What are the main uses of ondansetron. How is ondansetron administered. What are the potential side effects of ondansetron. Is ondansetron safe during pregnancy.

Overview of Ondansetron (Zofran)

Ondansetron, commonly known by the brand name Zofran, is a widely used antiemetic medication that effectively treats nausea and vomiting from various causes. As a 5-HT3 receptor antagonist, ondansetron blocks serotonin’s action in the areas of the brain responsible for triggering nausea and vomiting reflexes. This powerful antiemetic is considered an essential medicine by the World Health Organization due to its efficacy and safety profile.

FDA-Approved Uses of Ondansetron

The Food and Drug Administration (FDA) has approved ondansetron for several key indications:

• Prevention of chemotherapy-induced nausea and vomiting (CINV)
• Prevention of radiation-induced nausea and vomiting
• Prevention of postoperative nausea and vomiting (PONV)

Ondansetron is particularly effective against highly emetogenic chemotherapy regimens, including those containing cisplatin at doses of 50 mg/m2 or higher. For CINV, it is considered a first-line treatment option due to its high efficacy.

Off-Label Uses of Ondansetron

While not FDA-approved for these purposes, ondansetron is frequently prescribed off-label for other conditions associated with nausea and vomiting:

• Nausea and vomiting in pregnancy (NVP), including hyperemesis gravidarum
• Gastroenteritis-related nausea and vomiting
• Cyclic vomiting syndrome
• Nausea and vomiting associated with migraine headaches

Is ondansetron effective for all types of nausea and vomiting. While ondansetron is highly effective for many causes of nausea and vomiting, it has minimal efficacy against motion sickness. The mechanisms underlying motion sickness differ from those targeted by ondansetron, limiting its usefulness in this specific condition.

Dosage Forms and Administration

Ondansetron is available in various formulations to suit different patient needs and clinical situations:

• Oral tablets (4 mg, 8 mg, 16 mg, 24 mg)
• Orally disintegrating tablets (ODT) (4 mg, 8 mg)
• Oral solution (4 mg/5 mL)
• Injectable solution for intravenous (IV) or intramuscular (IM) use

The orally disintegrating tablets (ODT) are particularly useful for patients who have difficulty swallowing pills or those at risk of aspiration. These tablets dissolve rapidly on the tongue without the need for water, making them convenient for on-the-go use.

How should ondansetron be administered. The appropriate dosage and route of administration depend on the specific indication and patient factors. For chemotherapy-induced nausea and vomiting, a typical oral dose is 8 mg taken 30 minutes before chemotherapy, followed by 8 mg 8 hours later, and then 8 mg twice daily for 1-2 days after chemotherapy. Intravenous dosing may be used in hospital settings or for patients unable to tolerate oral medication.

Mechanism of Action

Ondansetron’s antiemetic effects stem from its action as a selective serotonin 5-HT3 receptor antagonist. These key points explain its mechanism:

• Blocks serotonin (5-HT) from binding to 5-HT3 receptors in the chemoreceptor trigger zone (CTZ) of the brain
• Inhibits serotonin’s action in the gastrointestinal tract, reducing intestinal motility and secretions
• May have additional central antiemetic effects by modulating other neurotransmitter systems

By targeting these specific receptors, ondansetron effectively reduces the nausea and vomiting reflexes triggered by various stimuli, including chemotherapy agents, radiation, and surgical procedures.

Side Effects and Safety Profile

While ondansetron is generally well-tolerated, it can cause side effects in some patients. Common side effects include:

• Headache
• Constipation
• Dizziness
• Fatigue

More serious but rare side effects may include:

• QT interval prolongation (potentially leading to abnormal heart rhythms)
• Serotonin syndrome (when used with other serotonergic medications)
• Allergic reactions, including anaphylaxis

What precautions should be taken when using ondansetron. Healthcare providers should consider the following precautions:

• Assess for potential drug interactions, especially with other QT-prolonging medications
• Use caution in patients with liver impairment, as ondansetron is primarily metabolized in the liver
• Monitor for signs of serotonin syndrome in patients taking multiple serotonergic drugs
• Consider ECG monitoring in patients with risk factors for QT prolongation

Use in Special Populations

Pregnancy

The use of ondansetron during pregnancy, particularly for nausea and vomiting of pregnancy (NVP), has been a topic of ongoing research and debate. While not FDA-approved for this indication, ondansetron is frequently prescribed off-label for severe cases of NVP or hyperemesis gravidarum.

Is ondansetron safe to use during pregnancy. The safety of ondansetron in pregnancy has been studied extensively, with mixed results:

• Some studies have suggested a small increased risk of certain birth defects, particularly orofacial clefts, when used in the first trimester
• Other large-scale studies have found no significant increase in overall birth defect risk
• The absolute risk, if any, appears to be low

Healthcare providers must weigh the potential risks and benefits when considering ondansetron for pregnant patients, taking into account the severity of symptoms and available alternative treatments.

Pediatric Use

Ondansetron is approved for use in children for the prevention of chemotherapy-induced nausea and vomiting. It has also been used off-label for other causes of nausea and vomiting in pediatric patients, such as gastroenteritis.

What considerations are important for pediatric dosing of ondansetron. Dosing in children is typically based on body weight or body surface area. Healthcare providers should consult current guidelines and prescribing information for appropriate pediatric dosing regimens.

Geriatric Use

Older adults may be more sensitive to the effects of ondansetron, particularly the risk of QT interval prolongation. Dose adjustments may be necessary based on renal and hepatic function, which tend to decline with age.

Drug Interactions

Ondansetron can interact with various medications, potentially affecting its efficacy or increasing the risk of side effects. Important drug interactions include:

• QT-prolonging medications (e.g., certain antiarrhythmics, antipsychotics, and antibiotics)
• Serotonergic drugs (e.g., SSRIs, SNRIs, MAOIs)
• CYP3A4 inducers or inhibitors (may affect ondansetron metabolism)
• Apomorphine (severe hypotension and loss of consciousness reported)

Healthcare providers should perform a thorough medication review before prescribing ondansetron to minimize the risk of adverse drug interactions.

Pharmacokinetics

Understanding the pharmacokinetics of ondansetron is crucial for optimal dosing and administration:

• Absorption: Rapidly absorbed after oral administration, with peak plasma concentrations achieved in about 1.5 hours
• Distribution: Widely distributed throughout the body, with a volume of distribution of approximately 160 L
• Metabolism: Primarily metabolized in the liver by cytochrome P450 enzymes, particularly CYP3A4
• Elimination: Excreted primarily in the urine, with a mean elimination half-life of 3-6 hours in adults

How does hepatic impairment affect ondansetron metabolism. Patients with hepatic dysfunction may have reduced clearance of ondansetron, potentially requiring dose adjustments to prevent accumulation and increased risk of side effects.

Cost and Availability

Ondansetron is available as both brand-name (Zofran) and generic formulations. The availability of generic versions has significantly reduced the cost of this medication, making it more accessible to patients. However, prices can vary depending on the specific formulation, dosage, and pharmacy.

Many insurance plans cover ondansetron, particularly for its FDA-approved indications. Patients should check with their insurance providers regarding coverage and any required prior authorizations.

For those without insurance or with high copays, patient assistance programs and discount cards may be available to help reduce out-of-pocket costs.

Future Directions and Research

While ondansetron has been a mainstay of antiemetic therapy for decades, ongoing research continues to explore its potential in new areas:

• Optimal dosing strategies for various indications
• Long-term safety and efficacy in chronic conditions
• Potential applications in psychiatric disorders, such as obsessive-compulsive disorder (OCD)
• Development of new formulations or delivery methods to enhance efficacy or reduce side effects

What new insights are emerging about ondansetron’s mechanism of action. Recent studies have suggested that ondansetron may have additional effects beyond its action on 5-HT3 receptors, including potential modulation of other neurotransmitter systems. This expanding understanding of its pharmacology may lead to new therapeutic applications in the future.

As research progresses, healthcare providers should stay informed about the latest findings and guidelines to ensure optimal use of ondansetron in clinical practice.

Ondansetron OD Tabs / 8mg / 30 Count – Rising Pharmaceuticals

January 19, 2021/by admin8mg / 30 Count
Back to Products

Brand name: Zofran ODT®

1 Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m2.

2 Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

3 Prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen.

4 Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively, ondansetron orally disintegrating tablets, USP are recommended even where the incidence of postoperative nausea and/or vomiting is low.

For more information please see the prescribing information on DailyMed.

*The brand names listed are not owned by Rising Pharma. Rising Pharma products are generic equivalents to the respective brand names listed on this website.

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Ondansetron – StatPearls – NCBI Bookshelf

Continuing Education Activity

Ondansetron is one of the medications most commonly used for the empiric treatment of nausea and vomiting. Ondansetron has excellent utility as an antiemetic drug, and it is effective against nausea and vomiting of various etiologies. Common uses of ondansetron include the prevention of chemotherapy-induced and radiation-induced nausea and vomiting, the prevention of postoperative nausea and vomiting, and off-label use for the prevention of nausea and vomiting associated with pregnancy. However, it is not effective for motion sickness-induced nausea. This activity will cover the mechanism of action, pharmacology, adverse event profiles, eligible patient populations, contraindications, and monitoring. It also highlights the interprofessional team’s role in managing patients needing ondansetron therapy.

Objectives:

• Identify the antiemetic mechanism of action of ondansetron.

• Outline the approved and off-label indications for using ondansetron.

• Summarize the adverse event profile of ondansetron.

• Review the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients who can benefit from therapy with ondansetron.

Access free multiple choice questions on this topic.

Indications

Nausea and vomiting are common complaints seen by emergency department physicians and primary care clinicians daily.[1] Ondansetron is on the World Health Organization’s (WHO) List of Essential Medicines, a list of medications considered effective and safe in meeting the essential needs of a health care system. Other antiemetics that appear on this list with ondansetron include dexamethasone and metoclopramide. In 2006 (the last year of its patent), the brand-name version of ondansetron was the 20th highest-selling brand-name drug in the United States, and its popularity continues today. Ondansetron has widespread utility as an antiemetic drug and is effective against nausea and vomiting of various etiologies.

The FDA-approved indications include the prevention of chemotherapy-induced nausea and vomiting(CINV), radiation-induced nausea and vomiting, and the prevention of postoperative nausea and vomiting (PONV). [2] It is considered first-line therapy for the treatment of chemotherapy-induced and radiation-induced nausea and vomiting.[3][4]

Off-label use for the prevention of nausea and vomiting associated with pregnancy. Ondansetron has minimal efficacy against nausea and vomiting caused by motion sickness, mediated by different control centers and pathophysiologic mechanisms. There are limited data available from pediatric populations. Ondansetron is used in pediatric populations for the acute treatment of cyclic vomiting syndrome; however, there is little information available on the efficacy of this disease.[5] Ondansetron is used off-label for severe refractory diarrhea associated with neuroendocrine tumors (carcinoid syndrome).[6]

Mechanism of Action

Ondansetron is a selective 5-HT3 serotonin-receptor antagonist used for its antiemetic properties. It is one of the four FDA-approved 5-HT3 serotonin-receptor antagonists used to combat nausea and vomiting, including granisetron, dolasetron, and the second-generation drug, palonosetron. [7]

Ondansetron acts both centrally and peripherally to prevent and treat nausea and vomiting. Central effects are mediated by the antagonism of 5HT-3 serotonin receptors in the area postrema. The area postrema, located on the fourth ventricle floor, contains the “chemoreceptor trigger zone.” This zone senses neurotransmitters like serotonin, toxins, and other signals and plays a role in mediating the sensation of nausea and subsequent vomiting. Ondansetron also has effects peripherally by acting on the vagus nerve. It works on the 5-HT3 receptors that can be found at the vagus nerve terminals. The vagus nerve can sense nausea and vomiting triggers within the GI tract, such as stomach irritants. It forms synapses within the nucleus tractus solitarius of the brainstem, another region important in vomiting. The peripheral actions of ondansetron are thought to be the predominant mechanism for its antiemetic effects.[8][9]

Pharmacokinetics

Absorption: Ondansetron undergoes rapid absorption from the GI tract, and the peak plasma concentration (Tmax) is approximately 1. 5 hours after an 8 mg single oral dose. The absolute bioavailability of ondansetron after oral administration is approximately 60%(50%-70%). The lower bioavailability is attributed to first-pass metabolism. The systemic bioavailability of ondansetron increases nonlinearly with increasing doses from 8 mg, 16 mg, 32 mg, and 64 mg because of saturation of the first-pass metabolism. The bioavailability of ondansetron is significantly higher in patients with cancer (85% to 87%) than in healthy individuals (50%-70%), possibly due to alterations in metabolism.

Distribution: Ondansetron and its metabolites are extensively distributed in tissues. The apparent volume of distribution(Vd) at a steady state is approximately 1.8 L/kg. Ondansetron crosses the blood-brain barrier to a lower extent, with the CSF concentration only about 10%-15% of the plasma concentration in human volunteers. Adenosine binding cassette subfamily 1(ABCB1) is a drug efflux transporter known to transport ondansetron across the blood-brain barrier, thus limiting its accumulation in the CNS. In a patient with decreased activity of ABCB1, the concentration of ondansetron in the brain increases and improves efficacy.[10]

Metabolism: The liver is the primary site of metabolism. The primary mechanism of metabolism is oxidation. 8-hydroxy ondansetron represents the major metabolite (40%), followed by 7-hydroxy ondansetron (< 20%) and 6-hydroxy ondansetron (<5%). Minor metabolism also occurs via N-demethylation to yield N-demethyl ondansetron. The active metabolite of ondansetron is  8-hydroxy ondansetron which is rapidly metabolized to glucuronide and sulfate conjugates in the liver, resulting in low blood concentrations and, thus, a very small contribution to ondansetron’s antiemetic activity. Cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4, are involved in the metabolism of ondansetron. In humans, CYP1A1/2 plays the most crucial role, while CYP2D6 plays a minor role in the metabolism of ondansetron. The role of CYP3A4 is important at higher concentrations of ondansetron. [11]

Excretion: Hepatic metabolism accounts for nearly 95% of ondansetron clearance, and less than 5% is excreted unchanged in the urine. The clearance and elimination half-life of ondansetron vary according to age. The elimination half-life after an 8 mg oral or intravenous dose is approximately 3-4 h in adults, but on average, it is 5.5 hours in the elderly. Clearance ranges from 0.381 L/h/kg to 0.262 L/h/kg, depending on age. In adults, clearance is 0.351 5L/h/kg. The clearance per body weight is higher in younger children. However, the clearance is decreased in infants due to the underdeveloped cytochrome P450 enzyme system.[12]

Administration

Routes of administration include oral, intramuscular (IM), and intravenous (IV). Oral formulations are available in dissolving tablet and soluble film forms. Ondansetron tablets should be administered 1 to 2 hours before radiotherapy, 30 minutes before chemotherapy, and an hour before anesthesia induction. Oral and IV formulations have been shown to have similar efficacy for treating emetogenic chemotherapy.

Dosing varies depending on the route of administration and the etiology. However, 16 mg per dose IV is the maximum recommended single dose due to the risk for QTc prolongation and arrhythmias. Standard dosing to prevent postoperative nausea and vomiting includes 8 mg every 12 hours orally or 4 mg given intravenously. No dosage adjustments are necessary for IV or oral administration in patients with renal impairment. The same holds for patients with mild to moderate hepatic impairment, but the maximum daily dosing is reduced to 8 mg IV or 8 mg orally in patients with severe hepatic impairment. Pediatric dosing is weight-based at 0.15 mg/kg per dose, with a maximum of 16 mg per dose.

Use in Specific Patient Populations

Patients with Hepatic Impairment: No dose adjustments of ondansetron are necessary for mild to moderate hepatic impairment. In patients with severe hepatic impairment, clearance of ondansetron is reduced; the volume of distribution and the plasma half-life is increased. Consequently, ondansetron should be used with caution, and the maximum recommended daily intravenous dose isis reduced to 8 mg.[11]

Patients with Renal Impairment: No dosage adjustments are necessary for IV or oral administration in patients with renal impairment.[11]

Pregnancy Considerations: Ondansetron is a former FDA  “Pregnancy Category B” drug. It should only be used when other medications have been trialed and failed to treat pregnancy-associated nausea, vomiting, and hyperemesis gravidarum.[8] According to ACOG(The American College of Obstetricians and Gynecologists) guidelines, pyridoxine alone or combined with doxylamine is the preferred pharmacological therapy for nausea and vomiting. However, in refractory cases with persistent symptoms, ondansetron, 4 mg orally every 8 hours, may be considered(if there is no dehydration).[13] A possible association between ondansetron use in the first trimester and cleft palate has been reported. Electrolyte and electrocardiogram monitoring are suggested in patients treated with ondansetron having risk factors for arrhythmia, such as a family history of prolonged QT interval, heart failure, and electrolyte disturbances. [14] Recommendations for pregnant women with gynecological cancer suggest that 5HT-3 antagonists (including ondansetron ) can be used as supportive medication.[15]

Breastfeeding Considerations: In a pharmacokinetic study, the relative infant exposure to ondansetron is less.[16] Ondansetron is commonly used for nausea during and after a cesarean section, usually in doses of 4 to 8 mg intravenously. Using ondansetron during cesarean section does not affect the onset of breastfeeding. No adverse drug reactions have been reported in infants. Additionally, ondansetron is indicated for use in infants as young as one month. No specific precautions are required.[17]

Adverse Effects

The most commonly reported side effects (occurring in more than 10% of adults) include headaches, fatigue, dry mouth, malaise, and constipation. Some less common effects range from central nervous system (CNS) manifestations, such as drowsiness and sedation, to local injection site reactions and pruritus. [18][19] A transient increase in liver function tests has been reported as well. The pattern of liver enzyme elevation is normally hepatocellular, with rare cases of clinically apparent acute liver injury or jaundice.[20]

Although typically clinically insignificant, EKG interval changes such as QTc elongation can be seen. These changes typically occur within 1 to 2 hours after administration, returning to baseline within 24 hours. As with any medication that causes QTc elongation, there is a concern for Torsade de Pointes and other arrhythmias.[21] IV administration has a higher risk for arrhythmias; consequently, the FDA does not recommend a single dose greater than 16 mg IV.[22] Isolated cases of sinus bradycardia and asystole have also been reported.[23] Cases of intestinal obstruction due to impaired gut motility have been reported.[24] Stevens-Johnson syndrome has been reported in patients with multiple comorbidities.[25]

Drug-Drug Interactions

Concurrent administration of pimozide with ondansetron should be avoided due to the risk of QTc prolongation. [26] Amiodarone may also prolong the QTc interval; hence administration with ondansetron requires monitoring.[27] There is a risk of serotonin syndrome when taking ondansetron in conjunction with other serotonergic medications.[28][26]

Contraindications

Ondansetron is contraindicated in patients with hypersensitivity to the drug or any components of it.[29] Severe hypersensitivity reactions, including anaphylaxis, have been reported.[30][31] Ondansetron is also contraindicated in patients currently taking apomorphine. Concomitant use of ondansetron and apomorphine can lead to profound hypotension and loss of consciousness, with ondansetron enhancing the hypotensive effects of apomorphine.[32] Patients with phenylketonuria (PKU) should be cautious, as the dissolving tablet formulation can contain phenylalanine, leading to irreversible neurological damage in PKU patients.[33]

Monitoring

Due to the potential for dose-dependent QTc interval elongation, the FDA recommends EKG monitoring along with potassium and magnesium in susceptible populations, such as the elderly or other at-risk groups. These at-risk groups include patients with electrolyte abnormalities such as hypokalemia, hypomagnesemia, heart failure, bradyarrhythmias, or patients on other medications that may prolong the QTc interval.[22][34] 

Pregnant patients should be monitored for adverse fetal outcomes associated with ondansetron therapy.[35][36][37] Current evidence does not suggest routine EKG and electrolyte monitoring for ondansetron without known risk factors. Monitoring should be done in high-risk patients receiving ondansetron intravenously.[23][35]

Toxicity

There is no known antidote to ondansetron, and supportive measures are used for overdose. A case report describes an ondansetron overdose in an infant presenting with seizures, QTc prolongation, hepatotoxicity, and serotonin syndrome. The patient required endotracheal intubation, supportive care, and lorazepam for seizures.[38]

Enhancing Healthcare Team Outcomes

Ondansetron is a widely prescribed medication for nausea and vomiting from various causes. The drug is relatively safe, but prescribers, including nurse practitioners, primary care providers, internists, surgeons, and emergency department physicians, need to monitor the drug in specific populations. Due to the potential for dose-dependent QTc interval prolongation, clinicians should monitor EKG, potassium, and magnesium levels in a susceptible population. It includes the elderly or patients with electrolyte abnormalities such as hypokalemia, hypomagnesemia, heart failure, bradyarrhythmias, or patients on other medications that may prolong the QTc interval. Current evidence does not demonstrate a need to pre-screen this population before administering ondansetron for patients without any of the above risk factors.

An interprofessional team approach is critical for diagnosing and managing symptoms, treating patients with nausea and vomiting, and managing the adverse effects of the treatments. Clinicians (MDs, DOs, NPs, PAs) usually prescribe ondansetron for labeled indications. Oncologist consultation is necessary for CINV. Pharmacists should ensure proper dose, perform medication reconciliation and consult prescribers about any concerns. Nursing staff should monitor patients administering medicine and inform clinicians of any side effects observed. Emergency department physicians should rapidly stabilize the patient in case of arrhythmia. Severe cases may require consultation with an intensivist and MICU/IMC level of care. Medical toxicologist consultation may become necessary in the overdose. If the overdose is intentional, psychiatric consultation is essential. An interprofessional team approach would maximize the efficacy and minimize potential adverse drug reactions for the patients requiring ondansetron, resulting in better patient outcomes. [Level 5] A prospective study involving 789 patients demonstrated that an interprofessional team approach among clinicians, residents, clinical pharmacists, and oncologists reduced potential medication errors, eventually enhancing patient safety. [Level 3]

Review Questions

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• Comment on this article.

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Disclosure: Alexandria Griddine declares no relevant financial relationships with ineligible companies.

Disclosure: Jeffrey Bush declares no relevant financial relationships with ineligible companies.

Zofran in the treatment of complications of cytostatic therapy | Abramov M.E., Lichinitser M.R.

Significant advances in chemotherapy in recent years are based on the development of supportive or concomitant therapy, which has made it possible to make the treatment of patients with cancer more effective. Almost the entire spectrum of cytostatic drugs has a number of pronounced side effects. Nausea and vomiting are among the most common complications of chemotherapy. More recently, about 10% of patients refused chemotherapy or interrupted it prematurely due to the development of intolerable nausea and vomiting. Complications in the form of uncontrolled nausea and vomiting can force the postponement of chemotherapy and significantly worsen the patient’s quality of life. These complications include refusal to eat, malnutrition, dehydration, water and electrolyte imbalance and, as a result, damage to the cardiovascular and other body systems. These side effects of chemotherapy lead to depression of the emotional status, the development of depression that is difficult to stop. The length of hospitalization is extended, which leads to an increase in the cost of treatment. Overcoming these symptoms is an important task of effective treatment of cancer patients, aimed at improving the quality of life of patients.

Nausea and vomiting induced by chemotherapy are divided into 3 groups: acute (within 24 hours after the start of treatment), delayed (occurring 24 hours or more after treatment), and preliminary (occurs before the start of chemotherapy).
A key role in the development of acute nausea and vomiting is played by the neurotransmitter serotonin (5-HT), the release of which occurs when exposed to radiation therapy or the introduction of cytostatic drugs from enterochromaffin cells of the small intestine mucosa. Serotonin acts on the 5-HT3 receptors of the trigger zone, impulses from which are transmitted to the center of vomiting in the CNS, which leads to the development of nausea and vomiting. Most 5-HT3-receptors are localized in the central structures of the brain, on the vagus nerve and neurons of the gastrointestinal tract. The effect of 5-HT3 receptor antagonists on 5-HT4 receptors is also important, which affects the mechanism of serotonin release when cytostatics are administered.
Another decisive mechanism for the development of nausea and vomiting is the stimulation of substance P neurokinin receptors (NK-1) [2,3,18].
In addition to cytostatic drugs and radiation therapy, the cause of nausea and vomiting can also be brain metastases, metabolic disorders, ulcerative lesions of the gastrointestinal mucosa, the use of non-steroidal anti-inflammatory drugs, opiates, digoxin, anticoagulants, anticholinergics, etc. The level of emetogenicity of cytostatics also depends on dose and route of administration. It has been shown that the intravenous drip route of administration reduces the emetogenicity of drugs (in contrast to bolus administration) [9]. Nausea and vomiting also depend on the characteristics of the patients themselves. It has been noted that the risk of nausea and vomiting increases with insufficient control of previous chemotherapy, it is most susceptible to women and patients under 65 years of age, as well as patients who rarely drink alcohol [4,10].
A full understanding of the neuropathophysiology of the development of nausea and vomiting in the future will require a large number of scientific studies.
The neuropharmacological mechanism for the development of delayed nausea and vomiting is still unclear and requires further study, but most likely, the leading role belongs to the mechanism of action of serotonin on 5-HT3 receptors.
Inadequate control of acute and delayed nausea and vomiting in the first courses (stages) of treatment often leads to nausea and vomiting before the next administration of the chemotherapy drug – nausea and vomiting of waiting. The risk of waiting nausea and vomiting has been shown to increase in the absence of adequate control in previous courses of chemotherapy [6].
All chemotherapy drugs are divided into 4 groups depending on the development and intensity of nausea and vomiting. This classification was developed based on the consensus of the International Association for Supportive Care in Oncology (MASCC) in September 2005 (Tables 1 and 2).
However, the presented classifications show the emetogenic potential of drugs when used in monotherapy. Currently, the most commonly used combination chemotherapy (2, 3 or more cytotoxic drugs). To determine the emetogenicity of combinations, an algorithm was developed, presented in Table 3 [20].
Table 3 illustrates the algorithm for correctly assessing the emetogenicity of ongoing chemotherapy. The algorithm starts by identifying the most emetogenic drug in a given combination. Next, the degree of emetogenicity of other drugs included in the combination is assessed. When combined with a minimally emetogenic drug, the degree of emetogenicity of the combination is not enhanced. When combined with drugs from the group of low emetogenicity, the overall emetogenicity of the combination is increased by 1 level more than the most emetogenic drug from this combination. When adding level 3 or 4 drugs to the treatment regimen, the emetogenicity of the combination is increased by the level of each agent.
A retrospective analysis of a large number of studies on the emetogenicity of total body irradiation (TBI) showed high efficacy of 5-HT3 receptor antagonists. According to the literature, the use of ondansetron (Zofran) at a dose of 8 mg allows 75–97% to achieve complete control of nausea and vomiting [9,12,14,15,19]. Table 4 presents data on emetogenicity depending on body areas during radiation therapy [6].
Based on a large number of studies and NCCN consensus, recommendations were made in 2004 for the prevention of nausea and vomiting during radiotherapy (Table 5).
With total body or abdominal radiotherapy, the emetogenic potential may be high. In these cases, according to clinical studies, oral forms of ondansetron – Zofran (including a new unique form of the drug – lozenges) can be successfully used to prevent nausea and vomiting.
The level of emetogenicity of combined radiation and chemotherapy is determined by the emetogenicity of cytostatics with recommendations, as in chemotherapy regimens.
More than 40 years ago, the work of Borison and Wang [9] on animals initiated the study of the neuropathophysiology of nausea and vomiting. Prior to the use of 5-HT3 receptor antagonists, various groups of drugs (phenothiazines, butyrophenones, corticosteroids, cannabinoids, benzodiazepines, etc.) were widely used over the past 30 years with minimal success [1]. For the first time in 1963, the Mayo Clinic demonstrated the effectiveness of prochlorperazine and thiopropazate in comparison with placebo in reducing nausea and vomiting when using drugs of 1-3 levels of emetogenicity [9]. But when using highly emetogenic regimens, unfortunately, the drugs of the above groups did not differ in effectiveness from placebo. Pronounced side effects when using these drugs in therapeutic doses severely limited their use. The development and introduction into wide practice at the beginning of 1990 of 5-HT3 receptor antagonists made it possible to radically reduce nausea and vomiting during chemotherapy. Due to the selective action, these drugs almost completely stop nausea and vomiting, while having minimal side effects [8,13].
The most common drugs from the group of 5-HT3 receptor antagonists – ondansetron (Zofran), tropisetron (Navoban), granisetron (Kitril) – differ slightly in pharmacokinetics. The most studied and most commonly used is Zofran.
According to the literature, drugs from the group of 5-HT3 receptor blockers are metabolized by liver cytochrome P450 (CYP) [1,4,16].
Table 6 summarizes the 2004 NCCN recommendations for the prevention of acute nausea and vomiting when using highly emetogenic chemotherapy [5].
The 2004 NCCN recommendations for the prevention of acute and delayed nausea and vomiting when using low emetogenic chemotherapy are shown in Table 7.
The 2004 NCCN recommendations for the prevention of acute and delayed nausea and vomiting when using low emetogenic chemotherapy.
• Dexamethasone 12 mg orally or IV
or
• Prochlorperazine 10 mg orally or IV every 6 hours
or
• Metoclopramide 20–40 mg orally every 6 hours or 1–2 mg/kg IV 3 times daily ± diphenhydratamine 25 –50 mg orally or IV every 6 hours
• ± Lorazepam 0.5–2 mg orally or IV every 6 hours.
According to the 2004 NCCN guidelines, prevention of acute and delayed nausea and vomiting is not required with minimally emetogenic chemotherapy.
According to various authors, it is not always possible to achieve complete relief of nausea. In the case of incomplete relief of NCCN nausea in 2004, the following treatment regimen was proposed [5].
• Prochlorperazine 25 mg suppositories per rectum every 12 hours or 10 mg orally or 10 mg IV every 6 hours
or
• Metoclopramide 20–40 mg orally every 6 hours or 1–2 mg/kg IV 3 times a day ± Diphenhydratamine 25–50 mg orally or IV every 6 hours
or
• Lorazepam 0. 5–2 mg orally every 6 hours
or
• Ondansetron 8 mg orally or IV daily
or
• Granisetron 1–2 mg orally or 1 mg twice daily orally or 0.01 mg/kg (maximum 1 mg) IV
or
• Dolasetron 100 mg orally or 1.8 mg/kg or 100 mg IV
or
• Haloperidol 1–2 mg orally every 6 hours or 1–3 mg IV every 6 hours
or
• Dronabinol 5–10 mg orally 3 times a day
or
• Dexamethasone 12 mg orally or IV if not previously given.
Many authors note that special attention should be paid to patients who receive high-dose chemotherapy, including as a conditioning agent before hematopoietic stem cell transplantation. In this context, the causes of nausea and vomiting, in addition to chemotherapy, can be antibiotics, opioid analgesics, without which the management of pain in mucositis is indispensable, and also (in some cases) radiation. Meta-analysis of different antiemetic regimens is difficult due to the diversity of high-dose chemotherapy regimens and the heterogeneity of patient groups.
Three randomized trials of 5HT3 antagonists have been published in which ondansetron was more effective than metoclopramide and droperidol, granisetron showed the same efficacy with this therapy, and chlorpromazine in the form of a long-term infusion was comparable in efficacy to ondansetron, but more toxic. Thus, the standard approach for the prevention of nausea and vomiting in patients receiving high-dose chemotherapy, in particular in the context of hematopoietic stem cell transplantation, is ondansetron (if necessary, in combination with dexamethasone). Neither palonosetron nor aprepitant have been studied in this patient population.
Since the mid-1980s, great progress has been made in the development of antiemetic drugs. Until that time, metoclopramide was used in highly emetogenic chemotherapy. Its effectiveness did not exceed 30-60%, with the development of side effects in the form of extrapyramidal disorders in 5% of cases. The development of antiemetics from among the blockers of serotonin type 3 receptors – 5-HT3 receptor antagonists, determined a breakthrough in chemotherapy.
Zofran (ondansetron) was first made available for general use on January 1991 g. A distinctive feature of this drug is the affinity not only for 5-HT3 receptors, but also for 5-HT1B, 5-HT1C, a1-adrenergic receptors, m-opioid receptors. This feature of Zofran to some extent can determine its effectiveness [1].
Zofran is currently considered the reference drug in antiemetic therapy. Recommended doses by the International Association for Supportive Care in Oncology (MASCC, see Annals of Oncology 17: 20-28, 2006) are 16-24 mg orally or 8 mg (0.15 mg/kg) intravenously for acute vomiting or 8 mg 2 times a day orally – for delayed.
A distinctive feature of Zofran is its equal effectiveness when using low doses (8 mg) and high doses (32 mg) (the latter are recommended in the USA for highly emetogenic chemotherapy). These data were first published in 1992 by Seynaeve C. [1,3]. The 8 mg dose of Zofran in combination with corticosteroids is as effective as the 32 mg dose of Zofran in emetogenic therapy [8].
According to the literature, the combination of corticosteroids with 5-HT3 receptor antagonists is significantly more effective than combinations of corticosteroids with other drugs. Roila F. [1] at 1993 published data on the effectiveness of 79% (complete protection against nausea and vomiting) of a combination of 5-HT3 receptor antagonists in combination with corticosteroids, in contrast to 59% – in a combination of corticosteroids with other drugs, but without 5-HT3-antagonists receptors.
T.M. Beck et al published data on the use of oral Zofran (in various doses) in moderately emetogenic chemotherapy [7]. A double-blind, placebo-controlled study included 349 chemotherapy-naive patients. Compared to placebo (19% efficiency), the effectiveness of three oral doses of Zofran at a dose of 1 mg, 4 mg, 8 mg was 57, 65 and 66%, respectively.
It should be noted that most chemotherapy regimens currently in use do not require hospitalization of the patient and can be administered on an outpatient basis. In these cases, with acute and delayed nausea and vomiting, it is convenient to use oral forms of Zofran. In some cases, when oral administration of drugs is difficult, it is possible to use syrup, suppositories, and lozenges, which are not inferior in effectiveness to intravenous administration of Zofran [12,17]. These dosage forms make an invaluable contribution to the prevention of delayed nausea and vomiting, and are also successfully used in multi-day, oral regimens using highly emetogenic drugs. In addition, an additional convenience of Zofran lozenges is that they can be administered to patients with severe mucositis when other drugs are difficult to take.
As mentioned earlier, ondansetron is the most studied drug from the group of 5-HT3 receptor antagonists, with a favorable safety profile. The main side effects of 5-HT3 receptor antagonists are headache, dry mouth, abdominal pain, diarrhea, asthenia, and drowsiness. As a rule, these side effects do not require medical correction and are not clinically significant [8].
It should also be noted that odinsetron is the only drug approved for the prevention of postoperative nausea and vomiting [11]. Ondansetron at a dose of 4 mg can be recommended in the preoperative and postoperative period in order to relieve nausea and vomiting.
The development of antiemetics and combined regimens in combination with 5-HT3 receptor antagonists, steroids, NK1 receptor antagonists and other drugs has significantly reduced the emetogenicity of ongoing chemotherapy, making chemotherapy treatment outpatient and economical in many cases.

Literature
1. Schnell F.M.. Chemotherapy – induced nausea and vomiting: the importance of acute antiemetic control. The Oncologist 2003, Vol. 8, No 2, 187–198.
2. Belle S.V., Lichinitser M.R. et all. Prevention of Cisplatin – Induced acute and delayed emesis by the selective Neurokinin – 1 antagonists, L–758, 298 and MK – 869. Cancer 2002; 94;3032–41.
3. Kris M.G., Hesketh P.J., et all. Consensus proposals for the prevention of acute and delayed vomiting and nausea following high-emetic-risk chemotherapy. Support Care Cancer 2005, 13:85–96.
4. By Rolf Kaiser, Orhan Sezer, Anja Papies, Steffen Bauer, Claudia Schelenz, Pierre–Benoit Tremblay, Kurt Possinger, Ivar Roots, J?rgen Brockm?ller. Patient–Tailored Antiemetic Treatment With 5–Hydroxytryptamine Type 3 Receptor Antagonists According to Cytochrome P–450 2D6 Genotypes Journal of Clinical Oncology, Vol 20, Issue 12 (June), 2002: 2805–2811
5. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology v. 1. 2004.
6. Perugia International cancer conference VII. Consensus conference on antiemetic therapy.
Multinational Association of Supportive Care in Cancer September 2005.
7. Thomas M. Beck; Arthur A. Ciociola; Stephen E. Jones; Walter H. Harvey; N. Simon Tchekmedian; Alex Chang; Daniel Galvin; Nan E. Hart, Ondansetron Study Group* Efficacy of Oral Ondansetron in the Prevention of Emesis in Outpatients Receiving Cyclophosphamide–based Chemotherapy. Annals of internal medicine, 15 March 1993, Volume 118 Issue 6, Pages 407–413
8. Goodin S., Cunningham R. 5–HT3 – receptor antagonists for the treatment of nausea and vomiting: a reappraisal of their side–effect profile.The Oncologist 2002, Vol. 7, 424–436.
9. Steven M. Grunberg, and Paul J. Hesketh. Control of Chemotherapy–Induced Emesis The New England journal of medicine, Volume 329:1790–1796, December 9, 1993, Number 24
10. Verna A. Rohodes, Eds and Roxanne W. McDaniel, Ph D. Nausea, vomiting, and retching: complex problems in palliative care. CA Cancer J. Clinical 2001, 51: 232–248.
11. Darkow T., Pharm. D., et all. Impact of antiemetic selection on postoperative nausea and vomiting and patient satisfaction. Pharmacotherapy 21(5):540-548. 2001.
12. Herrstedt J., Koeller J.M., Roila F., Warr D., et all. Acute emesis: moderately emetogenic chemotherapy. Support Care Cancer 2005, 13:97–103.
13. Herrington Jon D. Pharm. D., Peter Kwan, et all. Randomized, multicenter comparison of oral Granisetron and oral Ondansetron for emetogenic chemotherapy. Pharmacotherapy 20 (11): 1318 – 1323. 2000.
14. The Italian Group for Antiemetic Research Dexametasone alone or in combination with Ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. The New England journal of medicine, Volume 342:1554–1559, May 25, 2000, number 21.
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Zofran instructions, price in pharmacies of Ukraine

Zofran is a drug of a group of anti-diabetic drugs. The drug contains the active component ondansetron, a selective blocker of serotonin 5HT3 receptors. The drug may show an anti-diabetic effect. The mechanism of drug administration until the end of the term, it is therapeutically effective for the drug due to the influence of serotonin 5HT3 receptors in the central and peripheral nervous system, stimulation of these receptors during chemotherapy, which improves serotonin.

The drug does not have a sedative effect and does not affect plasma prolactin levels.

After oral administration, the drug is well absorbed in the intestinal tract. For ondansetron, the characteristic effect is the first passage through the liver. The peak plasma concentration of the active ingredient is observed 1.5 years after oral ingestion of the drug and 6 years after rectal ingestion. When taking the drug at once, the bioavailability of ondansetron is increased.

Metabolized in the liver, excreted most importantly in the presence of metabolites, about 5% of the drug is excreted in the unchanged form.

The period of administration of the drug is 3 years, in patients with a frail age – 5 years, after rectal ingestion of the drug – close to 6 years (as a result of greater absorption of the drug in the rectum). In patients with severe impairment of function, the period of drinking increases to 15-20 years.

The pharmacokinetics of the drug is the same for single and repeated doses.

In patients with impaired function, the systemic clearance and volume of distribution of the active ingredient are reduced. The period of administration in patients with impaired blood function and creatinine clearance of 15 to 60 ml / hv reaches 5.4 years.

In patients who are on hemodialysis, the pharmacokinetics of the drug are similar to those in patients with normal functioning of the drug.

In patients with severely impaired liver function, a decrease in systemic clearance of the active component of the drug, an increase in the period of administration (15-32 years) and oral bioavailability (100%) are indicated.

In women, systemic clearance and volume of ondansetron was lower, lower in humans.

Indication before congestion:

The drug is indicated for the treatment and prevention of vomiting in patients who are undergoing a course of cytostatic chemotherapy or radiotherapy.

The drug is also prescribed for the prevention and treatment of nausea and vomiting in patients who have undergone surgery. For the therapy of patients in the postoperative period, do not stop the drug Zofran in the form of suppositories.

Injection method:

Injection retailer

Prescription drug for parenteral infusion. The ampoule with the preparation should be taken out without delay before the infusion, in case, even though not all of the varieties are broken, I decide to dispose of it. Ready rozchin for infusion introduction is allowed to be taken at a temperature of 2 to 8 degrees Celsius for a duration of not more than 24 years. The drug in a dose of 8 mg and less is allowed to be administered intravenously, intravenously and at the same time as intravenous infusion. If the dose is higher than 8 mg, then the drug should be administered only in case of intravenous infusion. Intravenously, the drug should be injected regularly at the upper upper quadrant of the sydnychny m’yaza.

For preparation of a brand for internal infusion as a retailer, a variety is allowed:

• 0. 9% sodium chloride brand;
• Rozchin Ringer;
• 10% manitol;
• 5% glucose solution;
• 0.3% potassium chloride and 0.9% sodium chloride;
• 0.3% potassium chloride and 5% glucose.

The drug is stable in case of congestion of polyethylene infusion bags and glass bottles type 1. The drug is made in 5% glucose or 0.9% sodium chloride, as well as the drug in other total sizes for intravenous administration is stable in polypropylene syringes.

One-hour injection of a drug with a concentration of 16 to 160 µg / ml (8 mg / 500 ml and 8 mg / 50 ml) through a Y-shaped injector is allowed:

• Cysplate (concentration ia 0.48 mg / ml) for 1-8 years;
• 5-fluorouracil (concentration 0.8 mg/ml) at a rate not exceeding 20 ml per year;
• Carboplatin (concentration 0.18-9.9 mg / ml) with a stretch of 10-60 strands;
• Etoposide (concentration 0.14-0.25 mg/ml) with a draw of 30-60 strands;
• Ceftazidime (dose 250-2000mg), administered in water for injections according to the recommended instructions, stretching 5 strands at a time of intravenous bolus injection;
• Cyclophosphamide (dose 100-1000mg) is varied in water for injection according to the recommended instructions, with a stretch of 5 strands at the same time as an internal bolus injection;
• Doxorubicin (dose 10-100mg) is administered in water for injections according to the recommended instructions, stretching 5 strands at a time of internal bolus injection;
• The drug can also be mixed in a single urticaria with dexamethasone sodium phosphate phosphate (dose of ondansetron in a range of 8 µg/ml up to 1 mg/ml, dose of dexamethasone phosphate in a range of 32 µg/ml up to 2. 5 g/ml) entry hour 50- 100 ml rozchin not less than 15 quills.

The validity of the course of treatment and the dose of the drug is determined by the drug individually for the skin patient.

Older, if you are going to undergo a course of chemotherapy or radiotherapy, with nausea and vomiting, prescribe a proper injection of 8 mg of the drug before the start of therapy. In times like nudota or vomit, try for more than 24 years after the start of therapy, patients are prescribed the drug Zofran in medicinal forms for oral or rectal congestion.

Let’s grow up, if you want to avoid therapy with highly methogenic drugs, in case of nausea and vomiting, prescribe a proper injection of 8 mg of the drug before chemotherapy. The dose of the drug should be increased as a fallow drug (maximum dose 32 mg) and administered as an intravenous infusion.

In addition, during therapy with highly methogenic drugs, patients may be given the administration of ondansetron according to the regimen: 8 mg intravenously before chemotherapy, after which 2 repeated administrations of 8 mg of the drug with an interval of 2-4 godini. It is also possible to recognize ondansetron for intravenous infusion of 1 mg/year for 24 years.

To improve the effectiveness of the drug, a single intravenous injection of 20 mg of dexamethasone phosphate sodium salt is given to current patients before chemotherapy on the cob.

In times of nausea or vomiting, try for more than 24 years after the beginning of therapy, patients are prescribed the drug Zofran in medicinal forms for oral or rectal congestion.

Children should be given an intravenous dose of 5 mg/m2 before chemotherapy. After 12 years after parenteral administration, the drug should be administered orally 4 mg of ondansetron 2 times a day. The oral form of the drug should be taken for 5 days after completion of the course of chemotherapy.

Let’s grow up before the operative intervention for the prevention of nausea and vomit, administer 4 mg of the drug intravenously properly or internally during the period of induction anesthesia.

For the treatment of vomiting in the postoperative period, it is necessary to prescribe a one-time intravenous injection of 4 mg of the drug.

For children before surgery to prevent nausea and vomiting, prescribe the drug at a dose of 0.1 mg/kg of body weight intravenously properly during the period of induction anesthesia (it is also possible to introduce the drug before or after induction anesthesia).

For the treatment of vomiting in the post-operative period, children should be given a single intravenous injection of the drug at a dose of 0.1 mg/kg body weight.

The maximum dose of the drug for children with postoperative vomiting should be 4 mg of ondansetron.

The maximum additional dose for the drug for patients who suffer from impaired liver function is 8 mg.

Syrup, coated tablets, lingual tablets:

Indication for oral administration. Tablets, covered with a shell, are recommended to be taken in whole, not rotting and not sagging, drinking down the necessary amount of water. Lingual tablets are recommended to be taken in the mouth empty until they are full (1-2 quills) after which they are swallowed. The syrup is recommended to be taken in an undiluted form, dosing the drug in the form of a syrup is carried out with the help of a special peaceful spoon, which is put into the pack at once with the vial. The validity of the course of treatment and the dose of the drug depends on the drug individually for the skin patient.

Older, if you want to take a course of chemotherapy or radiotherapy, with nausea and vomiting, prescribe 8 mg of the drug 1-2 years before the start of therapy. After which the drug is taken again after 12 years at a dose of 8 mg. For the prevention of piznyoї vomit, we grow up to sound, prescribe 8 mg of the drug 2 times a day. The drug should be taken for 5 days after completion of the course of chemotherapy or radiotherapy.

Doroslimy, yakі otrimuyut therapy Highly methogenic drugs, with nausea and vomiting, prescribe 24 mg of the drug in combination with 12 mg of dexamethasone phosphate sodium sill for 1-2 years before chemotherapy on the cob. For the prevention of vomit in 24 years after the first drug taken, you should prescribe 8 mg of ondansetron 2 times a day. The drug should be taken for 5 days after completion of the course of chemotherapy.

Children should be given a parenteral drug before chemotherapy. After 12 years after parenteral administration, the drug should be administered orally 4 mg of ondansetron 2 times a day. The drug should be taken for 5 days after completion of the course of chemotherapy.

Let’s grow up before the operative intervention for the prevention of nudity and vomit, you should prescribe 16 mg of the drug once 60 minutes before the cob of general anesthesia. For the treatment of vomiting in the postoperative period, it is recommended to stop the drug in the form of parenteral administration.

Rectal suppositories:

Prescription drug for rectal infusion. The validity of the course of treatment and the dose of the drug depends on the drug individually for the skin patient.

Older, if you want to take a course of chemotherapy or radiotherapy, with nausea and vomiting, prescribe 1 suppository of the drug 1-2 years before the start of therapy.