PYLERA 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, 125 mg smaller capsule (size 3) containing tetracycline hydrochloride, 125 mg Tetracycline hydrochloride is encapsulated within a smaller capsule to create a barrier to avoid contact with bismuth subcitrate potassium. Each PYLERA capsule contains the following inactive ingredients: Magnesium Stearate NF, Lactose Monohydrate NF, Talc USP, Gelatin USP, and Titanium Dioxide NF, Printed in red ink. Bismuth subcitrate potassium is a white or almost white powder. 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 834.71. Metronidazole is a white to pale yellow crystalline powder. Metronidazole 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: Molecular weight: 171.2 Tetracycline hydrochloride is a yellow, odorless, crystalline powder. Tetracycline hydrochloride is stable in air, but exposure to strong sunlight causes it to darken. Tetracycline hydrochloride is (4S,4aS,5aS,6S,12aS)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-penta-hydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrochloride, with a molecular formula of C 22 H 24 N 2 O 8 ∙HCl and the following structural formula: Molecular weight: 480.90 Chemical Structure Chemical Structure

PYLERA is 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. To reduce the development of drug-resistant bacteria and maintain the effectiveness of PYLERA and other antibacterial drugs, PYLERA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria

Eradication of Helicobacter pylori in Patients with Active Duodenal Ulcer or History of Duodenal Ulcer Disease PYLERA 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

Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of PYLERA and other antibacterial drugs, PYLERA 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.

Each PYLERA capsule contains 140 mg of bismuth subcitrate potassium, 125 mg of metronidazole, and a smaller capsule inside containing 125 mg of tetracycline hydrochloride. The capsules are white and opaque, with the APTALIS ™ logo printed on the body and "BMT" printed on the cap. Each capsule of PYLERA contains: 140 mg of bismuth subcitrate potassium 125 mg metronidazole 125 mg of tetracycline hydrochloride

Administer three PYLERA 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 PYLERA after the morning and evening meal for 10 days ( Table 1 ). Table 1: Daily Dosing Schedule for PYLERA Time of dose Number of capsules of PYLERA 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 PYLERA 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 PYLERA capsules 4 times a day (after meals and at bedtime) for 10 days. Administer PYLERA with omeprazole 20 mg twice daily (after the morning and evening meals).

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. Maternal Toxicity: Risk of hepatotoxicity in pregnant women with high doses of intravenous tetracycline also resulting in stillborn or premature birth. 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). 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 PYLERA immediately and institute appropriate therapy. 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. Photosensitivity: avoid exposure to sun and sun lamps. Blood Dyscrasias: Use with caution in patients with a history of blood dyscrasias. Hepatic Impairment: Not recommended in patients with severe hepatic impairment. 5.1 Potential for Carcinogenicity Metronidazole, a component of PYLERA, 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 . It is unknown whether metronidazole is associated with carcinogenicity in humans

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 . Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in the newborn animals. If PYLERA is used during pregnancy, or if the patient becomes pregnant while taking PYLERA, advise the patient of the potential risk to the fetus

Maternal Toxicity Tetracycline, a component of PYLERA, administered during pregnancy at high doses (> 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

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. PYLERA, therefore, should not be used in this age group unless other drugs are not likely to be effective or are contraindicated

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 PYLERA 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 . If severe skin reactions occur, discontinue PYLERA immediately, and institute appropriate therapy

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 PYLERA therapy

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 PYLERA and institute appropriate therapy

Photosensitivity Photosensitivity, manifested by an exaggerated sunburn reaction, has been observed in patients taking tetracycline . 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 PYLERA to avoid exposure to the sun or sun lamps. Discontinue treatment at the first evidence of skin erythema

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 . Stool darkening should not be confused with melena

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

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. PYLERA is not recommended in patients with severe hepatic impairment (Child-Pugh C)

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+ <=> NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7

Development of Drug Resistant Bacteria Prescribing PYLERA 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

Drug Interactions Oral Contraceptives Concurrent use of PYLERA with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of PYLERA. Breakthrough bleeding has been reported. Advise women of child-bearing potential to use a different or additional form of contraception while taking PYLERA . Anticoagulants PYLERA 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 PYLERA is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding . Lithium In patients stabilized on relatively high doses of lithium, short-term use of PYLERA 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 PYLERA to detect any increase that may precede clinical symptoms of lithium toxicity . 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 PYLERA concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to PYLERA are available, and concomitant administration with busulfan is medically needed, monitor for busulfan toxicity and busulfan plasma concentrations and adjust the busulfan dose accordingly . Drugs that Prolong the QT interval QT prolongation has been reported with metronidazole, a component of PYLERA, particularly when administered with drugs with the potential for prolonging the QT interval.

Disulfiram: Psychotic reactions can occur; do not take concurrently or within the last 2 weeks of disulfiram. Alcohol: Abdominal cramps, nausea, vomiting, headaches, and flushing can occur; do not consume during therapy and for at least 3 days afterwards. Oral Contraceptives: Decreased efficacy possibly resulting in pregnancy; use a different or additional form of contraception. ( 5.14 , 7.3 ) Anticoagulants: Potentiation of the anticoagulant effect; Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored. ( 5.14 , 7.4 ) Lithium: Increased lithium serum concentrations; measure serum lithium and serum creatinine concentrations during therapy. ( 5.14 , 7.5 ) Antacids, Multivitamins or Dairy Products: Decreased absorption of PYLERA; do not take concomitantly. Busulfan: Increased busulfan serum concentrations; avoid concomitant use, monitor for busulfan toxicity. CYP inducers and CYP inhibitors: Prolonged or accelerated half-life of metronidazole or concomitant medications; use with caution

Disulfiram Psychotic reactions have been reported in alcoholic patients who are using metronidazole, a component of PYLERA and disulfiram concurrently. PYLERA should not be given to patients who have taken disulfiram within the last two weeks

Alcohol Consumption of alcoholic beverages or administration of other products containing propylene glycol during treatment with PYLERA 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 PYLERA. Discontinue alcoholic beverage or other products containing propylene glycol during and for at least 3 days after therapy with PYLERA

Oral Contraceptives Concurrent use of PYLERA with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of PYLERA. Breakthrough bleeding has been reported. Women of child-bearing potential should use a different or additional form of contraception while taking PYLERA

Anticoagulants PYLERA 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 PYLERA is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding

Lithium In patients stabilized on relatively high doses of lithium, short-term use of PYLERA 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 PYLERA to detect any increase that may precede clinical symptoms of lithium toxicity

Antacids, Multivitamins, or Dairy Products The absorption of PYLERA 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 PYLERA. 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

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 PYLERA concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to PYLERA are available, and concomitant administration with busulfan is medically needed, monitor for busulfan toxicity and busulfan plasma concentrations and adjust the busulfan dose accordingly

Inhibitors of CYP450 liver enzymes The simultaneous administration of PYLERA and drugs that inhibit microsomal liver enzymes, such as cimetidine, may result in a prolonged half-life and decreased plasma clearance of metronidazole

Inducers of CYP450 liver enzymes The simultaneous administration of PYLERA 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 PYLERA.