Talicia

1 INDICATIONS AND USAGE TALICIA is a three-drug combination of omeprazole, a proton pump inhibitor, amoxicillin, a penicillin-class antibacterial, and rifabutin, a rifamycin antibacterial, indicated for the treatment of Helicobacter pylori infection in adults. ( 1 ) 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 bacteria. (1.2) 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 DOSAGE AND ADMINISTRATION 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. ( 2.1 ) Swallow whole. Do not crush or chew. ( 2.1 ) Do not take TALICIA with alcohol. ( 2.1 ) 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.

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Serious and occasionally fatal reactions (e.g., anaphylaxis) have been reported with components of TALICIA. If hypersensitivity reactions occur, discontinue TALICIA and institute immediate therapy (e.g., anaphylaxis management). ( 5.1 ) Severe Cutaneous Adverse Reactions (SCAR): There have been reports of SCAR with the components of TALICIA. Monitor closely and discontinue TALICIA at the first signs of SCAR. ( 5.2 ) Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of TALICIA. If this occurs, discontinue TALICIA and institute appropriate therapy. ( 5.3 ) Clostridioides difficile -Associated Diarrhea (CDAD): Evaluate if diarrhea occurs. ( 5.4 ) Reduction in the Efficacy of Hormonal Contraceptives: Additional non-hormonal highly effective methods of contraception should be used while taking TALICIA. ( 5.5 ) Acute Tubulointerstitial Nephritis (TIN): Observed in patients taking Proton Pump Inhibitors (PPIs), including omeprazole and penicillins. Discontinue TALICIA and evaluate patients. ( 5.6 ) Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue TALICIA and evaluate. ( 5.8 ) 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 wi…

4 CONTRAINDICATIONS Known hypersensitivity to omeprazole, amoxicillin or any other beta-lactam antibacterial drugs, rifabutin or any other rifamycin, or any component of TALICIA. ( 4.1 ) Rilpivirine-containing products. ( 4.2 ) Delavirdine. ( 4.3 ) Voriconazole. ( 4.4 ) 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) ] .

7 DRUG INTERACTIONS Components of TALICIA have the potential for clinically important drug interactions. See Full Prescribing Information for important drug interactions with TALICIA. ( 4 , 5.7 ) 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 CYP2C19 or CYP3A4 Inducers Clinical Impact Decreased exposure of omeprazole when used concomitantly with strong inducers. Prevention or Management St. John’s Wort, rifampin : Avoid concomitant use with TALICIA [see Warnings and Precautions (5.7) ]. Ritonavir-containing products : See prescribing information for specific drugs. CYP2C19 or CYP3A4 Inhibitors Clinical Impact Increased blood levels of omeprazole and rifabutin. Prevention or Management Voriconazole : Concomitant use with TALICIA is contraindicated [see Contraindications (4) ] . Fluconazole, posaconazole and itraconazole : Avoid concomitant use with TALICIA. If coadministration cannot be avoided, monitor patients for rifabutin associated adverse events, and lack of anti-fungal efficacy. CYP2C19 Substrates (e.g., Clopidogrel, citalopram, cilostazol, phenytoin, diazepam) Clinical Impact Increased plasma concentrations of CYP2C19 substrate drugs or decreased/increased plasma concentrations of its active metabolite(s) [see Clinical Pharmacology (12.3) ] . Prevention or Management Clopidogrel : Consider use of alternative anti-platelet therapy [ see Warnings and Precautions (5.7) ] . Avoid concomitant use with TALICIA. Antiretrovirals/Protease Inhibitors Clinical Impact Antiretrovirals/protease inhibitors may increase rifabutin blood levels. The effect of PPIs (such as omeprazole in TALICIA) on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3) ]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3) ] . There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole. Prevention or Management Delavirdine : Combination treatment with TALICIA and delavirdine is contraindicated [see Contraindications (4) ]. Rilpivirine-containing products : Concomitant use with TALICIA is contraindicated [see Contraindications (4) ]. Avoid concomitant use of TALICIA with amprenavir, indinavir, lopinavir/ritonavir, saquinavir/ritonavir, ritonavir, tipranavir/ritonavir, fosamprenavir/ritonavir, or nelfinavir [see Warnings and Precautions (5.7) ] . Other antiretrovirals: See prescribing information for specific antiretroviral drugs. Probenecid Clinical Impact Increased and prolonged blood levels of amoxicillin. Allopurinol Clinical Impact Increase in the incidence of rashes is reported in patients receiving both allopurinol and amoxicillin together compared to patients receiving amoxicillin alone. It is not known whether th…

8.1 Pregnancy Risk Summary Based on animal reproduction studies, TALICIA may cause fetal harm when administered to pregnant women. There are no adequate and well controlled studies of amoxicillin, omeprazole, or rifabutin (used separately or together) in pregnant women. Use of TALICIA is generally not recommended for use in pregnancy. If TALICIA is used during pregnancy, advise pregnant women of the potential risk to a fetus. Omeprazole: Available epidemiologic data do not demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. Reproduction studies in rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 1.13 to 11 times an oral human dose of 120 mg. Fetal malformations were not observed in animal reproduction studies with administration of oral esomeprazole (an enantiomer of omeprazole) magnesium in rats and rabbits during organogenesis with doses about 23 times and 14 times, respectively, of an oral human dose of 120 mg esomeprazole or omeprazole. Changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 11 times an oral human dose of 120 mg esomeprazole or omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see Data ] . Amoxicillin: Available data from published epidemiologic studies and pharmacovigilance case reports over several decades with amoxicillin use have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes [see Data ] . No adverse developmental effects were observed in animal reproduction studies with administration of amoxicillin to pregnant mice and at doses up to 3 to 6 times an oral human dose of 3 grams. Rifabutin: Fetal malformations were not observed in rat or rabbit reproduction studies given rifabutin at dose levels up to 200 mg/kg (6 to 13 times the recommended human dose). In rats, given rifabutin at 200 mg/kg/day (about 6 times the recommended human daily dose), there was a decrease in fetal viability. Increased skeletal anomalies were observed in rats and rabbits at 40 and 80 mg/kg/day, respectively (corresponding to approximately an equivalent dose and 5 times the recommended human daily dose); maternal toxicity was noted at 80 mg/kg in rabbits [see Data ]. The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Omeprazole Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls. A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995 to 99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live bi…

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).

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2) ] Drug-Induced Enterocolitis Syndrome (DIES) [see Warnings and Precautions (5.3) ] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.4) ] Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.6) ] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.8) ] Rash in Patients with Mononucleosis [see Warnings and Precautions (5.9) ] Uveitis [see Warnings and Precautions (5.10) ] Most common adverse reactions (≥1%) were diarrhea, headache, nausea, abdominal pain, chromaturia, rash, dyspepsia, oropharyngeal pain, vomiting, and vulvovaginal candidiasis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact RedHill Biopharma Inc. at 1-833-ADRHILL (1-833-237-4455) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 a Headache includes: headache and migraine. b Abdominal pain includes: abdominal pain, abdominal pain upper, and abdominal pain lower. c Riboflavin was administered in Study 1 to prevent unintentional unblinding and may have contributed to under-reporting of chromaturia. d Rash includes: rash, rash maculo-papular, rash morbilliform, and urticaria. e Dyspepsia includes: dyspepsia and epigastric discomfort. f Vulvovaginal candidiasis includes: vulvovaginal candidiasis, vulvovaginal mycotic infection, fungal infection, and vaginal discharge + vulvovaginal burning sensation + vulvovaginal pruritus. Study 1 Study 2 Adverse Reaction TALICIA (N=228) n (%) Amoxicillin and Omeprazole (N=227) n (%) TALICIA (N=77) n (%) Placebo (N=41) n (%) Diarrhea 23 (10.1) 18 (7.9) 11 (14.3) 4 (9.8) Headache a 17 (7.5) 16 (7.0) 12 (15.6) 4 (9.8) Nausea 11 (4.8) 12 (5.3) 3 (3.9) 1 (2.4) Abdominal pain b 8 (3.5) 11 (4.8) 3 (3.9) 2 (4.9) Chromaturia c 0 0 10 (13.0) 1 (2.4) Rash d 6 (2.6) 2 (0.9) 4 (5.2) 0 Dyspepsia e 5 (2.2) 3 (1.3) 1 (1.3) 0 Vomiting 5 (2.2) 5 (2.2) 1 (1.3) 2 (4.9) Oropharyngeal pain 2 (0.9) 2 (0.9) 3 (3.9) 0 Vulvovaginal candidiasis f 5 (2.2) 5 (2.2) 0 0 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…