1.1 Helicobacter pylori Infection

TALICIA is indicated for the treatment of Helicobacter pylori infection in adults [see Clinical Studies (14)].  

1.2 Usage

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

2.1 Recommended Dosage

Administer four (4) TALICIA capsules three times daily (at least 4 hours apart, e.g., morning, mid-day, and evening) with food for 14 days. Instruct patients to swallow the TALICIA capsules whole, with a full glass of water (8 ounces). Each dose (4 capsules) of TALICIA includes rifabutin 50 mg, amoxicillin 1,000 mg and omeprazole 40 mg. Do not crush or chew TALICIA capsules. Do not take TALICIA with alcohol.

2.2 Missed Doses

• If a dose is missed and the next dose is not within 4 hours, administer the missed dose as soon as possible.
• If a dose is missed and the next dose is within 4 hours, administer the missed dose as soon as possible and delay the next dose to ensure there are at least 4 hours between two doses.

4.1 Hypersensitivity Reactions

TALICIA is contraindicated in patients with known hypersensitivity to the components of TALICIA: amoxicillin [or other β-lactam antibacterial drugs (e.g., penicillins and cephalosporins)], omeprazole (or other benzimidazoles [e.g. proton pump inhibitors (PPIs) and anthelmintics]), rifabutin (or any other rifamycins), or to any other component of TALICIA. Hypersensitivity reactions may include anaphylaxis or Stevens Johnson Syndrome, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, rash and urticaria [see Warnings and Precautions (5.1, 5.6, 5.8), Adverse Reactions (6.1)].

4.2 Rilpivirine-containing Products

Proton pump inhibitors (PPIs), including omeprazole (a component of TALICIA), are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7.1)].

4.3 Delavirdine

The use of rifabutin (a component of TALICIA), is contraindicated in patients receiving delavirdine [see Drug Interactions (7.1)].

4.4 Voriconazole

The use of rifabutin (a component of TALICIA), is contraindicated in patients receiving voriconazole [see Drug Interactions (7.1)].

5.1 Hypersensitivity Reactions

Serious and fatal hypersensitivity reactions, e.g., anaphylaxis, angioedema, erythema multiforme, exfoliative dermatitis, hypersensitivity vasculitis, acute tubulointerstitial nephritis, and serum sickness have been reported with the components of TALICIA: omeprazole, amoxicillin and rifabutin.

Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations).

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 TALICIA, inquire about history of hypersensitivity reactions to penicillins, cephalosporins, rifamycins, or PPIs. Discontinue TALICIA and institute immediate therapy, if hypersensitivity reactions occur.

5.2 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the components of TALICIA: rifabutin, amoxicillin, and omeprazole [see Warnings and Precautions (5.1) and Adverse Reactions (6.3)].

Monitor closely and discontinue TALICIA at the first signs of SCAR.

5.3 Drug-Induced Enterocolitis Syndrome (DIES)

Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of TALICIA [see Adverse Reactions (6.3)], with most cases occurring in pediatric patients ≤18 years of age. DIES is a non-IgE mediated hypersensitivity reaction characterized by protracted vomiting occurring 1 to 4 hours after drug ingestion in the absence of skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock, diarrhea within 24 hours after ingesting amoxicillin, and leukocytosis with neutrophilia. If DIES occurs, discontinue TALICIA and institute appropriate therapy.

5.4 Clostridioides difficile-Associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of omeprazole, a component of TALICIA and nearly all antibacterial agents, including amoxicillin and rifabutin, which are components of TALICIA 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.

CDAD must be considered in all patients who present with diarrhea following proton pump inhibitor and or antibacterial 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 confirmed, TALICIA should be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.5 Reduced Efficacy of Hormonal Contraceptives

TALICIA may reduce the efficacy of hormonal contraceptives. Therefore, an additional non-hormonal highly effective method of contraception should be used while taking TALICIA [see Drug Interactions (7.1)].

5.6 Acute Tubulointerstitial Nephritis

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs including omeprazole, a component of TALICIA. TIN may occur at any point during PPI therapy.

Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions, to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia).

TIN has also been observed in patients taking penicillins, such as amoxicillin, a component of TALICIA.

Discontinue TALICIA and evaluate patients with suspected acute TIN [see Contraindications (4)].

5.7 Risk of Adverse Reactions or Loss of Efficacy Due to Drug Interactions

Components of TALICIA have the potential for clinically important drug interactions [see Contraindications (4) and Drug Interactions (7)]. 

Avoid concomitant use of TALICIA with other CYP2C19 or CYP3A4 inducers (e.g., St. John’s Wort, rifampin) as they can substantially decrease omeprazole concentrations.  Avoid concomitant use of TALICIA with CYP2C19 and/or CYP3A4 inhibitors (e.g., fluconazole, itraconazole) as it may significantly increase the plasma concentration of component (s) of TALICIA.  Depending on the protease inhibitor, the concomitant use of TALICIA should be avoided (e.g., amprenavir, indinavir) or dose adjustments for a concomitantly administered protease inhibitor(s) may be required.  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. Avoid TALICIA in patients on high-dose methotrexate. Concomitant use of clopidogrel and omeprazole reduces the pharmacological activity of clopidogrel. Avoid TALICIA in patients on clopidogrel. When using TALICIA, consider alternative anti-platelet therapy [see Drug Interactions (7)].

5.8 Cutaneous and Systemic Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. 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. If signs or symptoms consistent with CLE or SLE develop in patients receiving TALICIA, discontinue the drug and evaluate as appropriate.

5.9 Rash in Patients with Mononucleosis

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Avoid TALICIA in patients with mononucleosis.

5.10 Uveitis

Due to the possible occurrence of uveitis, patients should be carefully monitored when rifabutin, a component of TALICIA, is given in combination with clarithromycin (or other macrolides) and/or fluconazole and related compounds. If uveitis is suspected, refer for an ophthalmologic evaluation and, if considered necessary, suspend treatment with rifabutin [see Adverse Reactions (6.2)].

5.11 Interactions with Diagnostic 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. Assess CgA levels at least 14 days after TALICIA treatment and consider repeating the test if initial CgA levels are high [see Drug Interactions (7)].

5.12 Development of Drug-Resistant Bacteria

Prescribing TALICIA either 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.

6.1 Clinical Trials Experience with TALICIA

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

The safety of TALICIA was assessed in adult patients who were screened and found to be positive for H. pylori infection in one active-controlled (Study 1) and one placebo-controlled (Study 2) clinical trial. Patients received TALICIA, amoxicillin and omeprazole, or placebo every eight hours for 14 consecutive days taken with food. A total of 305 patients received TALICIA in Studies 1 and 2, 227 patients received amoxicillin and omeprazole (as omeprazole magnesium) in Study 1, and 41 patients received placebo in Study 2. These patients had a mean age of 46.4 years (range 18 to 70 years); 62.3% were female, 80.3% were white with 64.2% Hispanic or Latino.

Adverse Reactions Leading to Discontinuation

Treatment discontinuation due to an adverse reaction occurred in 1% (4/305) of patients receiving TALICIA, <1% (1/227) of patients receiving amoxicillin and omeprazole, and 2% (1/41) of patients receiving placebo. Adverse reactions leading to discontinuation of TALICIA were nausea and vomiting, nausea, nasal congestion, and nasopharyngitis, in one patient each.

Most Common Adverse Reactions

Selected adverse reactions occurring in ≥1% of patients receiving TALICIA in Study 1 and 2 are described in Table 1.

Table 1: Selected Adverse Reactions Occurring in 1% or Greater of Patients Receiving TALICIA in Studies 1 and 2

6.2 Other Important Adverse Reactions from the Labeling of the Individual Components of TALICIA

Additional adverse reactions that occurred in 1% or greater of patients treated with omeprazole or rifabutin alone in clinical trials were as follows:

Omeprazole

Flatulence, acid regurgitation, upper respiratory infection, constipation, dizziness, asthenia, back pain, and cough.

Rifabutin

Flatulence, asthenia, chest pain, fever, pain, leucopenia, anemia, anorexia, eructation, myalgia, insomnia, and taste perversion.

The following selected adverse reactions occurred in less than 1% of patients treated with rifabutin alone: flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, dyspnea, skin discoloration, thrombocytopenia, pancytopenia, and jaundice.

6.3 Post-Marketing Experience with Components of TALICIA

Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure.

Omeprazole

Cardiovascular: angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema

Endocrine: gynecomastia

Gastrointestinal: pancreatitis including fatal pancreatitis, anorexia, irritable colon, fecal discoloration, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis, fundic gland polyps, gastroduodenal carcinoids in patients with Zollinger-Ellison syndrome on long-term treatment as a manifestation of the underlying condition associated with such tumors

Hepatic: fatal hepatic failure or necrosis, hepatic encephalopathy, hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice

Metabolism and Nutritional disorders: hypoglycemia, hypomagnesemia, with or without hypocalcemia and/or hypokalemia, hyponatremia, weight gain

Musculoskeletal: muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture.

Nervous System/Psychiatric: depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, dream abnormalities, tremors, paresthesia, vertigo

Respiratory: epistaxis

Skin and subcutaneous tissue disorders: SCAR such as SJS, TEN, DRESS, AGEP, photosensitivity, urticaria, pruritus, petechiae, purpura, alopecia, dry skin, hyperhidrosis

Special Senses: tinnitus, taste perversion

Ocular: optic atrophy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision

Urogenital: hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain, erectile dysfunction

Hematologic: Agranulocytosis, hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leukocytosis

Amoxicillin

Gastrointestinal: Drug-induced enterocolitis syndrome (DIES), black hairy tongue

Liver: hepatic dysfunction, cholestatic jaundice, cholestasis, acute cytolytic hepatitis

Renal: crystalluria [see Overdosage (10)]

Hemic and Lymphatic Systems: anemia, hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis

Central Nervous System: hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, aseptic meningitis, behavioral changes, and/or dizziness

Skin and subcutaneous tissue disorders: SCAR, such as SJS, TEN, DRESS, and AGEP, and linear IgA bullous dermatosis.

Rifabutin

Blood and lymphatic system disorders: agranulocytosis, lymphopenia

Skin and subcutaneous tissue disorders: SCAR, such as SJS, TEN, DRESS, and AGEP.

7.1 Interactions with Other Drugs and Diagnostics

Drug interaction studies with TALICIA have not been conducted. The drug interaction information described here is based on the prescribing information of individual TALICIA components: omeprazole, amoxicillin, and rifabutin.

Rifabutin is a substrate and inducer of cytochrome P450 (CYP) 3A enzymes.  Omeprazole is a substrate and an inhibitor of CYP2C19, and a substrate of CYP3A4.  Co-administration of TALICIA and other drugs that are substrates, inhibitors, or inducers of these enzymes may alter concentrations of rifabutin/omeprazole or other co-administered drugs [See Table 2 below and Clinical Pharmacology (12.3)].

Omeprazole magnesium is a PPI. Refer to the prescribing information of the drugs used concomitantly with TALICIA for further information on their interactions with PPIs.

Table 2: Interactions with TALICIA When Co-Administered with Other Drugs and Diagnostics

8.1 Pregnancy

8.2 Lactation

Risk Summary

Data from a published clinical lactation study reports that amoxicillin is present in human milk.  Published adverse effects with amoxicillin exposure in the breast-fed infant include diarrhea. There are no data on the effects of amoxicillin on milk production. Limited data suggest omeprazole may be present in human milk. There are no clinical data on the effects of omeprazole on the breast-fed infant or on milk production. There are no data on the presence of rifabutin in human milk or the effects of rifabutin on the breast-fed infant or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TALICIA and any potential adverse effects on the breast-fed child from TALICIA or from the underlying condition.

8.3 Females and Males of Reproductive Potential

Contraception

Both rifabutin and amoxicillin components of TALICIA interact with hormonal contraceptives resulting in lower levels of these contraceptives. Therefore, female patients taking hormonal contraceptives should use an additional non-hormonal highly effective method of contraception while taking TALICIA [see Drug Interactions (7.1)].

Infertility

Males

Based on findings in rodents, TALICIA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness of TALICIA in pediatric patients below the age of 18 years with H. pylori infection have not been established.

Esomeprazole, an enantiomer of omeprazole, was shown to decrease body weight, body weight gain, femur weight, femur length, and overall growth in juvenile rats at oral doses about 11 to 23 times a daily human dose of 120 mg esomeprazole or omeprazole based on body surface area [see Nonclinical Toxicology (13.2)].

8.5 Geriatric Use

Clinical studies of TALICIA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients.

Omeprazole

Omeprazole was administered to over 2000 elderly individuals (≥ 65 years of age) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Amoxicillin

An analysis of clinical studies of amoxicillin was conducted to determine whether subjects aged 65 and older 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.

This drug 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, it may be useful to monitor renal function in elderly patients taking TALICIA.

Rifabutin

Clinical studies of rifabutin did not include sufficient numbers of subjects aged 65 and older 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.

8.6 Renal Impairment

It is recommended to avoid the use of TALICIA in patients with severe renal impairment (GFR < 30 mL/min). Amoxicillin is primarily eliminated by the kidney [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

It is recommended to avoid the use of TALICIA in patients with hepatic impairment. In patients with hepatic impairment (Child-Pugh Class A, B, or C) exposure to omeprazole substantially increased compared to healthy subjects [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

TALICIA is a combination of antibacterial drugs (rifabutin, amoxicillin) and a proton pump inhibitor (omeprazole as omeprazole magnesium), an antisecretory drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

After oral administration, the onset of the antisecretory effect of omeprazole occurs within one hour, with the maximum effect occurring within two hours. The antisecretory effect lasts longer than would be expected from the short (approximately one hour) plasma half-life, apparently due to prolonged binding to the parietal H+/K+ ATPase enzyme. When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days. The inhibitory effect of omeprazole on acid secretion increases with repeated daily dosing.

12.3 Pharmacokinetics

12.4 Microbiology

Mechanism of Action

Amoxicillin acts through the inhibition of cell wall biosynthesis that leads to the death of bacteria.

Rifabutin inhibits DNA-dependent RNA polymerase in susceptible microorganisms but not in mammalian cells.

Mechanism of Resistance

Resistance to amoxicillin is mediated primarily through beta-lactamases that cleave the beta-lactam ring of amoxicillin, rendering it inactive.

Resistance to rifabutin occurs through mutations in the DNA-dependent RNA polymerase.

Antimicrobial Activity

TALICIA therapy has been shown to be active against most clinical isolates of H. pylori. In the clinical trials, 6.4% of the pretreatment isolates had amoxicillin MIC values >0.125 mcg/mL; 17.4% had clarithromycin MIC values ≥1 mcg/mL; 43.6% had metronidazole MIC values >8 mcg/mL. All isolates had rifabutin MIC values of <1 mcg/mL. The clinical significance of these MIC values is unknown.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Effects on Gastrointestinal Microbial Ecology

Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections due to pathogens such as Salmonella and Campylobacter and, in hospitalized patients, possibly also due to Clostridioides difficile.

12.5 Pharmacogenomics

CYP2C19, a polymorphic enzyme, is involved in the metabolism of omeprazole. The CYP2C19*1 allele is fully functional while the CYP2C19*2 and *3 alleles are nonfunctional. There are other alleles associated with no or decreased CYP2C19 function. Patients carrying two fully functional alleles are normal metabolizers and those carrying two nonfunctional alleles are poor metabolizers. The systemic exposure to omeprazole varies with a patient’s metabolism status: poor metabolizers > intermediate metabolizers > normal metabolizers. Approximately 3% of Caucasians and 15 to 20% of Asians are CYP2C19 poor metabolizers.

In a pharmacokinetic study of single 20 mg omeprazole dose, the AUC of omeprazole in Asian subjects was approximately four times higher than in Caucasians. In Study 1, the safety and tolerability of TALICIA was not substantially different in CYP2C19 poor metabolizers (n = 5) and intermediate metabolizers (n = 48) compared to normal metabolizers (n = 114).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies have been performed to evaluate the effect of TALICIA on carcinogenesis, mutagenesis, or impairment of fertility.

Omeprazole

In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.1 to 11.4 times a human dose of 120 mg/day, as expressed on a body surface area basis) produced gastric enterochromaffin-like (ECL) cell carcinoids in a dose-related manner in both males and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood concentrations of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 1 times a human dose of 120 mg/day, based on body surface area) for one year, and then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs. 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs. 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat, no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret.

In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about < 0.1 to 1.3 times the human dose of 120 mg/day, based on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males or females at the high dose of 140.8 mg/kg/day (about 11 times the human dose of 120 mg/day on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/–) transgenic mouse carcinogenicity study was not positive.

Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay, and an in vivo rat liver DNA damage assay. 

Omeprazole at oral doses up to 138 mg/kg/day in rats (about 11 times the human dose of 120 mg on a body surface area basis) was found to have no effect on fertility and reproductive performance.

In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists.

Amoxicillin

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Studies to detect mutagenic potential of amoxicillin alone have not been conducted; however, the following information is available from tests on a 4:1 mixture of amoxicillin and potassium clavulanate. Amoxicillin and potassium clavulanate were non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and potassium clavulanate were weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin and potassium clavulanate were negative in the mouse micronucleus test and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test and was negative in each of these assays. 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 2 times the 3 g human dose based on body surface area).

Rifabutin

Long-term carcinogenicity studies were conducted with rifabutin in mice and in rats. Rifabutin was not carcinogenic in mice at doses up to 180 mg/kg/day, or approximately 36 times the recommended human daily dose. Rifabutin was not carcinogenic in the rat at doses up to 60 mg/kg/day, about 12 times the recommended human dose.

Rifabutin was not mutagenic in the bacterial mutation assay (Ames Test) using both rifabutin-susceptible and resistant strains. Rifabutin was not mutagenic in Schizosaccharomyces pombe P1 and was not genotoxic in V-79 Chinese hamster cells, human lymphocytes in vitro, or mouse bone marrow cells in vivo.

Fertility was impaired in male rats given 160 mg/kg (32 times the recommended human daily dose).

13.2 Animal Toxicology and/or Pharmacology

A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg/kg/day (about 6 to 23 times a daily oral human dose of 120 mg esomeprazole or omeprazole on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 11 times a daily oral human dose of 120 mg esomeprazole or omeprazole on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.

Hypersensitivity Reactions

Advise the patient to call their healthcare provided immediately if they develop new rash, skin lesions, muscle or joint pains, swelling, severe flu-like symptoms, difficulty breathing or visual symptoms [see Warnings and Precautions (5.1)].

Severe Cutaneous Adverse Reactions

Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to stop taking TALICIA immediately and promptly report the first signs or symptoms of skin rash, mucosal lesions, or any other sign of hypersensitivity [see Warnings and Precautions (5.2)].

Diarrhea

Counsel patients that diarrhea is a common problem caused by antibiotics, and it usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools even as late as 2 or more months after having taken their last dose of the antibiotic. Patients should contact their physician as soon as possible if they experience bloody diarrhea, persistent abdominal pain, fever, or chronic diarrhea that does not resolve [see Warnings and Precautions (5.4)].

Brown-Orange Discoloration

Urine, feces, saliva, sputum, perspiration, tears, and skin may be colored brown-orange due to the rifabutin component of TALICIA and some of its metabolites. Soft contact lenses may be permanently stained. Advise patients to be treated with TALICIA of these possibilities and counsel the patient that these should resolve after therapy is completed.

Drug Interactions

Advise patients not to take St. John’s Wort, amoxicillin or other penicillin products, rifabutin or other rifamycins, over-the counter (OTC) omeprazole or other PPIs during treatment with TALICIA. Advise patients that they should not start any new medication while taking TALICIA without first speaking with their health care provider [see Warnings and Precautions (5.7)]. 

Contraception

Counsel females of reproductive potential who are taking oral or other forms of hormonal birth-control medications to use an additional non-hormonal highly effective method of contraception while taking TALICIA [see Warnings and Precautions (5.5)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential that TALICIA is not recommended during pregnancy because of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.

Cutaneous or Systemic Lupus

Advise patients to report any symptoms associated with cutaneous or systemic lupus erythematosus [see Warnings and Precautions (5.8)].

Acute Tubulointerstitial Nephritis

Advise the patient or caregiver to call the patient’s healthcare provider immediately if they experience signs and/or symptoms associated with acute tubulointerstitial nephritis [see Warnings and Precautions (5.6)].

Important Administration Instructions for TALICIA

• Advise patients to take four (4) TALICIA capsules three times daily (at least 4 hours apart, e.g., morning, mid-day, and evening) with food for 14 days. They should NOT crush or chew capsules.
• Advise patients to swallow TALICIA with at least 8 ounces of water.
• Advise patients not to take TALICIA with alcohol.
• Missed doses: Advise patients that if a dose is missed, and the next dose is not within 4 hours, administer as soon as possible. However, if a dose is missed and the next dose is within 4 hours, administer the missed dose as soon as possible and delay the next dose to ensure there are at least 4 hours between two doses.
  It is important for patients to complete the entire course of therapy.
• Counsel patients that antacids may be used concomitantly with TALICIA.
• Counsel patients to continue the full course of TALICIA regardless of whether or not their symptoms improve.  Although change in dyspepsia symptoms may occur (either improvement or worsening), these are unlikely to be related to the H. pylori infection. Counsel patients that treatment of H. pylori infection is important due to its association with stomach ulcers, atrophic gastritis and increased risk of gastric cancer. 

Antibacterial Resistance

Patients should be counseled that antibacterial drugs including TALICIA should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When TALICIA 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 TALICIA or other antibacterial drugs in the future [see Warnings and Precautions (5.12)].

TALICIA is distributed by RedHill Biopharma Inc. Raleigh, NC

TALICIA is manufactured in Sweden for RedHill Biopharma Ltd. Tel Aviv, Israel

TALICIA is a trademark registered with the U.S. Patent and Trademark Office and used under license by RedHill Biopharma Inc.

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