HELIDAC THERAPY- bismuth subsalicylate chewable tablets/metronidazole tablets/tetracycline hydrochloride capsules

Pharmacokinetics: Bismuth Subsalicylate: Bismuth: registered Salicylic Acid: Metronidazole: Metronidazole is the major component appearing in the plasma, with lesser quantities of the 2-hydroxymethyl metabolite also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole also appears in cerebrospinal fluid, saliva, and human milk in concentrations similar to those found in plasma. The average elimination half-life in normal volunteers is 8 hours. The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(ß-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1. 73 m 2 Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. In patients with decreased liver function, plasma clearance of metronidazole is decreased. Tetracycline Hydrochloride: WARNINGS PRECAUTIONS Nursing Mothers The relative contribution of systemic versus local antimicrobial activity against H. pylori Microbiology: Mechanism of Action Activity In Vitro and In Vivo Helicobacter pylori in vitro CLINICAL STUDIES INDICATIONS AND USAGE Susceptibility Testing.

The components of HELIDAC Therapy (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride), in combination with an H 2 H. pylori H. pylori H. pylori CLINICAL STUDIES DOSAGE AND ADMINISTRATION To reduce the development of drug-resistant bacteria and maintain the effectiveness HELIDAC Therapy and other antibacterial drugs, HELIDAC Therapy should be used only to treat or prevent 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.

Adults: 2 2 Ingestion of adequate amounts of fluid, particularly with the bedtime dose of tetracycline hydrochloride, is recommended to reduce the risk of esophageal irritation and ulceration (see ADVERSE REACTIONS Missed doses can be made up by continuing the normal dosing schedule until the medication is gone. Patients should not take double doses. If more than 4 doses are missed, the prescriber should be contacted.

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. HELIDAC Therapy, therefore, should not be used in this age group unless other drugs are not likely to be effective or are contraindicated (see PRECAUTIONS
Central and Peripheral Nervous System Effects
Metronidazole Tetracycline 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 The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see ADVERSE REACTIONS
Cutaneous Reactions
Skin and subcutaneous disorders including Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome (drug rash with eosinophilia and systemic symptoms) have been reported. Discontinue treatment at the first evidence of a cutaneous reaction (see ADVERSE REACTIONS
Darkening of the Tongue and/or Black Stool
Bismuth subsalicylate may cause a temporary and harmless darkening of the tongue and/or black stool, generally reversible within several days after treatment is stopped (see ADVERSE REACTIONS
ADVERSE REACTIONS:
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 most common adverse reactions (>= 1%) reported in clinical trials when all three components of this therapy were given concomitantly are listed in Table 1 below. The majority of the adverse reactions were related to the gastrointestinal tract, were reversible, and infrequently led to discontinuation of therapy. CLINICAL STUDIES The additional adverse reactions (< 1%) reported in clinical trials when all three components of this therapy were given concomitantly are listed below and divided by body system: Gastrointestinal: Skin: PRECAUTIONS Cardiovascular: CNS: Musculoskeletal: Metabolic: Urogenital: Other: Other Important Adverse Reactions from Labeling for the Individual Components of HELIDAC Therapy Metronidazole Blood and Lymphatic system disorders: PRECAUTIONS Cardiac disorders: Gastrointestinal disorders: PRECAUTIONS Hypersensitivity/Immune system disorders: CONTRAINDICATIONS Metabolism and nutrition disorders: Nervous system disorders: WARNINGS Dermatologic disorders: Renal and urinary disorders: Other: Tetracycline Hydrochloride Blood and lymphatic system disorders: Gastrointestinal disorders: Nervous system disorders: Renal and urinary disorders: Skin and subcutaneous tissue disorders: WARNINGS Liver: Hypersensitivity reactions: To report SUSPECTED ADVERSE REACTIONS, contact Casper Pharma LLC. at 1-844-5-CASPER (1-844-522-7737) or FDA at 1-800-FDA-1088 or www. gov/medwatch.

Methoxyflurane DRUG INTERACTIONS Disulfiram DRUG INTERACTIONS Alcohol DRUG INTERACTIONS Renal Impairment ADVERSE REACTIONS Hypersensitivity Reactions ADVERSE REACTIONS Allergy to Aspirin or other Salicylates

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. Use HELIDAC Therapy with caution in patients with mild to moderate hepatic impairment. HELIDAC Therapy may not be appropriate for patients with severe hepatic impairment (Child-Pugh C) (see DOSAGE AND ADMINISTRATION CLINICAL PHARMACOLOGY

Laboratory Test Interactions
Bismuth absorbs x-rays and may interfere with x-ray diagnostic procedures of the gastrointestinal tract. Bismuth subsalicylate may cause a temporary and harmless darkening of the stool. However, this change does not interfere with standard tests for occult blood. Metronizadole 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.
DRUG INTERACTIONS:
Do not administer methoxyflurane to patients taking HELIDAC Therapy. The concurrent use of tetracycline hydrochloride, a component of HELIDAC Therapy, with methoxyflurane has been reported to result in fatal renal toxicity (see CONTRAINDICATIONS Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. HELIDAC Therapy should not be given to patients who have taken disulfiram within the last 2 weeks (see CONTRAINDICATIONS Consumption of alcoholic beverages or administration of other products containing propylene glycol during treatment with HELIDAC Therapy 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 HELIDAC Therapy. Discontinue alcoholic beverage or other products containing propylene glycol during and for at least 3 days after therapy with HELIDAC Therapy (see CONTRAINDICATIONS Concurrent use of HELIDAC Therapy with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of HELIDAC Therapy. Breakthrough bleeding has been reported. Women of child-bearing potential should use a different or additional form of contraception while taking HELIDAC Therapy. HELIDAC Therapy may alter the anticoagulant effects of warfarin and other oral coumarin anticoagulants. Salicylates may cause an increased risk of bleeding when administered with anticoagulant therapy. 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 HELIDAC Therapy is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding. In patients stabilized on relatively high doses of lithium, short-term use of HELIDAC Therapy 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 HELIDAC Therapy to detect any increase that may precede clinical symptoms of lithium toxicity. The absorption of HELIDAC Therapy 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 HELIDAC Therapy. However, the clinical significance of reduced tetracycline systemic exposure is unknown as the relative contribution of systemic versus local antimicrobial activity against Helicobacter pylori Caution is advised in the administration of bismuth subsalicylate to patients taking medication for diabetes (possible enhanced hypoglycemic effect when given with salicylates) or patients taking aspirin (may increase the risk of salicylate toxicity), probenecid, or sulfinpyrazone (uricosuric effects of probenecid or sulfinpyrazone may be decreased) (see CONTRAINDICATIONS WARNINGS Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. HELIDAC Therapy should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to HELIDAC Therapy are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly. The simultaneous administration of HELIDAC Therapy and drugs that inhibit microsomal liver enzymes, such as cimetidine, may result in a prolonged half-life and decreased plasma clearance of metronidazole. The simultaneous administration of HELIDAC Therapy 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 HELIDAC Therapy. No long-term studies have been performed to evaluate the effect of HELIDAC Therapy on carcinogenesis, mutagenesis, or impairment of fertility. Bismuth subsalicylate Metronidazole in vitro in vivo Fertility studies have been conducted with male rats and mice with divergent results. Metronidazole, at doses up to 400 mg/kg/day (approximately 3 times the indicated human dose based on mg/m 2 Fertility studies have been performed in male mice at doses up to six times the maximum recommended human dose based upon mg/m 2 Tumors affecting the liver, lungs, mammary, and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters. Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). Malignant liver tumors were increased in male mice treated at approximately 1500 mg/m 2 Metronidazole has shown mutagenic activity in in vitro in vivo Metronidazole failed to produce any adverse effects on fertility or testicular function in male rats at doses up at 400 mg/kg/day (similar to the maximum recommended clinical dose, based on body surface area comparisons) for 28 days. However, rats treated at the same dose for 6 weeks or longer were infertile and showed severe degeneration of the seminiferous epithelium in the testes as well as marked decreases in testicular spermatid counts and epididymal sperm counts. Fertility was restored in most rats after an eight week, drug-free recovery period. Tetracycline hydrochloride There was evidence of mutagenicity by tetracycline hydrochloride in two in vitro mammalian cell assay systems (L51784y mouse lymphoma and Chinese hamster lung cells). Tetracycline hydrochloride had no effect on fertility when administered in the diet to male and female rats at a daily intake of 25 times the human dose. Pregnancy Category D WARNINGS The available human and animal data are summarized below for each of HELIDAC Therapy''s active ingredients: Tetracycline Tetracycline administered during pregnancy at high doses (greater than 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 WARNINGS Results of animal studies indicate that tetracycline crosses the placenta, is found in fetal tissues, and can have toxic effects on the developing fetus (often related to reversible retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. Multiple studies of limited design were conducted with pregnant and lactating female rats that resulted in fetuses and neonates with yellow discoloration of bones and teeth. Metronidazole Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. No fetotoxicity was observed when metronidazole was administered orally to pregnant mice at 10 mg/kg/day, approximately 5 percent of the indicated human dose (1500 mg/day) based on body surface area; however in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed. The relationship of these findings to the drug is unknown. Bismuth subsalicylate Animal reproductive studies have not been conducted with bismuth subsalicylate. It is also not known whether bismuth subsalicylate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Labor and Delivery: Nursing Mothers: Tetracycline is present in human milk at concentrations similar to maternal serum levels; however, it binds with calcium in human milk. Data indicate that oral absorption of tetracycline in infants is low due to the calcium binding in human milk. It is not known whether bismuth subsalicyate is excreted in human milk. Pediatric Use: H. pylori Tetracycline use in children may cause permanent discoloration of the teeth. Enamel hypoplasia has also been reported. HELIDAC Therapy should not be used in children up to 8 years of age (see WARNINGS Geriatric Use: CONTRAINDICATIONS Renal Impairment: CONTRAINDICATIONS Hepatic Impairment: PRECAUTIONS.

WARNINGS:
Metronidazole 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 PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility There are no adequate and well-controlled studies of HELIDAC Therapy in pregnant women. However, tetracycline can cause fetal harm when administered to a pregnant woman. The use of drugs of the tetracycline class during the second and third trimester of pregnancy can also cause permanent discoloration of the teeth (yellow-gray brown) and possibly inhibit bone development (See WARNINGS PRECAUTIONS, Pregnancy Tetracycline 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 (see PRECAUTIONS 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. HELIDAC Therapy, therefore, should not be used in this age group unless other drugs are not likely to be effective or are contraindicated (see PRECAUTIONS Metronidazole Tetracycline 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 The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see ADVERSE REACTIONS Use of HELIDAC Therapy is not recommended in children and teenagers who have or who are recovering from varicella (chicken pox) or influenza due to the risk of Reye’s syndrome, a rare but serious illness. If HELIDAC Therapy is used in this population and nausea or vomiting is present, patients are advised to consult a doctor because this could be an early sign of Reye’s syndrome. Skin and subcutaneous disorders including Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome (drug rash with eosinophilia and systemic symptoms) have been reported. Discontinue treatment at the first evidence of a cutaneous reaction (see ADVERSE REACTIONS.
OVERDOSAGE:
In case of an overdose, patients should contact a physician, poison control center, or emergency room. Bismuth Subsalicylate: Treatment: There is no specific antidote for salicylate poisoning. If there are no contraindications, vomiting should be induced as soon as possible with syrup of ipecac, or gastric lavage should be instituted, provided that no more than one hour has elapsed since ingestion. Activated charcoal and a cathartic may be administered as primary decontamination therapy in those cases where greater than one hour has elapsed since ingestion, or to further decontaminate the gastrointestinal tract in those who have already received ipecac or gastric lavage. Plasma salicylate levels may be useful; a common nomogram can be used to help predict the severity of intoxication. Supportive and symptomatic treatment should be provided, with emphasis on correcting fluid, electrolyte, blood glucose, and acid-base disturbances. Elimination may be enhanced by urinary alkalinization, hemodialysis, or hemoperfusion. Since hemodialysis aids in correcting acid-base disturbances, this method may be preferred over hemoperfusion. Metronidazole: Treatment: There is no specific antidote for metronidazole overdose. Management of the patient should consist of symptomatic and supportive therapy. Metronidazole is dialyzable. Tetracycline: Treatment: There is no specific antidote for tetracycline overdose. Management of the patient should consist of symptomatic and supportive therapy. Tetracycline is not dialyzable.
CLINICAL STUDIES:
Eradication of H. pylori Study 2 evaluated the long-term outcome in patients treated for active duodenal ulcer by frequently monitoring for ulcer recurrence for up to 1 year after therapy. This study compared patients who received bismuth subsalicylate (BSS), metronidazole (MTZ), and tetracycline hydrochloride (TCN) for 2 weeks with ranitidine to those who received ranitidine alone. The ulcer recurrence rates at 6 months (Table 3) and one year (Table 4) regardless of post-treatment eradication status are summarized below for duodenal ulcer patients who were H. pylori Eradication of H. pylori dagger Evaluable patients were defined as having a history of a confirmed duodenal ulcer prior to treatment and having taken >= 70% of each component of HELIDAC Therapy (bismuth subsalicylate, metronidazole, tetracycline hydrochloride) during the 14-day dosing period. Eradication was defined as no evidence of H. pylori double dagger Patients were included in the analysis if they had documented H. pylori Compliance with the triple therapy regimen was also evaluated in the clinical study. In the intent-to-treat population, 93% of the HELIDAC Therapy group took at least 75% of their medication. Tabel-2 Tabel-3-4 Tabel-5.

Casper Pharma LLC

HELIDAC THERAPY- bismuth subsalicylate chewable tablets/metronidazole tablets/tetracycline hydrochloride capsules Product manual source documgent