Omeprazole Magnesium, Amoxicillin And Rifabutin

1 INDICATIONS AND USAGE TALICIA is a three-drug combination of omeprazole, a proton pump inhibitor, amoxicillin, a penicillin-class antibacterial, and rifabutin, a rifamycin antibacterial, indicated for the treatment of Helicobacter pylori infection in adults. ( 1 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of TALICIA and other antibacterial drugs, TALICIA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.2) 1.1 Helicobacter pylori Infection TALICIA is indicated for the treatment of Helicobacter pylori infection in adults [see Clinical Studies (14 ) ] . 1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of TALICIA and other antibacterial drugs, TALICIA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION Administer four (4) TALICIA capsules three times daily (at least 4 hours apart, e.g., morning, mid-day, and evening) with food for 14 days. ( 2.1 ) Swallow whole. Do not crush or chew. ( 2.1 ) Do not take TALICIA with alcohol. ( 2.1 ) 2.1 Recommended Dosage Administer four (4) TALICIA capsules three times daily (at least 4 hours apart, e.g., morning, mid-day, and evening) with food for 14 days. Instruct patients to swallow the TALICIA capsules whole, with a full glass of water (8 ounces). Each dose (4 capsules) of TALICIA includes rifabutin 50 mg, amoxicillin 1,000 mg and omeprazole 40 mg. Do not crush or chew TALICIA capsules. Do not take TALICIA with alcohol. 2.2 Missed Doses If a dose is missed and the next dose is not within 4 hours, administer the missed dose as soon as possible. If a dose is missed and the next dose is within 4 hours, administer the missed dose as soon as possible and delay the next dose to ensure there are at least 4 hours between two doses.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2) ] Drug-Induced Enterocolitis Syndrome (DIES) [see Warnings and Precautions (5.3) ] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.4) ] Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.6) ] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.8) ] Rash in Patients with Mononucleosis [see Warnings and Precautions (5.9) ] Uveitis [see Warnings and Precautions (5.10) ] Most common adverse reactions (≥1%) were diarrhea, headache, nausea, abdominal pain, chromaturia, rash, dyspepsia, oropharyngeal pain, vomiting, and vulvovaginal candidiasis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact RedHill Biopharma Inc. at 1-833-ADRHILL (1-833-237-4455) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience with TALICIA Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of TALICIA was assessed in adult patients who were screened and found to be positive for H. pylori infection in one active-controlled (Study 1) and one placebo-controlled (Study 2) clinical trial. Patients received TALICIA, amoxicillin and omeprazole, or placebo every eight hours for 14 consecutive days taken with food. A total of 305 patients received TALICIA in Studies 1 and 2, 227 patients received amoxicillin and omeprazole (as omeprazole magnesium) in Study 1, and 41 patients received placebo in Study 2. These patients had a mean age of 46.4 years (range 18 to 70 years); 62.3% were female, 80.3% were white with 64.2% Hispanic or Latino. Adverse Reactions Leading to Discontinuation Treatment discontinuation due to an adverse reaction occurred in 1% (4/305) of patients receiving TALICIA, <1% (1/227) of patients receiving amoxicillin and omeprazole, and 2% (1/41) of patients receiving placebo. Adverse reactions leading to discontinuation of TALICIA were nausea and vomiting, nausea, nasal congestion, and nasopharyngitis, in one patient each. Most Common Adverse Reactions Selected adverse reactions occurring in ≥1% of patients receiving TALICIA in Study 1 and 2 are described in Table 1 . Table 1: Selected Adverse Reactions Occurring in 1% or Greater of Patients Receiving TALICIA in Studies 1 and 2 a Headache includes: headache and migraine. b Abdominal pain includes: abdominal pain, abdominal pain upper, and abdominal pain lower. c Riboflavin was administered in Study 1 to prevent unintentional unblinding and may have contributed to under-reporting of chromaturia. d Rash includes: rash, rash maculo-papular, rash morbilliform, and urticaria. e Dyspepsia includes: dyspepsia and epigastric discomfort. f Vulvovaginal candidiasis includes: vulvovaginal candidiasis, vulvovaginal mycotic infection, fungal infection, and vaginal discharge + vulvovaginal burning sensation + vulvovaginal pruritus. Study 1 Study 2 Adverse Reaction TALICIA (N=228) n (%) Amoxicillin and Omeprazole (N=227) n (%) TALICIA (N=77) n (%) Placebo (N=41) n (%) Diarrhea 23 (10.1) 18 (7.9) 11 (14.3) 4 (9.8) Headache a 17 (7.5) 16 (7.0) 12 (15.6) 4 (9.8) Nausea 11 (4.8) 12 (5.3) 3 (3.9) 1 (2.4) Abdominal pain b 8 (3.5) 11 (4.8) 3 (3.9) 2 (4.9) Chromaturia c 0 0 10 (13.0) 1 (2.4) Rash d 6 (2.6) 2 (0.9) 4 (5.2) 0 Dyspepsia e 5 (2.2) 3 (1.3) 1 (1.3) 0 Vomiting 5 (2.2) 5 (2.2) 1 (1.3) 2 (4.9) Oropharyngeal pain 2 (0.9) 2 (0.9) 3 (3.9) 0 Vulvovaginal candidiasis f 5 (2.2) 5 (2.2) 0 0 6.2 Other Important Adverse Reactions from the Labeling of the Individual Components of TALICIA Additional adverse reactions that occurred in 1% or greater of patients treated with omeprazole or rifabutin alone in clinical trials were as follows: Omeprazole Flatulence, acid regurgitation, upper respiratory infection, constipation, dizziness, asthenia, back pain, and cough. Rifabutin Flatulence, asthenia, chest pain, fever, pain, leucopenia, anemia, anorexia, eructation, myalgia, insomnia, and taste perversion. The following selected adverse reactions occurred in less than 1% of patients treated with rifabutin alone: flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, dyspnea, skin discoloration, thrombocytopenia, pancytopenia, and jaundice. 6.3 Post-Marketing Experience with Components of TALICIA Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure. Omeprazole Cardiovascular: angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema Endocrine: gynecomastia Gastrointestinal: pancreatitis including fatal pancreatitis, anorexia, irritable colon, fecal discoloration, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis, fundic gland polyps, gastroduodenal carcinoids in patients with Zollinger-Ellison syndrome on long-term treatment as a manifestation of the underlying condition associated with such tumors Hepatic: fatal hepatic failure or necrosis, hepatic encephalopathy, hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice Metabolism and Nutritional disorders: hypoglycemia, hypomagnesemia, with or without hypocalcemia and/or hypokalemia, hyponatremia, weight gain Musculoskeletal: muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture. Nervous System/Psychiatric: depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, dream abnormalities, tremors, paresthesia, vertigo Respiratory: epistaxis Skin and subcutaneous tissue disorders: SCAR such as SJS, TEN, DRESS, AGEP, photosensitivity, urticaria, pruritus, petechiae, purpura, alopecia, dry skin, hyperhidrosis Special Senses: tinnitus, taste perversion Ocular: optic atrophy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision Urogenital: hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain, erectile dysfunction Hematologic: Agranulocytosis, hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leukocytosis Amoxicillin Gastrointestinal: Drug-induced enterocolitis syndrome (DIES), black hairy tongue Liver: hepatic dysfunction, cholestatic jaundice, cholestasis, acute cytolytic hepatitis Renal: crystalluria [see Overdosage (10) ] Hemic and Lymphatic Systems: anemia, hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis Central Nervous System: hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, aseptic meningitis, behavioral changes, and/or dizziness Skin and subcutaneous tissue disorders : SCAR, such as SJS, TEN, DRESS, and AGEP, and linear IgA bullous dermatosis. Rifabutin Blood and lymphatic system disorders: agranulocytosis, lymphopenia Skin and subcutaneous tissue disorders: SCAR, such as SJS, TEN, DRESS, and AGEP.

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 TALICIA C max =Maximum plasma concentration, AUC 24 =Area under the concentration vs. 24-hour time curve a C max and AUC 24 , estimates derived from 15 healthy subjects following administration of four TALICIA capsules three times in a day (8 hours apart) resulting in the total daily oral doses of 150 mg rifabutin, 3000 mg amoxicillin, and 120 mg omeprazole. Pharmacokinetic Parameters a Amoxicillin Omeprazole Rifabutin C max (ng/mL) 15,860 (3,340) 1,281 (518) 88 (21) AUC 24 (ng*hr/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 T max = Time to reach C max , AUC ∞ = Area under the concentration vs. time profile extrapolated to infinity, t 1/2 = Elimination half-life, ↑ indicates increase, ↓ indicates decrease, ↔ indicates no significant change. a Changes in C max , AUC ∞ , and T max estimates reported from a crossover food-effect study in 18 healthy subjects following the administration of four TALICIA capsules administered once with a 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 T max and t 1/2 estimates are from the same study from 18 subjects (for rifabutin, from 17 subjects) who received TALICIA capsules without food. Pharmacokinetic Parameters Amoxicillin Omeprazole Rifabutin Absorption T max (h), median (range) a 2 (1.25-3) 1.25 (0.75-1.77) 3 (2-6) Effect of Food: With high-fat meal a (relative to fasting) ↓30% in C max ↔ AUC ∞ ↑T max by 1.5 hr ↓92% in C max ↓83% in AUC ∞ ↑T max by 3 hr ↑14% in C max ↑23% in AUC ∞ ↑T max by 2 hr Distribution Protein Binding 20% 95% 85% Elimination t 1/2 (h), mean (standard deviation) 1.4 (0.2) 1 (0.3) 34 (25) Metabolism Metabolic pathways Not significantly metabolized 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 a 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 Excretion Major route of elimination 60% 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 feces 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 Renal Impairment For omeprazole, no clinically meaningful change in bioavailability was reported in patients with chronic renal impairment (CL cr between 10-62 mL/min/1.73 m 2 ). 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 (CL cr <30 mL/min) compared to patients with creatinine clearance (CL cr ) between 61-74 mL/min. In patients with mild to moderate renal impairment (CL cr between 30-61 mL/min), the AUC of rifabutin increased by about 41%. Hepatic Impairment The 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 A (n=3), B (n=4), and C (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 3 hours compared with the half-life in healthy subjects of 0.5 to 1 hour. Plasma clearance averaged 70 mL/min, compared with a value of 500 to 600 mL/min in healthy subjects [see Use in Specific Populations (8.7) ]. Drug Interactions 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: rifabutin, omeprazole magnesium, and amoxicillin [see Drug Interactions (7) ] . Effect of Omeprazole on Other Drugs Omeprazole is a 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. Rifabutin’s predominant metabolite (25-desacetyl rifabutin) may also contribute to this effect. Metabolic induction due to rifabutin is likely to produce a 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 Components CYP enzymes are involved in the metabolism of omeprazole; therefore, rifabutin mediated induction of CYP enzymes is expected to reduce systemic exposure to omeprazole. Table 5 and Table 6 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, C max =Maximum serum/plasma concentrations, C min = Minimum serum/plasma concentrations. ‡ 3,4-dihydro-cilostazol has 4-7 times the activity of cilostazol Coadministered drug Dosing regimen of coadministered drug Dosing regimen of Omeprazole Results Rilpivirine Multiple doses of 150 mg/day Multiple doses of 20 mg/day Rilpivirine: ↓40% AUC, ↓40% C max , and ↓33% C min Nelfinavir Multiple doses of 1250 mg twice daily Multiple doses of 40 mg/day Nelfinavir: ↓36% AUC, ↓37% C max , and ↓39% C min M8: ↓92% in AUC, ↓89% C max , and ↓75% C min Atazanavir Multiple doses of 400 mg/day Multiple doses of 40 mg/day Atazanavir: ↓94% AUC, ↓96% C max , and ↓95% C min Saquinavir Saquinavir/ritonavir (1000/100 mg) twice daily for 15 days 40 mg/day on Days 11 to 15 Saquinavir: ↑82% AUC, ↑75% C max , and ↑106% C min Clopidogrel Three separate studies with 300 mg loading dose + 75 mg/day 80 mg/day at the same time as clopidogrel in two studies and 12 hours apart in the third studies Summary 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 interaction Mycophenolate Mofetil (MMF) 1000 mg dose after the last dose of omeprazole 20 mg twice daily for four days Mycophenolic acid (MPA)- active metabolite of MMF: ↓23% AUC and ↓52% C max Cilostazol ND 40 mg/day for a week Cilostazol: ↑26% AUC and ↑18% C max 3,4-dihydro-cilostazol ‡ : ↑69% AUC and ↑29% C max Diazepam 0.1 mg/kg given intravenously 20 mg/day concomitantly Diazepam: ↓27% clearance and ↑36% half-life Digoxin ND 20 mg/day concomitantly Digoxin: Up to ↑30% bioavailability Voriconazole 400 mg twice daily for one day + 200 mg/day for 6 days 40 mg/day for a week Voriconazole: Four-fold ↑ in AUC and two-fold ↑in C max 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, C max = Maximum serum/plasma concentrations, C min = Minimum serum/plasma concentrations. a Compared to rifabutin 300 mg once daily alone b Compared to historical control (fosamprenavir/ritonavir 700/100 mg twice daily) c Also taking zidovudine 500 mg once daily d Compared to rifabutin 150 mg once daily alone e Compared to rifabutin 300 mg once daily alone f Data from a case report g Compared to voriconazole 200 mg twice daily alone Coadministered drug Dosing regimen of coadministered drug Dosing regimen of Rifabutin Study population (n) Effect on rifabutin Effect on coadministered drug ANTIVIRALS Amprenavir 1200 mg twice daily x 10 days 300 mg once daily x 10 days Healthy male subjects (6) 193%↑ AUC, 119%↑ C max ↔ Delavirdine 400 mg TID 300 mg once daily HIV-infected patients (7) 230%↑ AUC, 128%↑ C max 80%↓ AUC, 75%↓ C max , 17%↓ C min Didanosine 167 or 250 mg twice daily x 12 days 300 or 600 mg once daily x 1 HIV-infected patients (11) ↔ ↔ Fosamprenavir/ ritonavir 700 mg twice daily plus ritonavir 100 mg twice daily x 2 weeks 150 mg every other day x 2 weeks Healthy subjects (15) ↔ AUC a 15%↓ C max 35%↑ AUC b , 36%↑ C max , 36%↑ Cmin Indinavir 800 mg TID x 10 days 300 mg once daily x 10 days Healthy subjects (10) 173%↑ AUC, 134%↑ C max 34%↓ AUC, 25%↓ C max , 39%↓ C min Lopinavir/ ritonavir 400/100 mg twice daily x 20 days 150 mg once daily x 10 days Healthy subjects (14) 203% c ↑ AUC 112%↓C max ↔ Saquinavir/ ritonavir 1000/100 mg twice daily x 14 or 22 days 150 mg every 3 days x 21-22 days Healthy subjects 53%↑ AUC d , 88% ↑ C max, (n=11) 13%↓ AUC, 15%↓ C max , (n=19) Ritonavir 500 mg twice daily x 10 days 150 mg once daily x 16 days Healthy subjects (5) 300%↑ AUC, 150%↑ C max ND Tipranavir/ ritonavir 500/200 mg twice daily x 15 doses 150 mg single dose Healthy subjects (20) 190%↑ AUC, 70% ↑ C max ↔ Nelfinavir 1250 mg twice daily x 7-8 days 150 mg once daily x 8 days HIV-infected patients (11) 83%↑ AUC e , 19%↑ C max ↔ Zidovudine 100 or 200 mg q4h 300 or 450 mg once daily HIV-infected patients (16) ↔ 32%↓ AUC, 48%↓ C max ANTIFUNGALS Fluconazole 200 mg once daily x 2 weeks 300 mg once daily x 2 weeks HIV-infected patients (12) 82%↑ AUC, 88% ↑ C max ↔ Posaconazole 200 mg once daily x 10 days 300 mg once daily x 17 days Healthy subjects (8) 72%↑ AUC, 31%↑ C max 49%↓ AUC, 43%↓ C max Itraconazole 200 mg once daily 300 mg once daily HIV-Infected patients (6) ↑ f 70%↓ AUC, 75%↓ C max Voriconazole 400 mg twice daily x 7 days (maintenance dose) 300 mg once daily x 7 days Healthy male subjects (12) 331%↑ AUC, 195%↑ C max ~100%↑ AUC, ~100%↑ C max g ANTI-PCP (Pneumocystis carinii pneumonia) Dapsone 50 mg once daily 300 mg once daily HIV-infected patients (16) ND 27-40%↓ AUC Sulfamethoxazole-Trimethoprim 800/160 mg 300 mg once daily HIV-infected patients (12) ↔ 15-20%↓ AUC ANTI-MAC (Mycobacterium avium intracellulare complex) Azithromycin 500 mg once daily x 1 day, then 250 mg once daily x 9 days 300 mg once daily Healthy subjects (6) ↔ ↔ Clarithromycin 500 mg twice daily 300 mg once daily HIV-infected patients (12) 75%↑ AUC 50%↓ AUC ANTI-TB (Tuberculosis) Ethambutol 1200 mg 300 mg once daily x 7 days Healthy subjects (10) ND ↔ Isoniazid 300 mg 300 mg once daily x 7 days Healthy subjects (6) ND ↔ OTHER Methadone 20-100 mg once daily 300 mg once daily x 13 days HIV-infected patients (24) ND ↔ Ethinylestradiol (EE)/ Norethindrone (NE) 35 mg EE / 1 mg NE x 21 days 300 mg once daily x 10 days Healthy female subjects (22) ND EE:35%↓ AUC, 20%↓ C max , NE: 46%↓ AUC Theophylline 5 mg/kg 300 mg x 14 days Healthy subjects (11) ND ↔