Interactions between Adagrasib and Duloxetine
1 drug interaction and 18 additional warnings found for the following 2 drugs:
- adagrasib
- duloxetine
Drug interactions
Moderate drug interactions
Moderate:
DULoxetine adagrasib
Applies to: duloxetine and adagrasib
Monitor
Coadministration with inhibitors of CYP450 2D6 may increase the plasma concentrations of duloxetine, which is partially metabolized by the isoenzyme. According to the product labeling, concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) resulted in an approximately 60% increase in duloxetine systemic exposure (AUC), and greater degrees of inhibition are expected with higher dosages of paroxetine. Although not studied, a similar interaction should be anticipated with other potent CYP450 2D6 inhibitors such as fluoxetine or quinidine. Theoretically, high plasma levels of duloxetine may increase the risk of serious adverse effects such as hypertension, hypertensive crisis, increased heart rate, orthostatic hypotension, syncope, and serotonin syndrome. Serotonin syndrome is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.
Management
Caution is advised if duloxetine is used in combination with CYP450 2D6 inhibitors, particularly potent ones like paroxetine, fluoxetine, or quinidine. Pharmacologic response to duloxetine should be monitored more closely whenever a CYP450 2D6 inhibitor is added to or withdrawn from therapy, and the dosage adjusted as necessary.
References (2)
- Skinner MH, Kuan HY, Pan A, et al. (2003) "Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers." Clin Pharmacol Ther, 73, p. 170-7
- (2004) "Product Information. Cymbalta (duloxetine)." Lilly, Eli and Company
Food/lifestyle interactions
Major food/lifestyle interactions
Major:
adagrasib Food/Lifestyle
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.
Moderate food/lifestyle interactions
Moderate:
DULoxetine Food/Lifestyle
Applies to: duloxetine
Generally avoid
Use of duloxetine in conjunction with chronic alcohol consumption may potentiate the risk of liver injury. Duloxetine alone can increase serum transaminase levels. In clinical trials, 0.3% of patients discontinued duloxetine due to liver transaminase elevations. The median time to detection was about two months. Three duloxetine-treated patients had liver injury as manifested by transaminase and bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, which may have contributed to the abnormalities observed. Duloxetine does not appear to enhance the central nervous system effects of alcohol. When duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, duloxetine did not increase the impairment of mental and motor skills caused by alcohol.
Management
Due to the risk of liver injury, patients prescribed duloxetine should be counseled to avoid excessive use of alcohol. Duloxetine should generally not be prescribed to patients with substantial alcohol use.
References (1)
- (2004) "Product Information. Cymbalta (duloxetine)." Lilly, Eli and Company
Disease interactions
16 potential interactions Applies to: 15 conditions, including High Blood Pressure, Depression, Bipolar Disorder, Urinary Tract Infection, and Seizures.
Bipolar Disorder
Major:
duloxetine
DULoxetine has a major potential interaction with Bipolar Disorder.
Adult and pediatric patients with depression and other psychiatric disorders may experience worsening of their symptoms and may have the emergence of suicidal thoughts and behavior. Patients should be monitored appropriately and observed closely for worsening of their symptoms, suicidality or changes in their behavior, especially during the first few months of treatment, and at times of dose changes. Discontinuing the medication should be considered if symptoms are persistently worse, or abrupt in onset. It may be prudent to refrain from dispensing large quantities of medication to these patients.
Moderate:
duloxetine
DULoxetine has a moderate potential interaction with Bipolar Disorder.
Therapy with SNRI antidepressants can cause activation of mania and hypomania and should be used with caution in patients with personal or family history of mania, hypomania, bipolar disorder, and other mood disorders.
Dehydration
Moderate:
duloxetine
DULoxetine has a moderate potential interaction with Dehydration.
Treatment with SNRI antidepressants can cause hyponatremia. Caution should be used when treating patients with hyponatremia or at greater risk of hyponatremia such as the elderly, patients taking diuretics or who are volume depleted.
Depression
Major:
duloxetine
DULoxetine has a major potential interaction with Depression.
Adult and pediatric patients with depression and other psychiatric disorders may experience worsening of their symptoms and may have the emergence of suicidal thoughts and behavior. Patients should be monitored appropriately and observed closely for worsening of their symptoms, suicidality or changes in their behavior, especially during the first few months of treatment, and at times of dose changes. Discontinuing the medication should be considered if symptoms are persistently worse, or abrupt in onset. It may be prudent to refrain from dispensing large quantities of medication to these patients.
Diabetes Mellitus
Moderate:
duloxetine
DULoxetine has a moderate potential interaction with Diabetes Mellitus.
In clinical trials, treatment with duloxetine delayed-release worsened the glycemic control in some patients with diabetes. Caution should be used when using duloxetine in diabetic patients and their glycemic levels should be checked regularly.
Glaucoma, Narrow Angle
Moderate:
duloxetine
DULoxetine has a moderate potential interaction with Glaucoma, Narrow Angle.
SNRI antidepressants cause pupillary dilation that may trigger an angle closure attack in patients with anatomically narrow angle without iridectomy.
High Blood Pressure
Moderate:
duloxetine
DULoxetine has a moderate potential interaction with High Blood Pressure.
Selective serotonin and norepinephrine reuptake inhibitor antidepressants (SNRIs) have been associated with sustained increases in blood pressure. Therapy with SNRI antidepressants should be administered cautiously in patients with preexisting hypertension. Blood pressure should be assessed prior to initiating treatment and monitored regularly. The dose should be reduced or discontinued if necessary.
Hyponatremia
Moderate:
duloxetine
DULoxetine has a moderate potential interaction with Hyponatremia.
Treatment with SNRI antidepressants can cause hyponatremia. Caution should be used when treating patients with hyponatremia or at greater risk of hyponatremia such as the elderly, patients taking diuretics or who are volume depleted.
Liver Disease
Major:
duloxetine
DULoxetine has a major potential interaction with Liver Disease.
Postmarketing studies have reported that duloxetine and some other SNRIs like milnacipran may aggravate preexisting liver disease. The use of duloxetine delayed-release and milnacipran should be avoided in patients with chronic liver disease or cirrhosis.
Long QT Syndrome
Moderate:
adagrasib
Adagrasib has a moderate potential interaction with Long QT Syndrome.
Adagrasib can cause QTc prolongation, which increases the risk of ventricular tachyarrhythmias or sudden death. Use should be avoided in patients with congenital long QT syndrome, in patients with concurrent QTc prolongation, and patients taking other medicines known to prolong the QTc interval. Monitor ECG and electrolytes prior to starting treatment and as indicated during therapy.
Mania
Moderate:
duloxetine
DULoxetine has a moderate potential interaction with Mania.
Therapy with SNRI antidepressants can cause activation of mania and hypomania and should be used with caution in patients with personal or family history of mania, hypomania, bipolar disorder, and other mood disorders.
Pulmonary Impairment
Moderate:
adagrasib
Adagrasib has a moderate potential interaction with Pulmonary Impairment.
Adagrasib can cause interstitial lung disease (ILD)/pneumonitis which can be fatal. Patients should be monitored for new or worsening symptoms indicative of ILD/pneumonitis during treatment. Caution is advised in patients with pulmonary impairment.
Renal Dysfunction
Major:
duloxetine
DULoxetine has a major potential interaction with Renal Dysfunction.
The use of duloxetine should be avoided in patients with severe renal impairment (GFR <30 mL/min).
Seizures
Moderate:
duloxetine
DULoxetine has a moderate potential interaction with Seizures.
SNRI antidepressants may trigger seizures and should be administered with caution in patients with a seizure disorder.
Urinary Tract Infection
Moderate:
duloxetine
DULoxetine has a moderate potential interaction with Urinary Tract Infection.
SNRI antidepressants have a noradrenergic effect and can affect urethral resistance. Caution should be used in patients with a history of dysuria, prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders.
Urinary Tract Obstruction
Moderate:
duloxetine
DULoxetine has a moderate potential interaction with Urinary Tract Obstruction.
SNRI antidepressants have a noradrenergic effect and can affect urethral resistance. Caution should be used in patients with a history of dysuria, prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders.
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More resources
adagrasib
A total of 701 drugs are known to interact with adagrasib.
- Adagrasib is in the drug class miscellaneous antineoplastics.
- Adagrasib is used to treat Non Small Cell Lung Cancer.
duloxetine
A total of 654 drugs are known to interact with duloxetine.
- Duloxetine is in the drug class serotonin-norepinephrine reuptake inhibitors.
-
Duloxetine is used to treat the following conditions:
- Anxiety
- Back Pain
- Bipolar Disorder (off-label)
- Chronic Fatigue Syndrome (off-label)
- Chronic Pain
- Depression
- Diabetic Peripheral Neuropathy
- Fibromyalgia
- Generalized Anxiety Disorder
- Hot Flashes (off-label)
- Major Depressive Disorder
- Osteoarthritis
- Pain (off-label)
- Peripheral Neuropathy (off-label)
- Persistent Depressive Disorder (off-label)
- Small Fiber Neuropathy (off-label)
- Somatoform Pain Disorder (off-label)
- Urinary Incontinence (off-label)
Drug Interaction Classification
| Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit. | |
| Moderately clinically significant. Usually avoid combinations; use it only under special circumstances. | |
| 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. | |
| No interaction information available. |
Further information
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