BISMUTH SUBCITRATE: 167 Adverse Event Reports & Safety Profile

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are a combination antimicrobial product containing bismuth subcitrate potassium, metronidazole, and tetracycline hydrochloride for oral administration. Each size 0 elongated capsule contains: bismuth subcitrate potassium, 140 mg metronidazole, USP, 125 mg two smaller film coated tablets containing tetracycline hydrochloride, USP, 125 mg Tetracycline hydrochloride is film coated to create a barrier to avoid contact with bismuth subcitrate potassium. Each bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsule contains the following inactive ingredients: colloidal silicon dioxide, FD&C blue#2 aluminum lake, FD&C red#40 aluminum lake, gelatin, lecithin (soya), magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, povidone, pregelatinized starch (maize), propylene glycol, shellac, sodium hydroxide, sodium lauryl sulphate, sodium stearyl fumarate, talc, titanium dioxide and xanthan gum. Bismuth subcitrate potassium is a white to off white powder, hygroscopic in nature. It is a soluble, complex bismuth salt of citric acid. The schematized empirical molecular formula of bismuth subcitrate potassium is Bi (Citrate) 2 K 5

• 3 H 2 O. The equivalent theoretical molecular formula is BiC 12 H 14 K 5 O 17 . The molecular mass of the theoretical molecular formula of a single unit of bismuth subcitrate potassium is 834.70. Metronidazole, USP is a white to pale yellow crystalline powder. Metronidazole, USP is 2-methyl-5-nitroimidazole-1-ethanol, with a molecular formula of C 6 H 9 N 3 O 3 and the following structural formula: Tetracycline hydrochloride, USP is a yellow crystalline powder. Tetracycline hydrochloride, USP is stable in air, but exposure to strong sunlight causes it to darken. Tetracycline hydrochloride, USP is (4S,4aS,5aS,6S,12aS)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacene-carboxamide monohydrochloride, with a molecular formula of C 22 H 24 N 2 O 8
• HCl and the following structural formula: metronidazole-stru-formula tetracycline-stru-formula

AND USAGE Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are a combination of metronidazole, a nitroimidazole antimicrobial, tetracycline, a tetracycline class antimicrobial and bismuth subcitrate potassium, indicated for use, in combination with omeprazole, for the treatment of patients with Helicobacter pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori . ( 1.1 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and other antibacterial drugs, bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.2 )

1.1 Eradication of Helicobacter pylori in Patients with Active Duodenal Ulcer or History of Duodenal Ulcer Disease Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules in combination with omeprazole are indicated for the treatment of patients with Helicobacter pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori . The eradication of Helicobacter pylori has been shown to reduce the risk of duodenal ulcer recurrence.

1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and other antibacterial drugs, bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules should be used to treat only indicated infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

AND ADMINISTRATION Administer three Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules 4 times a day (after meals and at bedtime) for 10 days. One omeprazole 20 mg capsule should be taken twice a day with Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules after the morning and evening meal for 10 days ( Table 1 ).

Table

1: Daily Dosing Schedule for Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules Time of dose Number of capsules of Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules Number of capsules of omeprazole 20 mg After morning meal 3 1 After lunch 3 0 After evening meal 3 1 At bedtime 3 0 Instruct patients to swallow the Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules whole with a full glass of water (8 ounces). Ingestion of adequate amounts of fluid, particularly with the bedtime dose, is recommended to reduce the risk of esophageal irritation and ulceration by tetracycline hydrochloride. If a dose is missed, patients should continue the normal dosing schedule until medication is gone. Patients should not take double doses. If more than 4 doses are missed, the prescriber should be contacted. Administer three Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules 4 times a day (after meals and at bedtime) for 10 days. ( 2 )

Administer Bismuth Subcitrate

Potassium, Metronidazole and Tetracycline Hydrochloride Capsules with omeprazole 20 mg twice daily (after the morning and evening meals). ( 2 )

Concurrent usage of Methoxyflurane. ( 4.1 , 7.1 ) Disulfiram usage within the last two weeks. ( 4.2 , 7.2 ) Alcoholic beverage consumption for at least three days during or after therapy. ( 4.3 , 7.3 ) Patients with Cockayne syndrome. ( 4.4 , 6.3 ) Severe renal impairment. ( 4.5 ) Women who are pregnant. ( 4.6 , 8.1 ) Known hypersensitivity to product components. ( 4.7 )

4.1 Methoxyflurane Do not administer methoxyflurane to patients taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride. The concurrent use of tetracycline hydrochloride, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride, with methoxyflurane has been reported to result in fatal renal toxicity <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> .

4.2 Disulfiram Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride is contraindicated in patients who have taken disulfiram within the last two weeks. Psychotic reactions have been reported in alcoholic patients who are using metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride, and disulfiram concurrently <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> .

4.3 Alcohol Alcoholic beverages or other products containing propylene glycol should not be consumed during and for at least 3 days after therapy with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride. A disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) may occur due to the interaction between alcohol or propylene glycol and metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span> .

4.4 Cockayne Syndrome Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride is contraindicated in patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole in patients with Cockayne syndrome <span class="opacity-50 text-xs">[see Adverse Reactions (6.3) ]</span>.

4.5 Severe Renal Impairment Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride is contraindicated in patients with severe renal impairment. The antianabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN) <span class="opacity-50 text-xs">[see Adverse Reactions (6.3) ]</span> . In patients with significantly impaired renal function, higher serum concentrations of tetracyclines may lead to azotemia, hyperphosphatemia, and acidosis.

4.6 Pregnancy Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride is contraindicated during pregnancy <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> .

4.7 Hypersensitivity Reactions Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride is contraindicated in patients with known hypersensitivity (e.g. urticaria, erythematous rash, flushing, and fever) to bismuth subcitrate potassium, metronidazole or other nitroimidazole derivatives, or tetracycline <span class="opacity-50 text-xs">[see Adverse Reactions (6.3) ]</span>.

REACTIONS Most frequently reported adverse reactions (≥5%): abnormal feces, diarrhea, nausea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules plus omeprazole (OBMT) to eradicate Helicobacter pylori was assessed in an open-label, randomized, active-controlled clinical trial conducted in North America. The duration of treatment was 10 days with 147 patients exposed to bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules plus omeprazole (OBMT) and 152 exposed to control, consisting of omeprazole, amoxicillin, and clarithromycin (OAC). The age of the population in the study ranged from 18 to 75 years, with 59% male patients and 59% Caucasian patients. Adverse drug reactions were reported in 58% of patients in the OBMT group and 59% of patients in the OAC group. There were no adverse reactions leading to discontinuation of the study during the clinical trial. Adverse reactions with an incidence of ≥ 5% in OBMT group include abnormal feces, diarrhea, nausea, and headache. Adverse drug reactions with an incidence of ≥ 5% in OAC group include diarrhea, dysgeusia, dyspepsia, nausea and headache.

Table

2 lists adverse reactions with an incidence of ≥ 1%, in either group (OBMT vs OAC) and in order of decreasing incidence for the OBMT group.

Table

2: Adverse reactions with an incidence of ≥ 1% from North American trial, [n (%)]

Preferred

Term OBMT OBMT = Omeprazole + Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules (n = 147) OAC OAC = Omeprazole + Amoxicillin + Clarithromycin; (n = 152) Gastrointestinal disorders Abnormal feces Dark stools [ see Warnings and Precautions ( 5.9 ) ] 23 (15.6%) 7 (4.6%)

Nausea

12 (8.2%) 14 (9.2%)

Diarrhea

10 (6.8%) 20 (13.2%)

Abdominal Pain

7 (4.8%) 2 (1.3%)

Dyspepsia

4 (2.7%) 10 (6.6%)

Constipation

2 (1.4%) 5 (3.3%)

Dry Mouth

2 (1.4%) 1 (0.7%)

Flatulence

0 4 (2.6%)

Glossitis

0 2 (1.3%) General disorders and administration site conditions Asthenia 5 (3.4%) 2 (1.3%) Infections and infestations Vaginal infection 4 (2.7%) 3 (2.0%) Nervous system disorders Headache 8 (5.4%) 8 (5.3%)

Dysgeusia

6 (4.1%) 18 (11.8%)

Dizziness

4 (2.7%) 4 (2.6%)

Investigations

Laboratory test abnormal 3 (2.0%) 4 (2.6%) Alanine aminotransferase increased 2 (1.4%) 0 Aspartate aminotransferase increased 2 (1.4%) 0 Renal and urinary disorders Urine abnormality 2 (1.4%) 0 Skin and subcutaneous tissue disorders Rash Maculo-Papular 2 (1.4%) 0 Rash 1 (0.7%) 3 (2.0%)

Pruritus

0 4 (2.6%) Adverse reactions with an incidence of <1% for OBMT group are: back pain, vomiting, tongue darkening [ see Warnings and Precautions ( 5.9 ) ] , anxiety, gastritis, gastroenteritis, myalgia, chest pain, increased appetite, blood creatine phosphokinase increased, malaise, somnolence, tachycardia, duodenal ulcer, visual disturbance, weight increased.

6.2 Postmarketing Experience Additionally, the following adverse reactions, presented by system organ class in alphabetical order, have been identified during post approval use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders : abdominal distention, eructation, flatulence General disorders and administration site conditions : chest discomfort, fatigue Infections and infestations : candidiasis, pseudomembranous colitis ( Clostridium difficile colitis)

Nervous

Systems : peripheral neuropathy Skin and subcutaneous disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome (drug rash with eosinophilia and systemic symptoms) [see Warnings and Precautions ( 5.5 )]

6.3 Other Important Adverse Reactions from Labeling for the Individual Components of Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules Metronidazole Blood and Lymphatic system disorders: Reversible neutropenia (leucopenia) in cases of prolonged treatment; rarely reversible thrombocytopenia however no persistent hematological abnormalities attributable to metronidazole have been observed [ see Warnings and Precautions ( 5.10 ) ] . Cardiac disorders: QT prolongation has been reported with metronidazole, particularly when administered with drugs with the potential for prolonging the QT interval. Flattening of the T-wave may be seen in electrocardiographic tracings. Gastrointestinal disorders: Nausea, vomiting, diarrhea, abdominal pain, constipation, anorexia, metallic taste, furry tongue, glossitis, stomatitis and candida overgrowth. Hypersensitivity/Immune system disorders: Acute generalized exanthematous pustulosis (AGEP) <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span>, urticaria, erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever <span class="opacity-50 text-xs">[see Contraindications ( 4.6 )]</span> . Metabolism and nutrition disorders: Pancreatitis. Nervous system disorders: Convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, headache, syncope, dizziness, vertigo, incoordination, ataxia, tinnitus, hearing impairment, hearing loss, confusion, dysarthria, irritability, depression, weakness, and insomnia [ see Warnings and Precautions ( 5.6 ) ] . Dermatologic disorders: Erythematous rash and pruritus. Renal and urinary disorders: Dysuria, cystitis, polyuria, incontinence, darkened urine, and a sense of pelvic pressure. Hepatic : Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne Syndrome (latency from drug start to signs of liver failure as short as 2 days) <span class="opacity-50 text-xs">[see Contraindications ( 4.3 ) ]</span> . Other: Dyspareunia, decrease of libido, proctitis, joint pains.

Tetracycline Hydrochloride

Blood and lymphatic system disorders: Hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, neutropenia, and eosinophilia. Gastrointestinal disorders: Nausea, vomiting, diarrhea, anorexia, glossitis, black hairy tongue, dysphagia, enterocolitis, inflammatory lesions (with Candida overgrowth) in the anogenital region, esophagitis and esophageal ulceration. Nervous system disorders: Intracranial hypertension including pseudotumor cerebri, tinnitus, and myasthenic syndrome. Renal and urinary disorders: Increased BUN. Skin and subcutaneous tissue disorders: Maculopapular and erythematous rashes, onycholysis, fixed drug eruption, discoloration of the nails, exfoliative dermatitis and photosensitivity have been rarely reported [ see Warnings and Precautions ( 5.8 ) ] . Liver : Hepatotoxicity and liver failure. Hypersensitivity reactions : Urticaria, angioedema, anaphylaxis, Henoch-Schonlein purpura, pericarditis, exacerbation of systemic lupus erythematosus, and serum sickness-like reactions.

AND PRECAUTIONS Fetal Toxicity: Advise pregnant women of the risk throughout pregnancy for retardation of skeletal development seen in animal studies and permanent discoloration of teeth with tetracycline if used during the second or third trimester. ( 5.2 , 8.1 )

Maternal

Toxicity: Risk of hepatotoxicity in pregnant women with high doses of intravenous tetracycline also resulting in stillborn or premature birth. ( 5.3 , 8.1 )

Tooth

Enamel discoloration and hypoplasia: permanent discoloration may develop with use during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years). ( 5.4 )

Severe Cutaneous Adverse

Reactions: Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with metronidazole. If symptoms or signs of SCARs develop, discontinue bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules immediately and institute appropriate therapy. ( 5.5 ) Central and Peripheral Nervous System Effects: encephalopathy, convulsive seizures, aseptic meningitis and peripheral neuropathy with metronidazole, intracranial hypertension with tetracycline and neurotoxicity with bismuth-containing products. Monitor patients with CNS conditions closely and discontinue promptly if abnormal neurologic signs develop. ( 5.6 ) Photosensitivity: avoid exposure to sun and sun lamps. ( 5.8 )

Blood

Dyscrasias: Use with caution in patients with a history of blood dyscrasias. ( 5.10 )

Hepatic

Impairment: Not recommended in patients with severe hepatic impairment. ( 5.11 )

5.1 Potential for Carcinogenicity Metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, has been shown to be carcinogenic in mice and rats. Tumors affecting the liver, lungs, mammary and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters [ see Nonclinical Toxicology ( 13 ) ] . It is unknown whether metronidazole is associated with carcinogenicity in humans.

5.2 Fetal Toxicity Tetracycline can cause fetal harm when administered to a pregnant woman. Based on animal data, use of drugs of the tetracycline class during the second and third trimester of pregnancy can cause permanent discoloration of the teeth (yellow-gray brown) and possibly inhibit bone development [ see Warnings and Precautions ( 5.4 ) ] . Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in the newborn animals. If bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are used during pregnancy, or if the patient becomes pregnant while taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, advise the patient of the potential risk to the fetus [ see Contraindications ( 4.5 ) and Use in Specific Populations ( 8.1 ) ] .

5.3 Maternal Toxicity Tetracycline, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, administered during pregnancy at high doses (&gt; 2 g IV) was associated with rare but serious cases of maternal hepatotoxicity. This syndrome may result in stillborn or premature birth due to maternal pathology [ see Contraindications ( 4.5 ) and Use in Specific Populations ( 8.1 ) ] .

5.4 Tooth Enamel Discoloration and Hypoplasia The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug, but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, therefore, should not be used in this age group unless other drugs are not likely to be effective or are contraindicated [ see Use in Specific Populations ( 8.4 ) ] .

5.5 Severe Cutaneous Adverse Reactions Metronidazole: Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of metronidazole. Symptoms can be serious and potentially life threatening. If symptoms or signs of SCARs develop, discontinue bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules immediately and institute appropriate therapy. Tetracycline: Fixed drug eruptions have occurred with tetracycline and have been associated with worsening severity upon subsequent administrations, including generalize bullous fixed drug eruption <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.3 )]</span>. If severe skin reactions occur, discontinue Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules immediately, and institute appropriate therapy.

5.6 Central and Peripheral Nervous System Effects Metronidazole : Convulsive seizures, encephalopathy, aseptic meningitis and peripheral neuropathy (including optic neuropathy) have been reported. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Aseptic meningitis symptoms may occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. Tetracycline : Intracranial hypertension (IH), including pseudotumor cerebri, has been associated with the use of tetracyclines. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin should be avoided because isotretinoin is also known to cause IH. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation, patients should be monitored until they stabilize. Bismuth-containing products: Cases of neurotoxicity associated with excessive doses of various bismuth-containing products have been reported. Effects have been reversible with discontinuation of bismuth therapy. The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules therapy [ see Adverse Reactions ( 6.3 ) ] .

5.7 Development of Potential for Microbial Overgrowth Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with an antifungal agent. As with other antibacterial drugs, use of tetracycline hydrochloride may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, discontinue bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules and institute appropriate therapy.

5.8 Photosensitivity Photosensitivity, manifested by an exaggerated sunburn reaction, has been observed in patients taking tetracycline [ see Adverse Reactions ( 6.3 ) ] . Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs. Instruct patients taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules to avoid exposure to the sun or sun lamps. Discontinue treatment at the first evidence of skin erythema.

5.9 Darkening of the Tongue and/or Black Stool Bismuth subcitrate potassium may cause temporary and harmless darkening of the tongue and/or black stools, generally reversible within several days after treatment is stopped [ see Adverse Reactions ( 6.1 ) ] . Stool darkening should not be confused with melena.

5.10 Use in Patients with Blood Dyscrasias Metronidazole is a nitroimidazole, and should be used with care in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy [ see Adverse Reactions ( 6.3 ) ] .

5.11 Increased Drug Plasma Concentrations in Patients with Hepatic Impairment Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse events. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are not recommended in patients with severe hepatic impairment (Child-Pugh C) [ see Clinical Pharmacology ( 12.3 ) ] .

5.12 Laboratory Test Interactions Bismuth absorbs x-rays and may interfere with x-ray diagnostic procedures of the gastrointestinal tract. Bismuth subcitrate potassium may cause a temporary and harmless darkening of the stool. However, this change does not interfere with standard tests for occult blood. Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide (NAD+ &lt;=&gt; NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

5.13 Development of Drug Resistant Bacteria Prescribing bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

5.14 Drug Interactions Oral Contraceptives Concurrent use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules. Breakthrough bleeding has been reported. Advise women of child-bearing potential to use a different or additional form of contraception while taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules [ see Drug Interactions ( 7.3 ) ] .

Anticoagulants

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules may alter the anticoagulant effects of warfarin and other oral coumarin anticoagulants. Metronidazole has been reported to potentiate the anticoagulant effect of warfarin, and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. Tetracycline has been shown to depress plasma prothrombin activity. Closely monitor prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests if bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [ see Drug Interactions ( 7.4 ) ] . Lithium In patients stabilized on relatively high doses of lithium, short-term use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules may cause elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Monitor serum lithium and serum creatinine concentrations daily for several days after beginning treatment with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules to detect any increase that may precede clinical symptoms of lithium toxicity [ see Drug Interactions ( 7.5 ) ] .

Busulfan

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Do not administer bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules are available, and concomitant administration with busulfan is medically needed, monitor for busulfan toxicity and busulfan plasma concentrations and adjust the busulfan dose accordingly [ see Drug Interactions ( 7.7 ) ] . Drugs that Prolong the QT interval QT prolongation has been reported with metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules, particularly when administered with drugs with the potential for prolonging the QT interval.

INTERACTIONS Methoxyflurane: Risk of fatal renal toxicity; do not co-administer. ( 4.1 , 7.1 ) Disulfiram: Psychotic reactions can occur; do not take concurrently or within the last 2 weeks of disulfiram. ( 4.2 , 7.2 ) Alcohol: Abdominal cramps, nausea, vomiting, headaches, and flushing can occur; do not consume during therapy and for at least 3 days afterwards. ( 4.3 , 7.3 )

Oral

Contraceptives: Decreased efficacy possibly resulting in pregnancy; use a different or additional form of contraception. ( 5.14 , 7.4 ) Anticoagulants: Potentiation of the anticoagulant effect; Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored. ( 5.14 , 7.5 ) Lithium: Increased lithium serum concentrations; measure serum lithium and serum creatinine concentrations during therapy. ( 5.14 , 7.6 ) Antacids, Multivitamins or Dairy Products: Decreased absorption of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride; do not take concomitantly. ( 7.7 ) Busulfan: Increased busulfan serum concentrations; avoid concomitant use, monitor for busulfan toxicity. ( 7.8 ) CYP inducers and CYP inhibitors: Prolonged or accelerated half-life of metronidazole or concomitant medications; use with caution. ( 7.9 , 7.10 )

7.1 Methoxyflurane Do not administer methoxyflurane to patients taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride. The concurrent use of tetracycline hydrochloride, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride, with methoxyflurane has been reported to result in fatal renal toxicity <span class="opacity-50 text-xs">[see Contraindications (4.1) ]</span> .

7.2 Disulfiram Psychotic reactions have been reported in alcoholic patients who are using metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride and disulfiram concurrently. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride should not be given to patients who have taken disulfiram within the last two weeks <span class="opacity-50 text-xs">[see Contraindications (4.2) ]</span> .

7.3 Alcohol Consumption of alcoholic beverages or administration of other products containing propylene glycol during treatment with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride and for at least 3 days afterwards may cause a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) due to the interaction between alcohol or propylene glycol and metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride. Discontinue alcoholic beverage or other products containing propylene glycol during and for at least 3 days after therapy with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride <span class="opacity-50 text-xs">[see Contraindications (4.3) ]</span> .

7.4 Oral Contraceptives Concurrent use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride. Breakthrough bleeding has been reported. Women of child-bearing potential should use a different or additional form of contraception while taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride <span class="opacity-50 text-xs">[see Warnings and Precautions (5.14) ]</span>.

7.5 Anticoagulants Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride may alter the anticoagulant effects of warfarin and other oral coumarin anticoagulants. Metronidazole has been reported to potentiate the anticoagulant effect of warfarin, and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. Tetracycline has been shown to depress plasma prothrombin activity. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding <span class="opacity-50 text-xs">[see Warnings and Precautions (5.14) ]</span>.

7.6 Lithium In patients stabilized on relatively high doses of lithium, short-term use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride may cause elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Serum lithium and serum creatinine concentrations should be monitored several days after beginning treatment with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride to detect any increase that may precede clinical symptoms of lithium toxicity <span class="opacity-50 text-xs">[see Warnings and Precautions (5.14) ]</span>.

7.7 Antacids, Multivitamins, or Dairy Products The absorption of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride may be reduced if administered with antacids containing aluminium, calcium, or magnesium; preparations containing iron, zinc, or sodium bicarbonate; or milk or dairy products due to the interaction between these products and tetracycline. These products should not be consumed concomitantly with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride. However, the clinical significance of reduced tetracycline systemic exposure is unknown as the relative contribution of systemic versus local antimicrobial activity against Helicobacter pylori has not been established.

7.8 Busulfan Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Do not administer bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride are available, and concomitant administration with busulfan is medically needed, monitor for busulfan toxicity and busulfan plasma concentrations and adjust the busulfan dose accordingly <span class="opacity-50 text-xs">[see Warnings and Precautions (5.14) ]</span>.

7.9 Inhibitors of CYP450 liver enzymes The simultaneous administration of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride and drugs that inhibit microsomal liver enzymes, such as cimetidine, may result in a prolonged half-life and decreased plasma clearance of metronidazole.

7.10 Inducers of CYP450 liver enzymes The simultaneous administration of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride and drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations of metronidazole. Impaired clearance of phenytoin has also been reported in this situation. Monitor phenytoin concentrations during treatment with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride.