Helicon

H. pylori Eradication To Reduce The Risk Of Duodenal Ulcer Recurrence

The components in Helicon (PREVACID, amoxicillin, and clarithromycin) are indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or one year history of a duodenal ulcer) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence (see Clinical Studies and DOSAGE AND ADMINISTRATION).

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

H. pylori Eradication To Reduce The Risk Of Duodenal Ulcer Recurrence

The recommended adult oral dose is 30 mg PREVACID, 1 g amoxicillin, and 500 mg clarithromycin administered together twice daily (morning and evening) for 10 or 14 days (see INDICATIONS AND USAGE).

Helicon is not recommended in patients with creatinine clearance less than 30 mL/min.

Helicon is contraindicated in patients with known severe hypersensitivity to any component of the formulation of PREVACID. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria (see ADVERSE REACTIONS). Proton Pump Inhibitors (PPIs), including PREVACID, are contraindicated with rilpivirine-containing products (see

WARNINGS

Acute Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy, including amoxicillin. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with Helicon careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and Henoch-Schonlein purpura Helicon should be discontinued immediately and appropriate treatment should be urgently initiated.

Use In Pregnancy

CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING CLARITHROMYCIN, THE PATIENT SHOULD BE INFORMED OF THE POTENTIAL HAZARD TO THE FETUS. CLARITHROMYCIN HAS DEMONSTRATED ADVERSE EFFECTS OF PREGNANCY OUTCOME AND/OR EMBRYO­FETAL DEVELOPMENT IN MONKEYS, RATS, MICE, AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS TWO TO 17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM RECOMMENDED HUMAN DOSES (see PRECAUTIONS, Pregnancy).

Hepatotoxicity

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur.

QT Prolongation

Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving clarithromycin. Fatalities have been reported. Clarithromycin should be avoided in patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia (see CONTRAINDICATIONS) and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval.

Presence Of Gastric Malignancy

In adults, symptomatic response to therapy with lansoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy.

Acute Interstitial Nephritis

Acute interstitial nephritis (AIN) has been observed in patients taking proton pump inhibitors (PPIs) including lansoprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue lansoprazole if AIN develops (see CONTRAINDICATIONS).

Cutaneous And Systemic Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including lansoprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.

The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.

Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving Helicon, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in four to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

Drug Interactions

Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia with disopyramide, and hypotension and acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine). Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older (see CONTRAINDICATIONS and DRUG INTERACTIONS). Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see DRUG INTERACTIONS).

Colchicine

Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and colchicine. Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses. If coadministration of clarithromycin and colchicine is necessary in patients with normal renal and hepatic function, the dose of colchicine should be reduced. Patients should be monitored for clinical symptoms of colchicine toxicity. Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and DRUG INTERACTIONS).

Benzodiazepines

Increased sedation and prolongation of sedation have been reported with concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and midazolam.

Oral Hypoglycemic Agents/Insulin

The concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia. With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycemia when used concomitantly. Careful monitoring of glucose is recommended.

Oral Anticoagulants

There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when clarithromycin is coadministered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.

HMG-CoA Reductase Inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see CONTRAINDICATIONS) as these statins are extensively metabolized by CYP3A4, and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.

Caution should be exercised when prescribing clarithromycin with statins. In situations where the concomitant use of clarithromycin with atorvastatin or pravastatin cannot be avoided, atorvastatin dose should not exceed 20 mg daily and pravastatin dose should not exceed 40 mg daily. Use of a statin that is not dependent on CYP3A metabolism (e.g., fluvastatin) can be considered. It is recommended to prescribe the lowest registered dose if concomitant use cannot be avoided.

Interactions With Investigations For Neuroendocrine Tumors

Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop lansoprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary (see CLINICAL PHARMACOLOGY, Drug Interaction Studies).

Interaction With Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients (see CLINICAL PHARMACOLOGY, Drug Interaction Studies).

Clostridium Difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clarithromycin and/or amoxicillin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

In addition, published observational studies suggest that PPI therapy, may be associated with an increased risk of CDAD, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve.

PRECAUTIONS

General

The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfections occur, Helicon should be discontinued and appropriate therapy instituted.

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

Clarithromycin is principally excreted via the liver and kidney. Clarithromycin may be administered without dosage adjustment to patients with hepatic impairment and normal renal function. However, in the presence of severe renal impairment with or without coexisting hepatic impairment, decreased dosage or prolonged dosing intervals may be appropriate.

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy.

Laboratory Tests

Amoxicillin

Periodic assessment of renal, hepatic, and hematopoietic function should be made during prolonged therapy.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

PREVACID

In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated with oral lansoprazole at doses of 5 to 150 mg/kg/day, about 0.5 to 20 times the recommended human dose of 60 mg/day, based on body surface area (BSA). Lansoprazole produced dose-related gastric enterochromaffin-like (ECL) cell hyperplasia and ECL cell carcinoids in both male and female rats. The incidences of intestinal metaplasia of the gastric epithelium were also increased in both sexes. In male rats, lansoprazole produced a dose-related increase in the incidence of testicular interstitial cell adenomas at doses two to 20 times the recommended human dose of 60 mg/day based on BSA.

In a 24-month carcinogenicity study, CD-1 mice were treated with oral lansoprazole at doses of 15 to 600 mg/kg/day (one to 40 times the recommended human dose of 60 mg/day based on BSA comparisons). Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. The incidence of liver tumors (hepatocellular adenoma plus carcinoma) was increased in male mice (at doses 20 to 40 times the recommended human dose of 60 mg/day based on BSA) and in female mice (treated at doses ten to 40 times the recommended human dose based on BSA). Lansoprazole treatment produced adenoma of rete testis in male mice receiving doses five to 40 times the recommended human dose of 60 mg/day based on BSA.

A 26 week p53 (+/-) transgenic mouse carcinogenicity study was not positive.

Lansoprazole was positive in the Ames test and the in vitro human lymphocyte chromosomal aberration assay. Lansoprazole was not genotoxic in the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test, or the rat bone marrow cell chromosomal aberration test.

Lansoprazole at oral doses up to 150 mg/kg/day (20 times the recommended human dose of 60 mg/day based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

Amoxicillin

Long-term studies in animals have not been performed to evaluate the mutagenic or carcinogenic potential of amoxicillin alone. A 4:1 mixture of amoxicillin and potassium clavulanate was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. The amoxicillin/potassium clavulanate mixture was also negative in the mouse micronucleus test, and in the dominant lethal assay in mice, but was weakly positive in the mouse lymphoma assay. In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were seen at doses up to 500 mg/kg, approximately three times the human dose based on BSA comparisons.

Clarithromycin

The following in vitro mutagenicity tests have been conducted with clarithromycin:

Salmonella/Mammalian Microsomes Test
Bacterial Induced Mutation Frequency Test
In Vitro Chromosome Aberration Test
Rat Hepatocyte DNA Synthesis Assay
Mouse Lymphoma Assay
Mouse Dominant Lethal Study
Mouse Micronucleus Test

All tests had negative results except the In Vitro Chromosome Aberration Test which was weakly positive in one test and negative in another.

In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed on clarithromycin metabolites with negative results.

Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/day (1.3 times the recommended maximum human dose based on mg/m²) to male and female rats caused no adverse effects on the estrous cycle, fertility, parturition, or number and viability of offspring. Plasma levels in rats after 150 mg/kg/day were two times the human serum levels.

In the 150 mg/kg/day monkey studies, plasma levels were three times the human serum levels. When given orally at 150 mg/kg/day (2.4 times the recommended maximum human dose based on mg/m²), clarithromycin was shown to produce embryonic loss in monkeys. This effect has been attributed to marked maternal toxicity of the drug at this high dose.

In rabbits, in utero fetal loss occurred at an intravenous dose of 33 mg/m², which is 17 times less than the maximum proposed human oral daily dose of 618 mg/m².

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of clarithromycin.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Category C is based on the pregnancy category for clarithromycin.

There are no adequate and well-controlled studies of lansoprazole, clarithromycin or amoxicillin (used separately or together) in pregnant women. Helicon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus and there is no appropriate alternative therapy (see WARNINGS).

Reproduction studies have been performed in pregnant rats at oral lansoprazole doses up to 20 times the recommended human dose (60 mg/day based on BSA) and in pregnant rabbits at oral doses up to eight times the recommended human dose (60 mg/day based on BSA) and have revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole.

Reproduction studies with amoxicillin have been performed in mice and rats at doses up to ten times the human dose and revealed no evidence of impaired fertility or harm to the fetus.

Four teratogenicity studies in rats with clarithromycin (three with oral doses and one with intravenous doses up to 160 mg/kg/day administered during the period of major organogenesis) and two in rabbits at oral doses up to 125 mg/kg/day (approximately two times the recommended maximum human dose based on mg/m²) or intravenous doses of 30 mg/kg/day administered during gestation days six to 18 failed to demonstrate any teratogenicity from clarithromycin. Two additional oral studies in a different rat strain at similar doses and similar conditions demonstrated a low incidence of cardiovascular anomalies at doses of 150 mg/kg/day administered during gestation days six to 15. Plasma levels after 150 mg/kg/day were two times the human serum levels. Four studies in mice revealed a variable incidence of cleft palate following oral doses of 1000 mg/kg/day (two and four times the recommended maximum human dose based on mg/m², respectively) during gestation days six to 15. Cleft palate was also seen at 500 mg/kg/day. The 1000 mg/kg/day exposure resulted in plasma levels 17 times the human serum levels. In monkeys, an oral dose of 70 mg/kg/day (an approximate equidose of the recommended maximum human dose based on mg/m²) produced fetal growth retardation at plasma levels that were two times the human serum levels.

Labor And Delivery

Oral ampicillin-class antibiotics are poorly absorbed during labor. Studies in guinea pigs showed that intravenous administration of ampicillin slightly decreased the uterine tone and frequency of contractions, but moderately increased the height and duration of contractions. However, it is not known whether use of these drugs in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.

Nursing Mothers

Lansoprazole and its metabolites are excreted in the milk of rats. It is not known whether lansoprazole is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Helicon, and the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue Helicon, taking into account the importance of the therapy to the mother.

Penicillins have been shown to be excreted in human milk. Amoxicillin use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin is administered to a nursing woman.

Clarithromycin and its active metabolite 14-hydroxy clarithromycin are excreted in human milk. Serum and milk samples were obtained after three days of treatment, at steady state, from one published study of 12 lactating women who were taking clarithromycin 250 mg orally twice daily. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively human milk-fed infant would receive an estimated average of 136 mcg/kg/day of clarithromycin and its active metabolite, with this maternal dosage regimen. This is less than 2% of the maternal weight-adjusted dose (7.8 mg/kg/day, based on the average maternal weight of 64 kg), and less than 1% of the pediatric dose (15 mg/kg/day) for children greater than six months of age.

A prospective observational study of 55 breastfed infants of mothers taking a macrolide antibiotic (six were exposed to clarithromycin) were compared to 36 breastfed infants of mothers taking amoxicillin. Adverse reactions were comparable in both groups. Adverse reactions occurred in 12.7% of infants exposed to macrolides and included rash, diarrhea, loss of appetite, and somnolence.

Caution should be exercised when clarithromycin is administered to nursing women. The development and health benefits of human milk feeding should be considered along with the mother's clinical need for clarithromycin and any potential adverse effects on the human milk-fed child from the drug or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of Helicon in pediatric patients infected with H. pylori have not been established (see CONTRAINDICATIONS and WARNINGS).

Geriatric Use

Elderly patients may suffer from asymptomatic renal and hepatic dysfunction. Care should be taken when administering Helicon to this patient population.

An analysis of clinical studies of amoxicillin was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. These analyses have not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.

Amoxicillin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg of clarithromycin every 12 hours, the maximum serum concentrations and area under the curves of clarithromycin and 14-OH clarithromycin were increased compared to those achieved in healthy young adults. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials of clarithromycin, elderly patients did not have an increased incidence of adverse events when compared to younger patients. Dosage adjustment should be considered in elderly patients with severe renal impairment. Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients (see WARNINGS AND PRECAUTIONS).

Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine) involved elderly patients 65 years of age or older (see WARNINGS).

Helicon

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most common adverse reactions (≥3%) reported in clinical trials when all three components of this therapy were given concomitantly for 14 days are listed in Table 8.

Table 8: Adverse Reactions Most Frequently Reported in Clinical Trials (≥3%)

The additional adverse reactions which were reported as possibly or probably related to treatment (less than 3%) in clinical trials when all three components of this therapy were given concomitantly are listed below and divided by body system:

Body as a Whole -abdominal pain

Digestive System -dark stools, dry mouth/thirst, glossitis, rectal itching, nausea, oral moniliasis, stomatitis, tongue discoloration, tongue disorder, vomiting

Musculoskeletal System -myalgia

Nervous System -confusion, dizziness

Respiratory System -respiratory disorders

Skin and Appendages -skin reactions

Urogenital System -vaginitis, vaginal moniliasis

There were no statistically significant differences in the frequency of reported adverse events between the 10 and 14 day triple therapy regimens.

PREVACID

The following adverse reactions from the labeling for PREVACID are provided for information:

Worldwide, over 10,000 patients have been treated with PREVACID in Phase 2 or Phase 3 clinical trials involving various dosages and durations of treatment. In general, PREVACID treatment has been well-tolerated in both short-term and long-term trials.

Incidence In Clinical Trials

The following adverse events were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of PREVACID-treated patients and occurred at a greater rate in PREVACID-treated patients than placebo-treated patients:

Table 9: Incidence of Possibly or Probably Treatment-Related Adverse Reactions in Short-Term, Placebo-Controlled PREVACID Studies

Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea was similar between patients who received placebo and patients who received 30 mg of PREVACID, but higher in the patients who received 60 mg of PREVACID (2.9%, 4.2%, and 7.4%, respectively).

The most commonly reported possibly or probably treatment-related adverse event during maintenance therapy was diarrhea.

Additional adverse experiences occurring in less than 1% of patients or subjects who received PREVACID in domestic trials are shown below:

Body as a Whole - abdomen enlarged, allergic reaction, asthenia, back pain, candidiasis, carcinoma, chest pain (not otherwise specified), chills, edema, fever, flu syndrome, halitosis, infection (not otherwise specified), malaise, neck pain, neck rigidity, pain, pelvic pain

Cardiovascular System - angina, arrhythmia, bradycardia, cerebrovascular accident/cerebral infarction, hypertension/hypotension, migraine, myocardial infarction, palpitations, shock (circulatory failure), syncope, tachycardia, vasodilation

Digestive System - abnormal stools, anorexia, bezoar, cardiospasm, cholelithiasis, colitis, dry mouth, dyspepsia, dysphagia, enteritis, eructation, esophageal stenosis, esophageal ulcer, esophagitis, fecal discoloration, flatulence, gastric nodules/fundic gland polyps, gastritis, gastroenteritis, gastrointestinal anomaly, gastrointestinal disorder, gastrointestinal hemorrhage, glossitis, gum hemorrhage, hematemesis, increased appetite, increased salivation, melena, mouth ulceration, nausea and vomiting, nausea and vomiting and diarrhea, gastrointestinal moniliasis, rectal disorder, rectal hemorrhage, stomatitis, tenesmus, thirst, tongue disorder, ulcerative colitis, ulcerative stomatitis

Endocrine System - diabetes mellitus, goiter, hypothyroidism

Hemic and Lymphatic System - anemia, hemolysis, lymphadenopathy

Metabolism and Nutritional Disorders - avitaminosis, gout, dehydration, hyperglycemia/hypoglycemia, peripheral edema, weight gain/loss

Musculoskeletal System - arthralgia, arthritis, bone disorder, joint disorder, leg cramps, musculoskeletal pain, myalgia, myasthenia, ptosis, synovitis

Nervous System - abnormal dreams, agitation, amnesia, anxiety, apathy, confusion, convulsion, dementia, depersonalization, depression, diplopia, dizziness, emotional lability, hallucinations, hemiplegia, hostility aggravated, hyperkinesia, hypertonia, hypesthesia, insomnia, libido decreased/increased, nervousness, neurosis, paresthesia, sleep disorder, somnolence, thinking abnormality, tremor, vertigo

Respiratory System - asthma, bronchitis, cough increased, dyspnea, epistaxis, hemoptysis, hiccup, laryngeal neoplasia, lung fibrosis, pharyngitis, pleural disorder, pneumonia, respiratory disorder, upper respiratory inflammation/infection, rhinitis, sinusitis, stridor

Skin and Appendages - acne, alopecia, contact dermatitis, dry skin, fixed eruption, hair disorder, maculopapular rash, nail disorder, pruritus, rash, skin carcinoma, skin disorder, sweating, urticaria

Special Senses - abnormal vision, amblyopia, blepharitis, blurred vision, cataract, conjunctivitis, deafness, dry eyes, ear/eye disorder, eye pain, glaucoma, otitis media, parosmia, photophobia, retinal degeneration/disorder, taste loss, taste perversion, tinnitus, visual field defect

Urogenital System - abnormal menses, breast enlargement, breast pain, breast tenderness, dysmenorrhea, dysuria, gynecomastia, impotence, kidney calculus, kidney pain, leukorrhea, menorrhagia, menstrual disorder, penis disorder, polyuria, testis disorder, urethral pain, urinary frequency, urinary retention, urinary tract infection, urinary urgency, urination impaired, vaginitis

Postmarketing

Additional adverse experiences have been reported since PREVACID has been marketed. The majority of these cases are foreign-sourced and a relationship to PREVACID has not been established. Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events are listed below by COSTART body system:

Body as a Whole - anaphylactic/anaphylactoid reactions, systemic lupus erythematosus

Digestive System - hepatotoxicity, pancreatitis, vomiting

Hemic and Lymphatic System - agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura

Infections and Infestations - Clostridium difficile-associated diarrhea

Metabolism and Nutritional Disorders - hypomagnesemia

Musculoskeletal System - bone fracture, myositis

Skin and Appendages - severe dermatologic reactions including erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, (some fatal), cutaneous lupus erythematosus

Special Senses - speech disorder

Urogenital System - interstitial nephritis, urinary retention

Amoxicillin

The following adverse reactions from the labeling for amoxicillin are provided for information:

The most common adverse reactions (>1%) observed in clinical trials of amoxicillin capsules were diarrhea, rash, vomiting and nausea.

The most frequently reported adverse events for patients who received triple therapy (amoxicillin/clarithromycin/lansoprazole) were diarrhea (7%), headache (6%), and taste perversion (5%).

Infections and Infestations - Mucocutaneous candidiasis

Gastrointestinal - Black hairy tongue, and hemorrhagic/pseudomembranous colitis.

Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (see WARNINGS).

Hypersensitivity Reactions - Anaphylaxis (see WARNINGS), serum sickness-like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens-Johnson Syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis and urticaria have been reported.

Liver - A moderate rise in AST and/or ALT has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis have been reported.

Renal - Crystalluria has also been reported (see OVERDOSAGE).

Hemic and Lymphatic Systems - Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.

Central Nervous System - Reversible hyperactivity, agitation, anxiety, insomnia, confusion, behavioral changes, and/or dizziness have been reported.

Miscellaneous - Tooth discoloration (brown, yellow, or gray staining) has been reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases.

Clarithromycin

The following adverse reactions from the labeling for clarithromycin are provided for information:

The most frequent and common adverse reactions related to clarithromycin therapy for both adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting, and dysgeusia. These adverse reactions are consistent with the known safety profile of macrolide antibiotics.

There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections.

Adverse Reactions Observed During Clinical Trials Of Clarithromycin

The following adverse reactions were observed in clinical trials with clarithromycin at a rate greater than or equal to 1%:

Gastrointestinal Disorders - Diarrhea, vomiting, dyspepsia, nausea, abdominal pain

Hepatobiliary Disorders - Liver function test abnormal

Immune System Disorders - Anaphylactoid reaction

Infections and Infestations - Candidiasis

Nervous System Disorders - Dysgeusia, headache

Psychiatric Disorders - Insomnia

Skin and Subcutaneous Tissue Disorders - Rash

Other Adverse Reactions Observed During Clinical Trials Of Clarithromycin

The following adverse reactions were observed in clinical trials with clarithromycin at a rate less than 1%:

Blood and Lymphatic System Disorders - Leukopenia, neutropenia, thrombocythemia, eosinophilia

Cardiac Disorders - Electrocardiogram QT prolonged, cardiac arrest, atrial fibrillation, extrasystoles, palpitations

Ear and Labyrinth Disorders - Vertigo, tinnitus, hearing impaired

Gastrointestinal Disorders - Stomatitis, glossitis, esophagitis, gastroesophageal reflux disease, gastritis, proctalgia, abdominal distention, constipation, dry mouth, eructation, flatulence

General Disorders and Administration Site Conditions - Malaise, pyrexia, asthma, chest pain, chills, fatigue

Hepatobiliary Disorders - Cholestasis, hepatitis

Immune System Disorders - Hypersensitivity

Infections and Infestations - Cellulitis, gastroenteritis, infection, vaginal infection

Investigations - Blood bilirubin increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, albumin globulin ratio abnormal

Metabolism and Nutrition Disorders - Anorexia, decreased appetite

Musculoskeletal and Connective Tissue Disorders - Myalgia, muscle spasms, nuchal rigidity

Nervous System Disorders - Dizziness, tremor, loss of consciousness, dyskinesia, somnolence

Psychiatric Disorders - Anxiety, nervousness

Renal and Urinary Disorders - Blood creatinine increased, blood urea increased

Respiratory, Thoracic and Mediastinal Disorders - Asthma, epistaxis, pulmonary embolism

Skin and Subcutaneous Tissue Disorders - Urticaria, dermatitis bollus, pruritus, hyperhidrosis, rash maculopapular

The following adverse reactions have been identified during post approval use of clarithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders - Thrombocytopenia, agranulocytosis

Cardiac Disorders - Torsades de pointes, ventricular tachycardia, ventricular arrhythmia

Ear and Labyrinth Disorders - Deafness was reported chiefly in elderly women and was usually reversible.

Gastrointestinal Disorders - Pancreatitis acute, tongue discoloration, tooth discoloration was reported and was usually reversible with professional cleaning upon discontinuation of the drug.

Hepatobiliary Disorders - Hepatic failure, jaundice hepatocellular. Adverse reactions related to hepatic dysfunction have been reported with clarithromycin (see WARNINGS, Hepatotoxicity)

Immune System Disorders - Anaphylactic reaction

Infections and Infestations - Pseudomembranous colitis

Investigations - Prothrombin time prolonged, white blood cell count decreased, international normalized ratio increased. Abnormal urine color has been reported, associated with hepatic failure.

Metabolism and Nutrition Disorders - Hypoglycemia has been reported in patients taking oral hypoglycemic agents or insulin.

Musculoskeletal and Connective Tissue Disorders - Myopathy, rhabdomyolysis was reported and in some of the reports, clarithromycin was administered concomitantly with statins, fibrates, colchicines or allopurinol (see CONTRAINDICATIONS and WARNINGS).

Nervous System Disorders - Convulsion, ageusia, parosmia, anosmia, paresthesia

Psychiatric Disorders - Psychotic disorder, confusional state, depersonalization, depression, disorientation, manic behavior, hallucination, abnormal behavior, abnormal dreams. These disorders usually resolve upon discontinuation of the drug.

There are no data on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.

Renal and Urinary Disorders - Nephritis interstitial, renal failure

Skin and Subcutaneous Tissue Disorders - Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, acne

Vascular Disorders - Hemorrhage

There have been reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see WARNINGS AND PRECAUTIONS).

Laboratory Values

Prevacid

The following changes in laboratory parameters in patients who received PREVACID were reported as adverse reactions:

Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased creatinine, increased alkaline phosphatase, increased globulins, increased GGTP, increased/decreased/abnormal WBC, abnormal AG ratio, abnormal RBC, bilirubinemia, blood potassium increased, blood urea increased, crystal urine present, eosinophilia, hemoglobin decreased, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increased/decreased/abnormal platelets, increased gastrin levels and positive fecal occult blood. Urine abnormalities such as albuminuria, glycosuria, and hematuria were also reported.

In the placebo-controlled studies, when SGOT (AST) and SGPT (ALT) were evaluated, 0.4% (4/978) and 0.4% (11/2677) patients, who received placebo and PREVACID, respectively, had enzyme elevations greater than three times the upper limit of normal range at the final treatment visit. None of these patients who received PREVACID reported jaundice at any time during the study.

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.

In the event of over-exposure, treatment should be symptomatic and supportive.

If over-exposure occurs, call your poison control center at 1-800-222-1222 for current information on the management of poisoning or over-exposure.

Amoxicillin

In case of amoxicillin overdosage, discontinue medication, treat symptomatically and institute supportive measures as needed. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.²

Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin.

Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin. Amoxicillin can be removed from circulation by hemodialysis.

Clarithromycin

Overdosage of clarithromycin can cause gastrointestinal symptoms such as abdominal pain, vomiting, nausea, and diarrhea.

Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum concentrations are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.

Prevacid

PREVACID is not removed from the circulation by hemodialysis. In one reported overdose, a patient consumed 600 mg of PREVACID with no adverse reaction. Oral PREVACID doses up to 5000 mg/kg in rats (approximately 650 times the recommended human dose of 60 mg/day based on BSA) and in mice (about 338 times the recommended human dose of 60 mg/day based on BSA) did not produce deaths or any clinical signs.

Pharmacokinetics when all three of the Helicon components (PREVACID capsules, amoxicillin capsules, clarithromycin tablets) were coadministered has not been studied. Studies have shown no clinically significant interactions of PREVACID and amoxicillin or PREVACID and clarithromycin when administered together. There is no information about the gastric mucosal concentrations of PREVACID, amoxicillin and clarithromycin after administration of these agents concomitantly. The systemic pharmacokinetic information presented below is based on studies in which each product was administered alone.