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Drug Interactions between adagrasib and Dutoprol

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

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Interactions between your drugs

Moderate

metoprolol hydroCHLOROthiazide

Applies to: Dutoprol (hydrochlorothiazide / metoprolol) and Dutoprol (hydrochlorothiazide / metoprolol)

MONITOR: Although they are often combined in clinical practice, diuretics and beta-blockers may increase the risk of hyperglycemia and hypertriglyceridemia in some patients, especially in patients with diabetes or latent diabetes. In addition, the risk of QT interval prolongation and arrhythmias (e.g. torsades de pointes) due to sotalol may be increased by potassium-depleting diuretics.

MANAGEMENT: Monitoring of serum potassium levels, blood pressure, and blood glucose is recommended during coadministration. Patients should be advised to seek medical assistance if they experience dizziness, weakness, fainting, fast or irregular heartbeats, or loss of blood glucose control.

References

  1. Dornhorst A, Powell SH, Pensky J (1985) "Aggravation by propranolol of hyperglycaemic effect of hydrochlorothiazide in type II diabetics without alteration of insulin secretion." Lancet, 1, p. 123-6
  2. Roux A, Le Liboux A, Delhotal B, Gaillot J, Flouvat B (1983) "Pharmacokinetics in man of acebutolol and hydrochlorothiazide as single agents and in combination." Eur J Clin Pharmacol, 24, p. 801-6
  3. Dean S, Kendall MJ, Potter S, Thompson MH, Jackson DA (1985) "Nadolol in combination with indapamide and xipamide in resistant hypertensives." Eur J Clin Pharmacol, 28, p. 29-33
  4. (2002) "Product Information. Lozol (indapamide)." Rhone Poulenc Rorer
  5. Marcy TR, Ripley TL (2006) "Aldosterone antagonists in the treatment of heart failure." Am J Health Syst Pharm, 63, p. 49-58
View all 5 references

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Moderate

metoprolol adagrasib

Applies to: Dutoprol (hydrochlorothiazide / metoprolol) and adagrasib

MONITOR: Coadministration with adagrasib may increase the plasma concentrations of drugs that are metabolized by the CYP450 3A4, 2D6 or 2C9 enzymatic pathways or are substrates of the P-glycoprotein (P-gp) efflux membrane transporter. When adagrasib 400 mg twice daily (two-thirds the approved recommended dosage) was administered with midazolam (a sensitive CYP450 3A4 substrate) and dextromethorphan (a sensitive CYP450 2D6 substrate) in pharmacokinetic studies, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 4.8- and 21-fold, respectively, while dextromethorphan Cmax and AUC increased by 1.9- and 1.8-fold, respectively. Adagrasib at the approved recommended dosage of 600 mg twice daily is predicted to increase midazolam Cmax by 3.1-fold and AUC by 31-fold; dextromethorphan Cmax by 1.7-fold and AUC by 2.4-fold; warfarin (a sensitive CYP450 2C9 substrate) Cmax by 1.1-fold and AUC by 2.9-fold; and digoxin (a P-gp substrate) Cmax by 1.9-fold and AUC by 1.5-fold. These results suggest that adagrasib is a potent inhibitor of CYP450 3A4 and may be a moderate inhibitor of CYP450 2D6 and 2C9 at the approved recommended dosage of 600 mg twice daily.

MANAGEMENT: Caution is advised when adagrasib is used concomitantly with drugs that are substrates of CYP450 3A4, CYP450 2D6, CYP450 2C9 and/or P-gp, particularly sensitive substrates or those with a narrow therapeutic range. Substitution for these medications is recommended when possible, or initiate with lower dosages and monitor patient clinical response/tolerance and titrate accordingly if coadministration is required. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.

References

  1. (2022) "Product Information. Krazati (adagrasib)." Mirati Therapeutics, Inc.

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Drug and food interactions

Major

adagrasib food

Applies to: adagrasib

ADJUST DOSING INTERVAL: Adagrasib can cause concentration-dependent, prolongation of the QT interval. Theoretically, coadministration with grapefruit juice before adagrasib has reached steady-state may significantly increase the plasma concentrations of adagrasib, which is primarily metabolized by CYP450 3A4. 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. The interaction has not been studied with grapefruit juice but has been reported for the potent CYP450 3A4 inhibitor, itraconazole. In a clinical drug interaction study, adagrasib peak plasma concentration (Cmax) and systemic exposure (AUC) were increased by 2.4-fold and 4-fold, respectively following concomitant use of a single dose of adagrasib (200 mg) with itraconazole. No clinically significant differences in the pharmacokinetics of adagrasib at steady state were predicted when used concomitantly with itraconazole. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to adagrasib may increase the risk of adverse effects such as QT prolongation, diarrhea, fatigue, musculoskeletal pain, hepatotoxicity, and renal impairment.

Adagrasib pharmacokinetics were not significantly affected when administered with a high-fat meal.

MANAGEMENT: Although clinical data are lacking, it may be advisable to avoid the consumption of grapefruit or grapefruit juice until adagrasib concentrations have reached steady state (after approximately 8 days). 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. Adagrasib may be administered with or without food.

References

  1. (2022) "Product Information. Krazati (adagrasib)." Mirati Therapeutics, Inc.

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Moderate

metoprolol food

Applies to: Dutoprol (hydrochlorothiazide / metoprolol)

ADJUST DOSING INTERVAL: The bioavailability of metoprolol may be enhanced by food.

MANAGEMENT: Patients may be instructed to take metoprolol at the same time each day, preferably with or immediately following meals.

References

  1. (2001) "Product Information. Lopressor (metoprolol)." Novartis Pharmaceuticals
  2. Darcy PF (1995) "Nutrient-drug interactions." Adverse Drug React Toxicol Rev, 14, p. 233-54

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Moderate

hydroCHLOROthiazide food

Applies to: Dutoprol (hydrochlorothiazide / metoprolol)

MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

References

  1. Sternbach H (1991) "Fluoxetine-associated potentiation of calcium-channel blockers." J Clin Psychopharmacol, 11, p. 390-1
  2. Shook TL, Kirshenbaum JM, Hundley RF, Shorey JM, Lamas GA (1984) "Ethanol intoxication complicating intravenous nitroglycerin therapy." Ann Intern Med, 101, p. 498-9
  3. Feder R (1991) "Bradycardia and syncope induced by fluoxetine." J Clin Psychiatry, 52, p. 139
  4. Ellison JM, Milofsky JE, Ely E (1990) "Fluoxetine-induced bradycardia and syncope in two patients." J Clin Psychiatry, 51, p. 385-6
  5. Rodriguez de la Torre B, Dreher J, Malevany I, et al. (2001) "Serum levels and cardiovascular effects of tricyclic antidepressants and selective serotonin reuptake inhibitors in depressed patients." Ther Drug Monit, 23, p. 435-40
  6. Cerner Multum, Inc. "Australian Product Information."
  7. Pacher P, Kecskemeti V (2004) "Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns?" Curr Pharm Des, 10, p. 2463-75
  8. Andrews C, Pinner G (1998) "Postural hypotension induced by paroxetine." BMJ, 316, p. 595
View all 8 references

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Moderate

metoprolol food

Applies to: Dutoprol (hydrochlorothiazide / metoprolol)

ADJUST DOSING INTERVAL: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers. The exact mechanism of interaction is unknown. In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively. The elimination half-life increased by 44%. Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone. However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments. The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

MANAGEMENT: It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours. Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.

References

  1. Kirch W, Schafer-Korting M, Axthelm T, Kohler H, Mutschler E (1981) "Interaction of atenolol with furosemide and calcium and aluminum salts." Clin Pharmacol Ther, 30, p. 429-35

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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.