DRUG INTERACTIONS SECTION.

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, 5.6). 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 substrate and inducer of cytochrome P450 (CYP) 3A enzymes. Omeprazole is substrate and an inhibitor of CYP2C19, and 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 below and Clinical Pharmacology (12.3)]. Omeprazole magnesium is 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 DiagnosticsCYP2C19 or CYP3A4 InducersClinical ImpactDecreased exposure of omeprazole when used concomitantly with strong inducers.Prevention or ManagementSt. Johns Wort, rifampin: Avoid concomitant use with TALICIA [see Warnings and Precautions (5.6)].Ritonavir-containing products: See prescribing information for specific drugs.CYP2C19 or CYP3A4 InhibitorsClinical ImpactIncreased blood levels of omeprazole and rifabutin. Prevention or ManagementVoriconazole: 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 ImpactIncreased plasma concentrations of CYP2C19 substrate drugs or decreased/increased plasma concentrations of its active metabolite(s) [see Clinical Pharmacology (12.3)].Prevention or ManagementClopidogrel: Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6) ]. Avoid concomitant use with TALICIA.Antiretrovirals/Protease InhibitorsClinical ImpactAntiretrovirals/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 ManagementDelavirdine: 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 (5.6)].Other antiretrovirals: See prescribing information for specific antiretroviral drugs.ProbenecidClinical ImpactIncreased and prolonged blood levels of amoxicillin.AllopurinolClinical ImpactIncrease 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 this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients.Prevention or ManagementDiscontinue allopurinol at the first appearance of skin rash. Assess benefit-risk of continuing TALICIA treatment.Warfarin, and Other Oral AnticoagulantsClinical ImpactAbnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants and in patients receiving PPIs, including omeprazole, and warfarin concomitantly.Increases in INR and prothrombin time may lead to abnormal bleeding and even death.Prevention or ManagementMonitor INR and prothrombin time and adjust the dose of warfarin or other oral anticoagulants to maintain the desired level of anticoagulation.MethotrexateClinical ImpactConcomitant use of omeprazole with methotrexate (primarily at high doses) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities [see Warnings and Precautions (5.6)].Prevention or ManagementAvoid concomitant use of TALICIA in patients receiving high-dose methotrexate.DigoxinClinical ImpactPotential for increased digoxin blood levels [see Clinical Pharmacology (12.3)].Prevention or ManagementMonitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)Clinical ImpactOmeprazole can alter the absorption of other drugs due to its effect of reducing intragastric acidity thereby increasing gastric pH.Prevention or ManagementMycophenolate mofetil (MMF): Use TALICIA with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].See the prescribing information of other drugs dependent on gastric pH for absorption. TacrolimusClinical ImpactPotential for increased tacrolimus blood levels, especially in patients who are intermediate or poor metabolizers of CYP2C19.Prevention or ManagementMonitor tacrolimus whole blood levels and adjust dose as per the prescribing information for tacrolimus.Drugs Metabolized via the CYP450 Enzymes (e.g., cyclosporine, disulfiram)Clinical ImpactInteractions are reported with omeprazole and other drugs metabolized via the CYP450 enzymes.Prevention or ManagementMonitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with TALICIA.Oral ContraceptivesClinical ImpactConcomitant use of amoxicillin and rifabutin with hormonal contraceptives may lead to loss of its efficacy due to lower estrogen reabsorption and decreased ethinylestradiol and norethindrone concentrations, respectively [see Warnings and Precautions (5.4)].Prevention or ManagementPatients should be advised to use additional or alternative non-hormonal methods of contraception.Diagnostic Investigations for Neuroendocrine TumorsClinical ImpactPPI-induced decrease in gastric acidity may lead to increased serum chromogranin (CgA) levels, which may cause false positive results in diagnostics for neuroendocrine tumors [see Warnings and Precautions (5.10)]. Prevention or ManagementAssess CgA levels at least 14 days after stopping TALICIA treatment 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.Urine Glucose TestClinical ImpactHigh urine concentrations of ampicillin or amoxicillin may result in false-positive reactions when using glucose tests based on the Benedicts copper reduction reaction that determines the amount of reducing substances like glucose in the urine.Prevention or ManagementGlucose tests based on enzymatic glucose oxidase reactions should be used.Interaction with Secretin Stimulation TestClinical ImpactHyper-response in gastrin secretion in response to secretin stimulation test may falsely suggest gastrinoma.Prevention or ManagementTest should be performed at least 14 days after stopping TALICIA treatment to allow gastrin levels to return to baseline.False Positive Urine Tests for Tetrahydrocannabinol (THC)Clinical ImpactThere have been reports of false positive urine screening tests for THC in patients receiving PPIs.Prevention or ManagementAn alternative confirmatory method should be considered to verify positive results.Other Laboratory TestsClinical ImpactFollowing administration of ampicillin or amoxicillin to pregnant women, transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted.. 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)].

ADVERSE REACTIONS SECTION.

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)] Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.3)]Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.5)] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.7)] Rash in Patients with Mononucleosis [see Warnings and Precautions (5.8)] Uveitis [see Warnings and Precautions (5.9)] Hypersensitivity Reactions [see Warnings and Precautions (5.1)] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.3)]. Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.5)] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.7)] Rash in Patients with Mononucleosis [see Warnings and Precautions (5.8)] Uveitis [see Warnings and Precautions (5.9)] 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 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. total of 305 patients received TALICIA in Studies 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 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 DiscontinuationTreatment 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 ReactionsSelected adverse reactions occurring in >=1% of patients receiving TALICIA in Study and are described in Table 1.Table 1: Selected Adverse Reactions Occurring in 1% or Greater of Patients Receiving TALICIA in Studies and 2a Headache includes: headache and migraine. Abdominal pain includes: abdominal pain, abdominal pain upper, and abdominal pain lower. Riboflavin was administered in Study to prevent unintentional unblinding and may have contributed to under-reporting of chromaturia. Rash includes: rash, rash maculo-papular, rash morbilliform, and urticaria. Dyspepsia includes: dyspepsia and epigastric discomfort. Vulvovaginal candidiasis includes: vulvovaginal candidiasis, vulvovaginal mycotic infection, fungal infection, and vaginal discharge vulvovaginal burning sensation vulvovaginal pruritus.Study 1Study Adverse ReactionTALICIA (N=228) (%)Amoxicillin and Omeprazole (N=227) (%)TALICIA (N=77) (%)Placebo (N=41) (%)Diarrhea23 (10.1)18 (7.9)11 (14.3)4 (9.8)Headachea 17 (7.5)16 (7.0)12 (15.6)4 (9.8)Nausea11 (4.8)12 (5.3)3 (3.9)1 (2.4)Abdominal painb (3.5)11 (4.8)3 (3.9)2 (4.9)Chromaturiac 0010 (13.0)1 (2.4)Rashd (2.6)2 (0.9)4 (5.2)0Dyspepsiae (2.2)3 (1.3)1 (1.3)0Vomiting5 (2.2)5 (2.2)1 (1.3)2 (4.9)Oropharyngeal pain2 (0.9)2 (0.9)3 (3.9)0Vulvovaginal candidiasisf (2.2)5 (2.2)00. 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:OmeprazoleFlatulence, acid regurgitation, upper respiratory infection, constipation, dizziness, asthenia, back pain, and cough.RifabutinFlatulence, 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 population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish causal relationship to drug exposure.OmeprazoleCardiovascular: angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edemaEndocrine: gynecomastiaGastrointestinal: 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 manifestation of the underlying condition associated with such tumorsHepatic: fatal hepatic failure or necrosis, hepatic encephalopathy, hepatocellular disease, cholestatic disease, mixed hepatitis, jaundiceMetabolism and Nutritional disorders: hypoglycemia, hypomagnesemia, with or without hypocalcemia and/or hypokalemia, hyponatremia, weight gainMusculoskeletal: 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, vertigoRespiratory: epistaxisSkin and subcutaneous tissue disorders: Severe cutaneous adverse reactions (SCAR) such as SJS, TEN, and AGEP, photosensitivity, urticaria, pruritus, petechiae, purpura, alopecia, dry skin, hyperhidrosisSpecial Senses: tinnitus, taste perversionOcular: optic atrophy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double visionUrogenital: hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular painHematologic: Agranulocytosis, hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leukocytosisAmoxicillinGastrointestinal: black hairy tongueLiver: hepatic dysfunction, cholestatic jaundice, cholestasis, acute cytolytic hepatitisRenal: crystalluria [see Overdosage (10)]Hemic and Lymphatic Systems: anemia, hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosisCentral Nervous System: hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizzinessSkin and subcutaneous tissue disorders: SCAR, such as SJS, TEN, and AGEP.RifabutinBlood and lymphatic system disorders: agranulocytosis, lymphopeniaSkin and subcutaneous tissue disorders: SCAR, such as SJS, TEN, DRESS, and AGEP.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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.OmeprazoleIn 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 human dose of 120 mg/day, as expressed on body surface area basis) produced gastric enterochromaffin-like (ECL) cell carcinoids in 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 times 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 finding involving only one tumor is difficult to interpret.In 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in 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 body surface area basis). No astrocytomas were observed in female rats in this study. In 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 body surface area basis). 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. 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 body surface area basis) was found to have no effect on fertility and reproductive performance.In 24-month carcinogenicity studies in rats, 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.AmoxicillinLong-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 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 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 times the g human dose based on body surface area).RifabutinLong-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 1 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. TALICIA is combination of antibacterial drugs (rifabutin, amoxicillin) and 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 to days. The inhibitory effect of omeprazole on acid secretion increases with repeated daily dosing.. 12.3 Pharmacokinetics. The pharmacokinetic parameters of the components of TALICIA are summarized in Table 3.Table 3: Mean (Standard Deviation) Pharmacokinetic Parameters of the Components of TALICIACmax =Maximum plasma concentration, AUC24 =Area under the concentration vs. 24-hour time curve Cmax and AUC24, estimates derived from 15 healthy subjects following administration of four TALICIA capsules three times in day (8 hours apart) resulting in the total daily oral doses of 150 mg rifabutin, 3000 mg amoxicillin, and 120 mg omeprazole.Pharmacokinetic Parametersa AmoxicillinOmeprazoleRifabutinCmax (ng/mL)15,860 (3,340)1,281 (518)88 (21)AUC24 (nghr/mL)145,788 (29,846)7,161 (3,533)1,320 (307)The absorption, distribution, and elimination related pharmacokinetic information on the components of TALICIA are provided in Table 4.Table 4: Pharmacokinetic Properties of the Components of TALICIA Tmax Time to reach Cmax, AUC Area under the concentration vs. time profile extrapolated to infinity, t1/2 Elimination half-life, indicates increase, indicates decrease, <-> indicates no significant change. Changes in Cmax, AUC, and Tmax estimates reported from crossover food-effect study in 18 healthy subjects following the administration of four TALICIA capsules administered once with high-fat, high calorie meal consisting approximately 1000 kcal (14% from protein, 53% from fat, and 33% from carbohydrates) compared to when four TALICIA capsules administered without food. Reported Tmax and t1/2 estimates are from the same study from 18 subjects (for rifabutin, from 17 subjects) who received TALICIA capsules without food.Pharmacokinetic Parameters AmoxicillinOmeprazoleRifabutinAbsorptionTmax (h), median (range)a (1.25-3)1.25 (0.75-1.77)3 (2-6)Effect of Food: With high-fat meala (relative to fasting)30% in Cmax <-> AUC Tmax by 1.5 hr92% in Cmax 83% in AUC Tmax by hr14% in Cmax 23% in AUC Tmax by hrDistributionProtein Binding20%95%85%Eliminationt1/2 (h), mean (standard deviation)1.4 (0.2)1 (0.3)34 (25) MetabolismMetabolic pathwaysNot significantly metabolizedExtensively metabolizedCYP2C19 (major) responsible for the formation of hydroxyomeprazoleCYP3A4 (minor) responsible for the formation of omeprazole-sulphoneThese metabolites have very little or no antisecretory activityOf the five metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant with plasma metabolite: parent AUC ratio of 0.10 and 0.07, respectively25-O-desacetylrifabutin has an activity equal to the parent drug with up to 10% to the total antimicrobial activity ExcretionMajor route of elimination60% of oral dose excreted in urine in 6-8 hours (mostly as unchanged drug)77% of dose excreted in urine as metabolites and the remainder of the dose recovered in feces53% of the oral dose was excreted in urine, primarily as metabolites About 30% of the dose is excreted in feces Renal and biliary clearance of unchanged drug each contribute approximately 5% to apparent oral clearance Renal ImpairmentFor omeprazole, no clinically meaningful change in bioavailability was reported in patients with chronic renal impairment (CLcr between 10-62 mL/min/1.73 m2). Amoxicillin is primarily eliminated by the kidney [see Use in Specific Populations (8.6)]. For rifabutin, the disposition was studied following 300 mg dose in 18 patients with varying degrees of renal function. Area under plasma concentration time curve (AUC) of rifabutin increased by about 71% in patients with severe renal impairment (CLcr <30 mL/min) compared to patients with creatinine clearance (CLcr) between 61-74 mL/min. In patients with mild to moderate renal impairment (CLcr between 30-61 mL/min), the AUC of rifabutin increased by about 41%.Hepatic ImpairmentThe pharmacokinetics of amoxicillin and rifabutin in patients with moderate and severe hepatic impairment are not known.For omeprazole, in patients with chronic hepatic disease classified as Child-Pugh Class (n=3), (n=4), and (n=1), the bioavailability increased to approximately 100% compared to healthy subjects, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly hours compared with the half-life in healthy subjects of 0.5 to hour. Plasma clearance averaged 70 mL/min, compared with value of 500 to 600 mL/min in healthy subjects [see Use in Specific Populations (8.7)]. Drug InteractionsDrug interaction studies with TALICIA have not been conducted. The drug interaction information described here is based on the prescribing information of individual TALICIA components: rifabutin, omeprazole magnesium, and amoxicillin [see Drug Interactions (7)].Effect of Omeprazole on Other Drugs Omeprazole is time-dependent inhibitor of CYP2C19 and can increase the systemic exposure of co-administered drugs that are CYP2C19 substrates. In addition, administration of omeprazole increases intragastric pH and can alter the systemic exposure of certain drugs that exhibit pH-dependent solubility [see Drug Interactions (7)].Effect of Rifabutin on Other Drugs Multiple dosing of rifabutin has been associated with induction of hepatic metabolic enzymes of the CYP3A subfamily. Rifabutins predominant metabolite (25-desacetyl rifabutin) may also contribute to this effect. Metabolic induction due to rifabutin is likely to produce decrease in plasma concentrations of concomitantly administered drugs that are primarily metabolized by the CYP3A enzymes. Similarly, concomitant medications that competitively inhibit the CYP3A activity may increase plasma concentrations of rifabutin [see Drug Interactions (7)].Drug Interactions Between TALICIA ComponentsCYP enzymes are involved in the metabolism of omeprazole; therefore, rifabutin mediated induction of CYP enzymes is expected to reduce systemic exposure to omeprazole. Table and Table summarizes the drug interactions information from the prescribing information of omeprazole and rifabutin, respectively.Table 5: Summary of Drug Interaction Studies with Omeprazole indicates increase, indicates decrease, ND=No data, AUC=Area under the concentration vs. time curve, Cmax =Maximum serum/plasma concentrations, Cmin Minimum serum/plasma concentrations. 3,4-dihydro-cilostazol has 4-7 times the activity of cilostazolCoadministered drugDosing regimen of coadministered drugDosing regimen of OmeprazoleResultsRilpivirineMultiple doses of 150 mg/dayMultiple doses of 20 mg/dayRilpivirine: 40% AUC, 40% Cmax, and 33% Cmin NelfinavirMultiple doses of 1250 mg twice dailyMultiple doses of 40 mg/dayNelfinavir: 36% AUC, 37% Cmax, and 39% Cmin M8: 92% in AUC, 89% Cmax, and 75% Cmin AtazanavirMultiple doses of 400 mg/dayMultiple doses of 40 mg/dayAtazanavir: 94% AUC, 96% Cmax, and 95% Cmin SaquinavirSaquinavir/ritonavir (1000/100 mg) twice daily for 15 days40 mg/day on Days 11 to 15Saquinavir: 82% AUC, 75% Cmax, and 106% Cmin ClopidogrelThree separate studies with 300 mg loading dose 75 mg/day80 mg/day at the same time as clopidogrel in two studies and 12 hours apart in the third studiesSummary results from three studies:41% to 46% in the exposure to the active metabolite of clopidogrel from Day 1.Administration of clopidogrel and omeprazole at different times does not prevent interactionMycophenolate Mofetil (MMF)1000 mg dose after the last dose of omeprazole20 mg twice daily for four daysMycophenolic acid (MPA)- active metabolite of MMF: 23% AUC and 52% Cmax CilostazolND40 mg/day for weekCilostazol: 26% AUC and 18% Cmax 3,4-dihydro-cilostazol: 69% AUC and 29% Cmax Diazepam0.1 mg/kg given intravenously20 mg/day concomitantlyDiazepam: 27% clearance and 36% half-lifeDigoxinND20 mg/day concomitantlyDigoxin: Up to 30% bioavailabilityVoriconazole400 mg twice daily for one day 200 mg/day for days40 mg/day for weekVoriconazole: Four-fold in AUC and two-fold in Cmax Table 6: Summary of Drug Interaction Studies with Rifabutin indicates increase, indicates decrease, <-> indicates no significant change, ND No data, AUC=Area under the concentration vs. time curve, Cmax Maximum serum/plasma concentrations, Cmin Minimum serum/plasma concentrations. Compared to rifabutin 300 mg once daily alone Compared to historical control (fosamprenavir/ritonavir 700/100 mg twice daily) Also taking zidovudine 500 mg once daily Compared to rifabutin 150 mg once daily alone Compared to rifabutin 300 mg once daily alone Data from case report Compared to voriconazole 200 mg twice daily aloneCoadministered drugDosing regimen of coadministered drugDosing regimen of RifabutinStudy population (n)Effect on rifabutinEffect on coadministered drugANTIVIRALSAmprenavir1200 mg twice daily 10 days300 mg once daily 10 daysHealthy male subjects (6)193% AUC,119% Cmax <->Delavirdine400 mg TID300 mg once dailyHIV-infected patients (7)230% AUC,128% Cmax 80% AUC,75% Cmax,17% Cmin Didanosine167 or 250 mg twice daily 12 days300 or 600 mg once daily 1HIV-infected patients (11)<-><->Fosamprenavir/ritonavir700 mg twice daily plus ritonavir 100 mg twice daily 2 weeks150 mg every other day 2 weeksHealthy subjects (15)<-> AUCa 15% Cmax 35% AUCb,36% Cmax,36% CminIndinavir800 mg TID 10 days300 mg once daily 10 daysHealthy subjects (10)173% AUC,134% Cmax 34% AUC,25% Cmax,39% Cmin Lopinavir/ritonavir400/100 mg twice daily 20 days150 mg once daily 10 daysHealthy subjects (14)203%c AUC112%Cmax <->Saquinavir/ritonavir1000/100 mg twice daily 14 or 22 days150 mg every days 21-22 daysHealthy subjects53% AUC d,88% Cmax, (n=11)13% AUC,15% Cmax,(n=19)Ritonavir500 mg twice daily 10 days150 mg once daily 16 daysHealthy subjects (5)300% AUC,150% Cmax NDTipranavir/ritonavir500/200 mg twice daily 15 doses150 mg single doseHealthy subjects (20)190% AUC,70% Cmax <->Nelfinavir1250 mg twice daily 7-8 days150 mg once daily 8 daysHIV-infected patients (11)83% AUC e,19% Cmax <->Zidovudine100 or 200 mg q4h300 or 450 mg once dailyHIV-infected patients (16)<->32% AUC,48% Cmax ANTIFUNGALSFluconazole200 mg once daily 2 weeks300 mg once daily 2 weeksHIV-infected patients (12)82% AUC,88% Cmax <->Posaconazole200 mg once daily 10 days300 mg once daily 17 daysHealthy subjects (8)72% AUC,31% Cmax 49% AUC,43% Cmax Itraconazole200 mg once daily300 mg once dailyHIV-Infected patients (6)f 70% AUC,75% Cmax Voriconazole400 mg twice daily 7 days (maintenance dose)300 mg once daily 7 daysHealthy male subjects (12)331% AUC,195% Cmax ~100% AUC,~100% Cmax ANTI-PCP (Pneumocystis carinii pneumonia)Dapsone50 mg once daily300 mg once dailyHIV-infected patients (16)ND27-40% AUCSulfamethoxazole-Trimethoprim800/160 mg300 mg once dailyHIV-infected patients (12)<->15-20% AUCANTI-MAC (Mycobacterium avium intracellulare complex)Azithromycin500 mg once daily 1 day, then 250 mg once daily 9 days300 mg once dailyHealthy subjects (6)<-><->Clarithromycin500 mg twice daily300 mg once dailyHIV-infected patients (12)75% AUC50% AUCANTI-TB (Tuberculosis)Ethambutol1200 mg300 mg once daily 7 daysHealthy subjects (10)ND<->Isoniazid300 mg300 mg once daily 7 daysHealthy subjects (6)ND<->OTHERMethadone20-100 mg once daily300 mg once daily 13 daysHIV-infected patients (24)ND<->Ethinylestradiol (EE)/Norethindrone (NE)35 mg EE 1 mg NE 21 days300 mg once daily 10 daysHealthy female subjects (22)NDEE:35% AUC, 20% Cmax,NE: 46% AUCTheophylline5 mg/kg300 mg 14 daysHealthy subjects (11)ND<->. Extensively metabolized. CYP2C19 (major) responsible for the formation of hydroxyomeprazole. CYP3A4 (minor) responsible for the formation of omeprazole-sulphone. These metabolites have very little or no antisecretory activity. Of the five metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant with plasma metabolite: parent AUC ratio of 0.10 and 0.07, respectively. 25-O-desacetylrifabutin has an activity equal to the parent drug with up to 10% to the total antimicrobial activity. 53% of the oral dose was excreted in urine, primarily as metabolites About 30% of the dose is excreted in feces Renal and biliary clearance of unchanged drug each contribute approximately 5% to apparent oral clearance 41% to 46% in the exposure to the active metabolite of clopidogrel from Day 1.. Administration of clopidogrel and omeprazole at different times does not prevent interaction. 12.4 Microbiology. Mechanism of ActionAmoxicillin 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 ResistanceResistance 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 ActivityTALICIA 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 TestingFor 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 EcologyDecreased 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, polymorphic enzyme, is involved in the metabolism of omeprazole. The CYP2C191 allele is fully functional while the CYP2C192 and 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 patients metabolism status: poor metabolizers intermediate metabolizers normal metabolizers. Approximately 3% of Caucasians and 15 to 20% of Asians are CYP2C19 poor metabolizers.In 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Hypersensitivity ReactionsAdvise 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 ReactionsAdvise 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)].DiarrheaCounsel patients that diarrhea is 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 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 (5.3)].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 InteractionsAdvise patients not to take St. Johns 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 (5.6)]. ContraceptionCounsel 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 (5.4)].Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential that TALICIA is not recommended during pregnancy because of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy.Cutaneous or Systemic LupusAdvise patients to report any symptoms associated with cutaneous or systemic lupus erythematosus [see Warnings and Precautions (5.7)].Acute Tubulointerstitial Nephritis Advise the patient or caregiver to call the patients healthcare provider immediately if they experience signs and/or symptoms associated with acute tubulointerstitial nephritis [see Warnings and Precautions (5.5)].Important Administration Instructions for TALICIAAdvise patients to take four (4) TALICIA capsules every eight hours with food for 14 days. They should NOT crush or chew capsules.Advise patients to swallow TALICIA with at least ounces of water.Advise patients not to take TALICIA with alcohol.Missed doses: Advise patients that if dose is missed, administer as soon as possible. However, if the next scheduled dose is due, take the next dose on time. Do not take two doses at one time to make up for missed dose. 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 ResistancePatients 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 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 (5.11)].TALICIA is distributed by RedHill Biopharma Inc. Raleigh, NCTALICIA is manufactured in Sweden for RedHill Biopharma Ltd. Tel Aviv, IsraelTALICIA is trademark registered with the U.S. Patent and Trademark Office and used under license by RedHill Biopharma Inc.(C) 2019 RedHill Biopharma Ltd. All rights reserved.. Advise patients to take four (4) TALICIA capsules every eight hours with food for 14 days. They should NOT crush or chew capsules.. Advise patients to swallow TALICIA with at least ounces of water.. Advise patients not to take TALICIA with alcohol.. Missed doses: Advise patients that if dose is missed, administer as soon as possible. However, if the next scheduled dose is due, take the next dose on time. Do not take two doses at one time to make up for missed dose. 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 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.OmeprazoleIn 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 human dose of 120 mg/day, as expressed on body surface area basis) produced gastric enterochromaffin-like (ECL) cell carcinoids in 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 times 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 finding involving only one tumor is difficult to interpret.In 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in 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 body surface area basis). No astrocytomas were observed in female rats in this study. In 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 body surface area basis). 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. 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 body surface area basis) was found to have no effect on fertility and reproductive performance.In 24-month carcinogenicity studies in rats, 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.AmoxicillinLong-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 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 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 times the g human dose based on body surface area).RifabutinLong-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 1 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. 28-day toxicity study with 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg/kg/day (about to 23 times daily oral human dose of 120 mg esomeprazole or omeprazole on 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 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 11 times daily oral human dose of 120 mg esomeprazole or omeprazole on 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetic parameters of the components of TALICIA are summarized in Table 3.Table 3: Mean (Standard Deviation) Pharmacokinetic Parameters of the Components of TALICIACmax =Maximum plasma concentration, AUC24 =Area under the concentration vs. 24-hour time curve Cmax and AUC24, estimates derived from 15 healthy subjects following administration of four TALICIA capsules three times in day (8 hours apart) resulting in the total daily oral doses of 150 mg rifabutin, 3000 mg amoxicillin, and 120 mg omeprazole.Pharmacokinetic Parametersa AmoxicillinOmeprazoleRifabutinCmax (ng/mL)15,860 (3,340)1,281 (518)88 (21)AUC24 (nghr/mL)145,788 (29,846)7,161 (3,533)1,320 (307)The absorption, distribution, and elimination related pharmacokinetic information on the components of TALICIA are provided in Table 4.Table 4: Pharmacokinetic Properties of the Components of TALICIA Tmax Time to reach Cmax, AUC Area under the concentration vs. time profile extrapolated to infinity, t1/2 Elimination half-life, indicates increase, indicates decrease, <-> indicates no significant change. Changes in Cmax, AUC, and Tmax estimates reported from crossover food-effect study in 18 healthy subjects following the administration of four TALICIA capsules administered once with high-fat, high calorie meal consisting approximately 1000 kcal (14% from protein, 53% from fat, and 33% from carbohydrates) compared to when four TALICIA capsules administered without food. Reported Tmax and t1/2 estimates are from the same study from 18 subjects (for rifabutin, from 17 subjects) who received TALICIA capsules without food.Pharmacokinetic Parameters AmoxicillinOmeprazoleRifabutinAbsorptionTmax (h), median (range)a (1.25-3)1.25 (0.75-1.77)3 (2-6)Effect of Food: With high-fat meala (relative to fasting)30% in Cmax <-> AUC Tmax by 1.5 hr92% in Cmax 83% in AUC Tmax by hr14% in Cmax 23% in AUC Tmax by hrDistributionProtein Binding20%95%85%Eliminationt1/2 (h), mean (standard deviation)1.4 (0.2)1 (0.3)34 (25) MetabolismMetabolic pathwaysNot significantly metabolizedExtensively metabolizedCYP2C19 (major) responsible for the formation of hydroxyomeprazoleCYP3A4 (minor) responsible for the formation of omeprazole-sulphoneThese metabolites have very little or no antisecretory activityOf the five metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant with plasma metabolite: parent AUC ratio of 0.10 and 0.07, respectively25-O-desacetylrifabutin has an activity equal to the parent drug with up to 10% to the total antimicrobial activity ExcretionMajor route of elimination60% of oral dose excreted in urine in 6-8 hours (mostly as unchanged drug)77% of dose excreted in urine as metabolites and the remainder of the dose recovered in feces53% of the oral dose was excreted in urine, primarily as metabolites About 30% of the dose is excreted in feces Renal and biliary clearance of unchanged drug each contribute approximately 5% to apparent oral clearance Renal ImpairmentFor omeprazole, no clinically meaningful change in bioavailability was reported in patients with chronic renal impairment (CLcr between 10-62 mL/min/1.73 m2). Amoxicillin is primarily eliminated by the kidney [see Use in Specific Populations (8.6)]. For rifabutin, the disposition was studied following 300 mg dose in 18 patients with varying degrees of renal function. Area under plasma concentration time curve (AUC) of rifabutin increased by about 71% in patients with severe renal impairment (CLcr <30 mL/min) compared to patients with creatinine clearance (CLcr) between 61-74 mL/min. In patients with mild to moderate renal impairment (CLcr between 30-61 mL/min), the AUC of rifabutin increased by about 41%.Hepatic ImpairmentThe pharmacokinetics of amoxicillin and rifabutin in patients with moderate and severe hepatic impairment are not known.For omeprazole, in patients with chronic hepatic disease classified as Child-Pugh Class (n=3), (n=4), and (n=1), the bioavailability increased to approximately 100% compared to healthy subjects, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly hours compared with the half-life in healthy subjects of 0.5 to hour. Plasma clearance averaged 70 mL/min, compared with value of 500 to 600 mL/min in healthy subjects [see Use in Specific Populations (8.7)]. Drug InteractionsDrug interaction studies with TALICIA have not been conducted. The drug interaction information described here is based on the prescribing information of individual TALICIA components: rifabutin, omeprazole magnesium, and amoxicillin [see Drug Interactions (7)].Effect of Omeprazole on Other Drugs Omeprazole is time-dependent inhibitor of CYP2C19 and can increase the systemic exposure of co-administered drugs that are CYP2C19 substrates. In addition, administration of omeprazole increases intragastric pH and can alter the systemic exposure of certain drugs that exhibit pH-dependent solubility [see Drug Interactions (7)].Effect of Rifabutin on Other Drugs Multiple dosing of rifabutin has been associated with induction of hepatic metabolic enzymes of the CYP3A subfamily. Rifabutins predominant metabolite (25-desacetyl rifabutin) may also contribute to this effect. Metabolic induction due to rifabutin is likely to produce decrease in plasma concentrations of concomitantly administered drugs that are primarily metabolized by the CYP3A enzymes. Similarly, concomitant medications that competitively inhibit the CYP3A activity may increase plasma concentrations of rifabutin [see Drug Interactions (7)].Drug Interactions Between TALICIA ComponentsCYP enzymes are involved in the metabolism of omeprazole; therefore, rifabutin mediated induction of CYP enzymes is expected to reduce systemic exposure to omeprazole. Table and Table summarizes the drug interactions information from the prescribing information of omeprazole and rifabutin, respectively.Table 5: Summary of Drug Interaction Studies with Omeprazole indicates increase, indicates decrease, ND=No data, AUC=Area under the concentration vs. time curve, Cmax =Maximum serum/plasma concentrations, Cmin Minimum serum/plasma concentrations. 3,4-dihydro-cilostazol has 4-7 times the activity of cilostazolCoadministered drugDosing regimen of coadministered drugDosing regimen of OmeprazoleResultsRilpivirineMultiple doses of 150 mg/dayMultiple doses of 20 mg/dayRilpivirine: 40% AUC, 40% Cmax, and 33% Cmin NelfinavirMultiple doses of 1250 mg twice dailyMultiple doses of 40 mg/dayNelfinavir: 36% AUC, 37% Cmax, and 39% Cmin M8: 92% in AUC, 89% Cmax, and 75% Cmin AtazanavirMultiple doses of 400 mg/dayMultiple doses of 40 mg/dayAtazanavir: 94% AUC, 96% Cmax, and 95% Cmin SaquinavirSaquinavir/ritonavir (1000/100 mg) twice daily for 15 days40 mg/day on Days 11 to 15Saquinavir: 82% AUC, 75% Cmax, and 106% Cmin ClopidogrelThree separate studies with 300 mg loading dose 75 mg/day80 mg/day at the same time as clopidogrel in two studies and 12 hours apart in the third studiesSummary results from three studies:41% to 46% in the exposure to the active metabolite of clopidogrel from Day 1.Administration of clopidogrel and omeprazole at different times does not prevent interactionMycophenolate Mofetil (MMF)1000 mg dose after the last dose of omeprazole20 mg twice daily for four daysMycophenolic acid (MPA)- active metabolite of MMF: 23% AUC and 52% Cmax CilostazolND40 mg/day for weekCilostazol: 26% AUC and 18% Cmax 3,4-dihydro-cilostazol: 69% AUC and 29% Cmax Diazepam0.1 mg/kg given intravenously20 mg/day concomitantlyDiazepam: 27% clearance and 36% half-lifeDigoxinND20 mg/day concomitantlyDigoxin: Up to 30% bioavailabilityVoriconazole400 mg twice daily for one day 200 mg/day for days40 mg/day for weekVoriconazole: Four-fold in AUC and two-fold in Cmax Table 6: Summary of Drug Interaction Studies with Rifabutin indicates increase, indicates decrease, <-> indicates no significant change, ND No data, AUC=Area under the concentration vs. time curve, Cmax Maximum serum/plasma concentrations, Cmin Minimum serum/plasma concentrations. Compared to rifabutin 300 mg once daily alone Compared to historical control (fosamprenavir/ritonavir 700/100 mg twice daily) Also taking zidovudine 500 mg once daily Compared to rifabutin 150 mg once daily alone Compared to rifabutin 300 mg once daily alone Data from case report Compared to voriconazole 200 mg twice daily aloneCoadministered drugDosing regimen of coadministered drugDosing regimen of RifabutinStudy population (n)Effect on rifabutinEffect on coadministered drugANTIVIRALSAmprenavir1200 mg twice daily 10 days300 mg once daily 10 daysHealthy male subjects (6)193% AUC,119% Cmax <->Delavirdine400 mg TID300 mg once dailyHIV-infected patients (7)230% AUC,128% Cmax 80% AUC,75% Cmax,17% Cmin Didanosine167 or 250 mg twice daily 12 days300 or 600 mg once daily 1HIV-infected patients (11)<-><->Fosamprenavir/ritonavir700 mg twice daily plus ritonavir 100 mg twice daily 2 weeks150 mg every other day 2 weeksHealthy subjects (15)<-> AUCa 15% Cmax 35% AUCb,36% Cmax,36% CminIndinavir800 mg TID 10 days300 mg once daily 10 daysHealthy subjects (10)173% AUC,134% Cmax 34% AUC,25% Cmax,39% Cmin Lopinavir/ritonavir400/100 mg twice daily 20 days150 mg once daily 10 daysHealthy subjects (14)203%c AUC112%Cmax <->Saquinavir/ritonavir1000/100 mg twice daily 14 or 22 days150 mg every days 21-22 daysHealthy subjects53% AUC d,88% Cmax, (n=11)13% AUC,15% Cmax,(n=19)Ritonavir500 mg twice daily 10 days150 mg once daily 16 daysHealthy subjects (5)300% AUC,150% Cmax NDTipranavir/ritonavir500/200 mg twice daily 15 doses150 mg single doseHealthy subjects (20)190% AUC,70% Cmax <->Nelfinavir1250 mg twice daily 7-8 days150 mg once daily 8 daysHIV-infected patients (11)83% AUC e,19% Cmax <->Zidovudine100 or 200 mg q4h300 or 450 mg once dailyHIV-infected patients (16)<->32% AUC,48% Cmax ANTIFUNGALSFluconazole200 mg once daily 2 weeks300 mg once daily 2 weeksHIV-infected patients (12)82% AUC,88% Cmax <->Posaconazole200 mg once daily 10 days300 mg once daily 17 daysHealthy subjects (8)72% AUC,31% Cmax 49% AUC,43% Cmax Itraconazole200 mg once daily300 mg once dailyHIV-Infected patients (6)f 70% AUC,75% Cmax Voriconazole400 mg twice daily 7 days (maintenance dose)300 mg once daily 7 daysHealthy male subjects (12)331% AUC,195% Cmax ~100% AUC,~100% Cmax ANTI-PCP (Pneumocystis carinii pneumonia)Dapsone50 mg once daily300 mg once dailyHIV-infected patients (16)ND27-40% AUCSulfamethoxazole-Trimethoprim800/160 mg300 mg once dailyHIV-infected patients (12)<->15-20% AUCANTI-MAC (Mycobacterium avium intracellulare complex)Azithromycin500 mg once daily 1 day, then 250 mg once daily 9 days300 mg once dailyHealthy subjects (6)<-><->Clarithromycin500 mg twice daily300 mg once dailyHIV-infected patients (12)75% AUC50% AUCANTI-TB (Tuberculosis)Ethambutol1200 mg300 mg once daily 7 daysHealthy subjects (10)ND<->Isoniazid300 mg300 mg once daily 7 daysHealthy subjects (6)ND<->OTHERMethadone20-100 mg once daily300 mg once daily 13 daysHIV-infected patients (24)ND<->Ethinylestradiol (EE)/Norethindrone (NE)35 mg EE 1 mg NE 21 days300 mg once daily 10 daysHealthy female subjects (22)NDEE:35% AUC, 20% Cmax,NE: 46% AUCTheophylline5 mg/kg300 mg 14 daysHealthy subjects (11)ND<->. Extensively metabolized. CYP2C19 (major) responsible for the formation of hydroxyomeprazole. CYP3A4 (minor) responsible for the formation of omeprazole-sulphone. These metabolites have very little or no antisecretory activity. Of the five metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant with plasma metabolite: parent AUC ratio of 0.10 and 0.07, respectively. 25-O-desacetylrifabutin has an activity equal to the parent drug with up to 10% to the total antimicrobial activity. 53% of the oral dose was excreted in urine, primarily as metabolites About 30% of the dose is excreted in feces Renal and biliary clearance of unchanged drug each contribute approximately 5% to apparent oral clearance 41% to 46% in the exposure to the active metabolite of clopidogrel from Day 1.. Administration of clopidogrel and omeprazole at different times does not prevent interaction.

PREGNANCY SECTION.

8.1 Pregnancy. . Risk SummaryBased 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 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 to times an oral human dose of 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 times the recommended human daily dose), there was 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 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 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. . DataHuman DataOmeprazole 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 births in Denmark from 1996 to 2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837,317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester.A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively.A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% with first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups.Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia.AmoxicillinWhile available studies cannot definitively establish the absence of risk, published epidemiological data and postmarketing case reports have not reported consistent association with amoxicillin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when amoxicillin was used during pregnancy. Available studies have methodologic limitations, including small sample size, retrospective data collection, under-capture of non-live births, exposure misclassification and inconsistent comparator groups.RifabutinSmall retrospective observational studies evaluated the use of rifabutin (in combination with other drugs) for treatment of tuberculosis during pregnancy. Available studies were inconclusive in determining whether rifabutin use during pregnancy was associated with adverse effects in the pregnant woman or neonates.Animal DataOmeprazoleReproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 11 times an oral human dose of 120 mg on body surface area basis) and in rabbits at doses up to 69.1 mg/kg/day (about 11 times an oral human dose of 120 mg on body surface area basis) during organogenesis did not show fetal malformations. In rabbits, omeprazole in dose range of 6.9 to 69.1 mg/kg/day (about to 11 times an oral human dose of 120 mg on body surface area basis) administered during organogenesis produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about to 11 times an oral human dose of 120 mg on body surface area basis), administered prior to mating through the lactation period.EsomeprazoleThe data described below was generated from studies using esomeprazole, an enantiomer of omeprazole. The animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 120 mg esomeprazole or 120 mg omeprazole.No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 23 times an oral human dose of 120 mg on body surface area basis) or in rabbits at oral doses up to 86 mg/kg/day (about 14 times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis) administered during organogenesis.A pre-and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about to 23 times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 11 times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg/kg/day (about times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about equivalent to the oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 11 times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis).Effects on maternal bone were observed in pregnant and lactating rats in the pre-and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about to 23 times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis). When rats were dosed from gestational day through weaning on postnatal day 21, statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 11 times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis).A pre-and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above.A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 23 times an oral human dose of 120 mg on body surface area basis) where esomeprazole administration was from either gestational day or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.AmoxicillinReproduction studies have been performed in mice and rats at doses up to 2000 mg/kg (3 and times the g human dose, based on body surface area). There was no evidence of harm to the fetus due to amoxicillin.RifabutinReproduction studies have been carried out in rats and rabbits given rifabutin using dose levels up to 200 mg/kg (about to 13 times the recommended human daily dose based on body surface area comparisons). No fetal malformations were observed in either species. In rats, given 200 mg/kg/day, (about times the recommended human daily dose based on body surface area comparisons), there was decrease in fetal viability. In rats, at 40 mg/kg/day (approximately equivalent to the recommended human daily dose based on body surface area comparisons), rifabutin caused an increase in fetal skeletal variations. In rabbits, at 80 mg/kg/day (about times the recommended human daily dose based on body surface area comparisons), rifabutin caused maternal toxicity and increase in fetal skeletal anomalies.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. TALICIA may cause fetal harm. (8.1)Renal Impairment: Avoid use in severe renal impairment. (8.6)Hepatic Impairment: Avoid use. (8.7). TALICIA may cause fetal harm. (8.1). Renal Impairment: Avoid use in severe renal impairment. (8.6). Hepatic Impairment: Avoid use. (8.7). 8.1 Pregnancy. . Risk SummaryBased 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 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 to times an oral human dose of 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 times the recommended human daily dose), there was 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 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 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. . DataHuman DataOmeprazole 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 births in Denmark from 1996 to 2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837,317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester.A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively.A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% with first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups.Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia.AmoxicillinWhile available studies cannot definitively establish the absence of risk, published epidemiological data and postmarketing case reports have not reported consistent association with amoxicillin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when amoxicillin was used during pregnancy. Available studies have methodologic limitations, including small sample size, retrospective data collection, under-capture of non-live births, exposure misclassification and inconsistent comparator groups.RifabutinSmall retrospective observational studies evaluated the use of rifabutin (in combination with other drugs) for treatment of tuberculosis during pregnancy. Available studies were inconclusive in determining whether rifabutin use during pregnancy was associated with adverse effects in the pregnant woman or neonates.Animal DataOmeprazoleReproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 11 times an oral human dose of 120 mg on body surface area basis) and in rabbits at doses up to 69.1 mg/kg/day (about 11 times an oral human dose of 120 mg on body surface area basis) during organogenesis did not show fetal malformations. In rabbits, omeprazole in dose range of 6.9 to 69.1 mg/kg/day (about to 11 times an oral human dose of 120 mg on body surface area basis) administered during organogenesis produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about to 11 times an oral human dose of 120 mg on body surface area basis), administered prior to mating through the lactation period.EsomeprazoleThe data described below was generated from studies using esomeprazole, an enantiomer of omeprazole. The animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 120 mg esomeprazole or 120 mg omeprazole.No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 23 times an oral human dose of 120 mg on body surface area basis) or in rabbits at oral doses up to 86 mg/kg/day (about 14 times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis) administered during organogenesis.A pre-and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about to 23 times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 11 times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg/kg/day (about times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about equivalent to the oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 11 times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis).Effects on maternal bone were observed in pregnant and lactating rats in the pre-and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about to 23 times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis). When rats were dosed from gestational day through weaning on postnatal day 21, statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 11 times an oral human dose of 120 mg esomeprazole or omeprazole on body surface area basis).A pre-and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above.A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 23 times an oral human dose of 120 mg on body surface area basis) where esomeprazole administration was from either gestational day or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.AmoxicillinReproduction studies have been performed in mice and rats at doses up to 2000 mg/kg (3 and times the g human dose, based on body surface area). There was no evidence of harm to the fetus due to amoxicillin.RifabutinReproduction studies have been carried out in rats and rabbits given rifabutin using dose levels up to 200 mg/kg (about to 13 times the recommended human daily dose based on body surface area comparisons). No fetal malformations were observed in either species. In rats, given 200 mg/kg/day, (about times the recommended human daily dose based on body surface area comparisons), there was decrease in fetal viability. In rats, at 40 mg/kg/day (approximately equivalent to the recommended human daily dose based on body surface area comparisons), rifabutin caused an increase in fetal skeletal variations. In rabbits, at 80 mg/kg/day (about times the recommended human daily dose based on body surface area comparisons), rifabutin caused maternal toxicity and increase in fetal skeletal anomalies.. 8.2 Lactation. Risk SummaryData from 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 mothers 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. ContraceptionBoth 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)].InfertilityMalesBased 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 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.OmeprazoleOmeprazole 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.AmoxicillinAn 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 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.RifabutinClinical 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)].

WARNINGS AND PRECAUTIONS SECTION.

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)Clostridioides difficile-Associated Diarrhea (CDAD): Evaluate if diarrhea occurs. (5.3)Reduction in the Efficacy of Hormonal Contraceptives: Additional non-hormonal highly effective methods of contraception should be used while taking TALICIA. (5.4)Acute Tubulointerstitial Nephritis (TIN): Observed in patients taking Proton Pump Inhibitors (PPIs), including omeprazole and penicillins. Discontinue TALICIA and evaluate patients. (5.5)Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue TALICIA and evaluate. (5.7). 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). Clostridioides difficile-Associated Diarrhea (CDAD): Evaluate if diarrhea occurs. (5.3). Reduction in the Efficacy of Hormonal Contraceptives: Additional non-hormonal highly effective methods of contraception should be used while taking TALICIA. (5.4). Acute Tubulointerstitial Nephritis (TIN): Observed in patients taking Proton Pump Inhibitors (PPIs), including omeprazole and penicillins. Discontinue TALICIA and evaluate patients. (5.5). Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue TALICIA and evaluate. (5.7). 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 reportedwith 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 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), 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)]. In addition, drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with rifabutin, component of TALICIA.Monitor closely and discontinue TALICIA at the first signs of SCAR.. 5.3 Clostridioides difficile-Associated Diarrhea. Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of omeprazole, 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.. 5.4 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)].. 5.5 Acute Tubulointerstitial Nephritis. Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs including omeprazole, 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, component of TALICIA.Discontinue TALICIA and evaluate patients with suspected acute TIN [see Contraindications (4)] . 5.6 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. Johns 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 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)]. 5.7 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.. 5.8 Rash in Patients with Mononucleosis. high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Avoid TALICIA in patients with mononucleosis.. 5.9 Uveitis. Due to the possible occurrence of uveitis, patients should be carefully monitored when rifabutin, 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)].. 5.10 Interactions with Diagnostic Investigations for Neuroendocrine Tumors. Serum chromogranin (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)].. 5.11 Development of Drug-Resistant Bacteria. Prescribing TALICIA either in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.