Drug Interactions between bismuth subsalicylate / metronidazole / tetracycline and quizartinib

CONTRAINDICATED: Use of alcohol or products containing alcohol during nitroimidazole therapy may result in a disulfiram-like reaction in some patients. There have been a few case reports involving metronidazole, although data overall are not convincing. The presumed mechanism is inhibition of aldehyde dehydrogenase (ALDH) by metronidazole in a manner similar to disulfiram. Following ingestion of alcohol, inhibition of ALDH results in increased concentrations of acetaldehyde, the accumulation of which can produce an unpleasant physiologic response referred to as the 'disulfiram reaction'. Symptoms include flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, weakness, vertigo, blurred vision, and confusion. Severe reactions may result in respiratory depression, cardiovascular collapse, arrhythmia, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death. However, some investigators have questioned the disulfiram-like properties of metronidazole. One study found neither elevations in blood acetaldehyde nor objective or subjective signs of a disulfiram-like reaction to ethanol in six subjects treated with metronidazole (200 mg three times a day for 5 days) compared to six subjects who received placebo.

MANAGEMENT: Because clear evidence is lacking concerning the safety of ethanol use during nitroimidazole therapy, patients should be apprised of the potential for interaction. Consumption of alcoholic beverages and products containing propylene glycol is specifically contraindicated during and for at least 3 days after completion of metronidazole and benznidazole therapy according to their product labeling.

ADJUST DOSING INTERVAL: Administration with food, particularly dairy products, significantly reduces tetracycline absorption. The calcium content in some foods can form nonabsorbable chelates with tetracycline.

MANAGEMENT: Tetracycline should be administered one hour before or two hours after meals. Because oral tetracycline has caused rare cases of esophagitis and esophageal ulceration, patients should be advised to take tetracycline with a large glass of water while standing or sitting upright and to avoid laying down immediately afterwards.

GENERALLY AVOID: The oral bioavailability of quinolone and tetracycline antibiotics may be reduced by concurrent administration of preparations containing polyvalent cations such as aluminum, calcium, iron, magnesium, and zinc. Therapeutic failure may result. The proposed mechanism is chelation of quinolone and tetracycline antibiotics by di- and trivalent cations, forming an insoluble complex that is poorly absorbed from the gastrointestinal tract. Reduced gastrointestinal absorption of the cations should also be considered.

MANAGEMENT: Concomitant administration of oral quinolone and tetracycline antibiotics with preparations containing aluminum, calcium, iron, magnesium, and/or zinc salts should generally be avoided. Otherwise, the times of administration should be staggered by as much as possible to minimize the potential for interaction. Quinolones should typically be dosed either 2 to 4 hours before or 4 to 6 hours after polyvalent cation preparations, depending on the quinolone and formulation. Likewise, tetracyclines and polyvalent cation preparations should typically be administered 2 to 4 hours apart. The prescribing information for the antibiotic should be consulted for more specific dosing recommendations.

The use of nitroimidazoles (e.g., metronidazole, tinidazole) has rarely been associated with hematologic adverse effects such as mild, transient leukopenia, thrombocytopenia, and bone marrow aplasia. The manufacturers recommend that therapy with nitroimidazoles be administered cautiously in patients with evidence of or a history of blood dyscrasias, and that total and differential leukocyte counts be performed before and after treatment with these drugs, particularly in patients receiving repeated courses of therapy.

The use of nitroimidazoles (e.g., metronidazole, tinidazole) has been associated with the development of nervous system toxicity including convulsive seizures and dose-related peripheral neuropathy, the latter characterized primarily by numbness or paresthesia of an extremity. Persistent peripheral neuropathy has been reported in some patients treated for prolonged periods. Other neurologic adverse effects include vertigo, incoordination, ataxia, confusion, agitation, hallucinations, and depression. Therapy with nitroimidazoles should be administered cautiously in patients with or predisposed to seizures or other nervous system abnormalities. Nitroimidazole therapy should be discontinued promptly if neurologic disturbances occur.

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.

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.

Quizartinib prolongs the QT interval in a dose and concentration dependent manner. Due to the serious risk of QTc prolongation, quizartinib is contraindicated in patients with long QT syndrome, a history of ventricular arrhythmias or torsades de points, severe hypokalemia, or severe hypomagnesemia. Additionally, avoid use in patients who are at significant risk of developing torsades de pointes, including uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, tachyarrhythmias, uncontrolled hypertension, high-degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism. Perform an ECG and correct electrolyte abnormalities before and during treatment as indicated, especially in high-risk patients or during concomitant use with strong CYP450 3A4 inhibitors or drugs known to prolong the QT interval. Do not initiate or escalate therapy in patients with QTcF interval greater than 450 ms; dose adjustments based on QTcF interval may be required.

The use of nitroimidazoles (e.g., metronidazole, tinidazole) has rarely been associated with hematologic adverse effects such as mild, transient leukopenia, thrombocytopenia, and bone marrow aplasia. The manufacturers recommend that therapy with nitroimidazoles be administered cautiously in patients with evidence of or a history of blood dyscrasias, and that total and differential leukocyte counts be performed before and after treatment with these drugs, particularly in patients receiving repeated courses of therapy.

Quizartinib prolongs the QT interval in a dose and concentration dependent manner. Due to the serious risk of QTc prolongation, quizartinib is contraindicated in patients with long QT syndrome, a history of ventricular arrhythmias or torsades de points, severe hypokalemia, or severe hypomagnesemia. Additionally, avoid use in patients who are at significant risk of developing torsades de pointes, including uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, tachyarrhythmias, uncontrolled hypertension, high-degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism. Perform an ECG and correct electrolyte abnormalities before and during treatment as indicated, especially in high-risk patients or during concomitant use with strong CYP450 3A4 inhibitors or drugs known to prolong the QT interval. Do not initiate or escalate therapy in patients with QTcF interval greater than 450 ms; dose adjustments based on QTcF interval may be required.

Quizartinib prolongs the QT interval in a dose and concentration dependent manner. Due to the serious risk of QTc prolongation, quizartinib is contraindicated in patients with long QT syndrome, a history of ventricular arrhythmias or torsades de points, severe hypokalemia, or severe hypomagnesemia. Additionally, avoid use in patients who are at significant risk of developing torsades de pointes, including uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, tachyarrhythmias, uncontrolled hypertension, high-degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism. Perform an ECG and correct electrolyte abnormalities before and during treatment as indicated, especially in high-risk patients or during concomitant use with strong CYP450 3A4 inhibitors or drugs known to prolong the QT interval. Do not initiate or escalate therapy in patients with QTcF interval greater than 450 ms; dose adjustments based on QTcF interval may be required.

Quizartinib prolongs the QT interval in a dose and concentration dependent manner. Due to the serious risk of QTc prolongation, quizartinib is contraindicated in patients with long QT syndrome, a history of ventricular arrhythmias or torsades de points, severe hypokalemia, or severe hypomagnesemia. Additionally, avoid use in patients who are at significant risk of developing torsades de pointes, including uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, tachyarrhythmias, uncontrolled hypertension, high-degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism. Perform an ECG and correct electrolyte abnormalities before and during treatment as indicated, especially in high-risk patients or during concomitant use with strong CYP450 3A4 inhibitors or drugs known to prolong the QT interval. Do not initiate or escalate therapy in patients with QTcF interval greater than 450 ms; dose adjustments based on QTcF interval may be required.

The use of salicylates, primarily aspirin, in children with varicella infections or influenza-like illnesses has been associated with an increased risk of Reye's syndrome. Although a causal relationship has not been established, the majority of evidence to date seems to support the association. Most authorities, including the American Academy of Pediatrics Committee on Infectious Diseases, recommend avoiding the use of salicylates in children and teenagers with known or suspected varicella or influenza and during presumed outbreaks of influenza. If antipyretic or analgesic therapy is indicated under these circumstances, acetaminophen may be an appropriate alternative. The same precautions should also be observed with related agents such as salicylamide or diflunisal because of their structural and pharmacological similarities to salicylate.

Quizartinib prolongs the QT interval in a dose and concentration dependent manner. Due to the serious risk of QTc prolongation, quizartinib is contraindicated in patients with long QT syndrome, a history of ventricular arrhythmias or torsades de points, severe hypokalemia, or severe hypomagnesemia. Additionally, avoid use in patients who are at significant risk of developing torsades de pointes, including uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, tachyarrhythmias, uncontrolled hypertension, high-degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism. Perform an ECG and correct electrolyte abnormalities before and during treatment as indicated, especially in high-risk patients or during concomitant use with strong CYP450 3A4 inhibitors or drugs known to prolong the QT interval. Do not initiate or escalate therapy in patients with QTcF interval greater than 450 ms; dose adjustments based on QTcF interval may be required.

The use of nitroimidazoles (e.g., metronidazole, tinidazole) has been associated with the development of nervous system toxicity including convulsive seizures and dose-related peripheral neuropathy, the latter characterized primarily by numbness or paresthesia of an extremity. Persistent peripheral neuropathy has been reported in some patients treated for prolonged periods. Other neurologic adverse effects include vertigo, incoordination, ataxia, confusion, agitation, hallucinations, and depression. Therapy with nitroimidazoles should be administered cautiously in patients with or predisposed to seizures or other nervous system abnormalities. Nitroimidazole therapy should be discontinued promptly if neurologic disturbances occur.

The use of salicylates, primarily aspirin, in children with varicella infections or influenza-like illnesses has been associated with an increased risk of Reye's syndrome. Although a causal relationship has not been established, the majority of evidence to date seems to support the association. Most authorities, including the American Academy of Pediatrics Committee on Infectious Diseases, recommend avoiding the use of salicylates in children and teenagers with known or suspected varicella or influenza and during presumed outbreaks of influenza. If antipyretic or analgesic therapy is indicated under these circumstances, acetaminophen may be an appropriate alternative. The same precautions should also be observed with related agents such as salicylamide or diflunisal because of their structural and pharmacological similarities to salicylate.

Nitroimidazoles (e.g., metronidazole, tinidazole, fexinidazole, secnidazole) may inhibit alcohol dehydrogenase and occasionally precipitate a disulfiram-like reaction in patients who consume alcohol while being treated. Symptoms may include abdominal cramps, nausea, vomiting, headache, flushing, rash, weakness, diarrhea, abdominal pain, dizziness, sweating, and hypotension. Patients should be instructed to avoid alcohol-containing products during nitroimidazole therapy and for at least 48 hours (fexinidazole, secnidazole) to 72 hours (metronidazole, tinidazole) after the last dose. Therapy with nitroimidazoles should be administered cautiously in patients who might be prone to acute alcohol intake. An alternative therapy may be appropriate.

All salicylates can interfere with the action of vitamin K and induce a dose-dependent alteration in hepatic synthesis of coagulation factors VII, IX and X. At usual recommended dosages, a slight increase in prothrombin time (PT) may occur. Therapy with salicylates, especially if given in high dosages, should be administered cautiously in patients with significant active bleeding or a hemorrhagic diathesis, including hemostatic and/or coagulation defects associated with hemophilia, vitamin K deficiency, hypoprothombinemia, thrombocytopenia, thrombocytopathy, or severe hepatic impairment. The same precaution should also be observed with the use of related agents such as salicylamide because of their structural and pharmacological similarities to salicylate.

All salicylates can interfere with the action of vitamin K and induce a dose-dependent alteration in hepatic synthesis of coagulation factors VII, IX and X. At usual recommended dosages, a slight increase in prothrombin time (PT) may occur. Therapy with salicylates, especially if given in high dosages, should be administered cautiously in patients with significant active bleeding or a hemorrhagic diathesis, including hemostatic and/or coagulation defects associated with hemophilia, vitamin K deficiency, hypoprothombinemia, thrombocytopenia, thrombocytopathy, or severe hepatic impairment. The same precaution should also be observed with the use of related agents such as salicylamide because of their structural and pharmacological similarities to salicylate.

Flagyl I.V. RTU (brand of metronidazole ready-to-use injection) contains 14 mEq of sodium per each 500 mg dose of metronidazole. The sodium content should be considered when this product is used in patients with conditions that may require sodium restriction, such as congestive heart failure, hypertension, and fluid retention.

The use of oral tetracycline capsules and tablets has been associated with esophageal irritation and ulceration in patients who ingested the drug without sufficient fluid shortly before bedtime. Therapy with solid formulations of tetracyclines should preferably be avoided in patients with esophageal obstruction, compression or dyskinesia. If the drugs are used, patients should be advised not to take the medication just before retiring and to drink fluids liberally.

Flagyl I.V. RTU (brand of metronidazole ready-to-use injection) contains 14 mEq of sodium per each 500 mg dose of metronidazole. The sodium content should be considered when this product is used in patients with conditions that may require sodium restriction, such as congestive heart failure, hypertension, and fluid retention.

Metronidazole and its metabolites are moderately removed by hemodialysis. Doses should either be scheduled for administration after dialysis or supplemental doses be given after dialysis.

Flagyl I.V. RTU (brand of metronidazole ready-to-use injection) contains 14 mEq of sodium per each 500 mg dose of metronidazole. The sodium content should be considered when this product is used in patients with conditions that may require sodium restriction, such as congestive heart failure, hypertension, and fluid retention.

Flagyl I.V. RTU (brand of metronidazole ready-to-use injection) contains 14 mEq of sodium per each 500 mg dose of metronidazole. The sodium content should be considered when this product is used in patients with conditions that may require sodium restriction, such as congestive heart failure, hypertension, and fluid retention.

Midostaurin and quizartinib should be used with caution in patients with severe hepatic or severe renal dysfunction as the pharmacokinetics of these agents have not been studied in these patients. No dosage adjustments are recommended in patients with mild or moderate hepatic or renal dysfunction.

Metronidazole is extensively metabolized by the liver to both pharmacologically active and inactive compounds. The plasma clearance of metronidazole may be decreased and the half-life prolonged in patients with impaired hepatic function. Therapy with metronidazole should be administered cautiously at reduced dosages in patients with severe liver disease.

The use of tetracyclines has rarely been associated with hepatotoxicity. Histologic fatty changes of the liver, elevated liver enzymes, and jaundice have been reported, primarily in patients treated with large doses of intravenous tetracycline hydrochloride (no longer available in the U.S.) but also in patients receiving high oral doses of these drugs. Therapy with tetracyclines should be administered cautiously in patients with preexisting liver disease or biliary obstruction. Reduced dosages may be appropriate, particularly with minocycline and doxycycline, since the former is metabolized by the liver and the latter undergoes enterohepatic recycling. Liver function tests are recommended prior to and during therapy, and the concomitant use of other potentially hepatotoxic drugs should be avoided.

Midostaurin and quizartinib should be used with caution in patients with severe hepatic or severe renal dysfunction as the pharmacokinetics of these agents have not been studied in these patients. No dosage adjustments are recommended in patients with mild or moderate hepatic or renal dysfunction.

Tetracyclines (except doxycycline) are eliminated by the kidney to various extent. Patients with renal impairment may be at greater risk for tetracycline-associated hepatic and/or renal toxicity (increased BUN with consequent azotemia, hyperphosphatemia, and acidosis) due to decreased drug clearance. Therapy with tetracyclines should be administered cautiously at reduced dosages in patients with renal impairment. Clinical monitoring of renal and liver function is recommended, and serum tetracycline levels may be necessary during prolonged therapy.

All salicylates can interfere with the action of vitamin K and induce a dose-dependent alteration in hepatic synthesis of coagulation factors VII, IX and X. At usual recommended dosages, a slight increase in prothrombin time (PT) may occur. Therapy with salicylates, especially if given in high dosages, should be administered cautiously in patients with significant active bleeding or a hemorrhagic diathesis, including hemostatic and/or coagulation defects associated with hemophilia, vitamin K deficiency, hypoprothombinemia, thrombocytopenia, thrombocytopathy, or severe hepatic impairment. The same precaution should also be observed with the use of related agents such as salicylamide because of their structural and pharmacological similarities to salicylate.

All salicylates can interfere with the action of vitamin K and induce a dose-dependent alteration in hepatic synthesis of coagulation factors VII, IX and X. At usual recommended dosages, a slight increase in prothrombin time (PT) may occur. Therapy with salicylates, especially if given in high dosages, should be administered cautiously in patients with significant active bleeding or a hemorrhagic diathesis, including hemostatic and/or coagulation defects associated with hemophilia, vitamin K deficiency, hypoprothombinemia, thrombocytopenia, thrombocytopathy, or severe hepatic impairment. The same precaution should also be observed with the use of related agents such as salicylamide because of their structural and pharmacological similarities to salicylate.

All salicylates can interfere with the action of vitamin K and induce a dose-dependent alteration in hepatic synthesis of coagulation factors VII, IX and X. At usual recommended dosages, a slight increase in prothrombin time (PT) may occur. Therapy with salicylates, especially if given in high dosages, should be administered cautiously in patients with significant active bleeding or a hemorrhagic diathesis, including hemostatic and/or coagulation defects associated with hemophilia, vitamin K deficiency, hypoprothombinemia, thrombocytopenia, thrombocytopathy, or severe hepatic impairment. The same precaution should also be observed with the use of related agents such as salicylamide because of their structural and pharmacological similarities to salicylate.