Approved on.
Revision Date.
Ondansetron Hydrochloride Tablets Instructions
Please read the instruction manual carefully and use under the guidance of a physician. Use
[Drug Name].
Generic Name: Ondansetron Hydrochloride Tablets
Trade Name: Obey
English Name: Ondansetron Hydrochloride Tablets
Hanyu Pinyin: Yansuan Angdansiqiong Pian
[Ingredients】
The main ingredient of this product is: Ondansetron hydrochloride.
Chemical name: 2,3-dihydro-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-4(1H)-carbazolone hydrochloride dihydrate
Chemical structure formula.
Molecular Formula:Molecular Formula =”font-family:Times New Roman”>C18H19N3O-HCl-2H2O
Molecular weight:365.86
[Properties].
This product is a film-coated tablet, which appears white or off-white after removing the coating. After removing the coating, it appears white or off-white.
[Indications].
Antiemetic. Used for.
① Nausea and vomiting caused by chemotherapy and radiation treatment with cytotoxic drugs;
②Prevention and treatment of post-surgical nausea and vomiting.
[Specifications
4mg (based on C18H19N3O)
[Dosage].
1. For vomiting caused by highly emetogenic chemotherapeutic agents: 8 mg of ondansetron hydrochloride injection intravenously 15 minutes before, 4 hours and 8 hours after chemotherapy, and 8 mg of ondansetron hydrochloride tablets orally every 8 to 12 hours after stopping chemotherapy for 5 days.
2. For moderately emetogenic chemotherapy drug-induced vomiting: 8 mg of ondansetron hydrochloride injection intravenously 15 minutes before chemotherapy, followed by 8 mg of ondansetron hydrochloride tablets orally every 8 to 12 hours for 5 days.
3. For radiation therapy-induced vomiting: the first dose must be given orally as a tablet 8 mg 1 to 2 hours before radiation therapy and 8 mg orally every 8 hours thereafter, depending on the course of radiation therapy.
4. For the prevention of postoperative nausea and vomiting: 8 mg of tablets orally 1 hour before anesthesia, followed by 8 mg of tablets orally twice every 8 hours.
Elderly
No adjustment of oral dose or dosing frequency is necessary.
Patients with hepatic impairment
In those with moderate or severe hepatic impairment, ondansetron hydrochloride clearance is significantly reduced and serum half-life is significantly prolonged. In these patients, the total daily dose should not exceed 8 mg.
Patients with renal insufficiency
No adjustment of oral dose or dosing frequency is required.
[Adverse Reactions
Clinical trial experience
Because clinical trials are conducted under a variety of conditions, the rates of adverse reactions observed in clinical trials of a drug cannot be directly compared to the incidence in clinical trials of another drug and may not reflect the actual rates of adverse reactions observed in the clinic.
The following adverse reactions have been reported in clinical trials in ondansetron-treated patients. Ondansetron is the active ingredient in ondansetron hydrochloride tablets. In many cases, the causal relationship between adverse events and ondansetron hydrochloride treatment is not known.
Prevention of chemotherapy-induced nausea and vomiting
In two clinical trials in 300 patients in which patients received a single oral dose of ondansetron hydrochloride tablets 24 mg to prevent nausea and vomiting caused by highly emetogenic chemotherapy (cisplatin ≥50 mg/m2), the most common adverse reactions with an incidence of ≥4% were: headache (11%) and diarrhea (4%).
Table 1 shows the most common adverse reactions in 4 clinical trials (primarily cyclophosphamide-based regimens) conducted in adult patients for the prevention of nausea and vomiting caused by moderately emetogenic chemotherapy.
Table 1 Most common adverse reactions to ondansetron hydrochloride in adult patients for the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy (primarily cyclophosphamide-based regimens)a
Adverse eventsOndansetron hydrochloride 8 mg twice daily
(n = 242)Placebo
(n = 262)headache58 (24%) 34 (13%)Lack of energy/fatigue32 (13%)6 (2%)Constipation22 (9%)1 (<1%)Diarrhea15 (6%)10 (4%)a These adverse reactions occurred in ≥5% of patients in the ondansetron hydrochloride treatment group and occurred more frequently than in the placebo group.
Less common adverse reactions
Central nervous system: extrapyramidal reactions (less than 1% of patients)
Liver: Clinical trials conducted in the United States showed that in approximately 1% to 2% of the 723 patients who received basic chemotherapy with ondansetron hydrochloride and cyclophosphamide, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) values exceeded twice the upper limit of normal. This increase was a one-time event and did not appear to be related to the dose or duration of treatment. Similar transient elevations in transaminases occurred during some courses of repeated exposures, but without symptomatic liver disease. The role of oncologic chemotherapy in these biochemical changes is unclear.
Hepatic failure and death have been reported in patients on a combination of other agents, including potentially cytotoxic chemotherapeutic agents and antibiotics. The etiology of liver failure is not known.
Skin: rash (in about 1% of patients).
Other (less than 2%): allergic reactions, bronchospasm, tachycardia, angina pectoris, hypokalemia, electrocardiographic changes, vaso-occlusive events, and grand mal seizures. The relationship with ondansetron hydrochloride, except for bronchospasm and allergy, is unclear.
Prevention of radiation therapy-induced nausea and vomiting
In patients receiving both ondansetron hydrochloride tablets and radiotherapy, the most common adverse reactions (incidence ≥2%) were similar to those in patients receiving both ondansetron hydrochloride and chemotherapy, mainly headache, constipation, and diarrhea.
Prevention of postoperative nausea and vomiting
Table 2 shows the most common adverse effects in clinical trials conducted in adult patients for the prevention of postoperative nausea and vomiting. In these trials, patients in both groups received multiple perioperative and postoperative medications.
Table 2 Most common adverse reactions to ondansetron hydrochloride in the prevention of postoperative nausea and vomiting in adult patientsa
Adverse effectsOndansetron hydrochloride 16 mg administered as a single dose
(n = 550)Placebo
Placebo (n = 531)Headache49 (9%)27 (5%)Tissue hypoxia49 (9%)35 (7%)Fever45 (8%)34 (6%)Dizziness36 (7%)34 (6%)Endocrine disorders36 (7%)33 (6%)Anxiety/excitement33 (6%)29 (5%)Urinary retention28 (5%)18 (3%)Scratching disorder27 (5%)20 (4%)a Ondansetron hydrochloride The incidence of adverse reactions in the ondansetron group was ≥5%, and the incidence of these adverse reactions exceeded that of the placebo group.
A crossover study in 25 subjects showed headache in 6 (24%) subjects who were given ondansetron hydrochloride with water and 2 (8%) subjects who were given ondansetron hydrochloride without water.
Postmarketing Experience
The following adverse reactions have been identified with ondansetron post-marketing. Because these adverse reactions were reported voluntarily by an uncertain population, it was not always possible to reliably estimate their incidence or to determine a causal relationship with drug exposure.
Cardiovascular
Arrhythmias (including ventricular and supraventricular tachycardia, premature ventricular beats, and atrial fibrillation), bradycardia, electrocardiographic changes (including second-degree heart block, prolonged QT/QTC intervals, and ST-segment depression), palpitations, and syncope.
General Conditions
Flushing. Rare hypersensitivity reactions have been reported, sometimes severe (e.g., allergic reactions, angioedema, bronchospasm, shortness of breath, hypotension, laryngeal edema, wheezing).
Hepatobiliary
Liver enzyme abnormalities
lower respiratory tract
Hiccups
Neurology
Motor nerve crisis, which can occur alone as well as other dystonia.
skin
Urticaria, Stevens-Johnson syndrome, and toxic epidermolysis bullosa
Ophthalmology
Transient cases of ocular blindness have been reported to occur primarily during intravenous injections. Transient ophthalmoplegia has been reported to subside in minutes to 48 hours.
[Contraindication].
Ondansetron hydrochloride is contraindicated in patients who.
This product is contraindicated in patients with known hypersensitivity to any of the ingredients in the formulation.
Ondansetron is contraindicated in combination with apomorphine based on reports of severe hypotension and loss of consciousness when used in combination with apomorphine hydrochloride.
[Precautions].
Hypersensitivity reactions
Hypersensitivity reactions, including allergic reactions and bronchospasm, have been reported in patients who have demonstrated hypersensitivity reactions to other selective 5-HT3 receptor antagonists. If hypersensitivity reactions occur, discontinue ondansetron hydrochloride; treat promptly according to the standard of care and monitor until signs and symptoms of hypersensitivity reactions resolve.
Prolonged QT interval
Patients treated with ondansetron hydrochloride have experienced electrocardiographic (ECG) changes including prolonged QT intervals. In addition, tip-twisting ventricular tachycardia has been reported after ondansetron hydrochloride became available. Avoid the use of ondansetron hydrochloride in patients with congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities (eg, hypokalemia or hypomagnesemia), congestive heart failure, slow arrhythmias, or on other drugs that cause QT prolongation.
Serotonin syndrome
Serotonin syndrome has been reported with the use of 5-hydroxytryptamine receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (eg, selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal, and serotonin syndrome due to ondansetron hydrochloride overdose alone has been reported. Most serotonin syndromes associated with 5-hydroxytryptamine receptor antagonists occur in postanesthesia care units or infusion centers.
Symptoms of 5-hydroxytryptamine syndrome may include the following signs and symptoms: altered mental status (e.g., anxiety, hallucinations, confusion, and coma), autonomic instability (e.g., tachycardia, blood pressure instability, dizziness, sweating, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, tonicity, myoclonus, hyperreflexia, ataxia), seizures, with or without gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea). Patients should be monitored for the development of serotonin syndrome, especially with concomitant use of ondansetron hydrochloride and other serotonin analogues. If symptoms of serotonin syndrome develop, discontinue ondansetron hydrochloride and initiate supportive therapy. Patients should be informed of the increased risk of 5-hydroxytryptamine syndrome, especially if ondansetron hydrochloride is taken concomitantly with other serotonin medications.
Masking progressive bowel obstruction and gastric dilatation
Ondansetron is known to prolong large bowel transport, so its use in patients after abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask progressive bowel obstruction and/or gastric dilatation. It is important to monitor for decreased bowel activity, especially in patients with risk factors for gastrointestinal obstruction.
Ondansetron hydrochloride is not a drug that stimulates gastric or intestinal motility and should not be used as a substitute for nasogastric tube suctioning.
Effects on the ability to drive and operate machines
Psychomotor tests have demonstrated that ondansetron does not affect behavioral efficacy and has no sedative effect. Pharmacological studies of ondansetron have shown that the product does not have deleterious effects on such activities.
Other
In patients undergoing surgery for adenotonsillitis, the use of ondansetron to prevent nausea and vomiting can mask occult bleeding. Therefore, such patients should be followed carefully after the use of ondansetron.
Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.
[For pregnant and lactating women
Pregnancy
The safety of ondansetron in humans during pregnancy is not known, and animal studies have not shown direct or indirect harmful effects during the embryonic, fetal formation, gestational, perinatal, and postpartum periods. However, because studies in animals are not fully predictive of human response, ondansetron is not recommended for use during pregnancy.
Lactation
Ondansetron has been shown to be secreted from the milk of lactating animals, and therefore mothers who are using this product are advised not to breastfeed.
Fertility
There is no information on the effect of ondansetron on human fertility.
[Pediatric Dosage].
Unclear.
[Geriatric Use].
Of the patients with chemotherapy-induced or surgery-induced nausea and vomiting enrolled in controlled clinical trials in the United States and abroad, 938 (19%) were 65 years of age or older. Subgroup analysis of age subgroups showed no overall differences in safety or efficacy between patients aged ≥65 years and those <65 years. Patients older than 75 years had reduced clearance and increased elimination half-life compared with younger patients. In clinical trials, there were insufficient patients over 75 years of age to draw conclusions about safety or efficacy in this age group. Other reported clinical experiences have not established differences in response between older and younger patients, but greater sensitivity in some older adults cannot be ruled out. No dose adjustment for elderly patients is required.
[Drug Interactions].
5-hydroxytryptamines
in combination 5-serotonin syndrome (including altered mental status, autonomic dysregulation, and neuromuscular symptoms) has been reported following the combination of serotonin receptor antagonists and other serotonin medications . Other serotonin medications include selective5-hydroxytryptamine reuptake inhibitors(SSRIs), 5-hydroxytryptamine and noradrenaline reuptake inhibitors (SNRIs). Monitor for the appearance of 5-hydroxytryptamine syndrome. If symptoms develop, ondansetron hydrochloride should be discontinued and supportive therapy initiated.
Drugs that affect cytochrome P-450 enzymes
Ondansetron by itself does not induce or inhibit the hepatic cytochromeP-450drug metabolizing enzyme system. Since ondansetron is produced by the hepatic cytochromeP-450drug-metabolizing enzyme(CYP3A4, CYP2D6,CYP1A2)metabolized by these enzymes, the inducers or inhibitors may alter the clearance of ondansetron and thus the half-life of ondansetron. After the use of CYP3A4potent inducers(i.e., phenytoin, carbamazepine, and rifampin). However, based on the available data, ondansetron hydrochloride dose adjustment is not recommended for patients on these drugs.
Tramadol
Although no interaction between ondansetron hydrochloride and tramadol has been observed pharmacokinetic interactions between ondansetron hydrochloride and tramadol have not been observed,data from 2small trials suggest that ondansetron hydrochloride, when combined with tramadol, increases patient’s self-administered tramadol dosage. Monitor patients when ondansetron hydrochloride is administered concomitantly with tramadol to ensure adequate analgesia.
chemotherapy
Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.
In76 pediatric patients in a crossover trial, intravenous ondansetron did not increase systemic concentrations of high-dose methotrexate.
Alfentanil and atracurium
Ondansetron hydrochloride does not alter the respiratory depression produced by alfentanil, nor does it alter the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied.
[Drug overdose
There is no specific antidote for ondansetron hydrochloride overdose, and the patient should be given appropriate supportive therapy.
In addition to known adverse reactions, the following adverse reactions have occurred with ondansetron hydrochloride overdose: one patient experienced “sudden blindness” (blackout) for 2 to 3 minutes with severe constipation during a single intravenous dose of 72 mg of ondansetron hydrochloride. Hypotension (and syncope) occurred in patients taking 48 mg of ondansetron hydrochloride, and a transient vasovagal episode of second-degree heart block was observed with only 4 minutes of 32 mg IV dosing. Adverse reactions in all cases completely subsided.
Serotonin syndrome has been reported in pediatric patients who were overdosed (5 mg/kg above the predicted intake). Reported symptoms included drowsiness, agitation, tachycardia, tachypnea, hypertension, flushing, dilated pupils, sweating, myoclonus, horizontal nystagmus, hyperreflexia, and seizures. Patients require supportive care, including intubation, and usually recover completely without sequelae within 1 to 2 days.
[Pharmacology and Toxicology
Pharmacologic effects
Ondansetron is a selective 5-HT3 receptor antagonist. Although the mechanism of action of ondansetron is not fully understood, it is not a dopamine receptor antagonist. 5-HT3 receptors are mainly located in the peripheral vagal nerve terminals and in the chemosensory trigger zone of the central posterior pole region. It is uncertain whether the antiemetic effect of ondansetron is mediated centrally or peripherally or both. However, cytotoxic chemotherapy is associated with the release of 5-HT from small intestinal chromophores. Cisplatin causes an increase in the excretion of 5-HIAA (5-hydroxyindoleacetic acid) in human urine and causes vomiting. The released 5-HT activates the afferent branch of the vagus nerve via 5-HT receptors, triggering the vomiting reflex. Pre-administration of 5-HT synthesis inhibitors in animals, or severance of the bilateral abdominal vagus nerve and visceral greater nerve, or pre-administration of 5-HT3 receptor antagonists prevented cisplatin-induced vomiting.
Toxicological studies
Genotoxicity: Standard genotoxicity test results for ondansetron were negative.
Reproductive toxicity: No effects on fertility or reproductive behavior were seen in male and female rats given orally up to 15 mg/kg/day (approximately 8 times the recommended human dose of 16 mg/day based on body surface area) of ondansetron.
In embryo-fetal developmental toxicity assays, oral administration of ondansetron up to 15 mg/kg/day in pregnant rats and 30 mg/kg/day in pregnant rabbits (approximately 8 and 30 times the recommended human dose of 16 mg/day on a body surface area basis) did not result in ondansetron-related fertility impairment or fetal damage.
In a perinatal toxicity test, oral administration of ondansetron up to 15 mg/kg/day (approximately 6 times the maximum recommended human dose of 24 mg/day on a body surface area basis) to pregnant rats from gestation day 17 to day 21 after birth did not affect the perinatal development of pregnant rats and their offspring, including reproductive function of the F1 generation, except for a slight decrease in maternal body weight gain.
Carcinogenicity: No carcinogenic effect was seen in a 2-year oral carcinogenicity test in mice and rats with doses of ondansetron up to 10 mg/kg/day and 30 mg/kg/day (approximately 5 and 8 times the human dose of 16 mg/day based on body surface area), respectively.
[Pharmacokinetics
Absorption
Ondansetron Hydrochloride is absorbed via the gastrointestinal tract and some of the drug undergoes first-pass metabolism. The mean bioavailability of a single8 mgtablet in healthy subjects after administration was approximately56%.
Ondansetron Hydrochloride Systemic exposure increases disproportionately with dose. Area under the curve for 16 mg tablets(AUC)ratio8mgtablet dose at a higher predicted value24%. This may reflect a reduction in first-pass metabolism at higher oral doses.
Food effects: The food The presence of food also slightly increases bioavailability.
distribution
In10～500 ng/mLThe plasma protein binding rate of ondansetron hydrochloride was determined in vitro in the concentration range of 70%~76%. Circulating drugs are also distributed in red blood cells.
Metabolism
Metabolism and excretion. Ondansetron hydrochloride is extensively metabolized in humans, with approximately5% of the radioactive dose being recovered as the parent compound in urine. Metabolites are present in the urine.
The main metabolic pathways are hydroxylation on the indole ring followed by subsequent glucuronide or sulfate binding.
In vitro metabolism studies showed that ondansetron is a substrate for human hepatic cytochromeP-450enzymes, includingCYP1A2, CYP2D6andCYP3A4. In the overall turnover of ondansetron,CYP3A4 plays a dominant role. Due to the diversity of metabolic enzymes that can metabolize ondansetron, inhibition or loss of an enzyme(such asCYP2D6gene defect) may be compensated by others and may result in little change in ondansetron elimination rates.
Although some non-conjugated metabolites are pharmacologically active, no plasma concentrations of these metabolites were found to significantly enhance the pharmacological activity of ondansetron.
Special Populations
Age: Elderly population : Compared to younger subjects, older patients aged >75 years had reduced clearance and increased elimination half-life.
Gender: Ondansetron Hydrochloride There are gender differences in the pharmacokinetic profile of ondansetron administered as a single dose. The degree and rate of absorption was greater in women than in men. Women had slower clearance and apparent volume of distribution(weight-corrected)is smaller and has higher absolute bioavailability, resulting in higher plasma ondansetron concentrations. The higher plasma concentrations are somewhat explained by differences in body weight between men and women. It is not clear whether these gender differences are clinically significant. More detailed pharmacokinetic information is provided in Table 3 and Table 4.
Table3 Single oral dose of ondansetron hydrochloride in healthy male and female subjects8 mg Pharmacokinetics of Ondansetron
Age-Group
(years)
Gender (M/F)Weight mean
(kg)QuantityPeak concentration
(ng/mL)Time to peak
(h)Average elimination half-life
(h)Systemic plasma clearance L/h/kgAbsolute biology
Utilization degree18-40 18-40M69626.22.03.10.4030.483F62.7542.71.73.50.3540.66361-74M77.5624.12.14.10.3840.585F60.2652.41.94.90.2550.643≥75M78.05 537.02.24.5 4.50.2770.619F67.66 46.12.16.20.2490.747 Table4 Single oral dose of ondansetron hydrochloride in healthy male and female subjects =”font-family:Times New Roman”>24mg Pharmacokinetics of Ondansetron
Age -Group
(years)
Gender (M/Female)Weight Mean (kg)QuantityPeak concentration
(ng/mL)Peak time
(h)Average elimination half-life
(h)18-43M84.18125.81.94.7F F71.88194.41.65.8Renal injury: Renal injury is not expected to significantly affect the total clearance of ondansetron, as renal clearance only accounts for the total clearance5%. However, in severe renal impairment(creatinine clearance<30 mL/min)in patients, the mean plasma clearance of ondansetron was reduced by by about 50%. The decrease in clearance is variable and does not coincide with the increase in half-life.
Liver damage: compared to In healthy subjects, patients with mild to moderate liver damage had a reduced clearance2fold and a prolonged mean half-life to11.6hours, while the average half-life of the drug in healthy subjects was 5.7hours. In patients with severe liver damage(Chil-Pughscores of 10score or higher)in which the clearance rate is reduced by 2fold to3fold, with an increase in apparent volume of distribution and an extended half-life up to2020fold. Roman”>20hours.
Drug Interaction Studies
CYP 3A4Inducer: cytochromeP450enzyme inducers may affect the elimination of ondansetron. In a study of 16 patients receiving long-termCYP3A4inducing agents (carbamazepine or phenytoin) were observed in a trial of epilepsy patients treated with ondansetronAUC, Cmaxandt1/2decreases. This resulted in a significant increase in ondansetron clearance. However, this elevation is not considered to be clinically relevant.
Chemotherapy drugs: carmustine Statin, etoposide and cisplatin do not affect the pharmacokinetics of ondansetron.
Antacids: Concurrent The use of antacids does not alter the absorption of ondansetron.
[Storage] Store under shade, sealed, at room temperature.
[Execution Standard]
[Approval Number]
State Drug Authentication H10970062
[Drug Marketing Authorization Holder
Qilu Pharmaceutical Co.
[Manufacturer ]
Enterprise name: Qilu Pharmaceutical Co. style=”font-family:Times New Roman”>
Production Address: Xinro Street, High-tech Zone, Jinan317No.
Postal Code:250100
Tel: 400-127-7799
Fax Number: 0531-83126288, 83126545
Website: http://www.qilu-pharma.com