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Drug Interactions between MKO Troche and vandetanib

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

ketamine midazolam

Applies to: MKO Troche (ketamine / midazolam / ondansetron) and MKO Troche (ketamine / midazolam / ondansetron)

MONITOR CLOSELY: Coadministration of ketamine with other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. In addition, opioid analgesics, barbiturates, and benzodiazepines may prolong the time to complete recovery from anesthesia.

MANAGEMENT: During concomitant use of ketamine with other CNS depressants, including alcohol, close monitoring of neurologic status and respiratory parameters, including respiratory rate and pulse oximetry, is recommended. Dosage adjustments should be considered according to the patient's clinical situation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Cerner Multum, Inc. "Australian Product Information."
  3. (2009) "Product Information. Ketalar (ketamine)." JHP Pharmaceuticals

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Major

ondansetron vandetanib

Applies to: MKO Troche (ketamine / midazolam / ondansetron) and vandetanib

GENERALLY AVOID: Vandetanib can cause concentration-dependent prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In a phase 3 clinical trial where 231 medullary thyroid cancer patients were randomized to receive vandetanib 300 mg once daily, mean change in QTcF (Fridericia-corrected QT interval) from baseline based on the exposure-response relationship was 35 ms for the 300 mg dose. The QTcF increase remained above 30 ms for the duration of the trial (up to 2 years). In addition, 36% of patients experienced greater than 60 ms QTcF increases from baseline and 4.3% had QTcF greater than 500 ms. Vandetanib treatment alone has been associated with reported cases of torsade de pointes, ventricular tachycardia, and sudden death. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of vandetanib with other drugs that can prolong the QT interval should generally be avoided. Should treatment with other QT-prolonging drugs be required, the manufacturer recommends more frequent monitoring of the ECG as well as serum potassium, magnesium, and calcium levels. Given vandetanib's half-life of 19 days, ECGs and serum electrolytes should typically be obtained at baseline, at 2 to 4 weeks and 8 to 12 weeks after starting treatment, and every 3 months thereafter. Vandetanib should not be started if baseline QTcF is greater than 450 ms, and treatment should be interrupted if QTcF is greater than 500 ms. Treatment may resume when QTcF returns to less than 450 ms, but at a reduced dosage. In addition, hypokalemia, hypomagnesemia, and/or hypocalcemia must be corrected prior to vandetanib administration. Since diarrhea is a common side effect of vandetanib and may cause electrolyte imbalances, ECG and electrolyte levels should also be monitored more frequently when diarrhea develops. Vandetanib treatment should be stopped in the presence of severe diarrhea. Treatment may resume when diarrhea improves, but at a reduced dosage. Following any dosage reduction, or any interruption of treatment greater than 2 weeks, QT assessment and serum electrolytes should be conducted as described previously. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Because of the drug's long half-life, adverse reactions including a prolonged QT interval may not resolve quickly, thus appropriate monitoring is necessary.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Canadian Pharmacists Association (2006) e-CPS. http://www.pharmacists.ca/function/Subscriptions/ecps.cfm?link=eCPS_quikLink
  3. Cerner Multum, Inc. "Australian Product Information."
  4. (2011) "Product Information. Vandetanib (vandetanib)." Astra-Zeneca Pharmaceuticals
View all 4 references

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Drug and food interactions

Major

ketamine food

Applies to: MKO Troche (ketamine / midazolam / ondansetron)

MONITOR CLOSELY: Coadministration of ketamine with other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. In addition, opioid analgesics, barbiturates, and benzodiazepines may prolong the time to complete recovery from anesthesia.

MANAGEMENT: During concomitant use of ketamine with other CNS depressants, including alcohol, close monitoring of neurologic status and respiratory parameters, including respiratory rate and pulse oximetry, is recommended. Dosage adjustments should be considered according to the patient's clinical situation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Cerner Multum, Inc. "Australian Product Information."
  3. (2009) "Product Information. Ketalar (ketamine)." JHP Pharmaceuticals

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Moderate

ketamine food

Applies to: MKO Troche (ketamine / midazolam / ondansetron)

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of ketamine. Use in combination may result in additive central nervous system (CNS) depression and/or impairment of judgment, thinking, and psychomotor skills.

GENERALLY AVOID: Coadministration of oral ketamine with grapefruit juice may significantly increase the plasma concentrations of S(+) ketamine, the dextrorotatory enantiomer of ketamine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. When a single 0.2 mg/kg dose of S(+) ketamine was administered orally on study day 5 with grapefruit juice (200 mL three times daily for 5 days) in 12 healthy volunteers, mean S(+) ketamine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.1- and 3.0-fold, respectively, compared to administration with water. In addition, the elimination half-life of S(+) ketamine increased by 24% with grapefruit juice, and the ratio of the main metabolite norketamine to ketamine was decreased by 57%. The pharmacodynamics of ketamine were also altered by grapefruit juice. Specifically, self-rated relaxation was decreased and performance in the digit symbol substitution test was increased with grapefruit juice, but other behavioral or analgesic effects were not affected.

MANAGEMENT: Patients receiving ketamine should not drink alcohol. Caution is advised when ketamine is used in patients with acute alcohol intoxication or a history of chronic alcoholism. Following anesthesia with ketamine, patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination, such as driving or operating hazardous machinery, for at least 24 hours and until they know how the medication affects them. Patients treated with oral ketamine should also avoid consumption of grapefruit and grapefruit juice during treatment. Otherwise, dosage reductions of oral ketamine should be considered.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Cerner Multum, Inc. "Australian Product Information."
  3. (2009) "Product Information. Ketalar (ketamine)." JHP Pharmaceuticals
  4. Peltoniemi MA, Saari TI, Hagelberg NM, Laine K, Neuvonen PJ, Olkkola KT (2012) "S-ketamine concentrations are greatly increased by grapefruit juice." Eur J Clin Pharmacol, 68, p. 979-86
View all 4 references

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Moderate

midazolam food

Applies to: MKO Troche (ketamine / midazolam / ondansetron)

GENERALLY AVOID: The pharmacologic activity of oral midazolam, triazolam, and alprazolam may be increased if taken after drinking grapefruit juice. The proposed mechanism is CYP450 3A4 enzyme inhibition. In addition, acute alcohol ingestion may potentiate CNS depression and other CNS effects of many benzodiazepines. Tolerance may develop with chronic ethanol use. The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition. Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MANAGEMENT: The manufacturer recommends that grapefruit juice should not be taken with oral midazolam. Patients taking triazolam or alprazolam should be monitored for excessive sedation. Alternatively, the patient could consume orange juice which does not interact with these drugs. Patients should be advised to avoid alcohol during benzodiazepine therapy.

References

  1. (2002) "Product Information. Xanax (alprazolam)." Pharmacia and Upjohn
  2. (2002) "Product Information. Valium (diazepam)." Roche Laboratories
  3. (2001) "Product Information. Halcion (triazolam)." Pharmacia and Upjohn
  4. (1995) "Grapefruit juice interactions with drugs." Med Lett Drugs Ther, 37, p. 73-4
  5. Kupferschmidt HHT, Ha HR, Ziegler WH, Meier PJ, Krahenbuhl S (1995) "Interaction between grapefruit juice and midazolam in humans." Clin Pharmacol Ther, 58, p. 20-8
  6. Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ (1995) "Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice." Clin Pharmacol Ther, 58, p. 127-31
  7. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR (2000) "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther, 68, p. 468-77
View all 7 references

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.


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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.