TALICIA delayed-release capsules contain omeprazole magnesium, amoxicillin and rifabutin for oral administration. Omeprazole magnesium is included in the delayed-release component of the capsule, and amoxicillin and rifabutin are included in the immediate-release component of the capsule. Each delayed-release capsule contains: omeprazole 10 mg (equivalent to 10.3 mg of omeprazole magnesium) amoxicillin 250 mg (equivalent to 286.9 mg of amoxicillin trihydrate) rifabutin 12.5 mg Omeprazole magnesium is a proton pump inhibitor. Amoxicillin and rifabutin are antibacterial drugs. Each TALICIA delayed-release capsule contains the following inactive ingredients: crospovidone, FD&C Red 3, FD&C Yellow 6, gelatin, hydroxypropyl cellulose, hypromellose, magnesium stearate, mannitol-starch, methacrylic acid copolymer, meglumine, pregelatinized starch, silica, sodium bicarbonate, sodium lauryl sulfate, talc, titanium dioxide and triethyl citrate. Omeprazole Magnesium Omeprazole magnesium is a white to off-white powder with a melting point with degradation at 200 °C. The salt is slightly soluble (0.25 mg/mL) in water at 25 °C, and it is soluble in methanol. Omeprazole magnesium is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl]benzimidazole, (RS) magnesium salt (2:1). Omeprazole magnesium has a molecular formula of (C 17 H 19 N 3 O 3 S) 2 Mg, and a molecular weight of 713.12. The structural formula is: Amoxicillin Amoxicillin is a semisynthetic antibacterial drug, an analog of ampicillin. Chemically it is (2 S ,5 R ,6 R )-6-[( R )-(-)-2- amino-2-( p -hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid trihydrate. Amoxicillin has a molecular formula of C 16 H 19 N 3 O 5 S•3 H 2 O, and a molecular weight of 419.45. The structural formula is: Rifabutin Rifabutin is a red-violet powder soluble in chloroform and methanol, sparingly soluble in ethanol, and very slightly soluble in water (0.19 mg/mL). Its log P value (the base 10 logarithm of the partition coefficient between n-octanol and water) is 3.2 (n-octanol/water). Rifabutin is (9S,12E,14S,15R,16S,17R,18R,19R,20S,21S,22E,24Z)-6-16,18,20-tetrahydroxy-1'-isobutyl-14-methoxy-7,9,15,17,19,21,25-heptamethylspiro [9,4-(epoxypentadeca[1,11,13]trienimino)-2H-furo[2',3':7,8]naphth[1,2-d] imidazole-2,4'-piperidine]-5,10,26-(3H,9H)-trione-16-acetate. Rifabutin has a molecular formula of C 46 H 62 N 4 O 11 , and a molecular weight of 847.02. The structural formula is: Rifabutin Chemical Structure Amoxicillin Chemical Structure Omeprazole Magnesium Chemical Structure

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. 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

Helicobacter pylori Infection TALICIA is indicated for the treatment of Helicobacter pylori infection in adults

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.

Each TALICIA delayed-release capsule contains omeprazole 10 mg (equivalent to 10.3 mg of omeprazole magnesium), amoxicillin 250 mg and rifabutin 12.5 mg. The capsules are orange, opaque, with “RHB” imprinted in black on the capsule cap and “105” imprinted in black on the capsule base. Delayed Release Capsule: Omeprazole 10 mg, (equivalent to 10.3 mg of omeprazole magnesium) amoxicillin 250 mg and rifabutin 12.5 mg.

Administer four TALICIA capsules three times daily (at least 4 hours apart, e.g., morning, mid-day, and evening) with food for 14 days. Swallow whole. Do not crush or chew. Do not take TALICIA with alcohol

Recommended Dosage Administer four 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

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.

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). 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. Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of TALICIA. If this occurs, discontinue TALICIA and institute appropriate therapy. Clostridioides difficile -Associated Diarrhea (CDAD): Evaluate if diarrhea occurs. Reduction in the Efficacy of Hormonal Contraceptives: Additional non-hormonal highly effective methods of contraception should be used while taking TALICIA. Acute Tubulointerstitial Nephritis (TIN): Observed in patients taking Proton Pump Inhibitors (PPIs), including omeprazole and penicillins. Discontinue TALICIA and evaluate patients. Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue TALICIA and evaluate. 5.1 Hypersensitivity Reactions Serious and fatal hypersensitivity reactions, e.g., anaphylaxis, angioedema, erythema multiforme, exfoliative dermatitis, hypersensitivity vasculitis, acute tubulointerstitial nephritis, and serum sickness have been reported with the components of TALICIA: omeprazole, amoxicillin and rifabutin. Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with TALICIA, inquire about history of hypersensitivity reactions to penicillins, cephalosporins, rifamycins, or PPIs. Discontinue TALICIA and institute immediate therapy, if hypersensitivity reactions occur

Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the components of TALICIA: rifabutin, amoxicillin, and omeprazole . Monitor closely and discontinue TALICIA at the first signs of SCAR

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

Clostridioides difficile -Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of omeprazole, a component of TALICIA and nearly all antibacterial agents, including amoxicillin and rifabutin, which are components of TALICIA and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. CDAD must be considered in all patients who present with diarrhea following proton pump inhibitor and or antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is confirmed, TALICIA should be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated

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

Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs including omeprazole, a component of TALICIA. TIN may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions, to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). TIN has also been observed in patients taking penicillins, such as amoxicillin, a component of TALICIA. Discontinue TALICIA and evaluate patients with suspected acute TIN

Risk of Adverse Reactions or Loss of Efficacy Due to Drug Interactions Components of TALICIA have the potential for clinically important drug interactions . Avoid concomitant use of TALICIA with other CYP2C19 or CYP3A4 inducers (e.g., St. John’s Wort, rifampin) as they can substantially decrease omeprazole concentrations. Avoid concomitant use of TALICIA with CYP2C19 and/or CYP3A4 inhibitors (e.g., fluconazole, itraconazole) as it may significantly increase the plasma concentration of component (s) of TALICIA. Depending on the protease inhibitor, the concomitant use of TALICIA should be avoided (e.g., amprenavir, indinavir) or dose adjustments for a concomitantly administered protease inhibitor(s) may be required. Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. Avoid TALICIA in patients on high-dose methotrexate. Concomitant use of clopidogrel and omeprazole reduces the pharmacological activity of clopidogrel. Avoid TALICIA in patients on clopidogrel. When using TALICIA, consider alternative anti-platelet therapy

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

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

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

Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Assess CgA levels at least 14 days after TALICIA treatment and consider repeating the test if initial CgA levels are high

Development of Drug-Resistant Bacteria Prescribing TALICIA either in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Components of TALICIA have the potential for clinically important drug interactions. See Full Prescribing Information for important drug interactions with TALICIA

Interactions with Other Drugs and Diagnostics Drug interaction studies with TALICIA have not been conducted. The drug interaction information described here is based on the prescribing information of individual TALICIA components: omeprazole, amoxicillin, and rifabutin. Rifabutin is a substrate and inducer of cytochrome P450 (CYP) 3A enzymes. Omeprazole is a substrate and an inhibitor of CYP2C19, and a substrate of CYP3A4. Co-administration of TALICIA and other drugs that are substrates, inhibitors, or inducers of these enzymes may alter concentrations of rifabutin/omeprazole or other co-administered drugs . Omeprazole magnesium is a PPI. Refer to the prescribing information of the drugs used concomitantly with TALICIA for further information on their interactions with PPIs. Table 2: Interactions with TALICIA When Co-Administered with Other Drugs and Diagnostics CYP2C19 or CYP3A4 Inducers Clinical Impact Decreased exposure of omeprazole when used concomitantly with strong inducers. Prevention or Management St. John’s Wort, rifampin : Avoid concomitant use with TALICIA . Ritonavir-containing products : See prescribing information for specific drugs. CYP2C19 or CYP3A4 Inhibitors Clinical Impact Increased blood levels of omeprazole and rifabutin. Prevention or Management Voriconazole : Concomitant use with TALICIA is contraindicated . Fluconazole, posaconazole and itraconazole : Avoid concomitant use with TALICIA. If coadministration cannot be avoided, monitor patients for rifabutin associated adverse events, and lack of anti-fungal efficacy. CYP2C19 Substrates (e.g., Clopidogrel, citalopram, cilostazol, phenytoin, diazepam) Clinical Impact Increased plasma concentrations of CYP2C19 substrate drugs or decreased/increased plasma concentrations of its active metabolite(s) . Prevention or Management Clopidogrel : Consider use of alternative anti-platelet therapy [ see Warnings and Precautions ] . Avoid concomitant use with TALICIA. Antiretrovirals/Protease Inhibitors Clinical Impact Antiretrovirals/protease inhibitors may increase rifabutin blood levels. The effect of PPIs (such as omeprazole in TALICIA) on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance . Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity . There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole. Prevention or Management Delavirdine : Combination treatment with TALICIA and delavirdine is contraindicated . Rilpivirine-containing products : Concomitant use with TALICIA is contraindicated . Avoid concomitant use of TALICIA with amprenavir, indinavir, lopinavir/ritonavir, saquinavir/ritonavir, ritonavir, tipranavir/ritonavir, fosamprenavir/ritonavir, or nelfinavir . Other antiretrovirals: See prescribing information for specific antiretroviral drugs. Probenecid Clinical Impact Increased and prolonged blood levels of amoxicillin. Allopurinol Clinical Impact Increase in the incidence of rashes is reported in patients receiving both allopurinol and amoxicillin together compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients. Prevention or Management Discontinue allopurinol at the first appearance of skin rash. Assess benefit-risk of continuing TALICIA treatment. Warfarin, and Other Oral Anticoagulants Clinical Impact Abnormal 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 Management Monitor INR and prothrombin time and adjust the dose of warfarin or other oral anticoagulants to maintain the desired level of anticoagulation. Methotrexate Clinical Impact Concomitant 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 . Prevention or Management Avoid concomitant use of TALICIA in patients receiving high-dose methotrexate. Digoxin Clinical Impact Potential for increased digoxin blood levels . Prevention or Management Monitor 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 Impact Omeprazole can alter the absorption of other drugs due to its effect of reducing intragastric acidity thereby increasing gastric pH. Prevention or Management Mycophenolate mofetil (MMF) : Use TALICIA with caution in transplant patients receiving MMF . See the prescribing information of other drugs dependent on gastric pH for absorption. Tacrolimus Clinical Impact Potential for increased tacrolimus blood levels, especially in patients who are intermediate or poor metabolizers of CYP2C19. Prevention or Management Monitor 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 Impact Interactions are reported with omeprazole and other drugs metabolized via the CYP450 enzymes. Prevention or Management Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with TALICIA. Oral Contraceptives Clinical Impact Concomitant 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 . Prevention or Management Patients should be advised to use additional or alternative non-hormonal methods of contraception. Diagnostic Investigations for Neuroendocrine Tumors Clinical Impact PPI-induced decrease in gastric acidity may lead to increased serum chromogranin A (CgA) levels, which may cause false positive results in diagnostics for neuroendocrine tumors . Prevention or Management Assess 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 Test Clinical Impact High urine concentrations of ampicillin or amoxicillin may result in false-positive reactions when using glucose tests based on the Benedict’s copper reduction reaction that determines the amount of reducing substances like glucose in the urine. Prevention or Management Glucose tests based on enzymatic glucose oxidase reactions should be used. Interaction with Secretin Stimulation Test Clinical Impact Hyper-response in gastrin secretion in response to secretin stimulation test may falsely suggest gastrinoma. Prevention or Management Test 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 Impact There have been reports of false positive urine screening tests for THC in patients receiving PPIs. Prevention or Management An alternative confirmatory method should be considered to verify positive results. Other Laboratory Tests Clinical Impact Following administration of ampicillin or amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted.