Pylera

Drug overview for PYLERA (colloidal bismuth subcitrate/metronidazole/tetracycline hcl):

Generic name: COLLOIDAL BISMUTH SUBCITRATE/METRONIDAZOLE/TETRACYCLINE HCL (BIZ-muth sub-SIT-rate/MET-roe-NYE-da-zole/TET-ra-SYE-kleen)
Drug class: Bismuth Salts
Therapeutic class: Gastrointestinal Therapy Agents

Metronidazole is a synthetic, nitroimidazole-derivative antibacterial and Tetracycline is an antibiotic derived from Streptomyces aureofaciens or antiprotozoal agent. produced semisynthetically from oxytetracycline.

No enhanced Uses information available for this drug.

DRUG IMAGES

PYLERA CAPSULE

The following indications for PYLERA (colloidal bismuth subcitrate/metronidazole/tetracycline hcl) have been approved by the FDA:

Indications:
Duodenal ulcer due to H. pylori
Helicobacter pylori gastritis

Professional Synonyms:
Campylobacter gastritis
DU due to H. pylori
Duodenal ulcer due to Campylobacter pylori
Duodenal ulcer due to Helicobacter pylori
H. pylori gastritis

The following dosing information is available for PYLERA (colloidal bismuth subcitrate/metronidazole/tetracycline hcl):

Dosing
Administration
PYLERA
BISMUTH-METRONIDAZOLE-TETRACYC

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

The usual adult oral dosage of tetracycline hydrochloride is 1-2 g daily given in 2-4 divided doses. A dosage of 500 mg twice daily or 250 mg 4 times daily may be adequate for mild to moderate infections; a dosage of 500 mg 4 times daily may be required for severe infections.

The usual oral dosage of tetracycline hydrochloride for children older than 8 years of age is 25-50 mg/kg daily given in 4 divided doses. The American Academy of Pediatrics (AAP) states that oral tetracycline is inappropriate for severe infections.

Dosage of metronidazole hydrochloride is expressed in terms of metronidazole. Because the pharmacokinetics of metronidazole may be altered in geriatric individuals, monitoring of plasma metronidazole concentrations may be necessary to properly adjust dosage of the drug in such patients.

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.

In patients with severe hepatic impairment, doses and/or frequency of administration of metronidazole should be modified in response to the degree of hepatic impairment and plasma concentrations of the drug should be monitored.

No enhanced Administration information available for this drug.

Dosing information for PYLERA
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
PYLERA CAPSULE	Maintenance	Adults take 3 capsules by oral route 4 times per day after meals and at bedtime

Generic dosing information for BISMUTH-METRONIDAZOLE-TETRACYC
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
BISMUTH-METRO-TETR 140-125-125	Maintenance	Adults take 3 capsules by oral route 4 times per day after meals and at bedtime

The following drug interaction information is available for PYLERA (colloidal bismuth subcitrate/metronidazole/tetracycline hcl):

Contraindicated
Severe
Moderate

There are 4 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
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)	DISULFIRAM
Live Typhoid Vaccine/Antimicrobials 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)	VIVOTIF
Propylene Glycol/Metronidazole; Tinidazole 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.	PROPYLENE GLYCOL
Selected Retinoids (Systemic)/Tetracyclines 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)	ABSORICA, ABSORICA LD, ACCUTANE, ACITRETIN, AMNESTEEM, CLARAVIS, ISOTRETINOIN, RETINOIC ACID, SOHONOS, TRETINOIN, TRETINOIN ACID, ZENATANE

There are 7 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Selected Anticoagulants (Vit K antagonists)/Metronidazole; Tinidazole 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 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 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 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)	ANISINDIONE, DICUMAROL, JANTOVEN, PHENINDIONE, WARFARIN SODIUM
Fluorouracil/Metronidazole; Tinidazole 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)	ADRUCIL, CAPECITABINE, FLUOROURACIL, XELODA
Ethyl Alcohol/Fexinidazole;Metronidazole;Tinidazole 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)	ALCOHOL,DEHYDRATED, DILUENT FOR BICNU, DILUENT FOR CARMUSTINE, DILUENT FOR ISTODAX, DILUENT FOR IXEMPRA, DILUENT FOR JEVTANA, DILUENT FOR MELPHALAN, DILUENT FOR ROMIDEPSIN, DILUENT FOR TEMSIROLIMUS
Busulfan/Metronidazole 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)	BUSULFAN, BUSULFEX, MYLERAN
Topical Tretinoin/Tetracyclines 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)	KATARYA, KATARYAXN, KETARYA, KEVARYA, KUTARYAXM, KUTARYAXMPA, KUVARYA, KUVARYE, MECORIX, MECORIX HP, MECORIX PLUS, MEKAM, MEKAM HP, MELIDU, MELONDIS, MELONDIS PLUS, MOLEXI, MYTHIUS, REFISSA, RENOVA, RENOVA PUMP, TRETINOIN, TRI-LUMA, YAXATARXYN, YOKATAR
Mebendazole/Metronidazole SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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)	EMVERM, MEBENDAZOLE
Atovaquone/Tetracycline 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: 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)	ATOVAQUONE, ATOVAQUONE-PROGUANIL HCL, MALARONE, MEPRON

There are 6 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
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) 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)	ACCRUFER, ALUMINUM HYDROXIDE, ATTAPULGITE, AUROVELA 24 FE, AUROVELA FE, AURYXIA, BALCOLTRA, BISMUTH CITRATE, BISMUTH SUBSALICYLATE, BLISOVI 24 FE, BLISOVI FE, CALCIUM ACETATE, CALCIUM CHLORIDE, CALCIUM GLUCONATE, CALCIUM GLUCONATE MONOHYDRATE, CARAFATE, CHARLOTTE 24 FE, CLENPIQ, FEIRZA, FERRIC CITRATE, FINZALA, FOSRENOL, GEMMILY, HAILEY 24 FE, HAILEY FE, JOYEAUX, JUNEL FE, JUNEL FE 24, KAITLIB FE, KAOLIN, LANTHANUM CARBONATE, LARIN 24 FE, LARIN FE, LAYOLIS FE, LEVONORG-ETH ESTRAD-FE BISGLYC, LO LOESTRIN FE, LOESTRIN FE, MAGNESIUM CHLORIDE, MAGNESIUM CITRATE, MAGNESIUM OXIDE, MAGNESIUM SULFATE, MERZEE, MIBELAS 24 FE, MICROGESTIN FE, MINZOYA, NORETHIN-ETH ESTRA-FERROUS FUM, NORETHINDRONE-E.ESTRADIOL-IRON, SOD SULF-POTASS SULF-MAG SULF, SUCRALFATE, SUFLAVE, SUPREP, SUTAB, TARINA 24 FE, TARINA FE, TARINA FE 1-20 EQ, TAYTULLA, TILIA FE, TRI-LEGEST FE, VELPHORO, WYMZYA FE, XARAH FE, XELRIA FE, ZINC CHLORIDE, ZINC OXIDE, ZINC SULFATE
Contraceptives/Tetracyclines; Tigecycline 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)	2-METHOXYESTRADIOL, AFIRMELLE, ALTAVERA, ALYACEN, AMETHIA, AMETHYST, APRI, ARANELLE, ASHLYNA, AUBRA, AUBRA EQ, AUROVELA, AUROVELA 24 FE, AUROVELA FE, AVIANE, AYUNA, AZURETTE, BALCOLTRA, BALZIVA, BEYAZ, BLISOVI 24 FE, BLISOVI FE, BRIELLYN, CAMILA, CAMRESE, CAMRESE LO, CAZIANT, CHARLOTTE 24 FE, CHATEAL EQ, CRYSELLE, CYRED, CYRED EQ, DASETTA, DAYSEE, DEBLITANE, DESOGESTR-ETH ESTRAD ETH ESTRA, DIETHYLSTILBESTROL, DOLISHALE, DROSPIRENONE-ETH ESTRA-LEVOMEF, DROSPIRENONE-ETHINYL ESTRADIOL, ELINEST, ELLA, EMZAHH, ENPRESSE, ENSKYCE, ERRIN, ESTARYLLA, ESTRADIOL, ESTRADIOL BENZOATE, ESTRADIOL CYPIONATE, ESTRADIOL HEMIHYDRATE, ESTRADIOL HEMIHYDRATE MICRO, ESTRADIOL MICRONIZED, ESTRADIOL VALERATE, ESTRIOL, ESTRIOL MICRONIZED, ESTRONE, ETHINYL ESTRADIOL, ETHYNODIOL-ETHINYL ESTRADIOL, FALMINA, FEIRZA, FEMLYV, FINZALA, GEMMILY, HAILEY, HAILEY 24 FE, HAILEY FE, HEATHER, ICLEVIA, INCASSIA, ISIBLOOM, JAIMIESS, JASMIEL, JENCYCLA, JOLESSA, JOYEAUX, JULEBER, JUNEL, JUNEL FE, JUNEL FE 24, KAITLIB FE, KALLIGA, KARIVA, KELNOR 1-35, KELNOR 1-50, KURVELO, LARIN, LARIN 24 FE, LARIN FE, LAYOLIS FE, LEENA, LESSINA, LEVONEST, LEVONORG-ETH ESTRAD ETH ESTRAD, LEVONORG-ETH ESTRAD-FE BISGLYC, LEVONORGESTREL-ETH ESTRADIOL, LEVORA-28, LO LOESTRIN FE, LO-ZUMANDIMINE, LOESTRIN, LOESTRIN FE, LOJAIMIESS, LORYNA, LOW-OGESTREL, LUTERA, LYLEQ, LYZA, MARLISSA, MERZEE, MIBELAS 24 FE, MICROGESTIN, MICROGESTIN FE, MILI, MINZOYA, MONO-LINYAH, NATAZIA, NECON, NEXTSTELLIS, NIKKI, NORA-BE, NORETHIN-ETH ESTRA-FERROUS FUM, NORETHINDRON-ETHINYL ESTRADIOL, NORETHINDRONE, NORETHINDRONE-E.ESTRADIOL-IRON, NORGESTIMATE-ETHINYL ESTRADIOL, NORTREL, NYLIA, OCELLA, ORTHO TRI-CYCLEN, ORTHO-NOVUM, PHILITH, PIMTREA, PORTIA, RECLIPSEN, RIVELSA, SAFYRAL, SETLAKIN, SHAROBEL, SIMLIYA, SIMPESSE, SLYND, SPRINTEC, SRONYX, SYEDA, TARINA 24 FE, TARINA FE, TARINA FE 1-20 EQ, TAYTULLA, TILIA FE, TRI-ESTARYLLA, TRI-LEGEST FE, TRI-LINYAH, TRI-LO-ESTARYLLA, TRI-LO-MARZIA, TRI-LO-MILI, TRI-LO-SPRINTEC, TRI-MILI, TRI-SPRINTEC, TRI-VYLIBRA, TRI-VYLIBRA LO, TRIVORA-28, TULANA, TURQOZ, TYBLUME, VALTYA, VELIVET, VESTURA, VIENVA, VIORELE, VOLNEA, VYFEMLA, VYLIBRA, WERA, WYMZYA FE, XARAH FE, XELRIA FE, YASMIN 28, YAZ, ZARAH, ZOVIA 1-35, ZUMANDIMINE
Digoxin, Oral/Tetracyclines SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: In approximately 10% of patients receiving digoxin, a considerable amount of an administered dose of the drug is metabolized by GI bacteria to inactive digoxin reduction products (DRPs). Concomitant administration of tetracycline may alter the GI flora, enabling an increased amount of digoxin to be absorbed. CLINICAL EFFECTS: Increased serum digoxin levels with possible toxicity may occur. This effect may persist for several months after tetracycline is discontinued. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias. PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity. PATIENT MANAGEMENT: Monitor serum digoxin levels and observe the patient for toxicity. The dosage of digoxin may need to be decreased by 30-50% or the frequency of administration may be reduced.(3) DISCUSSION: Approximately 10% of the patients receiving digoxin metabolize 30% or more of an ingested dose of digoxin to inactive DRPs. Concurrent current administration of tetracycline may alter the GI flora, decreasing the conversion of digoxin to DRPs. In these patients this could produce an increase in plasma digoxin concentration. The effect of tetracycline on the metabolism of digoxin to DRPs may persist for several months after the antibiotic is discontinued. Concomitant administration of tetracycline and digoxin increased the digoxin serum concentration 100%. (3)	DIGITEK, DIGOXIN, DIGOXIN MICRONIZED, LANOXIN
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.	ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, DONNATAL, FIORICET, FIORICET WITH CODEINE, MYSOLINE, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PRIMIDONE, SEZABY, TENCON
Coumarin Anticoagulants/Tetracyclines 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.	DICUMAROL, JANTOVEN, WARFARIN SODIUM
Lithium/Metronidazole 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.	LITHIUM CARBONATE, LITHIUM CARBONATE ER, LITHIUM CITRATE, LITHIUM CITRATE TETRAHYDRATE, LITHOBID

The following contraindication information is available for PYLERA (colloidal bismuth subcitrate/metronidazole/tetracycline hcl):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

No enhanced Contraindications information available for this drug.

There are 4 contraindications. Absolute contraindication.

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

There are 8 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
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

There are 7 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
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

The following adverse reaction information is available for PYLERA (colloidal bismuth subcitrate/metronidazole/tetracycline hcl):

Overview
Severe
Less Severe

Adverse reaction overview.

No enhanced Common Adverse Effects information available for this drug.

There are 43 severe adverse reactions.

More Frequent	Less Frequent
Dental discoloration	Dyschromia Peripheral neuropathy

Rare/Very Rare
Acute eruptions of skin Acute generalized exanthematous pustulosis Acute hepatic failure Acute pancreatitis Anaphylaxis Angioedema Ataxia Bullous dermatitis Clostridioides difficile infection Cystitis 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 Non-infective meningitis Onycholysis Optic neuropathy Purpura Seizure disorder Serum sickness Skin rash Stevens-johnson syndrome Thrombocytopenic disorder Thrombotic thrombocytopenic purpura Toxic epidermal necrolysis Urticaria Vision impairment

Rare/Very Rare

Acute eruptions of skin
Acute generalized exanthematous pustulosis
Acute hepatic failure
Acute pancreatitis
Anaphylaxis
Angioedema
Ataxia
Bullous dermatitis
Clostridioides difficile infection
Cystitis
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
Non-infective meningitis
Onycholysis
Optic neuropathy
Purpura
Seizure disorder
Serum sickness
Skin rash
Stevens-johnson syndrome
Thrombocytopenic disorder
Thrombotic thrombocytopenic purpura
Toxic epidermal necrolysis
Urticaria
Vision impairment

There are 55 less severe adverse reactions.

More Frequent	Less Frequent
Abdominal pain with cramps Anorexia Black stools Diarrhea Gastrointestinal irritation Headache disorder Nausea Skin photosensitivity Tongue discoloration Vomiting	Alcohol intolerance Anorexia Dysgeusia Genital organ pruritus Glossitis Mouth irritation Oral candidiasis Pruritus ani Stomatitis Tongue discoloration Vaginal dryness Xerostomia

Rare/Very Rare
Acute cognitive impairment Anorectal disorders Constipation Depression Dizziness Dysarthria Dyspareunia Dyspepsia Dysphagia Dysuria Fever Flushing 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

Rare/Very Rare

Acute cognitive impairment
Anorectal disorders
Constipation
Depression
Dizziness
Dysarthria
Dyspareunia
Dyspepsia
Dysphagia
Dysuria
Fever
Flushing
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

The following precautions are available for PYLERA (colloidal bismuth subcitrate/metronidazole/tetracycline hcl):

Pediatric
Pregnant
Lactation
Geriatric

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

There was no evidence of fetotoxicity when metronidazole was administered orally at a dosage of 20 mg/kg daily (approximately 1.5 times the usual human dosage based on mg/kg of body weight) or at a dosage of 60 mg/m2 daily (approximately 10% of the usual human dosage) to pregnant mice; however, fetotoxicity did occur when the drug was administered intraperitoneally to pregnant mice at doses approximately equal to the usual human dose. There are no adequate or well-controlled studies to date using metronidazole in pregnant women, and the drug should be used during pregnancy only when clearly needed. The manufacturers, the CDC, and other experts state that use of the drug during the first trimester of pregnancy is contraindicated.

Although evidence from case-controlled studies, pooled analysis of cohort and case-controlled studies, and other information, including some experience during first-trimester exposure, suggests that metronidazole is not associated with a clinically important teratogenic or fetotoxic risk, conflicting evidence potentially implicating an association between the drug and certain fetal effects (e.g., cleft palate) also has been reported. Because of conflicting data and theoretical concerns regarding the mutagenic and carcinogenic potentials of the drug, use of metronidazole during the first trimester remains controversial and is considered contraindicated by the manufacturers and others. Because no therapy other than metronidazole currently has been shown to produce adequate response in the treatment of trichomoniasis, the manufacturers, CDC, and other experts state that oral metronidazole should be used to treat this infection in pregnant women only when severe symptoms cannot be controlled with local palliative treatment and only during the second or third trimester.

In addition, the manufacturers state that because the single-dose regimen may result in slightly higher serum concentrations of the drug, the 7-day regimen (see Dosage and Administration: Dosage) should be used to treat trichomoniasis during pregnancy. However, the CDC suggests the single-dose regimen when therapy with the drug is considered necessary. It has been suggested that 100 mg of clotrimazole administered intravaginally at bedtime for 7 days may produce symptomatic improvement but only occasionally cures in pregnant women with trichomoniasis; therefore, such therapy generally should be considered palliative.

Screening and/or treatment for bacterial vaginosis in pregnant women as clinically indicated (see Bacterial Vaginosis: Pregnant Women, in Uses) should be conducted early in the pregnancy (i.e., first prenatal visit for women at high-risk). For the treatment of bacterial vaginosis and reduction in the incidence of adverse pregnancy outcomes associated with bacterial vaginosis (e.g., preterm birth), particularly in pregnant women at high risk for complications of pregnancy, a 7-day regimen of oral metronidazole currently is preferred. the manufacturer and some experts state that the single-dose regimen of metronidazole should not be used in pregnant women because it may result in slightly higher serum concentrations of the drug, which can reach the fetal circulation. The safety and efficacy of oral metronidazole administered as extended-release tablets for the treatment of bacterial vaginosis have not been established in pregnant women.

Metronidazole is distributed into milk. Because of the tumorigenic potential of metronidazole in mice and rats, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. The AAP states that, if a single 2-g dose of oral metronidazole is indicated in the mother, breast-feeding should be interrupted for 12-24 hours following the dose.

No enhanced Geriatric Use information available for this drug.

Duodenal ulcer due to h. pylori
B96.81	Helicobacter pylori [h. pylori] as the cause of diseases classified elsewhere
Helicobacter pylori gastritis
B96.81	Helicobacter pylori [h. pylori] as the cause of diseases classified elsewhere