Bismuth-Metronidazole-Tetracyc (colloidal bismuth subcitrate/metronidazole/tetracycline HCl)

Dosage of tetracycline and tetracycline hydrochloride is expressed in terms of tetracycline hydrochloride.

If tetracycline is used in patients with impaired renal function, doses and/or frequency of administration must be modified in response to the degree of renal impairment.

Metronidazole is administered orally or by continuous or intermittent IV infusion.

Cytochrome P-450 (CYP) isoenzymes, including CYP3A, CYP2E1, and CYP2A6, are involved in the metabolism of metronidazole.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antimicrobials/Live Typhoid Vaccine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Metronidazole/Mebendazole

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The exact mechanism is unknown. Both mebendazole and metronidazole have been documented to cause Stevens-Johnson syndrome/toxic epidermal necrolysis. Concurrent use may result in additive or synergistic risk.(1)

CLINICAL EFFECTS: Concurrent use of mebendazole and metronidazole may increase the risk of Stevens-Johnson syndrome/toxic epidermal necrolysis.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian manufacturer of mebendazole states that concurrent use of metronidazole should be avoided.(2) If concurrent use is warranted, monitor patients closely for signs and symptoms of Stevens-Johnson syndrome/toxic epidermal necrolysis. Instruct patients to discontinue therapy and seek medical attention for any peeling skin rash or blisters.

DISCUSSION: In a retrospective review, 46 cases of Stevens-Johnson syndrome/toxic epidermal necrolysis that were reported to the Taiwan Department of Health for the period between February, 1996 and February, 1997 were matched to 2 case controls each. The odds ratio for developing Stevens-Johnson syndrome/toxic epidermal necrolysis was 9.5 among subjects who had used both metronidazole and mebendazole in the preceding 6 weeks. All 46 workers were Filipino. Following a change in practice in the Philippines that stopped routine prescription of anthelmintic drugs to workers going abroad, no new cases were reported.(1)

Metronidazole; Tinidazole/Propylene Glycol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Metronidazole(1) and tinidazole(2) inhibit the alcohol and aldehyde dehydrogenase pathway, which is responsible for the metabolism of propylene glycol.(1,2)

CLINICAL EFFECTS: The concurrent administration of metronidazole(1) and tinidazole(2) may result in the accumulation of propylene glycol, which may result in adverse effects such as seizures, stupor, tachycardia, hyperosmolality, lactic acidosis, renal toxicity, and hemolysis.

PREDISPOSING FACTORS: Certain ethnic populations (Asians, Eskimos, and Native Americans) and women may have a decreased ability to metabolize propylene glycol.(1,2)

PATIENT MANAGEMENT: Patients should be advised of the possible affects that may result from ingestion or application of products that contain propylene glycol while taking metronidazole or tinidazole.(1,2) Patients receiving metronidazole or tinidazole should be instructed to avoid products containing propylene glycol during and for 3 days after taking metronidazole or tinidazole.(1,2) Patients should be informed about unsuspected sources of propylene glycol such as elixirs and topical preparations. Caution is also warranted when using intravenous preparations containing propylene glycol solvents in patients receiving metronidazole or tinidazole.

DISCUSSION: Concurrent use of products that contain propylene glycol may cause a disulfiram-like reaction to alcohol when used with metronidazole or tinidazole.

Oral Tetracyclines/Strontium Ranelate

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strontium may form a complex with oral tetracyclines, preventing their absorption.(1,2)

CLINICAL EFFECTS: Simultaneous administration of strontium with oral tetracyclines may result in decreased levels and effectiveness of the tetracycline.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK(1) and US(2) manufacturers of strontium states that strontium therapy should be suspended during the treatment with an oral tetracycline.

DISCUSSION: Divalent cations such as strontium can form complexes with oral tetracyclines.(1,2)

Selected Nitroimidazole Antimicrobials/Disulfiram

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Since disulfiram has been associated with psychotic behavior in some patients, this interaction has been attributed to a combined toxicity with metronidazole or benznidazole.(1)

CLINICAL EFFECTS: May observe psychotic reactions of confusional states.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of benznidazole,(2) fexinidazole,(3) metronidazole,(4) and tinidazole(5) state that these agents should not be administered to patients who have received disulfiram in the previous two weeks.

DISCUSSION: In a study in hospitalized alcoholics, six of 29 patients receiving concurrent disulfiram and metronidazole developed acute psychosis or confusion. Of these six, five had paranoid delusions and three experienced visual and auditory hallucinations. These reactions were not reported in any of the 29 patients who received placebo with disulfiram.(6,7) An increased central effect of ethyl alcohol was observed in a single patient during concurrent disulfiram and metronidazole.(8) Psychotic symptoms were reported during concurrent use in another case report.(9)

Tetracycline/Atovaquone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: The concurrent administration of tetracycline may result in decreased levels and effectiveness of atovaquone.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The CDC states that tetracycline should not be administered with atovaquone.(1) If concurrent use of tetracycline and atovaquone is warranted, parasitemia should be closely monitored.(2)

DISCUSSION: Concurrent tetracycline has been associated with a 40% decrease in atovaquone plasma concentrations.(1)

Tetracyclines/Selected Retinoids (Systemic)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both systemic tetracyclines(1-4,14) and systemic retinoids(5-14) have been independently associated with medication-induced intracranial hypertension.

CLINICAL EFFECTS: The concurrent use of oral retinoids(5-12) with tetracyclines has been associated with pseudotumor cerebri (benign intracranial hypertension). Early signs of pseudotumor cerebri include papilledema (inflammation of the optic nerve), headache, nausea, vomiting, and visual disturbances such as blurred vision, double vision, and loss of vision.(15)

PREDISPOSING FACTORS: Women of childbearing age who are overweight or have a previous history of intracranial hypertension are at a greater risk of developing intracranial hypertension.(15)

PATIENT MANAGEMENT: The UK(5) and US(6) manufacturers of acitretin state state that concurrent use with tetracyclines is contraindicated. The UK manufacturer of isotretinoin states that concurrent use with tetracyclines is contraindicated.(7) The US manufacturer of isotretinoin states that the concurrent use of tetracyclines should be avoided.(8) The US manufacturer of minocycline states that the administration of isotretinoin should be avoided shortly before, during and shortly after minocycline therapy.(2) The UK manufacturers of oral tretinoin and alitretinoin states that concurrent use with tetracyclines is contraindicated.(9,11) The Canadian manufacturer of palovarotene states that coadministration of tetracycline derivatives should be avoided.(12) Patients who present with symptoms of pseudotumor cerebri should be screened for papilledema. If papilledema is present, they should discontinue the drug and be referred to a neurologist for further treatment.(5-13)

DISCUSSION: The concurrent use of isotretinoin and tetracyclines has been associated with pseudotumor cerebri.(5-13) A review of ocular side effects from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization, the Food and Drug Administration, and medical journals from 1979 to 2003 found 6 patients who developed intracranial hypertension while taking concurrent minocycline or tetracycline with tretinoin, acitretin, or etretinate.(13)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Fexinidazole;Metronidazole;Tinidazole/Ethyl Alcohol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: In vitro studies show that metronidazole produces an inhibition of aldehyde dehydrogenase and other alcohol-oxidizing enzymes.(1-5) This results in the accumulation of acetaldehyde, which is responsible for the disulfiram-like reaction. A similar process may occur with fexinidazole(6) and tinidazole.(7)

CLINICAL EFFECTS: Concurrent use of oral metronidazole with alcohol has been associated with a disulfiram-type reaction resulting in symptoms of hypotension, tachycardia, nausea, sweating, facial flushing, headache, and vomiting.(7-10) It has been suggested that some patients find this combination of agents a pleasant experience, citing giddiness and excitement as rationale for abuse.(11)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving fexinidazole should be instructed to avoid alcohol during and for at least 48 hours after taking fexinidazole.(6) Patients should be advised of the possible affects that may result from ingestion or application of products that contain alcohol while taking metronidazole. Patients receiving tinidazole should be instructed to avoid alcohol during and for 3 days after taking tinidazole.(7) Patients should be informed about unsuspected sources of alcohol such as elixirs and topical preparations. Caution is also warranted when using intravenous preparations containing alcohol solvents in patients receiving metronidazole or tinidazole. Alcohol is used to improve docetaxel and paclitaxel solubility. - The quantity of alcohol in paclitaxel injection formulations (0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg dose contains approximately 13 grams of alcohol. - The quantity of alcohol in docetaxel formulations varies approximately 3-fold depending upon the manufacturer. FDA data on alcohol content (22): Product Manufacturer Alcohol/200 mg dose Docetaxel Inj. Pfizer 6.4 grams Docetaxel Inj. Sandoz 5.5 grams Docetaxel Inj. Accord 4.0 grams Taxotere-one vial Sanofi 4.0 grams formulation Docetaxel Inj. Hospira 3.7 grams Docefrez Sun Pharma 2.9 grams Taxotere-two vial Sanofi 2.0 grams formulation

DISCUSSION: In a case report,(13) a patient developed disulfiram-like reactions after receiving concurrent metronidazole and intravenous sulfamethoxazole-trimethoprim, which is solubilized in a 10% alcohol base. In another case report, a female patient using vaginal inserts containing metronidazole once daily at bedtime ingested two or three drinks containing 30ml of vodka on the fifth day of metronidazole therapy.(14) About a half hour later, the patient inserted the metronidazole vaginal tablet and awoke one hour later with a severe burning sensation in her stomach, a severe headache, and nausea accompanied by a cold sweat. These symptoms resolved in about four hours. Other studies have failed to observe a disulfiram-like reaction between alcohol and metronidazole.(15-21)

Metronid; Secnidazole; Tinidazole/Slt Anticoag (Vit K Antag)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Possible inhibition of anticoagulant metabolism by metronidazole, secnidazole, or tinidazole. Metronidazole is a weak CYP2C9 inhibitor and may inhibit the metabolism of the more potent warfarin isomer, S-warfarin.(1)

CLINICAL EFFECTS: Concurrent use of anticoagulants with metronidazole, secnidazole, or tinidazole may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be most susceptible to this interaction. Patients with a pre-existing CYP2C9 poor metabolizer genotype would be less susceptible to this interaction. However, patients with reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) have an inherently higher risk for bleeding at usual anticoagulant doses and thus generally require lower doses to achieve effective and safe anticoagulation. In addition, CYP2C9 poor metabolizers may require more time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: INR values should be closely monitored during and for several days after the conclusion of concurrent metronidazole, secnidazole, or tinidazole. Anticoagulant dosage may need to be adjusted up to 10 days after concurrent therapy ends. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In two studies, metronidazole significantly enhanced the hypoprothrombinemic effect of warfarin.(2,3) The onset of the interaction occurred within four(2) to ten days(3) and appeared as excessive bruising of the legs. In eight normal subjects, metronidazole significantly increased the half-life of racemic warfarin and the S-enantiomer of warfarin. The R-enantiomer of warfarin, which is metabolized primarily by the reduction of side chains, was unaffected by metronidazole.(4) In an animal study, metronidazole preferentially inhibited the S-enantiomer of warfarin.(5) This interaction should also be considered during concurrent administration and for eight days after concurrent anticoagulants and tinidazole.(6)

Metronidazole/Busulfan

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of metronidazole may result in elevated levels of and toxicity from busulfan.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of metronidazole and high-dose busulfan is not recommended.(1)

DISCUSSION: A study in stem-cell transplantation recipients examined 3 groups of patients. Group A (n=5) received concurrent metronidazole and busulfan. Group B (n=9) received busulfan alone for 2 days, then concurrent busulfan and metronidazole for 2 days. Group C (n=10) received busulfan without metronidazole. Busulfan levels were 87% higher in Group A compared Group C. In Group B, busulfan levels were 79% higher during metronidazole therapy than during busulfan alone. In Group A, elevated liver transaminases and bilirubin were seen in all patients, 1 patient died of multiorgan failure, 3 developed veno-occlusive disease, and 1 developed hemorrhagic cystitis. In Group B, 6 patients had elevated liver function tests, but there were no reports of veno-occlusive disease.(2)

Metronidazole;Tinidazole/Fluorouracil & Fluorouracil Prodrug

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Metronidazole(1) and tinidazole(2) may decrease the clearance of fluorouracil.

CLINICAL EFFECTS: Concurrent use of metronidazole(1) or tinidazole with fluorouracil may result in elevated levels of fluorouracil and toxicity, including severe and fatal myelosuppression including neutropenia, thrombocytopenia, or anemia, severe diarrhea, cardiotoxicity, or neurotoxicity.

PREDISPOSING FACTORS: Patients who are intermediate or poor dihydropyrimidine dehydrogenase (DPYD) metabolizers have diminished or no DPYD function. Since DPYD is the rate-limiting enzyme involved in fluoropyrimidine metabolism, these patients may be more susceptible to the effects of this interaction.(3)

PATIENT MANAGEMENT: Avoid using metronidazole as an adjunct agent to fluorouracil therapy. If possible, also avoid treating infections with metronidazole or tinidazole in patients receiving fluorouracil. If concurrent therapy for the treatment of infection is required, the dosage of fluorouracil may need to be reduced. Patients receiving concurrent therapy should be closely monitored for signs of fluorouracil toxicity.

DISCUSSION: In a study in 27 patients, metronidazole (750 mg/m2) was given one hour before fluorouracil (600 mg/m2) daily for five days. The regimen was repeated every 4 weeks. Fluorouracil toxicity was greatly enhanced, with 74% of patients experiencing granulocytopenia (less than 1500/ml). Pharmacokinetic studies showed that metronidazole decreased fluorouracil clearance by 26.9%. In vitro studies revealed no synergism with the two agents on the HCT-8 colon cancer cell line.(1)

Tetracyclines/Methoxyflurane

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown. However, combined renal toxicity appears to be a factor.

CLINICAL EFFECTS: Nephrotoxicity may occur.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible use alternative therapy.

DISCUSSION: Renal toxicity and death have been reported in patients receiving methoxyflurane and tetracycline. Since both drugs have been associated with nephrotoxicity, it is difficult to determine whether the effects are due to the drug combination or either drug alone. Additional studies are needed to clarify this potential interaction.

Tetracyclines/Topical Tretinoin (Photodamage)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of topical tretinoin with tetracyclines may increase the risk of phototoxicity(1) in some patients.(2)

PREDISPOSING FACTORS: Patients using topical tretinoin for the treatment of photodamage may be predisposed to photosensitivity.(2)

PATIENT MANAGEMENT: Concurrent use of topical tretinoin and tetracycline is standard practice in the treatment of acne.(3) However, patients taking tetracyclines should not use topical tretinoin (e.g Renova) for the treatment of photodamage.(1,2)

DISCUSSION: The concurrent use of topical tretinoin and tetracyclines may result in an increased risk of phototoxicity.(1,2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Metronidazole/Barbiturates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The metabolism of metronidazole may be increased by barbiturate administration via induction of CYP2A6. Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Serum metronidazole concentrations may be reduced producing a decrease in the therapeutic effects of metronidazole.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Observe the patient for possible metronidazole treatment failure. Adjust the dose of metronidazole accordingly.

DISCUSSION: Therapeutic failure with corresponding increases in metronidazole elimination rate has been reported with concurrent administration of phenobarbital.

Metronidazole/Lithium

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of action is not fully known. Possible renal damage may occur with concurrent use leading to decreased renal clearance of lithium.(1,2)

CLINICAL EFFECTS: Concurrent use of metronidazole may result in elevated lithium levels and lithium toxicity. Lithium has a narrow therapeutic range. Unintended increases in lithium concentrations may lead to lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, bradycardia, tinnitus, or nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.(3)

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: acute renal impairment, chronic renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ACEI, ARBs, NSAIDs, diuretics).(3) Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: The US prescribing information for metronidazole states patients should be monitored closely with concurrent lithium therapy by obtaining serum lithium and creatinine levels several days after initiation of metronidazole.(2) If possible, lithium treatment should be tapered or withdrawn before administering metronidazole.(1) If concurrent therapy cannot be avoided, monitor closely. Evaluate renal function and most recent lithium levels. If renal function is not stable, whenever possible delay initiation of concurrent therapy until renal function is stable. If an interacting drug is discontinued, the lithium level may fall. Monitor lithium concentration and adjust dose if needed.(3) Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing.

DISCUSSION: Lithium has a narrow therapeutic index with potential fatal consequences.(2) Other factors, such as dehydration, acute or worsening of chronic renal impairment, or acute changes in sodium intake may increase the occurrence of a clinically important interaction.

Tetracyclines/Coumarin Anticoagulants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Tetracyclines may interfere with vitamin-K producing gut flora.

CLINICAL EFFECTS: The addition of a tetracycline to a patient maintained on a coumarin anticoagulant may result in increased anticoagulant effects, including bleeding.

PREDISPOSING FACTORS: he risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients maintained on coumarin anticoagulants should be closely monitored when tetracyclines are initiated and discontinued. The dosage of the anticoagulant may need to be adjusted. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In a retrospective review of patients receiving either acenocoumarol or phenprocoumon, use of doxycycline and tetracycline was associated with relative risk of major bleeding of 3 and 9, respectively.(1) There are several case reports of bleeding following the addition of doxycycline(2-4) and tetracycline(5,6) to warfarin therapy.

Tetracyclines/Divalent & Trivalent Cations

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Di- and trivalent cations may form chelation complexes with tetracyclines, preventing their absorption.(1,2)

CLINICAL EFFECTS: Simultaneous administration of di- or trivalent cations may result in decreased levels of and therapeutics effects from tetracyclines.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Administer tetracyclines at least two hours before or after the di- or trivalent cations. When used for the treatment of H. pylori infection, tetracyclines and bismuth should be given simultaneously. The US manufacturer of omadacycline states to fast for at least four hours, administer omadacycline, and then wait four hours before taking di- or trivalent cations.(21) The US manufacturer of ferric maltose recommends separation of ferric maltose by at least 4 hours.(22)

DISCUSSION: Concurrent administration of aluminum hydroxide or divalent cations (such as calcium, magnesium, or zinc) has been shown to significantly decrease the gastrointestinal absorption of tetracycline.(3-5) Concurrent administration of tetracycline and magnesium-aluminum hydroxide gel has been shown to decrease the tetracycline area-under-curve (AUC) by 90%.(6) Magnesium-aluminum silicate has been shown to decrease the AUC of tetracycline by 27%.(7) Demeclocycline(8,9) methacycline,(10) chlortetracycline,(11) and oxytetracycline(10,12) have been shown to interact with aluminum hydroxide and/or dairy products. Doxycycline has been reported to interact with aluminum hydroxide gel.(13) Aluminum magnesium hydroxide has been shown to decrease doxycycline absorption by 84%.(14) Minocycline absorption has been shown to be impaired by aluminum, calcium, and magnesium.(15) Bismuth subsalicylate has been shown to decrease absorption of doxycycline and tetracycline by 37%(16) and 34%,(17) respectively. Since sucralfate is an aluminum salt of a sulfated disaccharide, it may also prevent absorption of tetracyclines. This complex has been used to provide site-specific delivery of tetracycline to gastric ulcers in the treatment of Helicobacter pylori gastric ulcer disease and may be useful in some indications.(18) Quinapril tablets contain a high percentage of magnesium and have been shown to decrease the absorption of tetracycline by 28-37%.(19) Lanthanum is expected to interact with tetracyclines as well.(20)

Tetracyclines; Tigecycline/Contraceptives

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not established.

CLINICAL EFFECTS: Reduced pharmacologic effects of oral contraceptives with resultant breakthrough bleeding and pregnancy may occur.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Current guidelines suggest that additional precautions are not necessary when non-enzyme inducing antibiotics are used concurrently with hormonal contraceptives; however, some patients may still prefer to use an additional method of contraception.

DISCUSSION: Evidence for this interaction is limited and conflicting; however, the CDC and the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit no longer recommend use of a backup contraceptive method during use of a non-enzyme inducing antibiotic. Pregnancy has been reported following the addition of tetracycline to oral contraceptive therapy.(1) In contrast, a study in 7 healthy women found no effect of tetracycline on ethinyl estradiol or norethindrone levels.(2) A study in 24 healthy women found no significant effects of doxycycline on ethinyl estradiol, norethindrone, or progesterone levels. However, the authors noted that there large inter-patient and inter-patient variability in these levels and that the interaction may just manifest itself in a small proportion of women.(3)

*Metronidazole is contraindicated in individuals with a history of hypersensitivity to the medication or other nitroimidazole derivatives.

*Metronidazole is contraindicated in patients who have received disulfiram within the last 2 weeks.

*Because metronidazole has been thought to be associated with a disulfiram-like reaction to alcohol (e.g., cramps, nausea, vomiting, headache, flushing), the manufacturers state that consumption of alcohol or products containing propylene glycol are contraindicated during and for at least 3 days after stopping metronidazole therapy. However, the Centers for Disease Control and Prevention (CDC) states that patients taking metronidazole do not need to abstain from alcohol because the medication does not inhibit acetaldehyde dehydrogenase and therefore does not have a disulfiram-like interaction with alcohol.

*Metronidazole is contraindicated for the treatment of trichomoniasis in patients during the first trimester of pregnancy. Combination bismuth subcitrate, metronidazole, and tetracycline (Pylera(R)) capsules are contraindicated for use throughout pregnancy.

*Combination bismuth subcitrate, metronidazole, and tetracycline (Pylera(R)) capsules are contraindicated in severe renal impairment.

*Metronidazole is contraindicated in patients with Cockayne syndrome because of severe, potentially fatal irreversible hepatotoxicity and/or acute liver failure that has occurred.

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Cockayne syndrome
• Pregnancy

• Alcohol intoxication
• Alcohol use disorder
• Child-pugh class C hepatic impairment
• Clostridioides difficile infection
• Disease of liver
• Idiopathic intracranial hypertension
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Peripheral neuropathy

• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Disease of liver
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Neutropenic disorder
• Suicidal ideation

The most common adverse effects reported with oral metronidazole include GI reactions such as nausea (sometimes accompanied by headache, anorexia, and vomiting), diarrhea, epigastric distress, abdominal cramping, and constipation.

Adverse effects reported in at least 5% of patients receiving the fixed combination bismuth subcitrate, metronidazole, and tetracycline capsules (Pylera(R)) include abnormal feces, diarrhea, nausea, and headache.

More Frequent

• Dental discoloration

Less Frequent

• Dyschromia
• Peripheral neuropathy

Rare or Very Rare

• Acute eruptions of skin
• Acute generalized exanthematous pustulosis
• Acute hepatic failure
• Acute pancreatitis
• Acute pancreatitis
• Anaphylaxis
• Angioedema
• Ataxia
• Bullous dermatitis
• Clostridioides difficile infection
• Cystitis
• DRESS syndrome
• DRESS syndrome
• Drug-induced hepatitis
• Encephalopathy
• Enterocolitis
• Eosinophilia
• Erythema
• Esophagitis
• Exfoliative dermatitis
• Hearing loss
• Hemolytic anemia
• Hepatic failure
• Hepatocellular damage
• Idiopathic intracranial hypertension
• Leukopenia
• Maculopapular rash
• Neuromuscular blockade
• Neutropenic disorder
• Neutropenic disorder
• Non-infective meningitis
• Onycholysis
• Optic neuropathy
• Purpura
• Seizure disorder
• Serum sickness
• Skin rash
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Thrombocytopenic disorder
• Thrombotic thrombocytopenic purpura
• Toxic epidermal necrolysis
• Urticaria
• Urticaria
• Vision impairment

More Frequent

• Abdominal pain with cramps
• Anorexia
• Black stools
• Diarrhea
• Diarrhea
• Gastrointestinal irritation
• Headache disorder
• Nausea
• Nausea
• Skin photosensitivity
• Tongue discoloration
• Vomiting

Less Frequent

• Alcohol intolerance
• Anorexia
• Dysgeusia
• Genital organ pruritus
• Glossitis
• Mouth irritation
• Oral candidiasis
• Pruritus ani
• Stomatitis
• Tongue discoloration
• Vaginal dryness
• Xerostomia

Rare or Very Rare

• Acute cognitive impairment
• Anorectal disorders
• Constipation
• Depression
• Dizziness
• Dysarthria
• Dyspareunia
• Dyspepsia
• Dysphagia
• Dysuria
• Fever
• Fever
• Flushing
• Furred tongue
• Furred tongue
• General weakness
• Glossitis
• Insomnia
• Irritability
• Libido changes
• Nail discoloration
• Nasal congestion
• Polyuria
• Proctitis
• Pruritus of skin
• Skin rash
• Stomatitis
• Syncope
• Tinnitus
• Tooth enamel hypoplasia
• Urinary incontinence
• Urine discoloration
• Vertigo
• Vomiting
• Vulvovaginal candidiasis

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Safety and efficacy of metronidazole injection for the treatment of intra-abdominal infections have been established in pediatric patients from birth up to 4 months of age. Safety and efficacy for the treatment of intra-abdominal infections in pediatric patients >=4 months of age have not been established.

Safety and efficacy of metronidazole injection in pediatric patients <4 months of age have not been established for the treatment of anaerobic infections (other than intra-abdominal infections), or for postoperative infection.

Safety and efficacy of oral metronidazole have been established for the treatment of amebiasis in pediatric patients, but not for the treatment of trichomoniasis or anaerobic bacterial infections.

Safety and efficacy of combination bismuth subcitrate, metronidazole, and tetracycline (Pylera(R)) have not been established for the treatment of Helicobacter pylori infection in pediatric patients. Pylera(R) should not be used in children <8 years of age because of the risk of tooth discoloration and enamel hypoplasia from tetracycline.

There are no adequate or well-controlled studies to date using metronidazole in pregnant females. Published data include case-control studies, cohort studies, and 2 meta-analyses of over 5000 pregnant females who received metronidazole during pregnancy, many during the first trimester. Although these findings have not been confirmed, 1 study found an increased risk of cleft lip, with or without cleft palate in infants exposed to metronidazole in utero. Most other data, which include more than 10 randomized, placebo-controlled trials that assessed the effect of antibiotic treatment (including metronidazole) for bacterial vaginosis on preterm delivery, did not show an increased risk for congenital anomalies or other adverse fetal outcomes. Three studies assessed the risk of infant cancer following in utero exposure; however these studies were limited in their ability to assess risk. Metronidazole does cross the placental barrier, and its effects on human fetal organogenesis are not known.

Combination bismuth subcitrate, metronidazole, and tetracycline (Pylera(R)) capsules are contraindicated in women who are pregnant. Use of tetracyclines (a component of Pylera(R)) during the second and third trimester can cause permanent discoloration of the teeth in infants. All tetracyclines form a stable calcium complex in any bone forming tissue and can potentially inhibit bone development; however, a long-term follow-up study in children exposed to tetracycline in utero showed no adverse effects on bone growth and development.

Healthcare providers should weigh the potential risks and benefits of therapy prior to initiating metronidazole.

Metronidazole is distributed into human milk at concentrations similar to human plasma levels. Because of the tumorigenic potential of metronidazole in mice and rats, a decision should be made whether to discontinue nursing or the medication, taking into account the risk/benefit of treatment. Alternately, choosing to pump and discard milk throughout metronidazole therapy and for 24 hours after discontinuing metronidazole may be an option.

Patients receiving combination bismuth subcitrate, metronidazole, and tetracycline (Pylera(R)) should pump and discard milk throughout therapy and for 2 days after the last dose.

Although there are not specific dosage adjustments in geriatric patients, dosage of metronidazole should generally be undertaken with caution, reflecting the greater frequency of reduced hepatic, renal, cardiac function, concomitant disease or other medication therapies in geriatric individuals.

The manufacturers recommend monitoring for metronidazole-associated adverse effects in geriatric patients.

Following administration of a single 500 mg oral or IV dose of metronidazole, geriatric individuals >70 years of age with no apparent renal or hepatic dysfunction experienced 40-80% higher mean exposures of the active metabolite, hydroxy-metronidazole, compared to healthy patients <40 years of age. Therefore, monitoring for metronidazole-associated adverse events is recommended in geriatric patients.