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Product
Anti-emetic Products (Emeset)
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Anti-emetic Products (Emeset)
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Emeset
Ondansetron Injection, Tablets and Syrup
COMPOSITION
EMESET (2 ml and 4 ml)
Each ml contains
Ondansetron hydrochloride dihydrate
Equivalent to Ondansetron ……………… 2 mg
Water for injection IP …………………… q.s.
EMESET 4 Tablets
Each film coated tablet contains
Ondansetron hydrochloride dihydrate
Equivalent to Ondansetron ……………… 4 mg
DOSAGE FORM
Injection for intravenous or intramuscular use .
Tablets and syrup for oral use.
PHARMACOLOGY
Pharmacodynamics Ondansetron is a selective 5-HT 3 receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT 3 type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron`s antiemetic action is mediated centrally, peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary 5-HIAA (5-hydroxyindoleacetic acid) excretion increases after cisplatin administration in parallel with the onset of emesis. The released serotonin may stimulate the vagal afferents through the 5-HT 3 receptors and initiate the vomiting reflex. In animals, the emetic response to cisplatin can be prevented by pretreatment with an inhibitor of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or pretreatment with a serotonin 5-HT 3 receptor antagonist. In normal volunteers, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations. Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied.
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Pharmacokinetics
Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine . The primary metabolic pathway is hydroxylation on the indole ring followed by glucuronide or sulfate conjugation.
Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron.
In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 enzymes , including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination. Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic study of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, C max , and T½ of ondansetron was observed. This resulted in a significant increase in clearance. However, on the basis of available data, no dosage adjustment for ondansetron is recommended .
In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.
In normal adult volunteers, the following mean pharmacokinetic data have been determined following a single 0.15-mg/kg I.V. dose.
Table 1. Pharmacokinetics in Normal Adult Volunteers |
| Age-group (years) |
n |
Peak Plasma Concentration (ng/mL) |
Mean Elimination Half-life (h) |
Plasma Clearance (L/h/kg) |
| 19-40 |
11 |
102 |
3.5 |
0.381 |
| 61-74 |
12 |
106 |
4.7 |
0.319 |
| ≥75 |
11 |
170 |
5.5 |
0.262 |
A reduction in clearance and increase in elimination half-life are seen in patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy were similar in patients over 65 years of age and those under 65 years of age; there was an insufficient number of patients over 75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the elderly.
In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in normals. In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded.
Due to the very small contribution (5%) of renal clearance to the overall clearance, renal impairment was not expected to significantly influence the total clearance of ondansetron. However, ondansetron mean plasma clearance was reduced by about 41% in patients with severe renal impairment ( creatinine clearance <30 ml/min). This reduction in clearance is variable and was not consistent with an increase in half-life. No reduction in dose or dosing frequency in these patients is warranted.
In adult cancer patients, the mean elimination half-life was 4.0 hours, and there was no difference in the multidose pharmacokinetics over a 4-day period. In a study of 21 pediatric cancer patients (4 to 18 years of age) who received three I.V. doses of 0.15 mg/kg of ondansetron at 4-hour intervals, patients older than 15 years of age exhibited ondansetron pharmacokinetic parameters similar to those of adults. Patients 4 to 12 years of age generally showed higher clearance and somewhat larger volume of distribution than adults. Most pediatric patients younger than 15 years of age with cancer had a shorter (2.4 hours) ondansetron plasma half-life than patients older than 15 years of age. It is not known whether these differences in ondansetron plasma half-life may result in differences in efficacy between adults and some young pediatric patients .Pharmacokinetic samples were collected from 74 cancer patients 6 to 48 months of age, who received a dose of 0.15 mg/kg of I.V. ondansetron every 4 hours for 3 doses during a safety and efficacy trial. These data were combined with sequential pharmacokinetics data from 41 surgery patients 1 month to 24 months of age, who received a single dose of 0.1 mg/kg of I.V. ondansetron prior to surgery with general anesthesia , and a population pharmacokinetic analysis was performed on the combined data set. The results of this analysis are included in Table 2 and are compared to the pharmacokinetic results in cancer patients 4 to 18 years of age.
| Table 2. Pharmacokinetics in Pediatric Cancer Patients 1 Month to 18 Years of Age |
| Subjects and Age Group |
N |
CL(L/h/kg) |
| |
Geometric Mean |
| Pediatric Cancer Patients 4 to 18 years of age |
N = 21 |
0.599 |
| Population PK Patients* 1 month to 48 months of age |
N = 115 |
0.582 |
| * Population PK (Pharmacokinetic) Patients: 64% cancer patients and 36% surgery patients. |
Based on the population pharmacokinetic analysis, cancer patients 6 to 48 months of age who receive a dose of 0.15 mg/kg of I.V. ondansetron every 4 hours for 3 doses would be expected to achieve a systemic exposure (AUC) consistent with the exposure achieved in previous pediatric studies in cancer patients (4 to 18 years of age) at similar doses.
In a study of 21 pediatric patients (3 to 12 years of age) who were undergoing surgery requiring anesthesia for a duration of 45 minutes to 2 hours, a single I.V. dose of ondansetron, 2 mg (3 to 7 years) or 4 mg (8 to 12 years), was administered immediately prior to anesthesia induction. Mean weight-normalized clearance and volume of distribution values in these pediatric surgical patients were similar to those previously reported for young adults. Mean terminal half-life was slightly reduced in pediatric patients ( range , 2.5 to 3 hours) in comparison with adults (range, 3 to 3.5 hours).
In a study of 51 pediatric patients (1 month to 24 months of age) who were undergoing surgery requiring general anesthesia, a single I.V. dose of ondansetron, 0.1 or 0.2 mg/kg, was administered prior to surgery. As shown in Table 3, the 41 patients with pharmacokinetic data were divided into 2 groups, patients 1 month to 4 months of age and patients 5 to 24 months of age, and are compared to pediatric patients 3 to 12 years of age.
| Table 3. Pharmacokinetics in Pediatric Surgery Patients 1 Month to 12 Years of Age |
| Subjects and Age Group |
N |
CL(L/h/kg) |
Vdss(L/kg) |
T½(h) |
| |
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Geometric Mean |
Mean |
| Pediatric Surgery Patients 3 to 12 years of age |
N = 21 |
0.439 |
1.65 |
2.9 |
| Pediatric Surgery Patients 5 to 24 months of age |
N = 22 |
0.581 |
2.3 |
2.9 |
| Pediatric Surgery Patients 1 month to 4 months of age |
N = 19 |
0.401 |
3.5 |
6.7 |
In general, surgical and cancer pediatric patients younger than 18 years tend to have a higher ondansetron clearance compared to adults leading to a shorter half-life in most pediatric patients. In patients 1 month to 4 months of age, a longer half-life was observed due to the higher volume of distribution in this age group.
In normal volunteers (19 to 39 years old, n = 23), the peak plasma concentration was 264 ng/mL following a single 32-mg dose administered as a 15-minute I.V. infusion. The mean elimination half-life was 4.1 hours. Systemic exposure to 32 mg of ondansetron was not proportional to dose as measured by comparing dose-normalized AUC values to an 8-mg dose. This is consistent with a small decrease in systemic clearance with increasing plasma concentrations.
A study was performed in normal volunteers (n = 56) to evaluate the pharmacokinetics of a single 4-mg dose administered as a 5-minute infusion compared to a single intramuscular injection. Systemic exposure as measured by mean AUC was equivalent, with values of 156 [95% CI 136, 180] and 161 [95% CI 137, 190] ng•h/mL for I.V. and I.M. groups, respectively. Mean peak plasma concentrations were 42.9 [95% CI 33.8, 54.4] ng/mL at 10 minutes after I.V. infusion and 31.9 [95% CI 26.3, 38.6] ng/mL at 41 minutes after I.M. injection. The mean elimination half-life was not affected by route of administration.
Plasma protein binding of ondansetron as measured in vitro was 70% to 76%, with binding constant over the pharmacologic concentration range (10 to 500 ng/mL). Circulating drug also distributes into erythrocytes.
A positive lymphoblast transformation test to ondansetron has been reported, which suggests immunologic sensitivity to ondansetron.
INDICATIONS
EMESET is indicated for the prevention of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention and treatment of post-operative nausea and vomiting (PONV).
DOSAGE AND ADMINISTRATION
Prevention of Chemotherapy-Induced Nausea and Vomiting
Adults: Prevention of Nausea and Vomiting Associated With Highly Emetogenic Cancer Chemotherapy:
The recommended I.V. dosage of EMESET for adults is a single 32-mg dose or three 0.15-mg/kg doses. A single 32-mg dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. With the three-dose (0.15-mg/kg) regimen, the first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose of EMESET .
The recommended adult oral dosage of EMESET is a single 24-mg dose administered 30 minutes before the start of single-day highly emetogenic chemotherapy.
Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Cancer Chemotherapy:
The recommended adult oral dosage is one 8-mg EMESET Tablet given twice a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. One 8-mg EMESET Tablet should be administered twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy.
Children: Prevention of Nausea and Vomiting Associated With highly or Moderately Emetogenic Cancer Chemotherapy:
The dosage in pediatric cancer patients 6 months to 18 years of age should be three 0.15-mg/kg doses. The first dose is to be administered 30 minutes before the start of moderately to highly emetogenic chemotherapy, subsequent doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose of EMESET . The drug should be infused intravenously over 15 minutes. Little information is available about dosage in pediatric cancer patients younger than 6 months of age.
Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Cancer Chemotherapy:
For pediatric patients 12 years of age and older, the dosage is the same as for adults For pediatric patients 4 through 11 years of age, the dosage is one 4-mg EMESET Tablet or 5ml solution given 3 times a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. One 4-mg EMESET Tablet or 5 ml solution should be administered 3 times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy.
Prevention of Nausea and Vomiting Associated With Radiotherapy, Either Total Body Irradiation, or Single High-Dose Fraction or Daily Fractions to the Abdomen:
Adults:
The recommended oral dosage is one 8-mg EMESET Tablet given 3 times a day.
For total body irradiation, one 8-mg EMESET Tablet should be administered 1 to 2 hours before each fraction of radiotherapy administered each day.
For single high-dose fraction radiotherapy to the abdomen, one 8-mg EMESET Tablet should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy.
For daily fractionated radiotherapy to the abdomen, one 8-mg EMESET Tablet should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given.
Children:
There is no experience with the use of EMESET Tablets or solution in the prevention of radiation-induced nausea and vomiting in pediatric patients.
Prevention of Postoperative Nausea and Vomiting:
Adults:
The recommended I.V. dosage of EMESET for adults is 4 mg undiluted administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if the patient experiences nausea and/or vomiting occurring shortly after surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for adults. While recommended as a fixed dose for patients weighing more than 40 kg, few patients above 80 kg have been studied. In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, I.V. dose of ondansetron 4 mg, administration of a second I.V. dose of 4 mg ondansetron postoperatively does not provide additional control of nausea and vomiting.
The recommended oral dosage is 16 mg given as two 8-mg EMESET Tablets 1 hour before induction of anesthesia.
Children:
The recommended I.V. dosage of EMESET for pediatric surgical patients (1 month to 12 years of age) is a single 0.1-mg/kg dose for patients weighing 40 kg or less, or a single 4-mg dose for patients weighing more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the patient experiences nausea and/or vomiting occurring shortly after surgery.
There is no experience with the use of EMESET Tablets or solution in the prevention of postoperative nausea and vomiting in pediatric patients.
CONTRAINDICATIONS
Hypersensitivity to any components of the preparations.
WARNINGS AND PRECAUTIONS
Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and /or gastric distention. Rarely and predominantly with intravenous ondansetron , transient ECG changes including QT interval prolongation have been reported.
Drug Interactions
Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs.
Phenytoin, Carbamazepine, and Rifampicin : In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.
Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.
Renal impairment
No alteration of daily dosage or frequency of dosing or route of administration is required.
Hepatic impairment
Clearance of ondansetron is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg should not be exceeded.
Pregnancy
EMESET should be used during pregnancy only if clearly needed.
Lactation
It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ondansetron is administered to a nursing woman.
Paediatric use
Little information is available about use of EMESET in children under 4 years of age.
Geriatric use
Dosage adjustment is not needed in patients over the age of 65 years.
UNDESIRABLE EFFECTS
The following have been reported as adverse events in clinical trials of patients treated with ondansetron . A causal relationship to therapy with Ondansetron has been unclear in many cases.
Chemotherapy-Induced Nausea and Vomiting: The adverse events depicted below have been reported in >/=5% of adult patients receiving a single 24-mg ondansetron Tablet in 2 trials. These patients were receiving concurrent highly emetogenic cisplatin-based chemotherapy regimens
(cisplatin dose >/=50mg/m2).
| Event |
Ondansetron
24 mg q.d.
n = 300 |
Ondansetron
8 mg b.i.d.
n = 124 |
Ondansetron
32 mg q.d.
n = 117 |
| Headache |
33 (11%) |
16 (13%) |
17 (15%) |
| Diarrhea |
13 (4%) |
9 (7%) |
3 (3%) |
The adverse events depicted below have been reported in >/=5% of adults receiving either 8 mg of Ondansetron Tablets 2 or 3 times a day for 3 days or placebo in 4 trials. These patients were receiving concurrent moderately emetogenic chemotherapy, primarily cyclophosphamide-based regimens.
| Event |
Ondansetron 8 mg b.i.d.
n = 242 |
Ondansetron 8 mg t.i.d.
n = 415 |
Placebo
n = 262 |
| Headache |
58 (24%) |
113 (27%) |
34 (13%) |
| Malaise/fatigue |
32 (13%) |
37 (9%) |
6 (2%) |
| Constipation |
22 (9%) |
26 (6%) |
1 (<1%) |
| Diarrhea |
15 (6%) |
16 (4%) |
10 (4%) |
| Dizziness |
13 (5%) |
18 (4%) |
12 (5%) |
Central Nervous System : There have been rare reports consistent with, but not diagnostic of, extrapyramidal reactions in patients receiving ondansetron.
Hepatic : In 723 patients receiving cyclophosphamide-based chemotherapy in US clinical trials, AST and/or ALT values have been reported to exceed twice the upper limit of normal in approximately 1% to 2% of patients receiving Ondansetron Tablets. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur. The role of cancer chemotherapy in these biochemical changes cannot be clearly determined.
There have been reports of liver failure and death in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear.
Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron.
Other: Rare cases of anaphylaxis, bronchospasm, tachycardia, angina (chest pain), hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures have been reported. Except for bronchospasm and anaphylaxis, the relationship to Ondansetron was unclear.
Radiation-Induced Nausea and Vomiting: The adverse events reported in patients receiving Ondansetron Tablets and concurrent radiotherapy were similar to those reported in patients receiving ondansetron Tablets and concurrent chemotherapy. The most frequently reported adverse events were headache, constipation, and diarrhea.
Postoperative Nausea and Vomiting: The adverse events depicted below have been reported in >/=5% of patients receiving Ondansetron Tablets at a dosage of 16 mg orally in clinical trials. With the exception of headache, rates of these events were not significantly different in the ondansetron and placebo groups. These patients were receiving multiple concomitant perioperative and postoperative medications.
| Adverse Event |
Ondansetron 16 mg (n = 550) |
Placebo (n = 531) |
| Wound problem |
152 (28%) |
162 (31%) |
| Drowsiness/sedation |
112 (20%) |
122 (23%) |
| Headache |
49 (9%) |
27 (5%) |
| Hypoxia |
49 (9%) |
35 (7%) |
| Pyrexia |
45 (8%) |
34 (6%) |
| Dizziness |
36 (7%) |
34 (6%) |
| Gynecological disorder |
36 (7%) |
33 (6%) |
| Anxiety/agitation |
33 (6%) |
29 (5%) |
| Bradycardia |
32 (6%) |
30 (6%) |
| Shiver(s) |
28 (5%) |
30 (6%) |
| Urinary retention |
28 (5%) |
18 (3%) |
| Hypotension |
27 (5%) |
32 (6%) |
| Pruritus |
27 (5%) |
20 (4%) |
Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of oral formulations of Ondansetron. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Ondansetron.
Cardiovascular: Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported.
General: Flushing . Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, shortness of breath, hypotension, laryngeal edema, stridor) have also been reported. Laryngospasm, shock, and cardiopulmonary arrest have occurred during allergic reactions in patients receiving injectable ondansetron.
Hepatobiliary: Liver enzyme abnormalities
Lower Respiratory: Hiccups
Neurology: Oculogyric crisis, appearing alone, as well as with other dystonic reactions
Skin: Urticaria
Special Senses: Eye Disorders: Cases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours.
OVERDOSAGE
There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual doses as large as 150 mg and total daily dosages (three doses) as large as 252 mg have been administered intravenously without significant adverse events. These doses are more than 10 times the recommended daily dose.
In addition to the adverse events listed above, the following events have been described in the setting of ondansetron overdose: "Sudden blindness" (amaurosis) of 2 to 3 minutes` duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of oral ondansetron. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the events resolved completely.
STORAGE AND HANDLING INSTRUCTIONS
EMESET injection, syrup and tablets should be kept in a cool place and protected from light. No other special storage conditions are necessary. Injection is stable at room temperature under normal lighting conditions for 48 hours after dilution with the following I.V. fluids: 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, and 3% Sodium Chloride Injection. Although EMESET injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative.
Dilutions of EMESET injection in compatible intravenous infusion fluids should be prepared at the time of infusion or stored at 2-8 o C for no more than 24 hours before administration. No protection from light is necessary while infusion takes place. EMESET injection should not be administered in the same syringe or infusion as any other medication. EMESET injection ampoules should not be autoclaved.
PACKAGING INFORMATION
EMESET Injection : Ampoules of 2 ml and 4 ml
EMESET 4 : Strip of 6 tablets
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