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    Serotonin/5HT3 Antagonist Antiemetics/antinauseants

    DEA CLASS

    Rx

    DESCRIPTION

    Antiemetic; 5-HT3 receptor antagonist
    Used for prevention and treatment of nausea and vomiting due to chemotherapy, radiation therapy and surgery
    Risk of dose-dependent QT prolongation and torsades de pointes

    COMMON BRAND NAMES

    Zofran, Zofran ODT, Zuplenz

    HOW SUPPLIED

    Ondansetron/Ondansetron Hydrochloride/Ondansetron Hydrochloride, Dextrose/Ondansetron, Dextrose/Zofran Intravenous Inj Sol: 1mL, 2mg, 32-5%
    Ondansetron/Ondansetron Hydrochloride/Zofran Intramuscular Inj Sol: 1mL, 2mg
    Ondansetron/Ondansetron Hydrochloride/Zofran Oral Sol: 4mg, 5mL
    Ondansetron/Ondansetron Hydrochloride/Zofran Oral Tab: 4mg, 8mg, 24mg
    Ondansetron/Zofran ODT Oral Tab Orally Dis: 4mg, 8mg
    Zuplenz Oral Film: 4mg, 8mg

    DOSAGE & INDICATIONS

    For chemotherapy-induced nausea/vomiting prophylaxis (CINV prophylaxis) and radiation-induced nausea/vomiting prophylaxis (RINV prophylaxis).
    Intravenous dosage
    Adults

    0.15 mg/kg (150 mcg/kg) IV infused over 15 minutes beginning 30 minutes prior to the initiation of emetogenic chemotherapy. No single dose should exceed 16 mg/dose IV. Dosage may be repeated twice, administered 4 and 8 hours after the initial dose. NOTE: In June, 2012, the FDA announced that ondansetron 32 mg IV single dose regimen is no longer indicated for chemotherapy-induced nausea/vomiting (CINV) prophylaxis because of the risk of QT prolongation.

    Infants 6 months and older, Children, and Adolescents

    0.15 mg/kg IV infused over 15 minutes beginning 30 minutes prior to the initiation of chemotherapy and repeat 4 and 8 hours later (3 doses total). Max: 16 mg/dose. The American Society of Clinical Oncology (ASCO) recommends 0.15 mg/kg/dose (Max: 8 mg) twice daily during chemotherapy and for 2 days after completion, or give 1 to 2 hours before each fraction of radiation and for 1 day after completion for highly emetogenic therapy. Alternatively, ondansetron has been administered every 8 hours and continued for 1 to 5 days after completion of therapy. A single dose of 0.6 mg/kg IV was as effective as standard therapy (0.15 mg/kg/dose up to 8 mg every 4 hours for 4 doses) in a prospective, double-blind study in chemotherapy-naive pediatric oncology patients; however, the maximum dose in the study was 32 mg, which is no longer recommended because of dose-dependent QT prolongation.

    Oral dosage
    Adults receiving moderately emetogenic chemotherapy

    8 mg PO twice daily. Give first dose 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the initial dose. Further doses may be given every 12 hours for 1 to 2 days after completion of chemotherapy.

    Adults receiving highly emetogenic chemotherapy

    24 mg dose PO once given 30 minutes before administration of single-day highly emetogenic chemotherapy, including cisplatin 50 mg/m2 or more. Multiday, single dose administration of ondansetron 24 mg has not been studied.

    Adults receiving radiotherapy (general dosage)

    8 mg PO 3 times daily.

    Adults receiving total body irradiation

    8 mg PO 1 to 2 hours prior to each fraction of radiotherapy each day.

    Adults receiving daily fractionated radiotherapy or single high-dose fraction radiotherapy to the abdomen

    Initially, 8 mg PO 1 to 2 hours prior to radiotherapy. Then, 8 mg PO every 8 hours after the first dose for 1 to 2 days following completion of radiotherapy.

    Children and Adolescents 12 years and older

    8 mg PO twice daily. Give the first dose 30 minutes prior to chemotherapy with a subsequent dose 8 hours after the initial dose. For radiation, give the first dose 1 to 2 hours prior to therapy. Further doses may be given every 8 to 12 hours for 1 to 5 days after completion of therapy. Alternatively, a single 24 mg PO dose may be given prior to chemotherapy.

    Children 4 to 11 years

    4 mg PO 3 times daily. Give the first dose 30 minutes prior to chemotherapy, with subsequent doses 4 and 8 hours after the initial dose. For radiation, give the first dose 1 to 2 hours prior to therapy. Further doses may be given every 8 hours for 1 to 5 days after completion of therapy. Alternatively, a single 12 mg PO dose may be given prior to chemotherapy.

    Infants† and Children less than 4 years† with a body surface area more than 1 m2

    4 mg PO 3 times daily. Give the first dose 30 minutes prior to chemotherapy or 1 to 2 hours prior to radiation. May be continued for 1 to 5 days after completion of therapy.

    Infants† and Children less than 4 years† with a body surface area 0.6 to 1 m2

    3 mg PO 3 times daily. Give the first dose 30 minutes prior to chemotherapy or 1 to 2 hours prior to radiation. May be continued for 1 to 5 days after completion of therapy.

    Infants† and Children less than 4 years† with a body surface area 0.3 to 0.6 m2

    2 mg PO 3 times daily. Give the first dose 30 minutes prior to chemotherapy or 1 to 2 hours prior to radiation. May be continued for 1 to 5 days after completion of therapy.

    Infants† and Children less than 4 years† with a body surface area less than 0.3 m2

    1 mg PO 3 times daily.Give the first dose 30 minutes prior to chemotherapy or 1 to 2 hours prior to radiation. May be continued for 1 to 5 days after completion of therapy.

    For post-operative nausea/vomiting (PONV) prophylaxis.
    Intravenous dosage
    Adults, Adolescents, and Children weighing more than 40 kg

    4 mg IV as single dose given immediately prior to or following anesthesia induction, or once postoperatively if patient experiences nausea/vomiting shortly after surgery. Administration of a second IV dose postoperatively in response to inadequate control is generally not effective; use of an antiemetic from another pharmacologic class should be considered.

    Infants and Children weighing 40 kg or less

    0.05 to 0.1 mg/kg IV as single dose given immediately prior to or following anesthesia induction, or once postoperatively if patient experiences nausea/vomiting shortly after surgery. Max: 4 mg/dose. Administration of a second IV dose postoperatively in response to inadequate control is generally not effective; use of an antiemetic from another pharmacologic class should be considered.

    Intramuscular dosage
    Adults and Adolescents

    4 mg IM as single dose given immediately before anesthesia induction, or once postoperatively if patient experiences nausea/vomiting shortly after surgery. Administration of a second dose postoperatively in response to inadequate control is generally not effective; use of an antiemetic from another pharmacologic class should be considered.

    Oral dosage
    Adults

    16 mg PO as single dose given 1 hour before anesthesia induction. Alteratively, 8 mg ODT PO as a single dose given at the end of surgery is as effective as 4 mg IV according to clinical practice guidelines.

    Infants†, Children†, and Adolescents†

    0.15 mg/kg PO as single dose, immediately prior to or after anesthesia induction, or once postoperatively if patient experiences nausea/vomiting shortly after surgery. Max: 8 mg/dose. Administration of a second dose postoperatively in response to inadequate control is generally not effective; use of an antiemetic from another pharmacologic class should be considered.

    For the treatment of post-operative nausea/vomiting (PONV)†.
    Intravenous dosage
    Adults and Adolescents

    4 mg IV once; a 5-HT3 antagonist is recommended if no prophylaxis was given, or for those who received a prophylactic antiemetic from another drug class. Administration of a second IV dose postoperatively in response to inadequate control is generally not effective; consider use of an antiemetic from another pharmacologic class.

    Children weighing more than 40 kg

    4 mg IV once; a 5-HT3 antagonist is recommended if no prophylaxis was given. Administration of a second IV dose postoperatively in response to inadequate control is generally not effective; consider use of an antiemetic from another pharmacologic class.

    Infants and Children weighing 40 kg or less

    0.05 to 0.1 mg/kg IV once; a 5-HT3 antagonist is recommended if no prophylaxis was given. Administration of a second IV dose postoperatively in response to inadequate control is generally not effective; consider use of an antiemetic from another pharmacologic class. Among children who had at least 2 postoperative episodes of retching or vomiting within 2 hours of surgery and who had not received prophylaxis, 53% had complete control of vomiting (no emesis and no rescue 24 hours after the dose) with a single 0.1 mg/kg (Max: 4 mg) IV ondansetron dose as compared with 17% of placebo recipients.

    For hyperemesis gravidarum† (severe pregnancy-induced nausea/vomiting) unresponsive to other antiemetics.
    Intravenous and Oral dosage
    Adult pregnant females

    Doses of 4—8 mg IV or PO given 2—3 times per day have been administered as early as 10 weeks gestation. Durations of daily treatment up to 14 days with ondansetron have been reported, and one case report exists of a patient taking 4 mg PO intermittently 1—2 times daily as needed from the 14th to 33rd week of gestation. No adverse effects on fetal outcome have been reported to date. Use of ondansetron is supported in ACOG guidelines when other agents have failed or when a patient is unresponsive to other measures and is at risk for dehydration or other adverse outcomes.

    For the short-term treatment of nausea/vomiting associated with acute gastroenteritis†.
    Intravenous dosage
    Infants, Children, and Adolescents

    0.15 mg/kg/dose IV (Max: 8 mg/dose) as a single dose has been used along with oral or IV rehydration. Although routine use of antiemetics is not recommended in acute gastroenteritis in guidelines available from the American Academy of Pediatrics and Centers for Disease Control, some studies have shown that single IV doses of ondansetron are safe and effective for reducing vomiting and increasing patients' ability to tolerate oral rehydration.

    Oral dosage
    Children and Adolescents weighing more than 30 kg

    6 to 8 mg PO as a single dose along with oral or IV rehydration. Alternatively, 0.2 mg/kg/dose PO every 8 hours for 3 doses has also been studied. Although routine use of antiemetics is not recommended for acute gastroenteritis in guidelines available from the American Academy of Pediatrics and Centers for Disease Control, some studies have found that single and multiple oral doses of ondansetron are safe and effective for reducing vomiting and increasing patients' ability to tolerate oral rehydration.

    Children weighing 15 to 30 kg

    4 mg PO as a single dose along with oral or IV rehydration. Alternatively, 0.2 mg/kg/dose PO every 8 hours for 3 doses has also been studied. Although routine use of antiemetics is not recommended for acute gastroenteritis in guidelines available from the American Academy of Pediatrics and Centers for Disease Control, some studies have found that single and multiple oral doses of ondansetron are safe and effective for reducing vomiting and increasing patients' ability to tolerate oral rehydration.

    Infants and Children 6 months and older weighing 8 to 15 kg

    2 mg PO as a single dose along with oral or IV rehydration. Alternatively, 0.2 mg/kg/dose PO every 8 hours for 3 doses has also been studied. Although routine use of antiemetics is not recommended for acute gastroenteritis in guidelines available from the American Academy of Pediatrics and Centers for Disease Control, studies have shown that single and multiple oral doses of ondansetron are safe and effective for reducing vomiting and increasing patients' ability to tolerate oral rehydration.

    For the treatment of pruritus† secondary to cholestasis.
    Intravenous and Oral dosage
    Adults

    Five patients with severe pruritus secondary to cholestasis were treated with ondansetron. An initial dose of 8 mg IV was administered. Pruritus was relieved completely in 3 patients and partially in 2 with effects lasting 5—16 hours. Three patients were continued on oral therapy of 8 mg PO twice daily, with decreased severity of symptoms. Dosage should be adjusted in hepatic impairment.

    For the maintenance treatment of alcohol dependence†.
    Oral dosage
    Adults

    A dosage of 4 mcg/kg PO twice per day, combined with weekly standardized group behavioral therapy, was effective in reducing alcohol consumption. Ondansetron was superior to placebo in increasing percentage of days abstinent and total days abstinent per study week. The results suggest that ondansetron is an effective treatment for patients with early-onset ethanol dependence, presumably by ameliorating an underlying serotonergic abnormality. NOTE: Pharmacotherapy should be used as a part of a comprehensive management program that includes psychosocial support and treatment.

    For the treatment of cyclic vomiting syndrome†.
    Intravenous dosage
    Children and Adolescents 2 years and older

    0.3 to 0.4 mg/kg/dose IV infusion every 4 to 6 hours as needed. Infuse over 15 minutes. Max: 16 mg/dose.

    Infants and Children less than 2 years

    Safety and efficacy have not been established. A diagnosis of cyclic vomiting syndrome is difficult in this age range.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    24 mg/day PO; 0.45 mg/kg/day IV (in 3 divided doses, max single dose = 16 mg IV).

    Geriatric

    24 mg/day PO; 0.45 mg/kg/day IV (in 3 divided doses, max single dose = 16 mg IV).

    Adolescents

    0.15 mg/kg/dose IV (Max: 16 mg/dose IV). 16 mg/day PO.

    Children

    < 4 years: 0.15 mg/kg/dose IV (Max: 16 mg/dose). Safety and efficacy have not been established for PO formulation.
    4—11 years: 0.15 mg/kg/dose IV (Max: 16 mg/dose). 12 mg/day PO.
    >= 12 years: 0.15 mg/kg/dose IV (Max: 16 mg/dose). 16 mg/day PO.

    Infants

    1—5 months: 0.1 mg/kg IV (single dose). Safety and efficacy have not been established for PO formulation.
    >= 6 months: 0.15 mg/kg/dose IV (Max: 16 mg/dose IV). Safety and efficacy have not been established for PO formulation.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Per the manufacturer, ondansetron dosage should not exceed 8 mg/day IV or PO in adult patients with severe hepatic impairment (Child-Pugh score >= 10). In such patients, plasma clearance is reduced, resulting in a dramatically prolonged elimination half-life. No specific pediatric recommendations are available.

    Renal Impairment

    No dosage adjustments are recommended. A small percentage (5%) of ondansetron is renally cleared. In patients with severe renal impairment (CrCl < 30 ml/min) the mean plasma clearance is reduced; however, the reduction is not consistent with an increase in half-life.

    ADMINISTRATION

    Oral Administration

    All oral dosage forms are considered interchangeable.
    All oral dosage forms may be administered without regard to meals.
    Antacids do not interfere with ondansetron absorption.

    Oral Solid Formulations

    Oral disintegrating tablets (ODT):
    DO NOT attempt to push ODT tablets through foil backing. With dry hands, peel back the foil of 1 blister and remove the tablet.
    Place tablet on the tongue; it will dissolve in seconds. Once dissolved, the patient may swallow with saliva. Administration with liquid is not necessary.
    Wash hands after administration.

    Oral Liquid Formulations

    Oral solution: Measure dose with a calibrated oral syringe or other calibrated container.

    Other Oral Formulations

    Oral soluble film (Zuplenz):
    With dry hands, fold the pouch along the dotted line to expose the tear notch. While still folded, tear the pouch carefully along the edge and remove the oral soluble film just prior to dosing.
    Place the film on the tongue; it will dissolve in 4 to 20 seconds. Once dissolved, the patient may swallow with saliva. Administration with liquid is not necessary.
    When administering oral soluble films successively to reach a desired dose (i.e., 16 mg given as two 8 mg films) allow each film to dissolve completely before administering the next one.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    IV Push
    Doses up to 4 mg may be administered undiluted (2 mg/mL) over at least 30 seconds and preferably over a period of 2 to 5 minutes.
     
    Intermittent IV Infusion
    For doses more than 4 mg and for chemotherapy-induced nausea and vomiting (CINV), dilute ondansetron in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
    For patients 6 months to 1 year of age and/or 10 kg or less: Doses may be diluted in 10 to 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection, depending on the fluid needs of the individual patient.
    Infuse IV over 15 minutes.
    Storage: Dilution is stable for 48 hours at room temperature.

    Intramuscular Administration

    In adults, a 4 mg undiluted dose may be administered intramuscularly as a single injection.
    Use aseptic technique. Inject deeply into a well-developed muscle mass. Aspirate prior to injection to avoid injection into a blood vessel.

    STORAGE

    Generic:
    - Protect from freezing
    - Protect from light
    - Store between 36 to 86 degrees F
    Zofran:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Zofran ODT:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Zuplenz:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    The fixed dose of ondansetron recommended for post-operative nausea and vomiting was established in patients weighing less than 80 kg. Patients with obesity (i.e., weight > 80 kg) have not been studied extensively.

    Hepatic disease, hepatitis

    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.

    Dolasetron hypersensitivity, granisetron hypersensitivity, ondansetron hypersensitivity, palonosetron hypersensitivity

    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. 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. Antagonism at serotonin (5-HT) receptors, and the subsequent increased concentrations of serotonin, may increase the risk of developing bronchospasm and/or vasoconstriction.

    Phenylketonuria

    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 < 0.03 mg phenylalanine.

    GI obstruction, ileus

    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. Ondansetron is not a drug that stimulates gastric or intestinal peristalsis; it should not be used instead of nasogastric suction.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Ondansetron 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. Avoid ondansetron in patients with congenital long QT syndrome. Other patients at risk for developing torsade de pointes include those with underlying heart conditions, such as those who are predisposed to electrolyte imbalance and those taking other medications that lead to QT prolongation. Use ondansetron with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic impairment may also be at increased risk for QT prolongation. 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). Electrocardiogram (ECG) monitoring is recommended in patients with hypokalemia, hypomagnesemia, congestive heart failure, significant bradycardia, or in patients taking other medications that can lead to QT prolongation.

    Children

    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.

    Infants, neonates

    Infants < 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 < 1 month of age receiving surgery or in pediatric cancer patients who are infants < 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.

    Pregnancy

     Data on the use of ondansetron during human pregnancy from clinical studies are inconsistent and do not reliably inform a drug associated risk of adverse fetal outcomes. Available data suggest that there may be an increased risk of certain birth defects, particularly when ondansetron is used during the first trimester. Until additional data are available, the most prudent course would be to reserve ondansetron use for cases in which safer alternatives have failed, and, if possible, avoid use during the period of organogenesis. 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. Ondansetron has been shown to cross the placenta in early pregnancy with a median fetal to maternal ratio of 0.41. The American College of Obstetricians and Gynecologists (ACOG) includes ondansetron as a treatment option for nausea and vomiting of pregnancy in patients who are dehydrated, require IV fluid replacement, and have failed other therapies. Since the publication of the ACOG guidelines, the off-label use of ondansetron in pregnant women has increased and several additional studies have been published evaluating the risk of birth defects when ondansetron is used during pregnancy. A cohort study that included patients from 2 medical registries in Sweden identified 1349 neonates born to mothers who were prescribed ondansetron during the first trimester. The risk of cardiovascular defects, and specifically septal defects, was statistically significantly higher in those neonates whose mothers were prescribed ondansetron (OR for cardiovascular defects 1.62, 95% CI 1.04—2.14; RR for septal defects 2.05, 95% CI 1.19-3.28). A limitation of this study, however, is that the actual ondansetron exposure is unknown because data were obtained from a combination of midwife interviews and prescription records. In addition, the authors state that the relatively wide confidence intervals may represent random variations of common risk. A case-control study using data from the National Birth Defects Prevention Study examined whether treatments of nausea and vomiting during pregnancy were associated with the most common non-cardiac birth defects (cleft lip, cleft palate, neural tube defects, and hypospadias). Ondansetron treatment during the first trimester was associated with a statistically significant increased risk of cleft palate (adjusted OR 2.37, 95% CI 1.18—4.76); however, the number of patients who received ondansetron was very small (n = 7). The authors state that due to the multiple comparisons performed in this study, the possibility exists that the findings are due to chance and warrant further research. A historical cohort study using data from medical registries in Denmark compared outcomes of neonates exposed to ondansetron to those not exposed (1:4 ratio; ondansetron exposed = 1849, not exposed = 7396). The study did not find a statistically significant increased risk of major birth defects, spontaneous abortion, stillbirth, preterm delivery, low-birth weight, or small for gestational age. However, the median time of exposure to ondansetron was 10 weeks gestation, indicating half of the patients were exposed at the end of or after the first trimester, and the study was not adequately powered to determine the risk of individual birth defects. Despite the relatively frequent use of ondansetron for the treatment of nausea and vomiting of pregnancy, the need for additional safety data remains.

    Breast-feeding

    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. Caution should be exercised when administering ondansetron to a breast-feeding woman.

    Geriatric

    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. No differences in responses for safety or efficacy have been observed between geriatric and younger patients during clinical trials or other reported clinical experience. However, greater sensitivity of some older individuals can not be ruled out. The manufacturer states that no dosage adjustments are needed in elderly patients.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 0-6.0
    bronchospasm / Rapid / 0-1.0
    seizures / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    atrial fibrillation / Early / Incidence not known
    AV block / Early / Incidence not known
    angioedema / Rapid / Incidence not known
    cardiac arrest / Early / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    laryngospasm / Rapid / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    visual impairment / Early / Incidence not known
    serotonin syndrome / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 6.0-11.0
    urinary retention / Early / 3.0-5.0
    elevated hepatic enzymes / Delayed / 1.0-5.0
    hypotension / Rapid / 5.0-5.0
    dystonic reaction / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    palpitations / Early / Incidence not known
    ST-T wave changes / Rapid / Incidence not known
    angina / Early / Incidence not known
    QT prolongation / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    blurred vision / Early / Incidence not known

    Mild

    headache / Early / 9.0-27.0
    drowsiness / Early / 8.0-20.0
    diarrhea / Early / 2.0-16.0
    malaise / Early / 9.0-13.0
    fatigue / Early / 9.0-13.0
    fever / Early / 2.0-8.0
    dizziness / Early / 4.0-7.0
    agitation / Early / 0-6.0
    anxiety / Delayed / 0-6.0
    chills / Rapid / 2.0-5.0
    injection site reaction / Rapid / 4.0-4.0
    paresthesias / Delayed / 2.0-2.0
    rash / Early / 1.0-1.0
    hiccups / Early / Incidence not known
    syncope / Early / Incidence not known
    flushing / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as codeine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Acetaminophen; Codeine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as codeine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Acetaminophen; Hydrocodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Acetaminophen; Oxycodone: (Major) Serotonin syndrome can occur during concomitant use of opiate agonists with serotonergic drugs, such as serotonin-receptor antagonists. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage increases of either agent. Instruct patients to immediately report symptoms of agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea.
    Acetaminophen; Tramadol: (Moderate) Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from a few small studies indicate that ondansetron may reduce the analgesic effects of tramadol. Since adverse effects may occur when tramadol is administered in excessive dosage as patients try to obtain pain relief, clinicians should be alert to increases in the patient reported frequency of tramadol administration during concurrent use.
    Albuterol: (Minor) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Albuterol; Ipratropium: (Minor) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Alfuzosin: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and alfuzosin should be used together cautiously. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). If ondansetron and alfuzosin must be coadministered, ECG monitoring is recommended.
    Amiodarone: (Major) If possible, avoid coadministration of amiodarone and ondansetron. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. In addition, amiodarone may inhibit ondansetron metabolism via multiple pathways (CYP1A2, CYP2D6, CYP3A4, P-glycoprotein), increasing the potential for ondansetron-related adverse events.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Monitor ECG for evidence of QT prolongation if coadministration of ondansetron and clarithromycin is necessary. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Monitor ECG for evidence of QT prolongation if coadministration of ondansetron and clarithromycin is necessary. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Anagrelide: (Major) If ondansetron and anagrelide must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
    Apomorphine: (Severe) The concurrent use of apomorphine and serotonin-receptor antagonists is contraindicated due to the possibility of an excessive lowering of blood pressure and unconsciousness. Additionally, dolasetron and ondansetron may cause additive QT prolongation with apomorphine.
    Aprepitant, Fosaprepitant: (Minor) Aprepitant, fosaprepitant is indicated for the prophylaxis of chemotherapy-induced nausea/vomiting in combination with a 5HT3 antagonist, one of which is ondansetron. Ondansetron is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer; substitution of fosaprepitant 115 mg IV on day 1 of the 3-day regimen may lessen the inhibitory effects of CYP3A4. The AUC of another CYP3A4 substrate, midazolam, was increased for several days after aprepitant dosing when the two drugs were coadministered; however, in clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron.
    Arformoterol: (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Aripiprazole: (Major) If ondansetron and aripiprazole must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), concurrent use of ondansetron and arsenic trioxide should be avoided if possible. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes and complete atrioventricular block have been reported. Ondansetron has also been associated with QT prolongation and post-marketing reports of TdP. If ondansetron and arsenic trioxide must be coadministered, ECG monitoring is recommended.
    Artemether; Lumefantrine: (Major) Avoid coadministration due to the potential for QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Artemether; lumefantrine is associated with prolongation of the QT interval.
    Asenapine: (Major) Avoid coadministration of asenapine and ondansetron due to the potential for QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended. Asenapine has been associated with QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as codeine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as codeine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Aspirin, ASA; Oxycodone: (Major) Serotonin syndrome can occur during concomitant use of opiate agonists with serotonergic drugs, such as serotonin-receptor antagonists. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage increases of either agent. Instruct patients to immediately report symptoms of agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea.
    Atazanavir: (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Atazanavir is an inhibitor of CYP3A4. Ondansetron is a CYP3A4 substrate.
    Atazanavir; Cobicistat: (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Atazanavir is an inhibitor of CYP3A4. Ondansetron is a CYP3A4 substrate. (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp) inhibitor. Ondansetron is a CYP3A4, CYP2D6, and P-gp substrate.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include ondansetron.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Azelastine; Fluticasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Azithromycin: (Major) If azithromycin and ondansetron must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Azithromycin has also been associated with cases of QT prolongation and TdP during the post-marketing period.
    Barbiturates: (Minor) Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic study of 16 patients with epilepsy who were maintained chronically on CYP3A4 inducers (e.g., barbiturates) a reduction in ondansetron AUC, Cmax, and half-life was observed, resulting in a significant increase in ondansetron clearance. However, these changes in ondansetron exposure are not thought to be clinically relevant; no dosage adjustment for ondansetron is recommended when CYP450 inducers are used concurrently.
    Beclomethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with ondansetron. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Ondansetron has also been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Bepridil: (Severe) Coadministration is contraindicated since there is an increased risk for QT prolongation and torsade de pointes (TdP). Bepridil is associated with a known risk for QT prolongation and torsade de pointes (TdP). Bepridil should not be given with other drugs that may prolong the QT interval. Ondansetron has been associated with QT prolongation and postmarketing reports of torsade de pointes (TdP).
    Betamethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include ondansetron.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include ondansetron.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering ondansetron with boceprevir due to an increased potential for ondansetron-related adverse events. If ondansetron dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of ondansetron. Ondansetron is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated ondansetron plasma concentrations.
    Bosentan: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes including ondansetron.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Budesonide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Budesonide; Formoterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Buprenorphine: (Major) Buprenorphine should be used cautiously and with close monitoring with ondansetron. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, ECG monitoring is recommended. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as ondansetron, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment with buprenorphine and ondansetron is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
    Buprenorphine; Naloxone: (Major) Buprenorphine should be used cautiously and with close monitoring with ondansetron. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, ECG monitoring is recommended. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as ondansetron, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment with buprenorphine and ondansetron is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
    Carbamazepine: (Moderate) Ondansetron elimination may be increased by cytochrome P-450 inducers, including carbamazepine.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Carvedilol: (Moderate) Increased concentrations of ondansetron may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ondansetron is a P-gp substrate.
    Ceritinib: (Major) Coadministration of ondansetron and ceritinib may increase the risk for QT prolongation. If ondansetron and ceritinib must be coadministered, ECG monitoring is recommended; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Ondansetron is also associated with dose-related QT prolongation; additionally, there are postmarketing reports of torsade de pointes (TdP).
    Chloroquine: (Major) Avoid coadministration of chloroquine with ondansetron if possible, due to the risk of QT prolongation and torsade de pointes (TdP). Chloroquine administration is associated with an increased risk of QT prolongation and TdP. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. If ondansetron and chloroquine must be coadministered, ECG monitoring is recommended.
    Chlorpheniramine; Codeine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as codeine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Chlorpheniramine; Hydrocodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Chlorpromazine: (Major) Monitor ECG for evidence of QT prolongation if coadministration of ondansetron and chlorpromazine is necessary. Ondansetron has been associated with a dose-related increase in the QT interval. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP).
    Ciclesonide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Ciprofloxacin: (Major) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Ondansetron should be administered with caution in patients taking drugs with potential to induce QT prolongation. Rare cases of TdP have been reported with ciprofloxacin during post-marketing surveillance. Although less likely than with most quinolones, coadministration of ciprofloxacin with drugs known to prolong the QT interval could increase the risk of developing TdP in predisposed patients. Additionally ciprofloxacin inhibits the CYP1A2 isoenzyme, while ondansetron is metabolized by hepatic CYP450 drug-metabolizing enzymes (i.e., CYP3A4, CYP2D6, CYP1A2). In theory, ciprofloxacin may change the clearance and, hence, the half-life of ondansetron.
    Cisapride: (Severe) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Because of the potential for TdP, use of cisapride with ondansetron is contraindicated.
    Citalopram: (Major) Coadministration of ondansetron and citalopram is not recommended due to the potential for QT prolongation. If concurrent therapy is considered essential, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Citalopram causes dose-dependent QT interval prolongation.
    Clarithromycin: (Major) Monitor ECG for evidence of QT prolongation if coadministration of ondansetron and clarithromycin is necessary. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Clozapine: (Major) Monitor ECG for evidence of QT prolongation if coadministration of ondansetron and clozapine is necessary. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
    Cobicistat: (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp) inhibitor. Ondansetron is a CYP3A4, CYP2D6, and P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp) inhibitor. Ondansetron is a CYP3A4, CYP2D6, and P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp) inhibitor. Ondansetron is a CYP3A4, CYP2D6, and P-gp substrate.
    Codeine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as codeine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Codeine; Guaifenesin: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as codeine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Codeine; Phenylephrine; Promethazine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as codeine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Major) If ondansetron and promethazine must be coadministered, ECG monitoring is recommended. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Codeine; Promethazine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as codeine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Major) If ondansetron and promethazine must be coadministered, ECG monitoring is recommended. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Conivaptan: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and ondansetron, a CYP3A4/P-gp substrate. Concurrent use may result in elevated ondansetron serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as ondansetron, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ondansetron. Treatment with ondansetron may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Corticosteroids: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Corticotropin, ACTH: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Cortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Crizotinib: (Major) Avoid coadministration of crizotinib with ondansetron due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Ondansetron has also been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Cyclophosphamide: (Minor) Ondansetron may cause a decrease in the serum concentration of cyclophosphamide if the two drugs are coadministered. It is unknown if patients receiving ondansetron continuous infusions would experience lowered tumor responses to cyclophosphamide treatment.
    Daclatasvir: (Moderate) Systemic exposure of ondansetron, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of ondansetron; monitor patients for potential adverse effects.
    Darunavir: (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4 and CYP2D6. Ondansetron is a CYP3A4 and CYP2D6, and substrate.
    Darunavir; Cobicistat: (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp) inhibitor. Ondansetron is a CYP3A4, CYP2D6, and P-gp substrate. (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4 and CYP2D6. Ondansetron is a CYP3A4 and CYP2D6, and substrate.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp) inhibitor. Ondansetron is a CYP3A4, CYP2D6, and P-gp substrate. (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4 and CYP2D6. Ondansetron is a CYP3A4 and CYP2D6, and substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Caution and close monitoring are advised if these drugs are administered together. Ondansetron exposure may be altered resulting in increased adverse effects or decreased efficacy. Ondansetron is metabolized by the hepatic isoenzymes CYP3A4, CYP2D6, and CYP1A2; ritonavir inhibits CYP3A4 and CYP2D6 and induces CYP1A2.
    Dasatinib: (Major) ECG monitoring is recommended if ondansetron and dasatinib must be coadministered. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
    Deflazacort: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Degarelix: (Major) If ondansetron and degarelix must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. QTc prolongation has been reported with the use of degarelix.
    Desflurane: (Major) If ondansetron and halogenated anesthetics must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Halogenated anesthetics can prolong the QT interval.
    Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as desvenlafaxine. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Deutetrabenazine: (Major) If ondansetron and deutetrabenazine must be coadministered, ECG monitoring is recommended. For patients taking a deutetrabenazine dosage more than 24 mg/day, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Dexamethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Dextromethorphan; Promethazine: (Major) If ondansetron and promethazine must be coadministered, ECG monitoring is recommended. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Dextromethorphan; Quinidine: (Severe) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine include ondansetron.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Disopyramide: (Major) Ondansetron should be used cautiously and with close monitoring with disopyramide. If ondansetron and disopyramide must be coadministered, ECG monitoring is recommended. Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP). Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001).
    Dofetilide: (Severe) Because of the increased risk for QT prolongation and torsade de pointes (TdP), the use of dofetilide with ondansetron is contraindicated. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Ondansetron has been associated with QT prolongation and postmarketing reports of TdP.
    Dolasetron: (Major) These drugs would not be expected to be given together due to therapeutic class duplication; side effects, such as serotonergic actions, may be additive. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Dolasetron is associated with a lower, but possible risk for QT prolongation and TdP.
    Dolutegravir; Rilpivirine: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and rilpivirine should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include ondansetron.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include ondansetron.
    Dronedarone: (Severe) Concomitant use of dronedarone and ondansetron is contraindicated. Dronedarone is an inhibitor of CYP2D6, CYP3A, and P-gp. Ondansetron is a substrate for CYP2D6, CYP3A4, and P-gp. Coadministration of dronedarone and ondansetron may result in elevated plasma concentrations of ondansetron. In addition, ondansetron has been established to have a possible risk of QT prolongation and Torsade de Pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as ondansetron. If coadministration cannot be avoided, ECG monitoring is recommended; initiate droperidol at a low dose and increase the droperidol dose as needed to achieve the desired effect. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
    Duloxetine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as duloxetine. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Efavirenz: (Major) Coadministration of efavirenz and ondansetron may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If these drugs must be coadministered, ECG monitoring is recommended. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as ondansetron.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Coadministration of efavirenz and ondansetron may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If these drugs must be coadministered, ECG monitoring is recommended. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as ondansetron.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of efavirenz and ondansetron may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If these drugs must be coadministered, ECG monitoring is recommended. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as ondansetron.
    Elbasvir; Grazoprevir: (Moderate) Administering ondansetron with elbasvir; grazoprevir may result in elevated ondansetron plasma concentrations. Ondansetron is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) Coadminister ondansetron and eliglustat cautiously with close monitoring; there may be an increased risk of QT prolongation and/or ondansetron-associated adverse effects. Ondansetron dosage reduction may be considered, depending on the clinical situation. Eliglustat is a CYP2D6 and P-glycoprotein (P-gp) inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Although ondansetron is primarily metabolized by other CYP450 isoenzymes (i.e., CYP3A4 and CYP1A2), it is metabolized to a lesser extent by CYP2D6 and is considered a P-gp substrate. In addition, ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP).
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and rilpivirine should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and rilpivirine should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Encorafenib: (Major) Avoid coadministration of encorafenib and ondansetron due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Enflurane: (Major) If ondansetron and halogenated anesthetics must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Halogenated anesthetics can prolong the QT interval.
    Eribulin: (Major) If eribulin and ondansetron must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Eribulin has been associated with QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Erythromycin: (Major) If ondansetron and erythromycin must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Erythromycin is also associated with QT prolongation and TdP.
    Erythromycin; Sulfisoxazole: (Major) If ondansetron and erythromycin must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Erythromycin is also associated with QT prolongation and TdP.
    Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as ondansetron, should be done with caution and close monitoring.
    Ester local anesthetics: (Major) Rarely and predominantly reported with intravenous ondansetron, transient ECG changes including QT prolongation have occurred. Use ondansetron with caution in combination with other drugs that may also prolong the QT interval, including local anesthetics.
    Etravirine: (Moderate) Etravirine is a CYP3A4 inducer/substrate and a P-glycoprotein (PGP) inhibitor and ondansetron is a CYP3A4 and PGP substrate. Caution is warranted if these drugs are coadministered.
    Ezogabine: (Major) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ondansetron include ezogabine.
    Fentanyl: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as fentanyl. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Fingolimod: (Major) If ondansetron and fingolimod must be coadministered, ECG monitoring is recommended. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
    Flecainide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering ondansetron with flecainide. If these drugs must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. Flecainide, a Class IC antiarrhythmic, is also associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Severe) Concomitant administration of fluconazole and drugs that both prolong the QT interval and are CYP3A4 substrates is contraindicated according to the FDA-approved product labeling. The exact risk for QT prolongation when fluconazole and ondansetron are administered together has not been clearly defined. If ondansetron and fluconazole are administered together, extreme caution and careful monitoring is advised, especially if higher doses are used or if other drugs that may affect CYP1A2 or CYP2D6 are also given. Fluconazole is a CYP3A4 inhibitor. Ondansetron is metabolized by CYP3A, CYP1A2, and CYP2D6. In vivo microsomal inhibition data has suggested that no single isoenzyme dominates ondansetron's metabolism thereby making clinically significant interactions due to inhibition of a single isoenzyme unlikely; however, since the publication of this data, ondansetron has been found to produce concentration-dependent QT prolongation. It is not clear what degree of enzyme inhibition or increased concentration is required to increase the risk of QT prolongation. Inhibition of CYP3A isoenzymes is likely to increase with higher fluconazole doses (>= 200 mg/day in adults).
    Fludrocortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Flunisolide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluoxetine: (Major) Taking these drugs together may result in serotonin syndrome. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include ondansetron.
    Fluoxetine; Olanzapine: (Major) Monitor ECG for evidence of QT prolongation if coadministration of ondansetron and olanzapine is necessary. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Major) Taking these drugs together may result in serotonin syndrome. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include ondansetron.
    Fluphenazine: (Minor) If ondansetron and fluphenazine must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Fluticasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluticasone; Salmeterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Vilanterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluvoxamine: (Major) Concomitant use of fluvoxamine and ondansetron may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. In addition, both fluvoxamine and ondansetron have central serotonin enhancing effects; therefore, serotonin syndrome is possible. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Formoterol: (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Formoterol; Mometasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fosamprenavir: (Moderate) Concomitant use of ondansetron and fosamprenavir may result in altered ondansetron plasma concentrations. Ondansetron is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is an inducer of P-gp and a potent inhibitor and moderate inducer of CYP3A4.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as ondansetron. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports TdP. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Minor) Fosphenytoin may reduce the efficacy of ondansetron by decreasing its systemic exposure; however, based on available data, no ondansetron dosage adjustment is recommended. If used together, monitor patients for antiemetic efficacy. Fosphenytoin is a strong CYP3A inducer. Ondansetron is a substrate for CY1A2, CYP2D6, and CYP3A4, with CYP3A4 playing a predominant role in ondansetron turnover. During pharmacokinetic studies, patients treated with strong CYP3A inducers (i.e., phenytoin, carbamazepine, rifampin) and ondansetron had significantly increased ondansetron clearance, resulting in significant reductions in AUC, Cmax, and half-life. However, these changes in ondansetron exposure are not thought to be clinically relevant.
    Gemifloxacin: (Major) Concurrent use of ondansetron and gemifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If concurrent therapy is considered essential, ECG monitoring is recommended. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and ondansetron together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
    Glasdegib: (Major) Avoid coadministration of glasdegib with ondansetron due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and ondansetron as coadministration may increase serum concentrations of ondansetron and increase the risk of adverse effects. Ondansetron is a substrate of P-glycoprotein (P-gp); glecaprevir is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and ondansetron as coadministration may increase serum concentrations of ondansetron and increase the risk of adverse effects. Ondansetron is a substrate of P-glycoprotein (P-gp); pibrentasvir is a P-gp inhibitor.
    Glycopyrrolate; Formoterol: (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Goserelin: (Major) Ondansetron should be used cautiously and with close monitoring with goserelin. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended.
    Granisetron: (Major) Granisetron has been associated with QT prolongation. According to the manufacturer, use of granisetron in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic, may result in clinical consequences. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with granisetron include ondansetron. The two drugs are from the same therapeutic class, and would not be expected to be prescribed together. Serotonergic actions of the two drugs might also increase the risk for additive serotonergic side effects.
    Guaifenesin; Hydrocodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Halogenated Anesthetics: (Major) If ondansetron and halogenated anesthetics must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Halogenated anesthetics can prolong the QT interval.
    Haloperidol: (Major) If ondansetron and haloperidol must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). QT prolongation and TdP have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) If ondansetron and halogenated anesthetics must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Halogenated anesthetics can prolong the QT interval.
    Histrelin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and ondansetron is necessary; correct any electrolyte abnormalities. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Homatropine; Hydrocodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydrocodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydrocodone; Ibuprofen: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydrocodone; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydrocodone; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydrocortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and ondansetron. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes (TdP) have been reported with the use of hydroxychloroquine. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include ondansetron.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Ibuprofen; Oxycodone: (Major) Serotonin syndrome can occur during concomitant use of opiate agonists with serotonergic drugs, such as serotonin-receptor antagonists. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage increases of either agent. Instruct patients to immediately report symptoms of agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea.
    Ibutilide: (Major) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. If ondansetron and ibutilide must be coadministered, ECG monitoring is recommended.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with ondansetron, a CYP3A substrate, as ondansetron toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as ondansetron. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended.
    Indacaterol: (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indacaterol; Glycopyrrolate: (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with ondansetron due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
    Ipecac: (Major) Ipecac has been shown to be effective in producing emesis in patients who have ingested antiemetics, provided ipecac is given promptly (usually within 1 hour of antiemetic consumption). If ipecac is administered after the antiemetic therapy has begun to exert therapeutic effects, ipecac may be less effective. The duration of the antiemetics action may need to be taken into account when selecting the appropriate clinical path for treating patients for overdosage. Patients on chronic or longer-acting antiemetic therapy, such as the 5HT-3 receptor antagonists, may be unresponsive to ipecac or other methods which induce vomiting.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with ondansetron may result in increased serum concentrations of ondansetron. Ondansetron is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium is an inhibitor of CYP3A4 and P-gp. Caution and close monitoring are advised if these drugs are used together.
    Isocarboxazid: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as Monoamine oxidase inhibitors. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Isoflurane: (Major) If ondansetron and halogenated anesthetics must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Halogenated anesthetics can prolong the QT interval.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Rifampin may reduce the efficacy of ondansetron by decreasing its systemic exposure; however, based on available data, no ondansetron dosage adjustment is recommended. If used together, monitor patients for antiemetic efficacy. In a pharmacokinetic study of 10 healthy subjects receiving a single-dose intravenous dose of ondansetron 8 mg after 600 mg rifampin once daily for 5 days, the AUC and the half-life of ondansetron were reduced by 48% and 46%, respectively. The proposed mechanism is rifampin-related induction of ondansetron metabolism through cytochrome P450 3A4. These changes in ondansetron exposure with CYP3A4 inducers are not thought to be clinically relevant.
    Isoniazid, INH; Rifampin: (Minor) Rifampin may reduce the efficacy of ondansetron by decreasing its systemic exposure; however, based on available data, no ondansetron dosage adjustment is recommended. If used together, monitor patients for antiemetic efficacy. In a pharmacokinetic study of 10 healthy subjects receiving a single-dose intravenous dose of ondansetron 8 mg after 600 mg rifampin once daily for 5 days, the AUC and the half-life of ondansetron were reduced by 48% and 46%, respectively. The proposed mechanism is rifampin-related induction of ondansetron metabolism through cytochrome P450 3A4. These changes in ondansetron exposure with CYP3A4 inducers are not thought to be clinically relevant.
    Itraconazole: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as ondansetron. Both ondansetron and itraconazole are associated with QT prolongation; coadministration may increase this risk. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with ondansetron (a CYP3A4 substrate) may result in elevated ondansetron plasma concentrations and an increased risk for adverse events, including QT prolongation. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with ondansetron due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Ixabepilone: (Minor) Ixabepilone is a weak inhibitor of P-glycoprotein (Pgp). Ondansetron is a Pgp substrate, and concomitant use of ixabepilone with a Pgp substrate may cause an increase in ondansetron concentrations. Use caution if ixabepilone is coadministered with a Pgp substrate.
    Ketoconazole: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as ondansetron. Both ondansetron and ketoconazole are associated with QT prolongation; coadministration may increase this risk. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with ondansetron (a CYP3A4 substrate) may result in elevated ondansetron plasma concentrations and an increased risk for adverse events, including QT prolongation.
    Lapatinib: (Major) Monitor serum electrolytes and ECG for evidence of QT prolongation if coadministration of ondansetron and lapatinib is necessary. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience. Correct hypokalemia or hypomagnesemia prior to lapatinib administration.
    Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of ondansetron-associated adverse reactions is advised with concomitant administration of ledipasvir. Ondansetron is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase ondansetron plasma concentrations.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with ondansetron due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Leuprolide: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include ondansetron.
    Leuprolide; Norethindrone: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include ondansetron.
    Levalbuterol: (Minor) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Levofloxacin: (Major) If ondansetron and levofloxacin must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Levofloxacin has been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Levomethadyl: (Severe) Rarely and predominantly reported with intravenous ondansetron, transient ECG changes including QT prolongation have occurred. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Drugs which have been established to have a causal association with QT prolongation and TdP (torsade de pointe) and are contraindicated for use with ondansetron include levomethadyl.
    Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as levomilnacipran. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Linezolid: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as linezolid. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Lithium: (Major) Ondansetron and lithium are associated with QT prolongation. Coadministration may increase the risk of QT prolongation; therefore, ondansetron and lithium should be coadministered with caution and close monitoring. Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as lithium. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. (Moderate) Moderate to significant dietary sodium changes, or changes in sodium and fluid intake, may affect lithium excretion. Systemic sodium chloride administration may result in increased lithium excretion and therefore, decreased serum lithium concentrations. In addition, high fluid intake may increase lithium excretion. For patients receiving sodium-containing intravenous fluids, symptom control and lithium concentrations should be carefully monitored. It is recommended that patients taking lithium maintain consistent dietary sodium consumption and adequate fluid intake during the initial stabilization period and throughout lithium treatment. Supplemental oral sodium and fluid should be only be administered under careful medical supervision.
    Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with ondansetron due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
    Long-acting beta-agonists: (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loop diuretics: (Moderate) The coadministration of ondansetron with diuretics associated with hypokalemia could increase the risk of QT prolongation. Potassium levels should be within the normal range prior to and during therapy with ondansetron.
    Loperamide: (Major) Coadminister loperamide and ondansetron together with caution and monitor the ECG. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Ondansetron has also been associated with an increased risk of QT prolongation and TdP. Among 42 patients receiving a 4 mg bolus of intravenous ondansetron, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after ondansetron administration. Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose of ondansetron must no longer be used for the prevention of chemotherapy-induced nausea and vomiting.
    Loperamide; Simethicone: (Major) Coadminister loperamide and ondansetron together with caution and monitor the ECG. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Ondansetron has also been associated with an increased risk of QT prolongation and TdP. Among 42 patients receiving a 4 mg bolus of intravenous ondansetron, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after ondansetron administration. Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose of ondansetron must no longer be used for the prevention of chemotherapy-induced nausea and vomiting.
    Lopinavir; Ritonavir: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering lopinavir; ritonavir with ondansetron. If these drugs must be coadministered, ECG monitoring is recommended. Lopinavir; ritonavir is associated with QT prolongation. Ondansetron has also been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). (Moderate) Caution and close monitoring are advised if these drugs are administered together. Ondansetron exposure may be altered resulting in increased adverse effects or decreased efficacy. Ondansetron is metabolized by the hepatic isoenzymes CYP3A4, CYP2D6, and CYP1A2; ritonavir inhibits CYP3A4 and CYP2D6 and induces CYP1A2.
    Lumacaftor; Ivacaftor: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of ondansetron by decreasing its systemic exposure; however, based on available data, no ondansetron dosage adjustment is recommended. If used together, monitor patients for antiemetic efficacy. Lumacaftor is a strong CYP3A inducer. Ondansetron is a substrate for CY1A2, CYP2D6, and CYP3A4, with CYP3A4 playing a predominant role in ondansetron turnover. During pharmacokinetic studies, patients treated with strong CYP3A inducers (i.e., phenytoin, carbamazepine, rifampin) and ondansetron had significantly increased ondansetron clearance, resulting in significant reductions in AUC, Cmax, and half-life. However, these changes in ondansetron exposure are not thought to be clinically relevant.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as ondansetron. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Maprotiline: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and maprotiline should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mefloquine: (Major) Monitor ECG for evidence of QT prolongation if coadministration of ondansetron and mefloquine is necessary. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
    Meperidine; Promethazine: (Major) If ondansetron and promethazine must be coadministered, ECG monitoring is recommended. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Mesoridazine: (Severe) Rarely and predominantly reported with intravenous ondansetron, transient ECG changes including QT prolongation have occurred. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Drugs which have been established to have a causal association with QT prolongation and TdP (torsade de pointe) and are contraindicated for use with ondansetron include mesoridazine.
    Metaproterenol: (Minor) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval, such as ondansetron, should be done with extreme caution and a careful assessment of treatment risks versus benefits. Monitor ECG for evidence of QT prolongation if coadministration is necessary. Methadone is associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Methylene Blue: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Methylprednisolone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include ondansetron.
    Midostaurin: (Major) The concomitant use of midostaurin and ondansetron may lead to additive QT interval prolongation. If these drugs are used together, perform electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Ondansetron has been associated with QT prolongation and torsade de pointes.
    Mifepristone: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), mifepristone and ondansetron should be used together cautiously. Mifepristone has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. To minimize the risk of QT prolongation, the lowest effective dose should always be used. Ondansetron has been associated with QT prolongation and postmarketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs partially metabolized by CYP2D6, such as ondansetron may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Major) Concomitant use of mirtazapine and ondansetron may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). In addition, both mirtazapine and ondansetron have central serotonin-enhancing effects; therefore, serotonin syndrome is possible. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Mitotane: (Minor) Use caution if mitotane and ondansetron are used concomitantly, and monitor for decreased efficacy of ondansetron and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and ondansetron is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ondansetron. During pharmacokinetic studies, patients treated with strong CYP3A inducers (i.e., phenytoin, carbamazepine, rifampin) and ondansetron had significantly increased ondansetron clearance, resulting in significant reductions in AUC, Cmax, and half-life. However, these changes in ondansetron exposure are not thought to be clinically relevant.
    Mometasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Monoamine oxidase inhibitors: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as Monoamine oxidase inhibitors. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Morphine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin-receptor antagonists. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Morphine; Naltrexone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin-receptor antagonists. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Moxifloxacin: (Major) Concurrent use of ondansetron and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If these drugs must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
    Nilotinib: (Major) Avoid coadministration of nilotinib with ondansetron due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of ondansetron may also be increased resulting in an increase in ondansetron-related adverse reactions. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Ondansetron is a CYP3A4 substrate that has also been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
    Norfloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering ondansetron with norfloxacin. If these drugs must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Octreotide: (Major) ECG monitoring is recommended if ondansetron and octreotide must be coadministered. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering ondansetron with ofloxacin. If these drugs must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
    Olanzapine: (Major) Monitor ECG for evidence of QT prolongation if coadministration of ondansetron and olanzapine is necessary. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Caution and close monitoring are advised if these drugs are administered together. Ondansetron exposure may be altered resulting in increased adverse effects or decreased efficacy. Ondansetron is metabolized by the hepatic isoenzymes CYP3A4, CYP2D6, and CYP1A2; ritonavir inhibits CYP3A4 and CYP2D6 and induces CYP1A2.
    Oritavancin: (Minor) Ondansetron is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of ondansetron may be reduced if these drugs are administered concurrently.
    Osimertinib: (Major) Avoid coadministration of ondansetron with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Ondansetron has also been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ondansetron with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). QT prolongation and ventricular arrhythmias including fatal TdP have also been reported with oxaliplatin use in postmarketing experience.
    Oxybutynin: (Moderate) The plasma concentrations of oxybutynin may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as increased anticholinergic activity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while oxybutynin is a CYP3A4 substrate.
    Oxycodone: (Major) Serotonin syndrome can occur during concomitant use of opiate agonists with serotonergic drugs, such as serotonin-receptor antagonists. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage increases of either agent. Instruct patients to immediately report symptoms of agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea.
    Paliperidone: (Major) Avoid coadministration of paliperidone and ondansetron if possible due to the potential for QT prolongation. If ondansetron and paliperidone must be coadministered, ECG monitoring is recommended and close monitoring is recommended in patients with known risk factors for cardiac disease or arrhythmias. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Panobinostat: (Major) The co-administration of panobinostat with antiemetic agents such as ondansetron may increase the risk of QT prolongation. If concomitant use cannot be avoided, obtain electrocardiograms frequently and closely monitor patients for signs and symptoms of ondansetron toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and ondansetron is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
    Paroxetine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as paroxetine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. In addition, because ondansetron is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Pasireotide: (Major) If ondansetron and pasireotide must be coadministered, ECG monitoring is recommended, as coadministration may have additive effects on the prolongation of the QT interval. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Coadministration of pazopanib and ondansetron is not advised. If coadministration is unavoidable, monitor ECG for evidence of QT prolongation. Pazopanib has been reported to prolong the QT interval. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Pentamidine: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and pentamidine should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Pentamidine has been associated with QT prolongation.
    Perphenazine: (Minor) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and perphenazine should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and perphenazine should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Phenelzine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as Monoamine oxidase inhibitors. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Phenylephrine; Promethazine: (Major) If ondansetron and promethazine must be coadministered, ECG monitoring is recommended. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Phenytoin: (Minor) Phenytoin may reduce the efficacy of ondansetron by decreasing its systemic exposure; however, based on available data, no ondansetron dosage adjustment is recommended. If used together, monitor patients for antiemetic efficacy. Phenytoin is a strong CYP3A inducer. Ondansetron is a substrate for CY1A2, CYP2D6, and CYP3A4, with CYP3A4 playing a predominant role in ondansetron turnover. During pharmacokinetic studies, patients treated with strong CYP3A inducers (i.e., phenytoin, carbamazepine, rifampin) and ondansetron had significantly increased ondansetron clearance, resulting in significant reductions in AUC, Cmax, and half-life. However, these changes in ondansetron exposure are not thought to be clinically relevant.
    Pimavanserin: (Major) Pimavanserin should be avoided in combination with ondansetron. Pimavanserin may cause QT prolongation. Ondansetron has also been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If coadministration is necessary, ECG monitoring is recommended.
    Pimozide: (Severe) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of ondansetron with pimozide is contraindicated.
    Pirbuterol: (Minor) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Posaconazole: (Severe) Concomitant administration of posaconazole and drugs that both prolong the QT interval and are CYP3A4 substrates is contraindicated according to the FDA-approved product labeling. The exact risk for QT prolongation when posaconazole and ondansetron are administered together has not been clearly defined. If ondansetron and posaconazole are administered together, extreme caution and careful monitoring is advised, especially if higher doses are used or if other drugs that may affect CYP1A2 or CYP2D6 are also given. Posaconazole is a strong CYP3A4 inhibitor. Ondansetron is metabolized by CYP3A, CYP1A2, and CYP2D6. In vivo microsomal inhibition data has suggested that no single isoenzyme dominates ondansetron's metabolism thereby making clinically significant interactions due to inhibition of a single isoenzyme unlikely; however, since the publication of this data, ondansetron has been found to produce concentration-dependent QT prolongation. It is not clear what degree of enzyme inhibition or increased concentration is required to increase the risk of QT prolongation.
    Prednisolone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Prednisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include ondansetron.
    Procainamide: (Major) Ondansetron should be used cautiously and with close monitoring with procainamide. If ondansetron and procainamide must be coadministered, ECG monitoring is recommended. Procainamide administration is associated with QT prolongation and torsades de pointes (TdP). Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001).
    Prochlorperazine: (Minor) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and prochlorperazine should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Phenothiazines have been reported to prolong the QT interval. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential.
    Promethazine: (Major) If ondansetron and promethazine must be coadministered, ECG monitoring is recommended. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Propafenone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with ondansetron. If these drugs must be coadministered, ECG monitoring is recommended. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Ondansetron has also been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001).
    Quetiapine: (Major) Avoid coadministration of ondansetron and quetiapine due to the risk of QT prolongation. Monitor ECG for evidence of QT prolongation if concurrent use cannot be avoided. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Quinidine: (Severe) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine include ondansetron.
    Quinine: (Major) Concurrent use of quinine and ondansetron should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with prolongation of the QT interval and rare cases of TdP. In addition, concentrations of ondansetron may be increased with concomitant use of quinine. Ondansetron is a CYP3A4 and CYP2D6 substrate and quinine is an inhibitor of both enzymes.
    Ranolazine: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and ranolazine should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ondansetron is a substrate for CYP3A4 and CYP2D6 and P-glycoprotein (P-gp). Ranolazine is an inhibitor of CYP3A4 and CYP2D6 and P-gp. Concurrent administration of ranolazine and ondansetron may result in increased ondansetron concentrations.
    Remifentanil: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Ribociclib: (Major) Avoid coadministration of ribociclib with ondansetron due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of ondansetron may also be increased resulting in an increase in ondansetron-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Ondansetron is a CYP3A4 substrate that has also been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with ondansetron due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of ondansetron may also be increased resulting in an increase in ondansetron-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Ondansetron is a CYP3A4 substrate that has also been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. Concomitant use may increase the risk for QT prolongation.
    Rifabutin: (Minor) Monitor for altered response to ondansetron during coadministration of rifabutin. Rifabutin may increase the clearance and decrease blood concentrations of ondansetron. However, no dosage adjustment for ondansetron is recommended during coadministration.
    Rifampin: (Minor) Rifampin may reduce the efficacy of ondansetron by decreasing its systemic exposure; however, based on available data, no ondansetron dosage adjustment is recommended. If used together, monitor patients for antiemetic efficacy. In a pharmacokinetic study of 10 healthy subjects receiving a single-dose intravenous dose of ondansetron 8 mg after 600 mg rifampin once daily for 5 days, the AUC and the half-life of ondansetron were reduced by 48% and 46%, respectively. The proposed mechanism is rifampin-related induction of ondansetron metabolism through cytochrome P450 3A4. These changes in ondansetron exposure with CYP3A4 inducers are not thought to be clinically relevant.
    Rifapentine: (Minor) Concomitant administration of ondansetron and rifapentine may lead to a decrease in the concentration of ondansetron. The proposed mechanism is rifapentine-related induction of ondansetron metabolism through CYP3A4.
    Rilpivirine: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and rilpivirine should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Risperidone: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP) with both ondansetron and risperidone, coadministration should be avoided if possible. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration. There are reports of QT prolongation and torsade de pointes during risperidone therapy, primarily in the setting of overdosage.
    Ritonavir: (Moderate) Caution and close monitoring are advised if these drugs are administered together. Ondansetron exposure may be altered resulting in increased adverse effects or decreased efficacy. Ondansetron is metabolized by the hepatic isoenzymes CYP3A4, CYP2D6, and CYP1A2; ritonavir inhibits CYP3A4 and CYP2D6 and induces CYP1A2.
    Rolapitant: (Major) Use caution if ondansetron and rolapitant are used concurrently, and monitor for ondansetron-related adverse effects. Ondansetron is a substrate of CYP2D6 and P-glycoprotein (P-gp) and rolapitant is an inhibitor of CYP2D6 and P-gp. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. When oral rolapitant was administered with another P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. When the P-gp substrate was administered with a single dose of intravenous rolapitant, no effect on AUC and a 21% increase in the Cmax of P-gp substrate was observed.
    Romidepsin: (Major) If ondansetron and romidepsin must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Romidepsin has been reported to prolong the QT interval.
    Salmeterol: (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and ondansetron as coadministration may result in increased systemic exposure of ondansetron. Ondansetron is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of ondansetron.
    Saquinavir: (Major) Concurrent use of saquinavir boosted with ritonavir and ondansetron should be avoided if possible due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ondansetron. Further, both saquinavir and ondansetron are substrates of P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug. This complex interaction may ultimately result in altered plasma concentrations of both ondansetron and saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as ondansetron. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
    Selegiline: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as Monoamine oxidase inhibitors. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Sertraline: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. In addition, taking these drugs together may increase the risk for serotinin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, discontinue all serotonergic agents and initiate appropriate medical treatment.
    Sevoflurane: (Major) If ondansetron and halogenated anesthetics must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Halogenated anesthetics can prolong the QT interval.
    Short-acting beta-agonists: (Minor) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of ondansetron, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently.
    Solifenacin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering solifenacin with ondansetron. If these drugs interval must be coadministered, ECG monitoring is recommended. Solifenacin has been associated with dose-dependent prolongation of the QT interval; TdP has been reported during post-marketing use, although causality was not determined. Ondansetron has also been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis.
    Sorafenib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of sorafenib with ondansetron is necessary; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib has been associated with QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Sotalol: (Major) Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. Drugs with a possible risk for QT prolongation and TdP, such as ondansetron, should be used cautiously with sotalol. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended.
    Sparfloxacin: (Major) Rarely and predominantly reported with intravenous ondansetron, transient ECG changes including QT prolongation have occurred. Use ondansetron with caution in combination with other drugs that may also prolong the QT interval, including sparfloxacin.
    St. John's Wort, Hypericum perforatum: (Minor) St. John's Wort may reduce the efficacy of ondansetron by decreasing its systemic exposure; however, based on available data, no ondansetron dosage adjustment is recommended. If used together, monitor patients for antiemetic efficacy. St. John's Wort is a strong CYP3A inducer. Ondansetron is a substrate for CY1A2, CYP2D6, and CYP3A4, with CYP3A4 playing a predominant role in ondansetron turnover. During pharmacokinetic studies, patients treated with strong CYP3A inducers (i.e., phenytoin, carbamazepine, rifampin) and ondansetron had significantly increased ondansetron clearance, resulting in significant reductions in AUC, Cmax, and half-life. However, these changes in ondansetron exposure are not thought to be clinically relevant.
    Sunitinib: (Major) Monitor ECG for evidence of QT prolongation if coadministration of ondansetron and sunitinib is necessary. Both drugs have been associated with a dose-related increase in the QT interval. Additionally, there have been postmarketing reports of torsade de pointes (TdP) with ondansetron treatment.
    Tacrolimus: (Major) ECG monitoring is recommended if ondansetron and tacrolimus must be coadministered. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Tacrolimus also causes QT prolongation.
    Tamoxifen: (Major) Monitor ECGs for QT prolongation if coadministration of ondansetron with tamoxifen is necessary. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering ondansetron with telaprevir due to an increased potential for ondansetron-related adverse events. If ondansetron dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of ondansetron. Ondansetron is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; telaprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated ondansetron plasma concentrations.
    Telavancin: (Major) Monitor ECG for evidence of QT prolongation if coadministration of ondansetron and telavancin is necessary. Telavancin has been associated with QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Telithromycin: (Major) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Telithromycin is associated with a lower, but possible risk for QT prolongation and TdP.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and ondansetron is necessary, as the systemic exposure of ondansetron may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of ondansetron; consider increasing the dose of ondansetron if necessary. Ondansetron is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Terbutaline: (Minor) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tetrabenazine: (Major) Avoid coadministration of tetrabenazine and ondansetron. If coadministration cannot be avoided, monitor ECG for evidence of QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Thiazide diuretics: (Moderate) The coadministration of ondansetron with diuretics associated with hypokalemia could increase the risk of QT prolongation. Potassium levels should be within the normal range prior to and during therapy with ondansetron.
    Thioridazine: (Severe) Because of the potential for torsade de pointes (TdP), use of thioridazine with granisetron is contraindicated. Thioridazine is associated with a well-established risk of QT prolongation and TdP; ondansetron has also been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. Thioridazine is considered contraindicated for use along with agents that may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension.
    Tiotropium; Olodaterol: (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tolterodine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with ondansetron. If these drugs must be coadministered, ECG monitoring is recommended. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis.
    Tolvaptan: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Toremifene: (Major) Avoid coadministration of ondansetron with toremifene due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Tramadol: (Moderate) Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from a few small studies indicate that ondansetron may reduce the analgesic effects of tramadol. Since adverse effects may occur when tramadol is administered in excessive dosage as patients try to obtain pain relief, clinicians should be alert to increases in the patient reported frequency of tramadol administration during concurrent use.
    Tranylcypromine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as Monoamine oxidase inhibitors. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Trazodone: (Major) Avoid coadministration due to the potential for QT prolongation. If ondansetron and trazodone must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP.
    Triamcinolone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Tricyclic antidepressants: (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). TCAs should be used cautiously and with close monitoring with ondansetron. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended.
    Trifluoperazine: (Minor) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and trifluoperazine should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Triptorelin: (Major) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include ondansetron.
    Umeclidinium; Vilanterol: (Moderate) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg IV bolus dose of ondansetron for postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ondansetron include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Vandetanib: (Major) Avoid coadministration of vandetanib with ondansetron due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Ondansetron has also been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
    Vardenafil: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and vardenafil should be used together cautiously. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).
    Vemurafenib: (Major) Monitor ECG for evidence of QT prolongation if coadministration of ondansetron and vemurafenib is necessary. Vemurafenib has been associated with QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Venlafaxine: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and venlafaxine should be used together cautiously. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use.
    Vilazodone: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as vilazodone. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Voriconazole: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as ondansetron. Ondansetron has been associated with QT prolongation and postmarketing reports of torsade de pointes (TdP). Voriconazole has been associated with QT prolongation and rare cases of TdP, cardiac arrest, and sudden death. Use of these drugs together increases the risk for QT prolongation. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with ondansetron (a CYP3A4 substrate) may result in elevated ondansetron plasma concentrations and could increase the risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
    Vorinostat: (Major) Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval, such as vorinostat, must be coadministered, ECG monitoring is recommended.
    Ziprasidone: (Major) Concomitant use of ziprasidone and ondansetron should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ondansetron is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

     Data on the use of ondansetron during human pregnancy from clinical studies are inconsistent and do not reliably inform a drug associated risk of adverse fetal outcomes. Available data suggest that there may be an increased risk of certain birth defects, particularly when ondansetron is used during the first trimester. Until additional data are available, the most prudent course would be to reserve ondansetron use for cases in which safer alternatives have failed, and, if possible, avoid use during the period of organogenesis. 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. Ondansetron has been shown to cross the placenta in early pregnancy with a median fetal to maternal ratio of 0.41. The American College of Obstetricians and Gynecologists (ACOG) includes ondansetron as a treatment option for nausea and vomiting of pregnancy in patients who are dehydrated, require IV fluid replacement, and have failed other therapies. Since the publication of the ACOG guidelines, the off-label use of ondansetron in pregnant women has increased and several additional studies have been published evaluating the risk of birth defects when ondansetron is used during pregnancy. A cohort study that included patients from 2 medical registries in Sweden identified 1349 neonates born to mothers who were prescribed ondansetron during the first trimester. The risk of cardiovascular defects, and specifically septal defects, was statistically significantly higher in those neonates whose mothers were prescribed ondansetron (OR for cardiovascular defects 1.62, 95% CI 1.04—2.14; RR for septal defects 2.05, 95% CI 1.19-3.28). A limitation of this study, however, is that the actual ondansetron exposure is unknown because data were obtained from a combination of midwife interviews and prescription records. In addition, the authors state that the relatively wide confidence intervals may represent random variations of common risk. A case-control study using data from the National Birth Defects Prevention Study examined whether treatments of nausea and vomiting during pregnancy were associated with the most common non-cardiac birth defects (cleft lip, cleft palate, neural tube defects, and hypospadias). Ondansetron treatment during the first trimester was associated with a statistically significant increased risk of cleft palate (adjusted OR 2.37, 95% CI 1.18—4.76); however, the number of patients who received ondansetron was very small (n = 7). The authors state that due to the multiple comparisons performed in this study, the possibility exists that the findings are due to chance and warrant further research. A historical cohort study using data from medical registries in Denmark compared outcomes of neonates exposed to ondansetron to those not exposed (1:4 ratio; ondansetron exposed = 1849, not exposed = 7396). The study did not find a statistically significant increased risk of major birth defects, spontaneous abortion, stillbirth, preterm delivery, low-birth weight, or small for gestational age. However, the median time of exposure to ondansetron was 10 weeks gestation, indicating half of the patients were exposed at the end of or after the first trimester, and the study was not adequately powered to determine the risk of individual birth defects. Despite the relatively frequent use of ondansetron for the treatment of nausea and vomiting of pregnancy, the need for additional safety data remains.

    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. Caution should be exercised when administering ondansetron to a breast-feeding woman.

    MECHANISM OF ACTION

    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. 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.
     
    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.

    PHARMACOKINETICS

    Ondansetron is administered orally and parenterally. It is approximately 70—76% bound to plasma protein; circulating drug also distributes into erythrocytes (approximately 36%). Animal data indicate it distributes into breast milk. Systemic exposure does not increase proportionately to the dose. Less than 5% of a dose is excreted in the urine unchanged. The mean elimination half-life in adults ranges 3.1 to 5.8 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  CYP3A4, CYP1A2, CYP2D6, CYP2C9, P-gp
    Ondansetron undergoes extensive metabolism, mainly by hydroxylation, followed by glucuronide or sulfate conjugation. In vitro studies indicate that ondansetron is metabolized by hepatic cytochrome P450 (CYP450) drug-metabolizing enzymes, including CYP1A2, CYP2D6, and CYP3A4; with CYP3A4 playing the largest role. Because multiple enzymes are involved in the metabolism of ondansetron, inhibition or loss of any one enzyme may not affect the overall rate of metabolism. Additionally, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination. Interactions with inhibitors or inducers of these enzymes have not been reported clinically; however, the potential exists for these interactions to change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients receiving CYP-interacting drugs. Ondansetron is also a substrate of P-glycoprotein. The inactive metabolites are eliminated in the urine.

    Oral Route

    Following oral administration, ondansetron is well absorbed from the gastrointestinal tract and undergoes first-pass metabolism. After a dose of a single 8-mg tablet, mean oral bioavailability in healthy adult subjects is 56%. The AUC from a 16 mg-tablet is 24% greater than predicted from an 8-mg tablet dose, indicating reduced first-pass metabolism at higher oral doses. Food slightly enhances tablet bioavailability, but antacids have no effect. Of note, 4- and 8-mg oral ondansetron tablets, orally disintegrating tablets (ODT), and oral solution are bioequivalent. After a single 8-mg dose of ondansetron oral soluble film in adult patients, peak plasma concentrations are achieved in 1.3 hours, and mean Cmax is 37.28 ng/mL and the mean AUC 225 n x h/mL. The Cmax and AUC of the oral soluble film is comparable to that of the same dose of ondansetron ODT. Water does not affect the exposure of ondansetron oral soluble film administration. Administration of the oral soluble film with a high-fat meal delays the Tmax by approximately 1 hour, but the AUC is unaffected.

    Intravenous Route

    In adults, a single 4-mg dose administered as a 5-minute intravenous (IV) infusion demonstrated a mean AUC of 156 ng x h/ml. Mean peak plasma concentrations were 42.9 ng/ml at 10 minutes after IV infusion.