Drug Interaction Report PDF [PDF]

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7/4/2019



Drug Interaction Report - Drugs.com



Drug Interaction Report Drug interactions for the following 61 drug(s):



My Interactions List: (Unsaved) amoxicillin tranexamic acid glimepiride loperamide ibuprofen guaifenesin methylprednisolone omeprazole kaolin / pectin



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aminophylline acyclovir hydrocortisone gentamicin diclofenac ciprofloxacin attapulgite



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amlodipine cefixime https://www.drugs.com/interactions-check.php?drug_list=187-0,2224-0,1176-0,1482-0,1310-0,1200-0,1607-0,1750-0,1410-0,161-0,100-0,2378-…



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lansoprazole dimenhydrinate hyoscyamine metoclopramide acetylcysteine nifedipine captopril sodium bicarbonate glycerin / phenol metformin ketoconazole metronidazole nystatin folic acid allopurinol doxycycline ketoconazole clindamycin chloramphenicol Cotrim (sulfamethoxazole / trimethoprim) albuterol mefenamic acid Aceta (acetaminophen) https://www.drugs.com/interactions-check.php?drug_list=187-0,2224-0,1176-0,1482-0,1310-0,1200-0,1607-0,1750-0,1410-0,161-0,100-0,2378-…



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Almacone (aluminum hydroxide / magnesium hydroxide / simethicone) ranitidine Zinc (zinc sulfate) isosorbide dinitrate chloramphenicol



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acyclovir miconazole



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permethrin Vitamin C (ascorbic acid) Vitamin B12 (cyanocobalamin) Vitamin B1 (thiamine) Vitamin B6 (pyridoxine) Vitamin K (phytonadione) calcium lactate ferrous fumarate / folic acid simvastatin dexamethasone chlorpheniramine loratadine cetirizine



Interactions between your drugs Major



captopril  allopurinol Applies to: captopril, allopurinol



https://www.drugs.com/interactions-check.php?drug_list=187-0,2224-0,1176-0,1482-0,1310-0,1200-0,1607-0,1750-0,1410-0,161-0,100-0,2378-…



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MONITOR CLOSELY: Coadministration of allopurinol with angiotensin converting enzyme (ACE) inhibitors has been associated with a risk of severe hypersensitivity reactions, neutropenia, agranulocytosis, and serious infections. The mechanism of interaction is unknown, but impaired renal function may be a predisposing factor. Case reports, albeit rare, have mostly involved captopril. Fever, myalgia, arthralgia, exfoliative dermatitis, and Stevens-Johnson syndrome (including one fatality) have been reported, with the latter occurring 3 to 5 weeks after initiation of allopurinol. In an isolated case involving enalapril, a man who had been receiving enalapril without incident developed generalized pruritus, urticaria, severe chest pain, severe nausea, peripheral cyanosis, hypotension, sinus tachycardia, and mild bronchospasm approximately 20 minutes after the first dose of allopurinol 100 mg prescribed for acute gout. Serial electrocardiograms and cardiac enzyme studies revealed evidence of acute myocardial infarction. Following recovery, the patient continued to take enalapril uneventfully without allopurinol. No pharmacokinetic interactions have been reported between allopurinol and ACE inhibitors. In a study of 12 healthy volunteers, allopurinol had no significant effect on the bioavailability of captopril. MANAGEMENT: Caution is advised if allopurinol is prescribed in combination with an ACE inhibitor, particularly in the elderly and patients with renal impairment. Periodic monitoring of white blood cell counts is recommended. Patients should be advised to promptly discontinue these medications and seek medical attention if they develop dyspnea; throat constriction; swelling of the face, lips, or tongue; urticaria; rash; fever; arthralgia; or myalgia. Patients should also contact their physician if they notice signs of infection or experience fever, chills, sore throat, lethargy, body aches, or other flu-like symptoms. References 1. Pennell DJ, Nunan TO, O'Doherty MJ, Croft DN "Fatal Stevens-Johnson syndrome in a patient on captopril and allopurinol." Lancet 1 (1984): 463 2. EMEA. European Medicines Agency "EPARs. European Union Public Assessment Reports. Available from: URL: http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landingpage.jsp&mid." 3. Ahmad S "Allopurinol and enalapril: drug induced anaphylactic coronary spasm and acute myocardial infarction." Chest 108 (1995): 586 View all 6 references



Major



captopril  trimethoprim



Applies to: captopril, Cotrim (sulfamethoxazole / trimethoprim)



MONITOR CLOSELY: The use of trimethoprim in combination with other potassium-sparing drugs or potassium salts may increase the risk of hyperkalemia. Trimethoprim inhibits sodium reabsorption and potassium excretion by blocking sodium channels in the renal distal tubules. Studies of patients treated with standard and high dosages of trimethoprim-sulfamethoxazole compared to similar controls treated with other antibiotics indicate that reversible increases in serum potassium are fairly common with trimethoprim use. Although generally asymptomatic, severe hyperkalemia including metabolic acidosis, paralysis, nonoliguric renal failure, and ventricular arrhythmia have been reported. Risk factors for developing hyperkalemia include use of high dosages of trimethoprim (e.g., for the treatment of MRSA skin infections or Pneumocystis jiroveci pneumonia (PCP) in AIDS patients); renal impairment or age-related decline in renal function; aldosterone or adrenal insufficiency; concomitant use of drugs that increase the risk of hyperkalemia (e.g., ACE inhibitors, angiotensin II receptor blockers, aldosterone antagonists; potassium-sparing diuretics); diets with potassium-rich foods (e.g., tomatoes, raisins, figs, baked potatoes, bananas, papayas, pears, cantaloupe, mangoes); and use of potassium salt substitutes. MANAGEMENT: Serum potassium and sodium levels as well as renal function should be closely monitored during coadministration of trimethoprim with other potassium-sparing drugs or https://www.drugs.com/interactions-check.php?drug_list=187-0,2224-0,1176-0,1482-0,1310-0,1200-0,1607-0,1750-0,1410-0,161-0,100-0,2378-…



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potassium salts, particularly in patients receiving high-dose or long-term trimethoprim treatment and in patients with renal impairment, diabetes, old age, severe or worsening heart failure, or dehydration. A dosage reduction of trimethoprim is recommended in renal dysfunction (50% reduction for CrCl between 15 and 30 mL/min). Patients should be given dietary counseling to avoid excessive intake of potassium-rich foods and salt substitutes, and advised to seek medical attention if they experience signs and symptoms of hyperkalemia such as nausea, vomiting, weakness, listlessness, tingling of the extremities, paralysis, confusion, weak pulse, and a slow or irregular heartbeat. Trimethoprim should be discontinued if hyperkalemia occurs. References 1. Canaday DH, Johnson JR "Hyperkalemia in elderly patients receiving standard doses of trimethoprim-sulfamethoxazole." Ann Intern Med 120 (1994): 438 2. Alappan R, Perazella MA, Buller GK "Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole." Ann Intern Med 124 (1996): 316-20 3. Witt JM, Koo JM, Danielson BD "Effect of standard-dose trimethoprim/sulfamethoxazole on the serum potassium concentration in elderly men." Ann Pharmacother 30 (1996): 347-50 View all 33 references



Major



ciprofloxacin  methylPREDNISolone Applies to: ciprofloxacin, methylprednisolone



MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy. MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks. References 1. Khaliq Y, Zhanel GG "Fluoroquinolone-Associated Tendinopathy: A Critical Review of the Literature." Clin Infect Dis 36 (2003): 1404-1410 2. van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Stricker BH "Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids." Arch Intern Med 163 (2003): 1801-7 3. "Product Information. Cipro (ciprofloxacin)." Bayer, West Haven, CT. View all 7 references



Major



ciprofloxacin  glimepiride Applies to: ciprofloxacin, glimepiride



MONITOR CLOSELY: Quinolone antibiotics may interfere with the therapeutic effects of insulin and other antidiabetic agents. The use of quinolones has been associated with disturbances in blood glucose homeostasis possibly stemming from effects on pancreatic beta cell ATP-sensitive potassium channels that regulate insulin secretion. Both hyperglycemia and hypoglycemia have been reported, https://www.drugs.com/interactions-check.php?drug_list=187-0,2224-0,1176-0,1482-0,1310-0,1200-0,1607-0,1750-0,1410-0,161-0,100-0,2378-…



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usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent or insulin. Although hyperglycemia is significantly more common and infection itself may be an underlying risk factor, hypoglycemia may cause greater morbidity and mortality. An internal safety review conducted by the U.S. Food and Drug Administration (FDA) identified at least 67 reports of severe hypoglycemia associated with quinolone use resulting in coma, death, or permanent and disabling injuries, primarily in elderly and diabetic patients with renal impairment and/or complicated infections. This is in addition to the numerous cases that have been reported for gatifloxacin, which led to its withdrawal from the U.S. market in 2008. Of the five quinolones that the FDA reviewed, levofloxacin had the most cases (44), followed by ciprofloxacin (12), moxifloxacin (9), ofloxacin (2), and gemifloxacin (0). Other quinolones such as nalidixic acid and norfloxacin, as well as some others that have never been marketed or are no longer marketed such as clinafloxacin and temafloxacin, have also been associated with dysglycemia, thus it is generally believed to be a class effect, albeit with varying risks amongst the individual agents. Available data also seem to indicate different time frames for the development of hypo- and hyperglycemia, with the former generally occurring within 1 to 3 days following quinolone initiation and the latter within 4 to 10 days later. Pharmacokinetically, ciprofloxacin is also a known inhibitor of CYP450 1A2 and 3A4 and may inhibit the hepatic metabolism of glyburide. Hypoglycemia in association with elevated serum glyburide level occurred in a patient after one week of ciprofloxacin therapy. MANAGEMENT: Blood glucose should be closely monitored whenever quinolones are prescribed to diabetic patients, especially if they are elderly, have renal impairment, or are severely ill. Due to the risk of profound and potentially life-threatening hypoglycemia, particular caution is advised during concomitant use of insulin and insulin secretagogues (e.g., sulfonylureas, meglitinides). Patients should also be apprised of the increased risk of hypoglycemia and be alert to potential signs and symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia. If hypoglycemia occurs, patients should initiate appropriate remedial therapy immediately, discontinue the quinolone, and contact their physician. Alternative antibiotics may need to be considered. References 1. "Product Information. Cipro (ciprofloxacin)." Bayer, West Haven, CT. 2. Park-Wyllie LY, Juurlink DN, Kopp A, et al. "Outpatient gatifloxacin therapy and dysglycemia in older adults." N Engl J Med 354 (2006): 1352-61 3. Saraya A, Yokokura M, Gonoi T, Seino S "Effects of fluoroquinolones on insulin secretion and beta-cell ATP-sensitive K(+) channels." Eur J Pharmacol 497 (2004): 111-7 View all 40 references



Major



ciprofloxacin  aminophylline Applies to: ciprofloxacin, aminophylline



GENERALLY AVOID: Coadministration with ciprofloxacin may significantly increase the serum concentrations of theophylline and the associated risk of toxicity. The mechanism is ciprofloxacin inhibition of theophylline metabolism via CYP450 1A2. Case reports and pharmacokinetic studies indicate that ciprofloxacin 500 mg to 750 mg twice daily can reduce the clearance of theophylline by approximately 20% to 65%, resulting in toxic theophylline levels and/or clinical toxicity in some patients. Up to fourfold increases in theophylline serum levels have been reported, with onset of clinical toxicity as early as two to three days and typically within a week of initiating ciprofloxacin. However, the interaction is subject to a high degree of interpatient variability and does not consistently produce clinically significant pharmacokinetic changes. Serious and severe reactions have included cardiac arrest, seizure, status epilepticus, respiratory failure, and even death. Seizures may also occur in the absence of toxic theophylline levels due to additive inhibitory effect of ciprofloxacin https://www.drugs.com/interactions-check.php?drug_list=187-0,2224-0,1176-0,1482-0,1310-0,1200-0,1607-0,1750-0,1410-0,161-0,100-0,2378-…



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and theophylline on gamma-aminobutyric acid (GABA) receptor sites. Because elderly patients and patients with chronic obstructive pulmonary disease, congestive heart failure, or cirrhosis generally have lower theophylline clearance rates, they may be particularly vulnerable to theophylline toxicity. Theophylline does not appear to alter the pharmacokinetics of ciprofloxacin and other quinolones. MANAGEMENT: The use of theophylline or its salts in combination with ciprofloxacin should generally be avoided. If coadministration is required, theophylline dosage may need to be reduced. Pharmacologic response and serum levels should be closely monitored following initiation, discontinuation or change of dosage of ciprofloxacin, and the theophylline dosage adjusted accordingly. Patients should be advised to contact their physician if they experience signs and symptoms suggestive of theophylline toxicity such as nausea, vomiting, diarrhea, anorexia, headache, tremor, irritability, confusion, insomnia, seizure, palpitation, and arrhythmia. Other quinolones including gemifloxacin, levofloxacin, moxifloxacin, and ofloxacin have been reported to cause minor or no changes in theophylline levels at normally recommended dosages and may be safer alternatives in theophylline-treated patients. References 1. Wijnands WJ, Vree TB "Interaction between the fluoroquinolones and the bronchodilator theophylline." J Antimicrob Chemother 22 (1988): 109-14 2. Davis RL, Quenzer RW, Kelly HW, Powell JR "Effect of the addition of ciprofloxacin on theophylline pharmacokinetics in subjects inhibited by cimetidine." Ann Pharmacother 26 (1992): 11-3 3. Bem JL, Mann RD "Danger of interaction between ciprofloxacin and theophylline." Br Med J (Clin Res Ed) 296 (1988): 1131 View all 29 references



Major



ciprofloxacin  dexamethasone Applies to: ciprofloxacin, dexamethasone



MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy. MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks. References 1. Khaliq Y, Zhanel GG "Fluoroquinolone-Associated Tendinopathy: A Critical Review of the Literature." Clin Infect Dis 36 (2003): 1404-1410 2. van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Stricker BH "Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids." Arch Intern Med 163 (2003): 1801-7 3. "Product Information. Cipro (ciprofloxacin)." Bayer, West Haven, CT. View all 7 references



https://www.drugs.com/interactions-check.php?drug_list=187-0,2224-0,1176-0,1482-0,1310-0,1200-0,1607-0,1750-0,1410-0,161-0,100-0,2378-…



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Major



Drug Interaction Report - Drugs.com



raNITIdine  loperamide Applies to: ranitidine, loperamide



MONITOR CLOSELY: Coadministration with drugs that enhance the gastrointestinal absorption or inhibit the metabolism of loperamide (e.g., potent CYP450 3A4 or 2C8 inhibitors) may increase the plasma concentrations and adverse effects of loperamide. When a single 16 mg dose of loperamide was administered to 12 healthy volunteers with a single 600 mg dose of ritonavir, a potent CYP450 3A4 inhibitor, median loperamide systemic exposure (AUC) increased by 223% compared to administration with placebo. Likewise, administration of a single 4 mg dose of loperamide to 12 healthy volunteers on day 3 of treatment with the potent CYP450 2C8 inhibitor gemfibrozil (600 mg twice day for 5 days) increased loperamide peak plasma concentration (Cmax) and AUC by 1.6- and 2.2-fold, respectively, and prolonged its elimination half-life from 11.9 to 16.7 hours. The same study also found that gemfibrozil had substantial additive effects with itraconazole, a strong CYP450 3A4 and P-glycoprotein inhibitor, on the pharmacokinetics of loperamide. Whereas itraconazole (100 mg twice daily for 5 days) alone increased the Cmax and AUC of loperamide by 2.9- and 3.8-fold, respectively, gemfibrozil combined with itraconazole increased loperamide Cmax and AUC by 4.2and 12.6-fold, respectively. The elimination half-life of loperamide was 18.7 hours during coadministration of itraconazole, compared to 36.9 hours during coadministration of gemfibrozil plus itraconazole. High levels of loperamide, including through abuse or misuse, has been associated with serious and potentially fatal cardiac adverse events such as syncope, cardiac arrest, and arrhythmia related to prolongation of the QT interval. According to the FDA, the agency received reports of 48 cases of serious heart problems associated with use of loperamide from when it was first approved in 1976 through 2015. Thirty-one of these cases resulted in hospitalizations, and 10 patients died. The serious heart problems occurred mostly in patients who were using loperamide dosages that were much higher than recommended in an attempt to achieve euphoria, prevent opioid withdrawal, or treat diarrhea. In the most severe cases, individuals self-treated with dosages ranging from 70 to 1600 mg/day, or 4 to 100 times the recommended dosage. In other cases, patients were taking the recommended dosage, but with concomitant interacting drugs that caused an increase in loperamide levels. There have been additional cases of serious heart problems associated with loperamide use reported in the medical literature. MANAGEMENT: Caution is recommended if loperamide is used with drugs that enhance its gastrointestinal absorption or inhibit its metabolism. Particular caution is advised when drugs that inhibit CYP450 3A4 (e.g., azole antifungal agents, clarithromycin, cobicistat, conivaptan, delavirdine, erythromycin, idelalisib, nefazodone, protease inhibitors, telithromycin) and CYP450 2C8 (e.g., gemfibrozil, clopidogrel) are used together with loperamide, or when one or more of these drugs are combined with inhibitors of P-glycoprotein transport (e.g., amiodarone, cyclosporine, diltiazem, dronedarone, quinidine, verapamil), since they may act synergistically to increase loperamide concentrations. Patients should be counseled to not exceed the recommended dosage and frequency or duration of use of loperamide, and 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. If loperamide-induced cardiotoxicity is suspected, promptly discontinue loperamide and initiate therapy to manage and prevent cardiac arrhythmias and adverse outcomes. Electrical pacing or cardioversion may be necessary if torsade de pointes persists despite pharmacotherapy. In many of the reported cases of loperamide-induced cardiotoxicity, standard antiarrhythmic drugs were ineffective, and electrical pacing or cardioversion was necessary. References 1. Tayrouz Y, Ganssmann B, Ding R, et al. "Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement." Clin Pharmacol Ther 70 (2001): 405-14 2. Eggleston W, Clark KH, Marraffa JM "Loperamide abuse associated with cardiac dysrhythmia and death." Ann Emerg Med 69 (2017): 83-6



https://www.drugs.com/interactions-check.php?drug_list=187-0,2224-0,1176-0,1482-0,1310-0,1200-0,1607-0,1750-0,1410-0,161-0,100-0,2378-…



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3. "Product Information. Imodium (loperamide)." Janssen Pharmaceutica, Titusville, NJ. View all 6 references



Major



ketoconazole  methylPREDNISolone Applies to: ketoconazole, methylprednisolone



ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of methylprednisolone. Various CYP450 3A4 inhibitors including clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, mibefradil, nefazodone, and troleandomycin have been shown to increase methylprednisolone systemic exposure (AUC) by approximately 100% to 300%, with increased adrenal suppression as evidenced by reduced plasma cortisol levels. MANAGEMENT: The possibility of increased corticosteroid effects should be considered when methylprednisolone is used with potent CYP450 3A4 inhibitors. Coadministration is not recommended unless the potential benefit to the patient outweighs the risk. If concomitant use is necessary, a 50% reduction in methylprednisolone dosage has been recommended by some investigators. Patients should be monitored for signs and symptoms of hypercorticism such as acne, striae, thinning of the skin, easy bruising, moon facies, dorsocervical "buffalo" hump, truncal obesity, increased appetite, acute weight gain, edema, hypertension, hirsutism, hyperhidrosis, proximal muscle wasting and weakness, glucose intolerance, exacerbation of preexisting diabetes, depression, and menstrual disorders. Other systemic glucocorticoid effects may include adrenal suppression, immunosuppression, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation in children and adolescents. Following extensive use with a potent CYP450 3A4 inhibitor, a progressive dosage reduction may be required over a longer period if methylprednisolone is to be withdrawn from therapy, as there may be a significant risk of adrenal suppression. Signs and symptoms of adrenal insufficiency include anorexia, hypoglycemia, nausea, vomiting, weight loss, muscle wasting, fatigue, weakness, dizziness, postural hypotension, depression, and adrenal crisis manifested as inability to respond to stress (e.g., illness, infection, surgery, trauma). References 1. Varis T, Backman JT, Kivisto KT, Neuvonen PJ "Diltiazem and mibefradil increase the plasma concentrations and greatly enhance the adrenalsuppressant effect of oral methylprednisolone." Clin Pharmacol Ther 67 (2000): 215-21 2. Varis T, Kaukonen KM, Kivisto KT, Neuvonen PJ "Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole." Clin Pharmacol Ther 64 (1998): 363-8 3. Agencia Española de Medicamentos y Productos Sanitarios Healthcare "Centro de información online de medicamentos de la AEMPS - CIMA. Available from: URL: https://cima.aemps.es/cima/publico/home.html." ([2018]): View all 8 references



Major



ketoconazole  loperamide Applies to: ketoconazole, loperamide



MONITOR CLOSELY: Coadministration with drugs that enhance the gastrointestinal absorption or inhibit the metabolism of loperamide (e.g., potent CYP450 3A4 or 2C8 inhibitors) may increase the plasma concentrations and adverse effects of loperamide. When a single 16 mg dose of loperamide was administered to 12 healthy volunteers with a single 600 mg dose of ritonavir, a potent CYP450 3A4 inhibitor, median loperamide systemic exposure (AUC) increased by 223% compared to administration with placebo. Likewise, administration of a single 4 mg dose of loperamide to 12 healthy volunteers on day 3 of treatment with the potent CYP450 2C8 inhibitor gemfibrozil (600 mg twice day for 5 days) increased loperamide peak plasma concentration (Cmax) and AUC by 1.6- and https://www.drugs.com/interactions-check.php?drug_list=187-0,2224-0,1176-0,1482-0,1310-0,1200-0,1607-0,1750-0,1410-0,161-0,100-0,2378-…



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2.2-fold, respectively, and prolonged its elimination half-life from 11.9 to 16.7 hours. The same study also found that gemfibrozil had substantial additive effects with itraconazole, a strong CYP450 3A4 and P-glycoprotein inhibitor, on the pharmacokinetics of loperamide. Whereas itraconazole (100 mg twice daily for 5 days) alone increased the Cmax and AUC of loperamide by 2.9- and 3.8-fold, respectively, gemfibrozil combined with itraconazole increased loperamide Cmax and AUC by 4.2and 12.6-fold, respectively. The elimination half-life of loperamide was 18.7 hours during coadministration of itraconazole, compared to 36.9 hours during coadministration of gemfibrozil plus itraconazole. High levels of loperamide, including through abuse or misuse, has been associated with serious and potentially fatal cardiac adverse events such as syncope, cardiac arrest, and arrhythmia related to prolongation of the QT interval. According to the FDA, the agency received reports of 48 cases of serious heart problems associated with use of loperamide from when it was first approved in 1976 through 2015. Thirty-one of these cases resulted in hospitalizations, and 10 patients died. The serious heart problems occurred mostly in patients who were using loperamide dosages that were much higher than recommended in an attempt to achieve euphoria, prevent opioid withdrawal, or treat diarrhea. In the most severe cases, individuals self-treated with dosages ranging from 70 to 1600 mg/day, or 4 to 100 times the recommended dosage. In other cases, patients were taking the recommended dosage, but with concomitant interacting drugs that caused an increase in loperamide levels. There have been additional cases of serious heart problems associated with loperamide use reported in the medical literature. MANAGEMENT: Caution is recommended if loperamide is used with drugs that enhance its gastrointestinal absorption or inhibit its metabolism. Particular caution is advised when drugs that inhibit CYP450 3A4 (e.g., azole antifungal agents, clarithromycin, cobicistat, conivaptan, delavirdine, erythromycin, idelalisib, nefazodone, protease inhibitors, telithromycin) and CYP450 2C8 (e.g., gemfibrozil, clopidogrel) are used together with loperamide, or when one or more of these drugs are combined with inhibitors of P-glycoprotein transport (e.g., amiodarone, cyclosporine, diltiazem, dronedarone, quinidine, verapamil), since they may act synergistically to increase loperamide concentrations. Patients should be counseled to not exceed the recommended dosage and frequency or duration of use of loperamide, and 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. If loperamide-induced cardiotoxicity is suspected, promptly discontinue loperamide and initiate therapy to manage and prevent cardiac arrhythmias and adverse outcomes. Electrical pacing or cardioversion may be necessary if torsade de pointes persists despite pharmacotherapy. In many of the reported cases of loperamide-induced cardiotoxicity, standard antiarrhythmic drugs were ineffective, and electrical pacing or cardioversion was necessary. References 1. Tayrouz Y, Ganssmann B, Ding R, et al. "Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement." Clin Pharmacol Ther 70 (2001): 405-14 2. Eggleston W, Clark KH, Marraffa JM "Loperamide abuse associated with cardiac dysrhythmia and death." Ann Emerg Med 69 (2017): 83-6 3. "Product Information. Imodium (loperamide)." Janssen Pharmaceutica, Titusville, NJ. View all 6 references



Major



ketoconazole  simvastatin Applies to: ketoconazole, simvastatin



CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of lovastatin and simvastatin as well as their pharmacologically active metabolites, all of which are primarily metabolized by the isoenzyme. The interaction has been https://www.drugs.com/interactions-check.php?drug_list=187-0,2224-0,1176-0,1482-0,1310-0,1200-0,1607-0,1750-0,1410-0,161-0,100-0,237…



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Drug Interaction Report - Drugs.com



reported with potent CYP450 3A4 inhibitors such as azole antifungal agents, macrolide antibiotics, HIV protease inhibitors, and nefazodone. Clinically, high levels of HMG-CoA reductase inhibitory activity in plasma may be associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death. MANAGEMENT: Due to the potential for severe interaction, concomitant use of lovastatin or simvastatin with potent CYP450 3A4 inhibitors is considered contraindicated. Red yeast rice, which contains lovastatin, should also be avoided during treatment with a potent CYP450 3A4 inhibitor. Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are probably safer alternatives, since they are not metabolized by CYP450 3A4. All patients treated with HMG-CoA reductase inhibitors should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. References 1. Neuvonen PJ, Kantola T, Kivisto KT "Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole." Clin Pharmacol Ther 63 (1998): 332-41 2. Akram K, Rao S, Parker M "A lesson for everyone in drug-drug interactions." Int J Cardiol 118 (2007): e19-20 3. Horn M "Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals." Arch Dermatol 132 (1996): 1254 View all 14 references



Major



miconazole  glimepiride Applies to: miconazole, glimepiride



MONITOR CLOSELY: Coadministration with inhibitors of CYP450 2C9 including certain azole antifungal agents such as fluconazole, miconazole, and voriconazole may increase the plasma concentrations of sulfonylureas, many of which have been found to be substrates of the isoenzyme. Pharmacokinetic data are available for single-dose administration of chlorpropamide (250 mg), tolbutamide (500 mg), glipizide (2.5 mg), glyburide (5 mg), and glimepiride (0.5 mg) in combination with fluconazole. In healthy study subjects, fluconazole 100 mg daily for 7 days increased the singledose systemic exposures (AUCs) of various sulfonylureas by an average of nearly 30% (chlorpropamide, tolbutamide) to almost 50% (glipizide, glyburide). Mean changes in blood glucose levels were not statistically significant in these studies, although approximately 48% of patients treated with fluconazole experienced symptoms consistent with hypoglycemia compared to 40% of patients treated with placebo. One in four of the fluconazole-treated patients in the glyburide study also required oral glucose. A higher dosage of fluconazole (400 mg for one day, followed by 200 mg daily for 3 days) increased single-dose glimepiride AUC by 138% and prolonged its half-life from 2.0 to 3.3 hours in healthy volunteers. In another study, low-dose fluconazole (50 mg/day) given to treat vulvovaginal candidiasis in 14 postmenopausal diabetic women receiving gliclazide or glyburide therapy demonstrated no effect on blood glucose control; pharmacokinetic data were not included. Based on available data, fluconazole use does not appear to be associated with a significant risk of severe hypoglycemia at dosages