FDA label 10e08da7-54b0-4d5e-a2e9-e00d85bf4471

WARNING: POTENTIAL FOR CARCINOGENICITY Metronidazole has been shown to be carcinogenic in mice and rats. It is unknown whether metronidazole is associated with carcinogenicity in humans (see WARNINGS ).

WARNINGS: Potential for Carcinogenicity 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 ). It is unknown whether metronidazole is associated with carcinogenicity in humans. Fetal Toxicity 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 ). Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in the newborn animals. Metronidazole usage in pregnancy has been evaluated in numerous studies. In one of these studies, an increased risk of cleft lip, with or without cleft palate, was noted in infants exposed to metronidazole in–utero; however these findings were not confirmed. If HELIDAC Therapy is used during pregnancy, or if the patient becomes pregnant while taking HELIDAC Therapy, the patient should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy ). Maternal Toxicity 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 ). 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 : Cases of convulsive seizures, encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole. 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. Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. Tetracycline : Intracranial hypertension (IH, 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, including bismuth subsalicylate have been reported. Effects have been reversible with discontinuation of therapy. 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 ). Risk of Reye's syndrome 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. 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 ).

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. Table 1: Incidence of Adverse Reactions Reported in Clinical Trials (≥ 1%) † * darkening of the tongue ** black or dark stools *** metallic taste † Includes reactions reported at ≥ 1% in patients taking bismuth subsalicylate, metronidazole, and tetracycline in Studies 1, 2, 3, and 4 (see CLINICAL STUDIES ). ‡ In Studies 1, 2, and 3(N = 197), most patients were on concomitant acid suppression therapy. Bismuth Subsalicylate, Metronidazole, and Tetracycline ‡ (N = 266) Adverse Reactions % Patients Nausea 12.0 Diarrhea 6.8 Abdominal Pain 6.8 Melena 3.0 Upper Respiratory Infection 2.3 Constipation 1.9 Anorexia 1.5 Asthenia 1.5 Vomiting 1.5 Discolored Tongue* 1.5 Headache 1.5 Dyspepsia 1.5 Dizziness 1.5 Stool Abnormality** 1.1 Duodenal Ulcer 1.1 Sinusitis 1.1 Taste Perversion*** 1.1 Flatulence 1.1 GI Hemorrhage 1.1 Pain 1.1 Insomnia 1.1 Anal Discomfort 1.1 Paresthesia 1.1 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: dry mouth, dysphagia, eructation, GI monilia, glossitis, intestinal obstruction, rectal hemorrhage, stomatitis Skin: acne, ecchymosis, photosensitivity reaction (see PRECAUTIONS ), pruritus, rash Cardiovascular: cerebral ischemia, chest pain, hypertension, myocardial infarction CNS: nervousness, somnolence Musculoskeletal: arthritis, rheumatoid arthritis, tendonitis Metabolic: SGOT increase, SGPT increase Urogenital: urinary tract infection Other: conjunctivitis, flu syndrome, infection, malaise, neoplasm, rhinitis, syncope, tooth disorder Other Important Adverse Reactions from Labeling for the Individual Components of HELIDAC Therapy Metronidazole Blood and Lymphatic system disorders: R eversible neutropenia (leucopenia) in cases of prolonged treatment; rarely reversible thrombocytopenia however no persistent hematological abnormalities attributable to metronidazole have been observed (see PRECAUTIONS ). Cardiac disorders: 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 (see PRECAUTIONS ). Hypersensitivity/Immune system disorders: Urticaria, erythematous rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever (see CONTRAINDICATIONS ). Metabolism and nutrition disorders: Pancreatitis. Nervous system disorders: Convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia (see WARNINGS ). Dermatologic disorders: Erythematous rash and pruritus. Renal and urinary disorders: Dysuria, cystitis, polyuria, incontinence, darkened urine, and a sense of pelvic pressure. Other: D yspareunia, 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, DRESS syndrome (drug rash with eosinophilia and systemic symptoms), Steven-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, onycholysis, discoloration of the nails, exfoliative dermatitis and photosensitivity have been rarely reported (see WARNINGS ). Liver : Hepatotoxicity and liver failure. Hypersensitivity reactions : Urticaria, angioedema, anaphylaxis, Henoch-Schonlein purpura, pericarditis, exacerbation of systemic lupus erythematosus, and serum sickness-like reactions.

<table ID="t1b" width="100%"> <caption>Table 1: Incidence of Adverse Reactions Reported in Clinical Trials (&#x2265; 1%)^&#x2020; </caption> <col width="50.350%" align="left"/> <col width="49.650%" align="left"/> <tfoot> <tr> <td colspan="2" align="left" valign="top"> <paragraph styleCode="footnote">* darkening of the tongue </paragraph> </td> </tr> <tr> <td colspan="2" align="left" valign="top"> <paragraph styleCode="footnote">** black or dark stools </paragraph> </td> </tr> <tr> <td colspan="2" align="left" valign="top"> <paragraph styleCode="footnote">*** metallic taste </paragraph> </td> </tr> <tr> <td colspan="2" align="left" valign="top"> <paragraph styleCode="footnote">&#x2020; Includes reactions reported at <content styleCode="bold">&#x2265;</content>1% in patients taking bismuth subsalicylate, metronidazole, and tetracycline in Studies 1, 2, 3, and 4 </paragraph> </td> </tr> <tr> <td colspan="2" align="left" valign="top"> <paragraph styleCode="footnote">(see <linkHtml href="#s95">CLINICAL STUDIES</linkHtml>). </paragraph> </td> </tr> <tr> <td colspan="2" align="left" valign="top"> <paragraph styleCode="footnote">&#x2021; In Studies 1, 2, and 3(N = 197), most patients were on concomitant acid suppression therapy. </paragraph> </td> </tr> </tfoot> <tbody> <tr> <td align="left" valign="top" styleCode="Toprule Botrule Lrule Rrule"/> <td align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Bismuth Subsalicylate, Metronidazole, and</content> <content styleCode="bold">Tetracycline &#x2021; (N = 266)</content> </td> </tr> <tr> <td align="center" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Adverse Reactions</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">% Patients</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Nausea </td> <td align="center" valign="top" styleCode="Botrule Rrule">12.0 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Diarrhea </td> <td align="center" valign="top" styleCode="Botrule Rrule">6.8 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Abdominal Pain </td> <td align="center" valign="top" styleCode="Botrule Rrule">6.8 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Melena </td> <td align="center" valign="top" styleCode="Botrule Rrule">3.0 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Upper Respiratory Infection </td> <td align="center" valign="top" styleCode="Botrule Rrule">2.3 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Constipation </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.9 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Anorexia </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.5 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Asthenia </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.5 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Vomiting </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.5 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Discolored Tongue* </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.5 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Headache </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.5 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Dyspepsia </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.5 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Dizziness </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.5 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Stool Abnormality** </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Duodenal Ulcer </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Sinusitis </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Taste Perversion*** </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Flatulence </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">GI Hemorrhage </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Pain </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Insomnia </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Anal Discomfort </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Paresthesia </td> <td align="center" valign="top" styleCode="Botrule Rrule">1.1 </td> </tr> </tbody> </table>