Drugs Details

Drugs Info of Helidac
Drugs Details
  • Drugs Type  : Multum
  • Date : 10th Jan 2015 04:07 am
  • Brand Name : Helidac
  • Generic Name : bismuth subsalicylate, metronidazole, and tetracycline (Pronunciation: BIZ muth sub sa LISS i late, MET roe NYE da zole, and tet ra SYE kleen)
Descriptions

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:

 

Bismuth subsalicylate Structural Formula Illustration

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:

 

Metronidazole Structural Formula Illustration

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:

 

Tetracycline hydrochloride Structural Formula Illustration

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.

What are the possible side effects of Helidac (Helidac)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • severe diarrhea, or diarrhea that is watery or bloody;
  • confusion, severe headache, ringing in your ears, dizziness;
  • vision problems, pain behind your eyes;
  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
  • seizure (convulsions); or
  • pale skin, feeling...

Read All Potential Side Effects and See Pictures of Helidac »

What are the precautions when taking bismuth subsalicylate (Helidac)?

See also Side Effects section.

Before taking this product, tell your doctor or pharmacist if you are allergic to bismuth subsalicylate, metronidazole, or tetracycline; or to aspirin or salicylates; or to other nitroimidazoles (e.g., tinidazole); or to other tetracyclines (e.g., doxycycline); or to other bismuth products; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: kidney disease, liver disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially...

Read All Potential Precautions of Helidac »

This monograph has been modified to include the generic and brand name in many instances.

Indications

The components of the HELIDAC Therapy (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride), in combination with an H2 antagonist, are indicated for the eradication of H. pylori for treatment of patients with H. pylori infection and duodenal ulcer disease (active or a history of duodenal ulcer). Appropriate doses of H2 antagonists for the treatment of active duodenal ulcers should be prescribed in all patients. The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence in patients with active duodenal ulcer disease. (See Clinical Studies and DOSAGE AND ADMINISTRATION.)

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 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.

Dosage Administration

Adults: The recommended dosages are: bismuth subsalicylate, 525 mg (two 262.4 mg-chewable tablets), metronidazole, 250 mg (one 250-mg tablet), and tetracycline hydrochloride, 500 mg (one 500-mg capsule) taken four times daily for 14 days plus an H2 antagonist approved for the treatment of acute duodenal ulcer. Patients should be instructed to take the medicines at mealtimes and at bedtime. The bismuth subsalicylate tablets should be chewed and swallowed. The metronidazole tablet and tetracycline hydrochloride capsule should be swallowed whole with a full glass of water (8 ounces). Concomitantly prescribed H2 antagonist therapy should be taken as directed.

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.

How Supplied

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

8 bismuth subsalicylate 262.4-mg chewable tablets, each pink round tablet engraved “PG 11”

4 metronidazole 250-mg tablets are round, white, debossed with “WPI” on one side and “3969” on the other.

4 tetracycline hydrochloride 500-mg capsules, each black/yellow capsule imprinted with “WPI” on the cap and “2235” on the body.

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

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

Bismuth subsalicylate tablets are manufactured by Norwich Pharmaceuticals, Inc. Metronidazole 250-mg tablets, USP and tetracycline hydrochloride 500-mg capsules, USP are manufactured by Watson Pharmaceuticals, Inc. for : Prometheus Laboratories Inc., San Diego, CA 92121. REVISED June 2012

This monograph has been modified to include the generic and brand name in many instances.

Side Effects

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%)†

Adverse Reactions Bismuth Subsalicylate, Metronidazole, and Tetracycline ‡
(N = 266)
% Patients
Nausea 12
Diarrhea 6.8
Abdominal Pain 6.8
Melena 3
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
* 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.

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 WARNINGS), 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: reversible neutropenia (leucopenia) in cases of prolonged treatment; rarely reversible thrombocytopenia however no persistent haematological abnormalities attributable to metronidazole have been observed. (See PRECAUTIONS)

Cardiac disorders: Flattening of the T-wave may be seen in electrocardiographic tracings.

Gastrointestinal disorders: Furry tongue, glossitis, stomatitis; these may be associated with a sudden overgrowth of candida which may occur during therapy; epigastric distress (See PRECAUTIONS)

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: Cases of pancreatitis have been reported, which abated on withdrawal of the drug, have been reported.

Nervous system disorders: The most serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. In addition, patients have reported syncope, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia. (See WARNINGS)

Renal disorders: Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance.

Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness.” Crohn's disease patients are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established.

Tetracycline Hydrochloride

Blood and lymphatic system disorders: Hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, neutropenia, and eosinophilia.

Gastrointestinal disorders: Anorexia, nausea, epigastric distress, glossitis, black hairy tongue, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region. Rare instances of esophagitis and esophageal ulceration have been reported in patients taking the tetracycline-class antibiotics in capsule and tablet form. Most of the patients who experienced esophageal irritation took the medication immediately before going to bed. Permanent discoloration of teeth may be caused when tetracycline is used during tooth development. Enamel hypoplasia has also been reported. (See WARNINGS)

Hypersensitivity: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis, exacerbation of systemic lupus erythematosus and serum sickness-like reactions, as fever, rash, and arthralgia.

Liver disorders: Hepatotoxicity and liver failure have been observed in patients receiving large doses of tetracycline and in tetracycline-treated patients with renal impairment. Increases in liver enzymes and hepatic toxicity have been reported rarely.

Nervous system disorders: Pseudotumor cerebri (benign intracranial hypertension) in adults and bulging fontanels in infants, Visual disturbances. Tinnitus and myasthenic syndrome have been reported rarely.

Renal and urinary disorders: Rise in BUN has been reported and is possibly dose related (See CONTRAINDICATIONS)

Skin and subcutaneous tissue disorders: Maculopapular and erythematous rashes have been reported. Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme have been reported. Onycholysis, discoloration of the nails, exfoliative dermatitis, and photosensitivity have been rarely reported. (See PRECAUTIONS)

Other: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function studies are known to occur.

Read the Helidac (bismuth subsalicylate) Side Effects Center for a complete guide to possible side effects

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Interactions

Methoxyflurane

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)

Disulfiram

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. (See CONTRAINDICATIONS)

Alcohol

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)

Oral Contraceptives

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. Women who become pregnant while on the HELIDAC Therapy should be advised to notify their prescriber immediately.

Anticoagulants

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.

Lithium

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 to detect any increase that may precede clinical symptoms of lithium toxicity.

Antacids, Multivitamins, or Dairy Products

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 has not been established.

Antidiabetic agents, Aspirin, Probenecid, or Sulfinpyrazone

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).

Penicillin

Bacteriostatic drugs, such as the tetracycline class of antibiotics, may interfere with the bactericidal action of penicillin; therefore pencillin should not be used concomitantly with HELIDAC Therapy.

Inhibitors of CYP450 liver enzymes

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.

Inducers of CYP450 liver enzymes

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.

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.

Read the Helidac Drug Interactions Center for a complete guide to possible interactions

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This monograph has been modified to include the generic and brand name in many instances.

Warnings

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 pregnancy can also 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 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. (See PRECAUTIONS)

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 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.

Tetracycline

Cases of pseudotumor cerebri (benign intracranial hypertension) in adults have been associated with the use of tetracycline. 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.

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 chicken pox or flu 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.

Pregnancy

Teratogenic Effects

HELIDAC Therapy contains bismuth subsalicylate, metronidazole, and tetracycline hydrochloride. 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 tetracycline during the second and third trimester pregnancy can cause permanent discoloration of the teeth (yellow-gray brown) and possibly inhibit bone development. Administration of oral tetracycline to pregnant animals at various doses resulted in yellow fluorescence in teeth and bones. 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.

The available human and animal data are summarized below for each of HELIDAC Therapy's active ingredients:

Tetracycline

Published case reports have described the yellowing of bones and teeth in human infants exposed to tetracycline during the second and third trimester of pregnancy. The yellowing is caused by the direct deposition of tetracycline during the mineralization process. This discoloration is more common during long-term use of the drug but has also been observed following repeated short-term courses. All tetracyclines form a stable calcium complex in any bone forming tissue. A decrease in fibula growth rate was observed in premature infants given oral tetracycline in doses of 25 mg/kg every six hours. This effect resolved when the drug was discontinued. One long-term follow-up study in children exposed to tetracycline in-utero showed no adverse effects on bone growth and development.

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 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

There are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero; however, these findings were not confirmed. In addition, more than ten randomized, placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited.

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.

Precautions

Development of Superinfections

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

As with other antibiotics, use of tetracycline hydrochloride may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs discontinue HELIDAC Therapy and institute appropriate therapy.

Photosensitivity

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.

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. Stool darkening should not be confused with melena.

Use in Patients with Blood Dyscrasias

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 in clinical studies. Total and differential leukocyte counts are recommended before and after therapy. (See ADVERSE REACTIONS)

Development of Drug Resistant Bacteria

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

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.

Bismuth subsalicylate

No long-term toxicity studies have been conducted with bismuth subsalicylate. Bismuth did not show mutagenic potential in the NTP salmonella plate assay. No reproductive toxicity studies have been conducted with bismuth subsalicylate.

Metronidazole

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 the highest dose, (approximately 500 mg/kg/day, which is approximately 1.6 times the indicated human dose for a 60 kg adult based on body surface area), 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. 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.

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 base on mg/m²) for 28 days, failed to produce any adverse effects on fertility and testicular function in male rats. In another study where rats were treated with up to 400 mg/kg/day for 8 weeks, there was severe degeneration of the seminiferous epithelium in the testes which was associated with a marked decrease in testicular spermatid counts and epididymal sperm counts and a marked decrease in fecundity. These effects were partially reversible.

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. Another fertility study was performed in male mice at oral doses of 500 mg/kg/day (approximately 2 times the indicated human dose based on mg/m²) for 14 days. Metronidazole significantly decreased testes and epididymides weight, decreased sperm viability, and increased the incidence of abnormal sperm. The viability of sperm was normal by 2 months after the start of the treatment.

Tetracycline hydrochloride

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.

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

Teratogenic Effects. Pregnancy Category D

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 pregnancy can also 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 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. (See WARNINGS)

Non-teratogenic Effects
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 WARNINGS)

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 WARNINGS)

Labor and Delivery

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

Nursing Mothers

HELIDAC Therapy contains bismuth subcitrate potassium, metronidazole, and tetracycline hydrochloride. Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential for tumorigenicity shown for metronidazole in animal studies, a decision should be made whether to discontinue nursing or to discontinue metronidazole, taking into account the importance of the therapy to the mother. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of HELIDAC Therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

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

Safety and effectiveness in pediatric patients infected with H. pylori have not been established. 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

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 therapies. Bismuth subsalicylate, a component of HELIDAC Therapy, is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, additional monitoring may be required. (See CONTRAINDICATIONS)

Renal Impairment

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. (See CONTRAINDICATIONS)

Hepatic Impairment

Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in plasma. Use HELIDAC Therapy with caution in patients with hepatic impairment.

This monograph has been modified to include the generic and brand name in many instances.

 

OverDose

In case of an overdose, patients should contact a physician, poison control center, or emergency room. There is neither a pharmacologic basis nor data suggesting an increased toxicity of the combination compared to individual components.

Bismuth Subsalicylate

The main concern of an acute bismuth subsalicylate (BSS) overdose focuses on the salicylate burden and not on bismuth, since less than 1% of the bismuth is normally absorbed. Each 262.4-mg tablet of BSS contains an amount of salicylate comparable to approximately 130 mg aspirin. Acute ingestion of less than 150 mg/kg of aspirin (i.e., less than one tablet of bismuth subsalicylate per kilogram of body weight) is not expected to lead to toxicity. Mild to moderate toxicity may result from the ingestion of 150 to 300 mg/kg, while severe toxicity may occur from ingestions over 300 mg/kg. Salicylate intoxication is well described in the literature and presents a complex clinical picture. Multiple respiratory and metabolic effects result in fluid, electrolyte, glucose, and acid-base disturbances. Initial symptoms of salicylate toxicity include hyperpnea, nausea, vomiting, tinnitus, hyperpyrexia, lethargy, tachycardia, and confusion. In severe cases, these symptoms may progress to severe hyperpnea, convulsions, pulmonary or cerebral edema, respiratory failure, cardiovascular collapse, coma, and death.

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. (Note: An acidotic blood pH increases the un-ionized salicylate form, allowing more to reach the central nervous system.) 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

Single oral doses of metronidazole, up to 19.5 g in adults, have been reported without resultant serious toxicity in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia.

Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day.

Treatment

There is no specific antidote for metronidazole overdose. Management of the patient should consist of symptomatic and supportive therapy. Metronidazole is dialyzable.

Tetracycline

The acute toxicity of tetracycline in overdose is not well established in the literature. Therapeutic and overdose quantities of tetracycline can cause gastrointestinal symptoms such as nausea, vomiting, and diarrhea.

Treatment

There is no specific antidote for tetracycline overdose. Management of the patient should consist of symptomatic and supportive therapy. Tetracycline is not dialyzable.

 

ContrainDications

Methoxyflurane

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 PRECAUTIONS: DRUG INTERACTIONS)

Disulfiram

HELIDAC Therapy 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 HELIDAC, Therapy and disulfiram concurrently. (See PRECAUTIONS: DRUG INTERACTIONS)

Alcohol

Alcoholic beverages or other products containing propylene glycol should not be consumed during and for at least 3 days after therapy with HELIDAC Therapy. 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 HELIDAC Therapy. (See PRECAUTIONS: DRUG INTERACTIONS)

Renal Impairment

HELIDAC Therapy is contraindicated in patients with severe renal impairment. The antianabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN) (See ADVERSE REACTIONS). In patients with significantly impaired renal function, higher serum concentrations of tetracyclines may lead to azotemia, hyperphosphatemia, and acidosis.

Hypersensitivity Reactions

HELIDAC Therapy 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. (See ADVERSE REACTIONS)

Allergy to Aspirin or other Salicylates

HELIDAC Therapy does not contain aspirin but should not be administered to those patients who have a known allergy to aspirin or salicylates.

This monograph has been modified to include the generic and brand name in many instances.

Clinical Pharamacology

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 2hydroxymethyl 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-1yl-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

Tetracycline hydrochloride is absorbed (60%-90%) in the stomach and upper small intestine. The presence of food, milk or cations may significantly decrease the extent of absorption. In the plasma, tetracycline is bound to plasma proteins in varying degrees. It is concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in biologically active form. Tetracycline hydrochloride is distributed into most body tissues and fluids. It is distributed into the bile and undergoes varying degrees of enterohepatic recirculation. Tetracycline hydrochloride tends to localize in tumors, necrotic or ischemic tissue, liver and spleen and form tetracycline-calcium orthophosphate complexes at sites of new bone formation or tooth development. Tetracycline readily crosses the placenta and is excreted in high amounts in breast milk. (See PRECAUTIONS, Nursing Mothers) 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

Mechanism of Action

Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride are antibacterial agents. Metronidazole is metabolized through reductive pathways into reactive intermediates that have cytotoxic action. Tetracycline hydrochloride interacts with the 30S subunit of the bacterial ribosome and inhibits protein synthesis. The antibacterial action of bismuth salts is not well understood.

Activity In Vitro and In Vivo

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.

Susceptibility Test Methods

In one study, susceptibility testing of Helicobacter pylori isolates was performed for metronidazole using agar dilution methodology1 and minimum inhibitory concentrations (MICs) were determined.

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.

Clinical Studies

Eradication of H. pylori in Patients with Active Duodenal Ulcer Disease

Three clinical trials in the U.S. (Studies 1, 2 and 3) evaluated the effect of therapy on the eradication of H. pylori using bismuth subsalicylate, metronidazole, and tetracycline hydrochloride. The patient population in these studies consisted predominantly of duodenal ulcer patients with active disease. In addition to bismuth subsalicylate, metronidazole, tetracycline hydrochloride triple therapy, most patients were also prescribed antisecretory therapy at doses recommended for ulcer healing, with the majority receiving ranitidine. The efficacy in these studies was assessed using H. pylori eradication, or cure of infection. Use of cure of infection as a surrogate for reduced ulcer recurrence is based on an extensive review of the literature. Eradication rates are derived from results of Studies 1 (randomized, controlled study) and Study 3 (uncontrolled, nonrandomized) and are shown in Table 2. H. pylori eradication was defined as no positive test (culture, histology, rapid urease, or 13C breath test) at least 4 weeks following the end of treatment. In the analysis performed, dropouts and patients with missing H. pylori tests post-treatment were excluded. HELIDAC Therapy (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride) was effective in eradicating H. pylori.

Table 2: H. pylori Eradication Rates in Patients with Active Duodenal Ulcer Disease (Studies 1 and 3)

Study Number Eradication Rate in Duodenal Ulcer Patients† 95% Confidence Intervals
Study 1 77% (N = 39) 61% - 89%
Study 3 82% (N = 51) 70% - 92%
† Evaluable patients were defined as having a confirmed duodenal ulcer within 2 years prior to treatment and having taken 14 days of bismuth subsalicylate, metronidazole, and tetracycline (range 11 to 17 days). Eradication was defined as no evidence of H. pylori infection by culture, histology, rapid urease test and/or urea breath test from at least 4 weeks post-treatment up to 1 year posttreatment.

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 positive at baseline.

Table 3: Duodenal Ulcer Recurrence Rates at 6 Months

Therapy All Patients H. pylori Negative Patients Post-Treatment
BSS/MTZ/TCN + Ranitidine 4% (1/25) 6% (1/18)
Ranitidine 85% (17/20) 100% (1/1)

Table 4: Duodenal Ulcer Recurrence Rates at 1 Year

Therapy All Patients H. pylori Negative Patients Post-Treatment
BSS/MTZ/TCN + Ranitidine 9% (2/22) 13% (2/16)
Ranitidine 95% (18/19) 100% (1/1)
† Includes all patients randomized to therapy who were H. pylori positive at baseline (by culture, histology, and/or urea breath test) who had ulcer healing and 24 or 48 weeks of endoscopic follow-up data.

Eradication of H. pylori in Patients with a History of Duodenal Ulcer Disease

A controlled, multicenter trial (Study 4) in the U.S. compared the rates of eradication of H. pylori following 14 days of treatment with HELIDAC Therapy (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride) or control (bismuth subsalicylate, metronidazole placebo, and tetracycline placebo) in 103 patients infected with H. pylori who had a history of duodenal ulcer disease. No H2-receptor antagonist was used. H. pylori eradication was assessed by rapid urease testing, histology, and culture at least 4 weeks after the last dose. HELIDAC Therapy was effective in eradicating H. pylori. The eradication rates are noted in the table below:

Table 5: H. pylori Eradication Rates in Patients with a History of Duodenal Ulcer Disease (Study 4)

Population Evaluable Population† Intent-To-Treat Population‡
Therapy HELIDAC Therapy Control HELIDAC Therapy Control
Eradication Rate 71% 7% 72% 6%
(Number of Patients) (40/56) (2/30) (41/57) (2/32)
95% confidence interval 60, 83 0a, 16 60, 84 0a, 15
a The lower limit for this calculation was -2.2 but was truncated to 0 for reporting purposes.
† 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, and tetracycline hydrochloride) during the 14-day dosing period. Eradication was defined as no evidence of H. pylori infection by two or three diagnostic tests (culture, histology, and rapid urease test) from at least 4 weeks to 6 weeks post-treatment. Excluded from the evaluable population were patients who were non-compliant with medication, patients who were not infected with H. pylori at baseline, and patients without ulcer documentation. Three patients in the HELIDAC Therapy group and one patient in the Control group were included as eradication failures because they withdrew from the study due to treatment-related adverse events.
‡ Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy. Eradication was defined as no evidence of H. pylori infection by culture, histology, or rapid urease test.

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.

REFERENCES

1. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial susceptibility Tests for Bacteria that Grow Aerobically—Approved Standard Seventh Edition. Clinical and Laboratory Standards Institute document M7-A8, Vol. 29, No.2, CLSI, Wayne, PA, January 2009.

This monograph has been modified to include the generic and brand name in many instances.

Patient Information

Pregnant Women

Advise pregnant women that HELIDAC Therapy can cause fetal harm due to the tetracycline it contains. Tetracycline use during the second and third trimesters of pregnancy can cause permanent discoloration of the teeth (yellow-gray brown) and may inhibit bone development. (See WARNINGS)

Human Milk Feeding

Advise women to avoid feeding their infants with their milk during HELIDAC Therapy. Women should either discontinue feeding or pump and discard their milk during treatment and for 24 hours after the last dose. (See PRECAUTIONS)

Hypersensitivity

Patients should be informed that HELIDAC Therapy may cause allergic reactions and should discontinue the drug at the first sign of urticaria, erythematous rash, flushing, and fever or other symptoms of an allergic reaction. (See CONTRAINDICATIONS)

Central Nervous System Effects

Metronidazole, tetracycline, and bismuth have all been associated with central nervous system effects, such as seizures, peripheral neuropathy, neurotoxicity and benign intracranial hypertension. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole, patients should be specifically warned about these reactions and should be told to stop the drug and report immediately to their physicians if any neurologic symptoms occur. (See WARNINGS)

Photosensitivity

Avoid exposure to sun or sun lamps while taking HELIDAC Therapy. (See WARNINGS)

Drug Interactions

Patients should be advised to report to their doctor the use of any other medications while taking HELIDAC Therapy. The administration of any of the following drugs with HELIDAC Therapy may result in clinically significant adverse reactions or insufficient drug efficacies. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: DRUG INTERACTIONS)

  • Methoxyflurane
  • Disulfiram
  • Alcoholic Beverages or Products Containing Propylene Glycol
  • Oral Contraceptives
  • Anticoagulants
  • Lithium
  • Antacids, Multivitamins, or Dairy Products
  • Antidiabetic agents
  • Aspirin
  • Probenecid or Sulfinpyrazone
  • Penicillin
  • Cimetidine
  • Phenytoin, or Phenobarbital

Darkening of the Tongue and/or Stool

HELIDAC Therapy may cause temporary and harmless darkening of the tongue and/or black stool and is generally reversible within several days after treatment is stopped. Stool darkening should not be confused with melena (blood in the stool). (See PRECAUTIONS)

Dosing Information

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.

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.)

Administration with Fluids

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)

Salicylate Toxicity

HELIDAC Therapy contains 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 (See OVERDOSE and PRECAUTIONS: DRUG INTERACTIONS).

Antibacterial Resistance

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.

This monograph has been modified to include the generic and brand name in many instances.

Consumer Overview Uses

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

 

BISMUTH SUBSALICYLATE/METRONIDAZOLE/TETRACYCLINE - ORAL

 

(BIZ-muth SUB-sa-LIS-i-late/MET-roe-NYE-da-zole/ TET-ra-SYE-kleen)

 

COMMON BRAND NAME(S): Helidac

 

USES: This product contains 3 medications: tetracycline, metronidazole, and bismuth subsalicylate. It is used with an acid blocker (e.g., H2 blockers such as ranitidine, proton pump inhibitors such as omeprazole) to treat stomach/intestinal ulcers caused by the bacteria H. pylori and to prevent the ulcers from returning.

Tetracycline and metronidazole are antibiotics used to treat a wide variety of bacterial infections. They work by stopping the growth of bacteria. Bismuth subsalicylate is often used to treat upset stomach, but it is used in this combination to help stop the growth of bacteria.

This product treats only bacterial infections. It will not work for viral infections (e.g., common cold, flu). Unnecessary use or misuse of any antibiotic can lead to its decreased effectiveness.

This product is not recommended for use in children.

 

HOW TO USE: Read the Patient Information Booklet contained in the package before you start using this product. If you have any questions, consult your doctor or pharmacist.

This product comes as a package with 14 separate dosing cards. Each card contains enough medication for 1 day (4 doses). Each dose contains 4 pills. For the 2 round pink tablets, chew thoroughly and swallow. For the 1 round white tablet and 1 orange/white capsule, swallow whole with a full glass of water (8 ounces or 240 milliliters) unless your doctor directs you otherwise. For best results, 1 dose (4 pills) must be taken 4 times daily.

Take this product at mealtimes and at bedtime for 14 days. Do not lie down for 10 minutes after taking this medication.

Take this medication 2-3 hours before or after taking any products containing magnesium, aluminum, or calcium. Some examples include quinapril, certain forms of didanosine (e.g., chewable/dispersible buffered tablets or pediatric oral solution), vitamins/minerals, and antacids. Dairy products (e.g., milk, yogurt), calcium-enriched juice, sucralfate, iron, and zinc are also included. These products bind with tetracycline, preventing its full absorption.

Take this medication regularly in order to get the most benefit from it. Continue to take this medication and the acid blocker until the full prescribed amount is finished, even if symptoms disappear after a few days. Stopping the medication too early may result in a return of the infection/ulcer.

Inform your doctor if your condition persists or worsens.

Consumer Overview Side Effect

SIDE EFFECTS: Nausea, vomiting, diarrhea, abdominal pain, constipation, loss of appetite, headache, metallic taste in mouth, or dizziness may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Your tongue may turn dark in color while taking this medication. This is harmless and the effect will disappear when you stop the medication.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: ringing in the ears, sore mouth, joint pain, numbness/tingling of arms/legs, frequent/painful urination, discolored teeth, mental/mood changes (e.g., nervousness, irritability, depression).

Tell your doctor immediately if any of these rare but very serious side effects occur: severe headache, stiff/painful neck, difficult/painful swallowing, heartburn, unusual tiredness, change in the amount of urine, dark urine, unusual weakness, yellowing eyes/skin, persistent nausea/vomiting, severe constipation, severe stomach/abdominal pain, signs of infection (e.g., fever, persistent sore throat), easy bruising/bleeding.

Seek immediate medical attention if any of these rare but very serious side effects occur: seizures, chest/jaw/left arm pain, confusion, slurred speech, vision changes.

This product can commonly cause dark stools that are usually not serious. However, you may not be able to tell this effect apart from blood in the stool, which could be a sign of a severe reaction. Therefore, tell your doctor immediately if you develop any dark stools.

Tetracycline may rarely cause a serious increase in pressure inside the skull (intracranial hypertension-IH). The risk of this side effect is greater for women of childbearing age who are overweight or who have had IH in the past. If IH develops, it usually goes away after tetracycline is stopped; however, there is a chance of permanent vision loss or blindness. Get medical help right away if you have: persistent/severe headache, vision changes (such as blurred/double vision, decreased vision, sudden blindness), persistent nausea/vomiting.

This medication may rarely cause a severe intestinal condition (Clostridium difficile-associated diarrhea) due to a type of resistant bacteria. This condition may occur weeks to months after treatment has stopped. Tell your doctor immediately if you develop persistent diarrhea, abdominal or stomach pain/cramping, blood/mucus in your stool. Do not use anti-diarrhea products or narcotic pain medications if you have any of these symptoms because these products may make them worse.

Use of this medication for prolonged or repeated periods may result in oral thrush or a new yeast infection. Contact your doctor if you notice white patches in your mouth, a change in vaginal discharge, or other new symptoms.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

 

Read the Helidac (bismuth subsalicylate) Side Effects Center for a complete guide to possible side effects

Learn More »

PRECAUTIONS: See also Side Effects section.

Before taking this product, tell your doctor or pharmacist if you are allergic to bismuth subsalicylate, metronidazole, or tetracycline; or to aspirin or salicylates; or to other nitroimidazoles (e.g., tinidazole); or to other tetracyclines (e.g., doxycycline); or to other bismuth products; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: kidney disease, liver disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood disorders, diabetes, brain/spinal cord disorders (e.g., seizures), trouble swallowing, esophagus problems (e.g., hiatal hernia, reflux disease-GERD), asthma, growths in the nose (nasal polyps).

Before having surgery, tell your doctor or dentist that you are using this product.

Tetracycline may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

This product may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic beverages or alcohol-containing products (e.g., certain cough-and-cold products) while taking this product and for at least 1 day afterward because alcohol may increase dizziness or cause a severe reaction with metronidazole (including abdominal cramping, nausea, vomiting, headache, and flushing).

The elderly may be at greater risk for side effects while using this product.

Children should not take this product because it contains an aspirin-related drug (bismuth subsalicylate) and tetracycline. Tetracycline may cause permanent tooth discoloration and other problems in children younger than 8 years. Tooth discoloration has also occurred in older children and young adults. Use of aspirin-related drugs in children, especially if they have chickenpox, flu, or any undiagnosed illness or if they have received the flu vaccine inhaled through the nose, has been associated with Reye's syndrome, a rare but serious illness. Consult your doctor for more information.

This product is not recommended for use during pregnancy because of possible harm to an unborn baby. Women of child-bearing age should use effective, non-hormonal birth control (e.g., condom, diaphragm with spermicide) while taking this medication. Consult your doctor for more details. See also Drug Interactions.

This combination product contains drugs that may pass into breast milk and could have undesirable effects on a nursing infant. Therefore, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

Consumer Overview Missed Dose

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: retinoid medications taken by mouth (such as acitretin, isotretinoin), strontium.

Avoid disulfiram within 2 weeks before and during treatment with this medication.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting this product.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: atovaquone, busulfan, capecitabine, carbonic anhydrase inhibitors (e.g., acetazolamide), certain drugs for gout (e.g., uricosuric drugs such as probenecid, sulfinpyrazone), corticosteroids (e.g., prednisone), digoxin, drugs affecting liver enzymes that remove metronidazole from your body (such as cimetidine, certain anti-seizure medicines including phenytoin, phenobarbital), fluorouracil, lithium, live bacterial vaccines, methotrexate, methoxyflurane, penicillins (e.g., amoxicillin, dicloxacillin), tretinoin applied to the skin, valproic acid.

This medication may increase the risk of bleeding when taken with other drugs that also may cause bleeding. Examples include anti-platelet drugs such as clopidogrel, "blood thinners" such as dabigatran/enoxaparin/warfarin, among others.

Check all prescription and nonprescription medicine labels carefully since many contain pain relievers/fever reducers (NSAIDs such as aspirin, ibuprofen, or naproxen) that are similar to the bismuth subsalicylate in this product and, if taken together, may increase your risk for side effects. Low-dose aspirin should be continued if it has been prescribed by your doctor for specific medical reasons such as heart attack or stroke prevention (usually at dosages of 81-325 milligrams per day). Consult your doctor or pharmacist for more details.

Although most antibiotics probably do not affect hormonal birth control such as pills, patch, or ring, some antibiotics may decrease their effectiveness. This could cause pregnancy. Examples include rifamycins such as rifampin or rifabutin. Be sure to ask your doctor or pharmacist if you should use additional reliable birth control methods while using this antibiotic.

This product may interfere with certain laboratory tests (including liver function tests, triglycerides, hexokinase glucose, lactate dehydrogenase), possibly causing false test results. This product may also interfere with X-ray exams of the stomach/intestines. Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

 

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: fast breathing, nausea, vomiting, ringing in the ears, fast heartbeat, seizures.

 

NOTES: Do not share this medication with others.

Laboratory and/or medical tests may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

This medication has been prescribed for your current condition only. Do not use it later for another infection unless told to do so by your doctor. A different medication may be necessary in that case.

 

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up. Contact your doctor if you miss more than 4 doses.

 

STORAGE: Store at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Taking outdated tetracycline can result in serious illness. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

 

Information last revised December 2013. Copyright(c) 2013 First Databank, Inc.

Patient Detailed Side Effect

Brand Names: Helidac

Generic Name: bismuth subsalicylate, metronidazole, and tetracycline (Pronunciation: BIZ muth sub sa LISS i late, MET roe NYE da zole, and tet ra SYE kleen)

  • What is bismuth subsalicylate, metronidazole, and tetracycline (Helidac) (Helidac)?
  • What are the possible side effects of Helidac (Helidac)?
  • What is the most important information I should know about bismuth subsalicylate, metronidazole, and tetracycline (Helidac) (Helidac)?
  • What should I discuss with my healthcare provider before taking Helidac (Helidac)?
  • How should I take Helidac (Helidac)?
  • What happens if I miss a dose (Helidac)?
  • What happens if I overdose (Helidac)?
  • What should I avoid while taking Helidac (Helidac)?
  • What other drugs will affect Helidac (Helidac)?
  • Where can I get more information?

What is bismuth subsalicylate, metronidazole, and tetracycline (Helidac) (Helidac)?

Bismuth subsalicylate is a mild antibiotic.

Metronidazole and tetracycline are also antibiotics that fight bacteria in your body.

Bismuth subsalicylate, metronidazole, and tetracycline is a combination medicine used to treat peptic ulcer (duodenal ulcer) with H pylori infection.

This medication may also be used for purposes not listed in this medication guide.

What are the possible side effects of Helidac (Helidac)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • severe diarrhea, or diarrhea that is watery or bloody;
  • confusion, severe headache, ringing in your ears, dizziness;
  • vision problems, pain behind your eyes;
  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
  • seizure (convulsions); or
  • pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating.

Common side effects may include:

  • stomach pain, indigestion, vomiting;
  • constipation, mild diarrhea;
  • cold symptoms such as stuffy nose, sneezing, sore throat;
  • mouth pain, metallic taste in your mouth;
  • vaginal itching or discharge;
  • mild headache; or
  • swollen tongue, black or "hairy" tongue, trouble swallowing.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Helidac (bismuth subsalicylate) Side Effects Center for a complete guide to possible side effects

Learn More »

What is the most important information I should know about bismuth subsalicylate, metronidazole, and tetracycline (Helidac) (Helidac)?

Do not use this medicine if you are pregnant or breast-feeding.

Tetracycline can make birth control pills less effective. Ask your doctor about using non-hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy while taking Helidac.

Do not give this medication to a child younger than 8 years old.

Do not drink alcohol while you are taking Helidac and for at least 1 day after you stop taking it.

Avoid taking Helidac with milk or other dairy products. Also avoid taking the medicine at the same time you take any multivitamins, mineral supplements, or antacids. These products can make it harder for your body to absorb Helidac.

Side Effects Centers
  • Helidac

Patient Detailed How Take

What should I discuss with my healthcare provider before taking Helidac (Helidac)?

You should not use this medication if:

  • you have kidney or liver disease;
  • you are pregnant or breast-feeding;
  • you have taken disulfiram (Antabuse) in the past 14 days; or
  • you are allergic to aspirin, bismuth subsalicylate (Kaopectate, Pepto-Bismol), metronidazole, or tetracycline.

To make sure Helidac is safe for you, tell your doctor if you have:

  • a history of kidney or liver disease;
  • a nervous system disorder such as Alzheimer's disease, multiple sclerosis, or Parkinson's disease;
  • a head injury or brain tumor; or
  • a seizure disorder.

Do not give this medication to a child younger than 8 years old. Tetracycline can cause permanent yellowing or graying of the teeth, and it can affect a child's growth.

FDA pregnancy category D. Do not use this medicine if you are pregnant. It could harm the unborn baby. Tetracycline can cause permanent tooth discoloration later in life and can also affect a child's growth.

Tetracycline can make birth control pills less effective. Ask your doctor about using non-hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy while taking Helidac.

Metronidazole and tetracycline can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine.

How should I take Helidac (Helidac)?

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Chew and swallow the bismuth subsalicylate tablets.

Do not chew the metronidazole or tetracycline pills. Swallow each pill whole.

To prevent heartburn and damage to the esophagus, be sure to take each dose (especially the bedtime dose) with a full glass of water (8 ounces).

Take all 4 pills four times daily with meals and at bedtime.

Take this medicine for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Bismuth subsalicylate, metronidazole, and tetracycline will not treat a viral infection such as the common cold or flu.

Store at room temperature away from moisture and heat.

Side Effects Centers
  • Helidac

Patient Detailed Avoid Taking

What happens if I miss a dose (Helidac)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

If you miss more than 4 doses in a row, call your doctor for instructions.

What happens if I overdose (Helidac)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking Helidac (Helidac)?

Avoid taking Helidac with milk or other dairy products. Also avoid taking the medicine at the same time you take any multivitamins, mineral supplements, or antacids. These products can make it harder for your body to absorb the medicine.

If you also take cholestyramine or colestipol, do not take these medicines within 2 hours before or after you take Helidac.

Do not drink alcohol while you are taking Helidac and for at least 1 day after you stop taking it. Drinking alcohol while taking Helidac may cause nausea, vomiting, headache, or flushing (warmth, redness, tingly feeling).

Check the labels of any medicines or food products you use to make sure they do not contain alcohol.

Avoid exposure to sunlight or tanning beds. Helidac can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or bloody, stop taking Helidac and call your doctor. Do not use anti-diarrhea medicine unless your doctor tells you to.

What other drugs will affect Helidac (Helidac)?

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with Helidac, especially:

  • aspirin;
  • cimetidine;
  • lithium;
  • probenecid;
  • any other type of antibiotic;
  • birth control pills;
  • a blood thinner such as warfarin, Coumadin;
  • oral diabetes medication; or
  • seizure medicine such as phenytoin or phenobarbital.

This list is not complete. Other drugs may interact with Helidac, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Where can I get more information?

Your pharmacist can provide more information about bismuth subsalicylate, metronidazole, and tetracycline.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 3.01. Revision date: 1/28/2013.

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