Helidac

HELIDAC Therapy consists of 112 bismuth subsalicylate 262.4-mg chewable tablets, 56 metronidazole 250-mg tablets, USP, and 56 tetracycline hydrochloride 500-mg capsules, USP, for oral administration.

Bismuth subsalicylate chewable tablets: Each pink round tablet contains 262.4 mg bismuth subsalicylate (102 mg salicylate) for oral administration.

Bismuth subsalicylate is a fine, white, odorless, and tasteless powder that is stable and non-hygroscopic. It is a highly insoluble salt of trivalent bismuth and salicylic acid.

Bismuth subsalicylate is 2-Hydroxybenzoic acid bismuth (3+) salt with the following structural formula:

Molecular weight: 362.11

Inactive Ingredients: Each bismuth subsalicylate chewable tablet contains calcium carbonate, D&C Red No. 27 aluminum lake, flavor, magnesium stearate, mannitol, povidone, saccharin sodium, and talc.

Metronidazole tablets, USP: Each round, white tablet contains 250 mg metronidazole. Metronidazole is 2-Methyl-5-nitroimidazole-1-ethanol, with the following structural formula:

Inactive Ingredients: Each metronidazole tablet contains colloidal silicon dioxide, hydroxypropyl cellulose, lactose (anhydrous), sodium starch glycolate, stearic acid, and microcrystalline cellulose

Tetracycline hydrochloride capsules, USP: Each black and yellow capsule contains 500 mg tetracycline hydrochloride. Tetracycline is a yellow, odorless, crystalline powder. Tetracycline is stable in air but exposure to strong sunlight causes it to darken. Its potency is affected in solutions of pH below 2 and is rapidly destroyed by alkali hydroxide solutions. Tetracycline is very slightly soluble in water, freely soluble in dilute acid and in alkali hydroxide solutions, sparingly soluble in alcohol, and practically insoluble in chloroform and ether.

Tetracycline hydrochloride is (4S,4aS,5aS,6S,12aS)-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride, with the following structural formula:

Inactive Ingredients:Each tetracycline hydrochloride capsule contains lactose, magnesium stearate and sodium lauryl sulfate; D & C yellow no.10, FD & C blue No 1, FD & C red no. 40, gelatin and titanium dioxide. It may also contain benzyl alcohol, butylparaben, edetate calcium disodium, FD & C yellow no. 6, methylparaben, propylparaben, silicon dioxide and sodium propionate.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid alcohol and products that have alcohol or propylene glycol in them while taking Helidac and for at least 72 hours after your last dose. Drinking alcohol or taking products that have alcohol or propylene glycol in them, like some cough syrups, may cause cramps, upset stomach, headaches, and flushing.
• You may get sunburned more easily. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.
• Do not use longer than you have been told. A second infection may happen.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take this medicine.
• Do not give to children and teenagers who have or are getting better from flu signs, chickenpox, or other viral infections due to the chance of Reye's syndrome. Reye's syndrome causes very bad problems to the brain and liver.
• Do not give to a child younger than 8 years of age.
• Birth control pills and other hormone-based birth control may not work as well to prevent pregnancy. Use some other kind of birth control also like a condom when taking Helidac.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• A burning, numbness, or tingling feeling that is not normal.
• Change in eyesight.
• Change in balance.
• Very bad dizziness or passing out.
• Seizures.
• Trouble speaking.
• Black, tarry, or bloody stools.
• Throwing up blood or throw up that looks like coffee grounds.
• Raised pressure in the brain has happened with this medicine. Most of the time, this will go back to normal after Helidac is stopped. Sometimes, loss of eyesight may happen and may not go away even after this medicine is stopped. Call your doctor right away if you have a headache or eyesight problems like blurred eyesight, seeing double, or loss of eyesight.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

[Prometheus Laboratories Inc.]

To reduce the development of drug-resistant bacteria and maintain the effectiveness of 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 bacteria.

Pharmacokinetics: Pharmacokinetics for the Helidac Therapy components (bismuth subsalicylate chewable tablets, metronidazole tablets, and tetracycline hydrochloride capsules) when coadministered has not been studied. There is no information about the gastric mucosal concentrations of bismuth, metronidazole, and tetracycline after administration of these agents concomitantly or in combination with an acid suppressive agent. The systemic pharmacokinetic information presented below is based on studies in which each product was administered alone.

Bismuth Subsalicylate: Upon oral administration, bismuth subsalicylate is almost completely hydrolyzed in the gastrointestinal tract to bismuth and salicylic acid. Thus, the pharmacokinetics of bismuth subsalicylate following oral administration can be described by the individual pharmacokinetics of bismuth and salicylic acid.

Bismuth: Less than 1% of bismuth from oral doses of bismuth subsalicylate is absorbed from the gastrointestinal tract into the systemic circulation. Absorbed bismuth is distributed throughout the body. Bismuth is highly bound to plasma proteins (> 90%). Bismuth has multiple disposition half-lives with an intermediate half-life of 5 to 11 days and a terminal half-life of 21 to 72 days. Elimination of bismuth is primarily through urinary and biliary routes with a renal clearance of 50 ± 18 mL/min. The mean trough blood bismuth concentration after 2 weeks oral administration of 787 mg bismuth subsalicylate (3 chewable tablets) four times daily under fasted condition was 5.1 ± 3.1 ng/mL. In another study, the mean trough blood bismuth concentration after 2 weeks oral administration of 525 mg bismuth subsalicylate (as PEPTO-BISMOL® liquid suspension) four times daily was 5 ng/mL with the highest value being 32 ng/mL.

Salicylic Acid: More than 80% of the salicylic acid is absorbed from oral doses of bismuth subsalicylate chewable tablets. Salicylic acid is about 90% plasma protein bound. The volume of distribution is about 170 mL/kg of body weight. Salicylic acid is extensively metabolized and about 10% is excreted unchanged in the urine. The metabolic clearance of salicylic acid is saturable; accordingly, nonlinear pharmacokinetics is observed at bismuth subsalicylate doses above 525 mg. Salicylic acid metabolic clearance is lower in females than in males. The terminal half-life of salicylic acid upon a single oral dose of 525 mg bismuth subsalicylate is between 2 to 5 hours. After a single oral dose of 525 mg bismuth subsalicylate (2 chewable tablets), the mean peak plasma salicylic acid concentration was 13.1 ± 3.4 μg/mL under fasted condition. The mean steady-state serum total salicylate concentration after 2 weeks oral administration of 525 mg bismuth subsalicylate (as PEPTO-BISMOL liquid suspension) four times daily was 24 μg/mL with the highest value being 70 μg/mL.

Metronidazole: Following oral administration, metronidazole is well absorbed, with peak plasma concentrations occurring between 1 and 2 hours after administration. Plasma concentrations of metronidazole are proportional to the administered dose, with oral administration of 250 mg producing a peak plasma concentration of 6 μg/mL. Studies reveal no significant bioavailability differences between males and females; however because of weight differences, the resulting plasma levels in males are generally lower.

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 m2.

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: Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in a biologically active form.

The relative contribution of systemic versus local antimicrobial activity against H. pylori for agents used in eradication therapy has not been established.

Microbiology: Bismuth subsalicylate, metronidazole, and tetracycline administered individually as combination therapy have been shown to be active against most strains of Helicobacter pylori in vitro, and in clinical infections as described in the CLINICAL STUDIES and INDICATIONS AND USAGE sections.

Helicobacter: Helicobacter pylori: In the Graham and Cutler studies, susceptibility testing was not performed for bismuth subsalicylate, metronidazole, or tetracycline. No adequate data were collected during the clinical studies to indicate that bismuth subsalicylate can either decrease or increase metronidazole MICs. (See CLINICAL STUDIES.)

Susceptibility testing of Helicobacter pylori isolates was performed in the P&GP study for metronidazole using agar dilution methodology1 and minimum inhibitory concentrations (MICs) were determined.

Susceptibility Testing of Helicobacter pylori: Susceptibility testing of Helicobacter pylori for metronidazole has not been standardized. No interpretive criteria have been established for testing metronidazole against H. pylori. The clinical significance of metronidazole MIC values against H. pylori is unknown.

This therapy is contraindicated in pregnant or nursing women, pediatric patients, in patients with renal or hepatic impairment, and in those with known hypersensitivity to bismuth subsalicylate, metronidazole or other nitroimidazole derivatives, or any of the tetracyclines. (See WARNINGS and PRECAUTIONS.) This product does not contain aspirin but should not be administered to those patients who have a known allergy to aspirin or salicylates.

Bismuth Subsalicylate

Children and teenagers who have or who are recovering from chicken pox or flu should NOT use this medicine to treat nausea or vomiting. If nausea or vomiting is present, patients are advised to consult a doctor because this could be an early sign of Reye's syndrome, a rare but serious illness.

There have been rare reports of neurotoxicity associated with excessive doses of bismuth subsalicylate. Effects have been reversible with discontinuation of therapy.

Metronidazole

Central Nervous System Effects: Encephalopathy and peripheral neuropathy: Cases of 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. Convulsive seizures have been reported in patients treated with metronidazole. Aseptic meningitis: 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.

The prevalence and severity of the neuropathy are directly related to the cumulative dose and duration of therapy, being most prevalent in patients taking high doses for prolonged treatment periods. The appearance of abnormal neurologic signs demands the prompt discontinuation of metronidazole therapy. Metronidazole should be administered with caution to patients with central nervous system diseases.

Pregnancy: Teratogenic Effects. 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 20 mg/kg/day approximately one and a half times the most frequently recommended human dose (750 mg/day) based on mg/kg body weight; 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.

Tetracycline

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 drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. TETRACYCLINE HYDROCHLORIDE IS A COMPONENT OF THE Helidac THERAPY, THEREFORE, Helidac THERAPY SHOULD NOT BE USED IN THESE PATIENT POPULATIONS. (See CONTRAINDICATIONS.)

Tetracycline hydrochloride, as a component of the Helidac Therapy, should not be used during pregnancy. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs. Treatment should be discontinued at the first evidence of skin erythema.

The antianabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN). While this is not a problem in those with normal renal function, in patients with significantly impaired renal function, higher serum levels of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis.

General

Prescribing Helidac Therapy in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Bismuth Subsalicylate

Bismuth subsalicylate may cause a temporary and harmless darkening of the tongue and/or black stool. Stool darkening should not be confused with melena.

Metronidazole

Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in plasma. (See CONTRAINDICATIONS.) Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of, or history of, blood dyscrasia. A mild leukopenia has been observed; however, no persistent hematologic abnormalities attributable to metronidazole have been observed.

Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with a candicidal agent.

Tetracycline

As with other antibiotics, use of tetracycline hydrochloride may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, tetracycline should be discontinued and appropriate therapy should be instituted.

Pseudotumor cerebri (benign intracranial hypertension) in adults has been associated with the use of tetracyclines. The usual clinical manifestations are headache and blurred vision. While this condition and related symptoms usually resolve soon after discontinuation of the tetracycline, the possibility for permanent sequelae exists.

Information for Patients: Each dose includes 4 pills: 2 pink round chewable tablets (bismuth subsalicylate), 1 white round tablet (metronidazole), and 1 black and yellow capsule (tetracycline hydrochloride). Each dose (all 4 pills) should be taken 4 times a day, at mealtimes and bedtime. Patients should be instructed to chew and swallow the pink round tablets (bismuth subsalicylate tablets) and to swallow the white round tablet (metronidazole tablet) and the black and yellow capsule (tetracycline hydrochloride capsule) whole with a full glass of water (8 ounces). Concomitantly prescribed H2 antagonist therapy should be taken as directed.

Administration 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.)

This treatment regimen includes salicylates. If taken with aspirin and ringing in the ears occurs, the prescriber should be consulted concerning discontinuation of the aspirin therapy until the Helidac Therapy is completed.

Concurrent use of tetracyclines may render oral contraceptives less effective. Patients should be advised to use a different or additional form of contraception. Breakthrough bleeding has been reported. Women who become pregnant while taking components of the Helidac Therapy should be advised to notify their prescriber immediately. (See CONTRAINDICATIONS and WARNINGS.)

Alcoholic beverages should be avoided while taking metronidazole and for at least 1 day afterward. (See Drug Interactions.)

Patients taking tetracycline hydrochloride should be cautioned to avoid exposure to sun or sun lamps. (See WARNINGS.)

Bismuth subsalicylate may cause temporary and harmless darkening of the tongue and/or black stool. Stool darkening should not be confused with melena (blood in the stool).

Patients should be counseled that antibacterial drugs, including Helidac Therapy, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Helidac Therapy is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Helidac Therapy or other antibacterial drugs in the future.

Drug Interactions: Individual components of the Helidac Therapy have a potential interaction with anticoagulants. Tetracycline has been shown to depress plasma prothrombin activity. Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. Salicylates may cause an increased risk of bleeding when administered with anticoagulant therapy. Therefore, monitoring anticoagulant therapy with appropriate adjustment of the anticoagulant dosage may be warranted if concurrent therapy is instituted.

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, probenecid, or sulfinpyrazone.

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium; preparations containing iron, zinc, or sodium bicarbonate; or milk or dairy products.

There is an anticipated reduction in tetracycline systemic absorption due to an interaction with bismuth and/or calcium carbonate, an excipient of bismuth subsalicylate tablets. The clinical significance of this is unknown as the relative contribution of systemic versus local antimicrobial activity against H. pylori for these agents has not been established.

Since bacteriostatic drugs, such as the tetracycline class of antibiotics, may interfere with the bactericidal action of penicillin, it is not advisable to administer these drugs concomitantly.

The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity.

Concurrent use of tetracycline may render oral contraceptives less effective. Patients should be advised to use a different or additional form of contraception. Breakthrough bleeding has been reported. Women who become pregnant while on the Helidac Therapy should be advised to notify their prescriber immediately.

The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole. The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported.

In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication.

Alcoholic beverages should not be consumed during metronidazole therapy and for at least 1 day afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur.

Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last 2 weeks.

Drug/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 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats. Prominent among the effects in the mouse was an increased incidence of pulmonary tumorigenesis. This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At very high dose levels, (approximately 500 mg/kg/day, which is approximately 33 times the most frequently recommended human dose for a 50 kg adult based on mg/kg body weight), there was a statistically significant increase in the incidence of malignant liver tumors in male mice. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects are statistically significant. Long-term, oral-dosing studies in the rat showed statistically significant increases in the incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats administered metronidazole over those noted in the concurrent female control groups. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.

There has been no evidence of carcinogenicity for tetracycline hydrochloride in studies conducted with rats and mice. Some related antibiotics (oxytetracycline, minocycline) have shown evidence of oncogenic activity in rats.

No long-term toxicity studies have been conducted with bismuth subsalicylate.

No long-term studies have been performed to evaluate the effect of the combined use of bismuth subsalicylate, metronidazole, and tetracycline on carcinogenesis, mutagenesis, or impairment of fertility.

Although metronidazole has shown mutagenic activity in a number of in vitro assay systems, studies in mammals (in vivo) have failed to demonstrate a potential for genetic damage.

In two in vitro mammalian cell assay systems (L51784y mouse lymphoma and Chinese hamster lung cells), there was evidence of mutagenicity by tetracycline hydrochloride at concentrations of 60 and 10 μg/mL, respectively.

Bismuth did not show mutagenic potential in the NTP salmonella plate assay.

No reproductive toxicity studies have been conducted with bismuth subsalicylate.

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.

Metronidazole, at doses up to 400 mg/kg/day (approximately 3.5 times the recommended maximum human dose based on mg/m2) for 28 days, failed to produce any adverse effects on fertility and testicular function in male rats. Fertility studies have been performed in mice at doses up to six times the maximum recommended human dose based on mg/m2 and have revealed no evidence of impaired fertility.

Pregnancy

Teratogenic Effects. Pregnancy Category D: Category D is based on the pregnancy category for tetracycline hydrochloride. (See CONTRAINDICATIONS and WARNINGS, Tetracycline and Metronidazole subsections.)

Non-teratogenic Effects: (See WARNINGS.)

Pregnant women with renal disease may be more prone to develop tetracycline-associated liver failure.

Labor and Delivery: The effect of this therapy on labor and delivery is unknown.

Nursing Mothers: Metronidazole and tetracycline are both secreted into human milk. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, and because of the potential for serious adverse reactions in nursing infants from tetracyclines, a decision should be made whether to discontinue nursing or to discontinue therapy, taking into account the importance of the therapy to the mother. Metronidazole is secreted in human milk in concentrations similar to those found in plasma. (See CONTRAINDICATIONS.)

Pediatric Use: Safety and effectiveness in pediatric patients infected with H. pylori have not been established. (See CONTRAINDICATIONS and WARNINGS.)

Geriatric Use: Clinical studies of Helidac Therapy did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Helidac Therapy. As stated in the CONTRAINDICATIONS section, this therapy is contraindicated in patients with renal or hepatic impairment.

The Helidac Therapy is supplied in a carton containing patient instructions, patient reminders, and 14 blister cards, each card containing the following daily dosage:

NDC 65483-495-14 carton containing 14 days of therapy

Store at controlled room temperature 20°-25°C (68°-77°F) [See USP].