Ondansetron Injection

Ondansetron is an oral and parenteral serotonin (5-HT3) receptor antagonist. Ondansetron is used as an antiemetic agent for the prevention and treatment of nausea and vomiting during chemotherapy, radiation therapy, and surgery.^[1] Ondansetron has occasionally been utilized for the treatment of hyperemesis gravidarum refractory to other treatments. Novel investigational uses of ondansetron include treatment of gastrointestinal motility disorders and drug dependence (e.g., alcoholism). In the pediatric population, ondansetron is also used off-label for cyclic vomiting syndrome and gastroenteritis-induced vomiting.^[2][3] Ondansetron is an extremely safe and highly effective antiemetic compared to older, traditional antiemetics (e.g., metoclopramide, droperidol); however, there is a risk of dose-dependent QT-prolongation and torsade de points.^[1][4] When administered at optimal doses, ondansetron and other 5HT3 receptor antagonists (e.g., granisetron) are equally effective.^[5] The American Society of Clinical Oncology (ASCO) guidelines recommend that adult patients who are treated with moderate to high-emetic-risk chemotherapy agents should be offered a 3-drug combination of a 5-HT3 receptor antagonist, a neurokinin 1 (NK1) receptor antagonist, and dexamethasone; olanzapine is also added to the 3-drug combination during use of high-emetic-risk agents.^[6] Children receiving moderate to high-emetic-risk agents should be offered a 2-drug combination of a 5-HT3 receptor antagonist and dexamethasone; aprepitant is also added to the 2-drug combination during use of high-emetic-risk agents.^[6][7] The Society for Ambulatory Anesthesia (SAMBA) guidelines recommend the use of a 5-HT3 receptor antagonist as the first choice for prophylaxis of postoperative nausea and vomiting in children.^[8]

Ondansetron is a 5-HT3 receptor antagonist. Although other neurotransmitters are involved, serotonin plays an important role in the emetogenic pathways associated with chemotherapy- and radiation-induced nausea and vomiting. During the early or acute phase, the primary site of emetogenesis in chemotherapy-induced nausea and vomiting (CINV) is thought to be the gut wall. Chemotherapy is cytotoxic to enterochromaffin cells in the small intestine. Enterochromaffin cell death leads to serotonin release and therefore increased serotonin binding on nerve endings, leading to sensory input that contributes to emesis.^[4][9] Peripherally, ondansetron preferentially blocks the serotonin 5-hydroxytryptamine, type 3 (5-HT3) receptors at the peripheral vagal nerve terminals in the intestines, blocking the signal transmission to the central nervous system and antagonizing the effects of serotonin. Ondansetron is also a weak antagonist of the 5-HT1B, 5-HT1C, alpha-adrenergic, and opioid mu receptors; the clinical implications of these actions is uncertain. It has no activity at dopamine receptors.^[1][4]

Much like chemotherapy-induced nausea and vomiting (CINV), postoperative nausea and vomiting (PONV) is not controlled by a single neurotransmitter, but serotonin is believed to play a major role. The process of postoperative nausea and vomiting is coordinated by the vomiting center in the central nervous system. Stimulation can be initiated centrally in areas such as the cerebral cortex and otic or vestibular nerves, or peripherally in areas such as the oropharynx, mediastinum, gastrointestinal track, renal pelvis, peritoneum, or genitalia. Stretching and inflammation that occur during or after surgery may trigger chemical stimulation that lead to nausea and vomiting. Centrally, ondansetron blocks the 5-HT3 receptor site at the chemoreceptor trigger zone, stopping the vomiting reflex produced by the vomiting center. Because of multiple neurochemical receptor sites involved during surgery, combination antiemetic therapy with drugs of different mechanisms is often necessary.^[1][10]

The fixed dose of ondansetron recommended for post-operative nausea and vomiting was established in patients weighing less than 80 kg. Patients weighing more than 80 kg or with obesity have not been studied extensively.

Ondansetron is extensively metabolized in the liver and should be used with caution in patients with hepatic disease, hepatitis, or elevated hepatic enzymes because of possible increased plasma levels, reduced clearance, and subsequent toxicity.^[1]

Ondansetron should not be used in patients with a known ondansetron hypersensitivity. Use with caution in patients with known granisetron hypersensitivity, palonosetron hypersensitivity, dolasetron hypersensitivity, or sensitivity to related drugs.^[1] Cross-sensitivity is possible between these agents; there have been several reports of anaphylactic/anaphylactoid reactions associated with the use of drugs in this class.^[11][12] Antagonism at serotonin (5-HT) receptors, and the subsequent increased concentrations of serotonin, may increase the risk of developing bronchospasm and/or vasoconstriction.^[13][14][15]

Patients with phenylketonuria should be informed that ondansetron orally disintegrating tablets (ODT) contain phenylalanine (a component of aspartame). Each 4 mg and 8 mg ODT contains less than 0.03 mg phenylalanine.^[1]

The use of ondansetron may mask the symptoms of adynamic ileus, GI obstruction, or gastric distention after abdominal surgery or during use to prevent chemotherapy-induced nausea and vomiting.^[1] Ondansetron is not a drug that stimulates gastric or intestinal peristalsis; it should not be used instead of nasogastric suction.^[16]

Myocardial ischemia has been reported in patients treated with ondansetron. In some cases, predominantly during intravenous administration, the symptoms appeared immediately after administration but resolved with prompt treatment. Coronary artery spasm (coronary vasospasm) appears to be the most common underlying cause. Therefore, monitor for or advise patients of signs or symptoms of myocardial ischemia during use of ondansetron.^[1][17] Ondansetron also increases the risk of developing QT prolongation in a dose-dependent manner, which can lead to abnormal and potentially fatal heart rhythms, including torsade de pointes. In June 2012, the FDA announced preliminary results from a study suggesting that intravenous (IV) ondansetron given as a single 32 mg dose causes QT prolongation. Single IV doses should not exceed 16 mg; the 32 mg IV single-dose regimen is no longer indicated for chemotherapy-induced nausea and vomiting prophylaxis. Oral dosing recommendations have not changed and the use of single oral doses up to 24 mg may be used for the prevention of chemotherapy-induced nausea and vomiting (CINV). Avoid ondansetron in patients with congenital long QT syndrome. Electrocardiogram (ECG) monitoring and cautious use is recommended in patients with hypokalemia, hypomagnesemia, congestive heart failure, significant bradycardia, or in patients taking other medications known to prolong the QT interval. Use ondansetron with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, stress-related cardiomyopathy, myocardial infarction, stroke, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. ^[1][17]

Little information is available about dosage in children 4 years of age or younger. Furthermore, there is no experience with the use of 24 mg ondansetron tablets in pediatric patients.^[1][17]

Infants younger than 4 months of age may accumulate ondansetron and should be closely monitored for toxicity. Limited information is available on the use of ondansetron in neonates younger than 1 month of age receiving surgery or in pediatric cancer patients who are infants younger than 6 months of age. The clearance of ondansetron in infants 1 to 4 months of age is slower and the half-life is roughly 2.5-fold longer than infant patients who are 4 to 24 months of age.^[1]

Data on the use of ondansetron during human pregnancy from published clinical and epidemiological studies are inconsistent and have important methodological limitations, including the uncertainty of whether women who filled a prescription actually took the medicine, the concomitant use of other medications or treatments, recall bias, and other unadjusted confounders, that do not reliably inform a drug associated risk of adverse fetal outcomes. In aggregate analysis, ondansetron exposure in utero has not been associated with major congenital malformations. Some studies have not shown a statistically significant increase in the risk of birth defects with the use of ondansetron; however, others have shown a possible increased risk of cleft palate and cardiovascular malformations.^[1][17] Ondansetron has been shown to cross the placenta in early pregnancy with a median fetal to maternal ratio of 0.41. Evidence is limited on the safety or efficacy of the serotonin 5-HT3 inhibitors for nausea and vomiting of pregnancy. There are more published data for ondansetron use during pregnancy than with other 5HT-3 antagonists. The American College of Obstetricians and Gynecologists (ACOG) includes oral ondansetron as a third-line pharmacologic treatment option for nausea and vomiting of pregnancy in patients who are not dehydrated and have failed other therapies and IV ondansetron for patients who are dehydrated, require IV fluid replacement, and have failed other therapies. Although some studies have shown an increased risk of birth defects with early ondansetron use, other studies have not and the absolute risk to any fetus is considered, per ACOG, to be low. Some studies have suffered from small sample sizes and potential methodological bias. However, women should be counseled regarding the available data, and the use of ondansetron before 10 weeks of gestation should be individualized weighing the risks and benefits.^{[18][19][20][21]}

It is not known whether ondansetron is excreted in human milk. However, because of its low molecular weight, transfer into breast milk should be expected.^[22] Caution should be exercised when administering ondansetron to a breastfeeding woman.

No differences in responses for safety or efficacy have been observed between geriatric and younger patients during clinical trials or other reported clinical experience. Of the total number of patients enrolled in US and foreign-controlled clinical trials for postoperative and chemotherapy-induced nausea and vomiting, for which there were subgroup analyses, 938 were 65 years of age or older. However, greater sensitivity of some older individuals cannot be ruled out. The manufacturer states that no dosage adjustments are needed in elderly patients. Geriatric patients may be at increased risk for developing a prolonged QT interval when using ondansetron.^[1]

Diarrhea (2—16%) and constipation (6—11%) were among the most frequently reported adverse events in patients receiving ondansetron during clinical trials for chemotherapy-induced nausea and vomiting (CINV) with moderate-high emetogenic agents.^{[1] [17]} Hiccups have been reported during post-marketing experience with ondansetron.^[1]

Urinary retention (5%) and gynecological disorder (7%) have been reported in patients receiving oral ondansetron for postoperative nausea and vomiting (PONV) during clinical trials.^[17]

Headache (9—27%) was the most frequently reported adverse event during clinical trials of ondansetron and appeared to be more common in patients receiving the drug for chemotherapy-induced nausea and vomiting (CINV). Preliminary observations in a small number of subjects suggest a higher incidence of headache when ondansetron orally disintegrating tablets are taken with water, when compared to without water. Other neurologic side effects reported include drowsiness (8—20%), malaise and fatigue (9—13%), anxiety or agitation (<= 6%), paresthesias (2%), and dizziness (4—7%). Transient dizziness associated with intravenous infusion has been reported post-marketing. Rarely, extrapyramidal reactions, including oculogyric crisis appearing alone or with other types of dystonic reaction, have been reported with ondansetron use.^[1][17] In one case, extrapyramidal reactions were confirmed by rechallenge. In addition, there have been rare reports of grand mal seizures in patients receiving ondansetron, although a casual relationship has not been established.^[1] Elevated hepatic enzymes were reported in patients receiving either cisplatin- or cyclophosphamide-based chemotherapy during clinical trials. The elevation did not appear to be related to ondansetron dose or duration of therapy. The enzyme levels exceeded twice the upper limit of normal (ULN) in approximately 5% of chemotherapy patients receiving injection dosing, and 1—2% of patients receiving oral therapy, but the increases were transient in nature and did not cause symptomatic hepatic disease. Repeat exposure showed similar elevations in some instances. In addition, hepatic failure and death have been reported in patients with cancer receiving concomitant medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics; the etiology of the hepatic failure is unclear.^[1][17] Rare cases of hypokalemia have been reported following treatment with ondansetron in oncology patients; the relationship to ondansetron is unclear.^[1][17] It may be prudent to monitor serum electrolytes in select patients, as hypokalemia is a risk factor for electrocardiogram (ECG) changes.^[1][17] Ondansetron has been associated with QT prolongation and torsade de pointes. Patients at risk for developing torsade de pointes include those with underlying heart conditions, such as congenital long QT syndrome (avoid use), those who are predisposed to hypokalemia and hypomagnesemia, and those taking other medications that lead to QT prolongation. Other cardiovascular adverse events reported during clinical trials with ondansetron include angina, chest pain (unspecified), ECG alterations (including second-degree AV block, QT prolongation, and ST-T wave changes), hypotension (5%), and sinus tachycardia. Bradycardia (6% vs. 6% placebo) was reported in patients receiving oral ondansetron for postoperative nausea and vomiting (PONV). Syncope, palpitations, and arrhythmias, including ventricular tachycardia and supraventricular tachycardia (SVT), bradycardia, premature ventricular contractions (PVCs), atrial fibrillation, and acute myocardial ischemia have been reported during postmarketing use of ondansetron. In some cases, predominantly during intravenous administration, the symptoms of myocardial ischemia appeared immediately after administration but resolved with prompt treatment. Coronary vasospasm (coronary artery spasm) appears to be the most common cause of the ischemia. To minimize the risk of these adverse events in patients receiving intravenous treatment, do not exceed the recommended ondansetron infusion rate and monitor patients for signs and symptoms of myocardial ischemia during and after administration. In patients receiving oral therapy, monitor or advise patients of these symptoms.^[1][17] Intravenous (IV) ondansetron given as a single 32 mg dose causes QT prolongation in a dose-dependent manner; therefore, single IV doses should not exceed 16 mg/dose IV; the 32 mg IV single-dose regimen is no longer indicated for chemotherapy-induced nausea and vomiting (CINV). Oral dosing recommendations have not changed. ECG monitoring is recommended in patients with electrolyte imbalance (e.g., hypokalemia or hypomagnesemia), congestive heart failure, significant bradycardia, or in patients taking other medications that can lead to QT prolongation.^[1][17] Several reports of anaphylactoid reactions have been associated with serotonin (5-HT3) receptor antagonists, such as ondansetron.^[11][12] Manifestations of anaphylactoid reactions have included angioedema, bronchospasm, dyspnea, hypotension, laryngeal edema, stridor, and/or urticaria. Laryngospasm, shock, cardiac arrest, and respiratory arrest have been reported during allergic reactions in patients receiving injectable ondansetron. Rash (unspecified) (1%), pruritus (2—5%), and flushing have been reported in clinical trials with both oral and injectable formulations.^[1][17] Stevens-Johnson syndrome and toxic epidermal necrolysis (TENS) have been reported with post-marketing use of ondansetron.^[1][17] An injection site reaction (4%) was reported in patients receiving ondansetron injection intravenously over 2 to 5 minutes during clinical trials for post-operative nausea/vomiting (PONV); symptoms included pain, erythema, and burning at the site.^[1] Visual impairment has occurred with ondansetron use. Cases of transient blindness, predominantly during intravenous (IV) administration, have been reported; resolution occurred within minutes up to 48 hours. Sudden blindness (amaurosis) of 2—3 minute duration occurred in one patient who was administered ondansetron 72 mg IV as a single dose.^[1][17] In another case, transient blindness was reported in a patient who received ondansetron 4mg as a post-operative rapid IV bolus dose. The mechanism by which ondansetron may cause visual impairment is not well understood. Clinicians in the latter case suggest that it may be related to the rate of administration. Transient blurred vision, in some cases associated with accommodation disorder, has also been reported during post-marketing experience.^[1] Fever (2—8%) and shivers or chills (2—5%) were reported in patients receiving ondansetron during clinical trials. Wound problems (28% vs. 31% placebo) were reported in patients receiving oral ondansetron for postoperative nausea and vomiting (PONV).^[1][17] Serotonin syndrome has been reported with 5-HT3 receptor antagonists, such as ondansetron, during concurrent use of other medications known to increase CNS or peripheral serotonin levels or during overdose. Some of the reported cases were fatal; most occurred in a post-anesthesia care unit or infusion center. If serotonin syndrome becomes evident during treatment, discontinue ondansetron and any other serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is a range of signs and symptoms that can include mental status changes (e.g., agitation, hallucinations, delirium, coma), gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and/or seizures. Cases consistent with serotonin syndrome have been reported in pediatric patients after inadvertent overdose of oral ondansetron (estimated ingestion > 5 mg/kg). Symptoms reported in these cases included somnolence, agitation, tachycardia, tachypnea, hypertension, flushing, mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia, and seizures. Patients required supportive care, including intubation in some cases, with complete recovery in 1—2 days.^[1][17]

Data on the use of ondansetron during human pregnancy from published clinical and epidemiological studies are inconsistent and have important methodological limitations, including the uncertainty of whether women who filled a prescription actually took the medicine, the concomitant use of other medications or treatments, recall bias, and other unadjusted confounders, that do not reliably inform a drug associated risk of adverse fetal outcomes. In aggregate analysis, ondansetron exposure in utero has not been associated with major congenital malformations. Some studies have not shown a statistically significant increase in the risk of birth defects with the use of ondansetron; however, others have shown a possible increased risk of cleft palate and cardiovascular malformations.^{[1] [17][21][19][20]} Ondansetron has been shown to cross the placenta in early pregnancy with a median fetal to maternal ratio of 0.41. Evidence is limited on the safety or efficacy of the serotonin 5-HT3 inhibitors for nausea and vomiting of pregnancy. There are more published data for ondansetron use during pregnancy than with other 5HT-3 antagonists. The American College of Obstetricians and Gynecologists (ACOG) includes oral ondansetron as a third-line pharmacologic treatment option for nausea and vomiting of pregnancy in patients who are not dehydrated and have failed other therapies and IV ondansetron for patients who are dehydrated, require IV fluid replacement, and have failed other therapies. Although some studies have shown an increased risk of birth defects with early ondansetron use, other studies have not and the absolute risk to any fetus is considered, per ACOG, to be low. Some studies have suffered from small sample sizes and potential methodological bias. However, women should be counseled regarding the available data, and the use of ondansetron before 10 weeks of gestation should be individualized weighing the risks and benefits.^{[18][19][20][21]}

It is not known whether ondansetron is excreted in human milk. However, because of its low molecular weight, transfer into breast milk should be expected.^[22] Caution should be exercised when administering ondansetron to a breastfeeding woman.

Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond-use date. Do not flush unused medications or pour down a sink or drain.

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