Drug Interaction Report
1 drug interaction and 19 additional warnings found for the following 2 drugs:
- clarithromycin
- guanfacine
Drug interactions
Major drug interactions
Major:clarithromycin guanFACINE
Applies to: clarithromycin, guanfacine
Adjust dose
Coadministration with inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of guanfacine, which is primarily metabolized by the isoenzyme. The risk of adverse reactions such as hypotension, bradycardia, and sedation may increase. Ketoconazole, a potent CYP450 3A4 inhibitor, has been reported to increase guanfacine peak plasma concentration (Cmax) and systemic exposure (AUC) by 2- and 3-fold, respectively. A computer simulation suggests that fluconazole, a moderate CYP450 3A4 inhibitor, would increase guanfacine Cmax and AUC by about 1.5- and 2-fold, respectively.
Management
Caution and dosage adjustment are advised when guanfacine is administered with potent and moderate CYP450 3A4 inhibitors. For extended-release guanfacine, the manufacturers recommend reducing the dosage to half the recommended level during concomitant use. Further dosage adjustments may be required based on patient tolerance and response. The dosage should be increased to the recommended level following discontinuation of the CYP450 3A4 inhibitor. The inhibitory effects of some agents may persist after discontinuation. The prescribing information for the specific inhibitor should be consulted for further guidance.
References (2)
- Cerner Multum, Inc. "UK Summary of Product Characteristics."
- (2009) "Product Information. Intuniv (guanfacine)." Shire US Inc
Food/lifestyle interactions
Major food/lifestyle interactions
Major:Food/Lifestyle guanFACINE
Applies to: guanfacine
Generally avoid
Grapefruit juice may increase the plasma concentrations of guanfacine. The risk of adverse reactions such as hypotension, bradycardia, and sedation may increase. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Ketoconazole, a potent CYP450 3A4 inhibitor, has been reported to increase guanfacine peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 2- and 3-fold, respectively. A computer simulation suggests that fluconazole, a moderate CYP450 3A4 inhibitor, would increase guanfacine Cmax and AUC by about 1.5- and 2-fold, respectively. 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.
Generally avoid
Alcohol may enhance the sedative and hypotensive effects of guanfacine.
Generally avoid
Administration of extended-release guanfacine with a high-fat meal may increase the bioavailability of guanfacine. When a single 4 mg dose of extended-release guanfacine was administered to adult volunteers with a high-fat breakfast, mean guanfacine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 75% and 40%, respectively, compared to dosing in a fasted state.
Management
Patients treated with guanfacine should avoid consumption of grapefruit and grapefruit juice. In addition, it is preferable to avoid or limit the use of alcohol during treatment. Patients should be advised against driving or operating hazardous machinery until they know how the medication affects them. The extended-release formulation of guanfacine should not be taken together with a high-fat meal.
References (3)
- (2001) "Product Information. Tenex (guanfacine)." Wyeth-Ayerst Laboratories
- Cerner Multum, Inc. "UK Summary of Product Characteristics."
- (2009) "Product Information. Intuniv (guanfacine)." Shire US Inc
Minor food/lifestyle interactions
Minor:Food/Lifestyle clarithromycin
Applies to: clarithromycin
Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.
References (1)
- Cheng KL, Nafziger AN, Peloquin CA, Amsden GW (1998) "Effect of grapefruit juice on clarithromycin pharmacokinetics." Antimicrob Agents Chemother, 42, p. 927-9
Disease interactions
17 potential interactionsApplies to: 15 conditions, including Depression, Arrhythmia, Hypokalemia, Hypotension, and Peripheral Arterial Disease.
Arrhythmia
Moderate:clarithromycin
Clarithromycin has a moderate potential interaction with Arrhythmia.
Macrolides have been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Clarithromycin and erythromycin should be avoided in: patients with known prolongation of the QT interval, ventricular cardiac arrhythmia, including torsades de pointes; patients with proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, or receiving other drugs that prolong the QT interval.
Cerebrovascular Insufficiency
Moderate:guanfacine
guanFACINE has a moderate potential interaction with Cerebrovascular Insufficiency.
Central alpha-2 adrenoreceptor agonists reduce sympathetic outflow from the central nervous system, resulting in decreases in heart rate, peripheral and renovascular resistance, and blood pressure. Therapy with these agents should be administered cautiously in patients with hypotension or conditions that may be exacerbated by decreased blood pressure and perfusion, such as coronary insufficiency, peripheral vascular disease (e.g., Raynaud's syndrome), cerebrovascular disease, or recent myocardial infarction.
Depression
Moderate:guanfacine
guanFACINE has a moderate potential interaction with Depression.
Central alpha-2 adrenoreceptor agonists may occasionally cause mental depression and should be used cautiously in patients with a history of depression.
Heart Block
Moderate:guanfacine
guanFACINE has a moderate potential interaction with Heart Block.
Central alpha-2 adrenoreceptor agonists reduce sympathetic outflow from the central nervous system. Heart rate is decreased, which may lead to or exacerbate sinus bradycardia and atrioventricular block. Therapy with central alpha-2 adrenoreceptor agonists should be administered cautiously in patients with conduction disturbances such as sinus node dysfunction or AV nodal disease.
Hyperkinetic Syndrome of Childhood
Moderate:guanfacine
guanFACINE has a moderate potential interaction with Hyperkinetic Syndrome of Childhood.
The safety and effectiveness of guanfacine in children under 12 years of age has not been demonstrated and its use in this age group is not recommended. However, there have been some spontaneous postmarketing reports of mania and aggressive behavioral changes in pediatric patients with attention- deficit hyperactivity disorder (ADHD) that received this drug. All patients had medical or family risks of bipolar disorder, and all of them recovered after treatment discontinuation. Hallucinations have also been reported in pediatric patients receiving guanfacine for the treatment of ADHD.
Hypokalemia
Moderate:clarithromycin
Clarithromycin has a moderate potential interaction with Hypokalemia.
Macrolides have been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Clarithromycin and erythromycin should be avoided in: patients with known prolongation of the QT interval, ventricular cardiac arrhythmia, including torsades de pointes; patients with proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, or receiving other drugs that prolong the QT interval.
Hypotension
Moderate:guanfacine
guanFACINE has a moderate potential interaction with Hypotension.
Central alpha-2 adrenoreceptor agonists reduce sympathetic outflow from the central nervous system, resulting in decreases in heart rate, peripheral and renovascular resistance, and blood pressure. Therapy with these agents should be administered cautiously in patients with hypotension or conditions that may be exacerbated by decreased blood pressure and perfusion, such as coronary insufficiency, peripheral vascular disease (e.g., Raynaud's syndrome), cerebrovascular disease, or recent myocardial infarction.
Ischemic Heart Disease
Moderate:guanfacine
guanFACINE has a moderate potential interaction with Ischemic Heart Disease.
Central alpha-2 adrenoreceptor agonists reduce sympathetic outflow from the central nervous system, resulting in decreases in heart rate, peripheral and renovascular resistance, and blood pressure. Therapy with these agents should be administered cautiously in patients with hypotension or conditions that may be exacerbated by decreased blood pressure and perfusion, such as coronary insufficiency, peripheral vascular disease (e.g., Raynaud's syndrome), cerebrovascular disease, or recent myocardial infarction.
Liver Disease
Moderate:clarithromycin
Clarithromycin has a moderate potential interaction with Liver Disease.
Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported in patients receiving clarithromycin. The hepatic dysfunction may be severe but in most cases is reversible. Fatal outcomes have also been reported and in general have been associated with serious underlying diseases and/or concomitant medications. Caution and monitoring is advised if using this drug in patients with hepatic impairment. Treatment must be discontinued immediately if signs and symptoms of hepatitis occur (e.g., anorexia, jaundice, dark urine, pruritus, or tender abdomen). The use of clarithromycin and combination medications containing this antibiotic are contraindicated in patients with a history of cholestatic jaundice or hepatic impairment associated with the prior use of clarithromycin.
Moderate:guanfacine
guanFACINE has a moderate potential interaction with Liver Disease.
Normally, approximately 50% of a guanfacine dose is eliminated unchanged by the kidney and the rest metabolized by the liver. However, neither the parent drug nor its metabolites accumulate significantly during chronic dosing in patients with severe renal impairment due to increased hepatic metabolism of the drug in these patients. Thus, initial dosage adjustments are generally not necessary in renal impairment. Dosage titration, however, should be made cautiously if hepatic function is also compromised. The pharmacokinetics of guanfacine has not been studied in patients with liver disease. The manufacturer recommends caution when the drug is used in such patients.
Magnesium Imbalance
Moderate:clarithromycin
Clarithromycin has a moderate potential interaction with Magnesium Imbalance.
Macrolides have been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Clarithromycin and erythromycin should be avoided in: patients with known prolongation of the QT interval, ventricular cardiac arrhythmia, including torsades de pointes; patients with proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, or receiving other drugs that prolong the QT interval.
Myasthenia Gravis
Moderate:clarithromycin
Clarithromycin has a moderate potential interaction with Myasthenia Gravis.
The use of macrolide antibiotics has been reported to exacerbate symptoms of myasthenia gravis and trigger new onset of symptoms of myasthenic syndrome. Therapy with these agents should be administered cautiously in patients with a history of myasthenia gravis.
Noninfectious Colitis
Major:clarithromycin
Clarithromycin has a major potential interaction with Noninfectious Colitis.
Clostridioides difficile-associated diarrhea (CDAD), formerly pseudomembranous colitis, has been reported with almost all antibacterial drugs and may range from mild diarrhea to fatal colitis. The most common culprits include clindamycin and lincomycin. Antibacterial therapy alters the normal flora of the colon, leading to overgrowth of C difficile, whose toxins A and B contribute to CDAD development. Morbidity and mortality are increased with hypertoxin-producing strains of C difficile; these infections can be resistant to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea after antibacterial use. Since CDAD has been reported to occur more than 2 months after antibacterial use, careful medical history is necessary. Therapy with broad-spectrum antibacterials and other agents with significant antibacterial activity should be administered cautiously in patients with history of gastrointestinal disease, particularly colitis; pseudomembranous colitis (generally characterized by severe, persistent diarrhea and severe abdominal cramps, and sometimes associated with the passage of blood and mucus), if it occurs, may be more severe in these patients and may be associated with flares in underlying disease activity. Antibacterial drugs not directed against C difficile may need to be stopped if CDAD is suspected or confirmed. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C difficile, and surgical evaluation should be started as clinically indicated.
Peripheral Arterial Disease
Moderate:guanfacine
guanFACINE has a moderate potential interaction with Peripheral Arterial Disease.
Central alpha-2 adrenoreceptor agonists reduce sympathetic outflow from the central nervous system, resulting in decreases in heart rate, peripheral and renovascular resistance, and blood pressure. Therapy with these agents should be administered cautiously in patients with hypotension or conditions that may be exacerbated by decreased blood pressure and perfusion, such as coronary insufficiency, peripheral vascular disease (e.g., Raynaud's syndrome), cerebrovascular disease, or recent myocardial infarction.
Renal Dysfunction
Moderate:clarithromycin
Clarithromycin has a moderate potential interaction with Renal Dysfunction.
Clarithromycin is primarily eliminated by the kidney and liver. A decreased dosage or prolonged dosing intervals are recommended in patients with severe renal impairment (CrCl < 30 mL/min). Dosage adjustments are usually not necessary in patients with mild to moderate renal impairment, although drug accumulation could occur in the presence of concomitant liver disease. Monitoring is advised.
Moderate:guanfacine
guanFACINE has a moderate potential interaction with Renal Dysfunction.
Normally, approximately 50% of a guanfacine dose is eliminated unchanged by the kidney and the rest metabolized by the liver. However, neither the parent drug nor its metabolites accumulate significantly during chronic dosing in patients with severe renal impairment due to increased hepatic metabolism of the drug in these patients. Thus, initial dosage adjustments are generally not necessary in renal impairment. Dosage titration, however, should be made cautiously if hepatic function is also compromised. The pharmacokinetics of guanfacine has not been studied in patients with liver disease. The manufacturer recommends caution when the drug is used in such patients.
Sinus Node Dysfunction
Moderate:guanfacine
guanFACINE has a moderate potential interaction with Sinus Node Dysfunction.
Central alpha-2 adrenoreceptor agonists reduce sympathetic outflow from the central nervous system. Heart rate is decreased, which may lead to or exacerbate sinus bradycardia and atrioventricular block. Therapy with central alpha-2 adrenoreceptor agonists should be administered cautiously in patients with conduction disturbances such as sinus node dysfunction or AV nodal disease.
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. |
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Further information
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