of radiation, but was not superior to placebo in patients receiving 20 fractions.
Patients treated with Em Ex (Em Ex) Tablets (n=134) had a significantly longer time to the first episode of vomiting (35 days vs. 9 days, P < 0.001) relative to those patients who received placebo (n=126), and a significantly longer time to the first episode of nausea (11 days vs. 1 day, P < 0.001). Em Ex (Em Ex) provided significantly greater protection from nausea and vomiting than placebo.
References
- DailyMed. "GRANISETRON: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Granisetron: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Granisetron: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
