AMOXICILLIN: 30,262 Adverse Event Reports & Safety Profile

Amoxicillin and Clavulanate Potassium is an oral antibacterial combination consisting of amoxicillin and the beta‑lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6‑aminopenicillanic acid. The amoxicillin molecular formula is C 16 H 19 N 3 O 5 S•3H 2 O, and the molecular weight is 419.46. Chemically, amoxicillin 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 and may be represented structurally as: Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus . It is a beta-lactam structurally related to the penicillins and possesses the ability to inactivate some beta‑lactamases by blocking the active sites of these enzymes. The clavulanate potassium molecular formula is C 8 H 8 KNO 5 , and the molecular weight is 237.25. Chemically, clavulanate potassium is potassium ( Z )(2 R ,5 R )-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate and may be represented structurally as: Amoxicillin and Clavulanate Potassium Tablets:

• 250 mg/125 mg: Each tablet contains 250 mg of amoxicillin as the trihydrate, and 125 mg of clavulanic acid (equivalent to 149 mg of clavulanate potassium).
• 500 mg/125 mg: Each tablet contains 500 mg of amoxicillin as the trihydrate, and 125 mg of clavulanic acid (equivalent to 149 mg of clavulanate potassium).
• 875 mg/125 mg: Each tablet contains 875 mg of amoxicillin as the trihydrate, and 125 mg of clavulanic acid (equivalent to 149 mg of clavulanate potassium). Amoxicillin and Clavulanate Potassium for Oral Suspension:
• 125 mg/31.25 mg : Following constitution, each 5 mL of oral suspension contains 125 mg of amoxicillin as the trihydrate, and 31.25 mg of clavulanic acid (equivalent to 37.23 mg of clavulanate potassium).
• 200 mg/28.5 mg : Following constitution, each 5 mL of oral suspension contains 200 mg of amoxicillin as the trihydrate, and 28.5 mg of clavulanic acid (equivalent to 34 mg of clavulanate potassium).
• 250 mg/62.5 mg : Following constitution, each 5 mL of oral suspension contains 250 mg of amoxicillin as the trihydrate, and 62.5 mg of clavulanic acid (equivalent to 74.5 mg of clavulanate potassium).
• 400 mg/57 mg : Following constitution, each 5 mL of oral suspension contains 400 mg of amoxicillin as the trihydrate, and 57 mg of clavulanic acid (equivalent to 68 mg of clavulanate potassium). Amoxicillin and Clavulanate Potassium Chewable Tablets:
• 125 mg/31.25 mg: Each chewable tablet contains 125 mg of amoxicillin as the trihydrate, and 31.25 mg of clavulanic acid (equivalent to 37.23 mg of clavulanate potassium).
• 200 mg/28.5 mg: Each chewable tablet contains 200 mg of amoxicillin as the trihydrate, and 28.5 mg of clavulanic acid (equivalent to 34 mg of clavulanate potassium).
• 250 mg/62.5 mg: Each chewable tablet contains 250 mg of amoxicillin as the trihydrate, and 62.5 mg of clavulanic acid (equivalent to 74.5 mg of clavulanate potassium).
• 400 mg/57 mg: Each chewable tablet contains 400 mg of amoxicillin as the trihydrate, and 57 mg of clavulanic acid (equivalent to 68 mg of clavulanate potassium).

Inactive

Ingredients:

• Amoxicillin and Clavulanate Potassium Tablets - Colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.
• Each tablet of Amoxicillin and Clavulanate Potassium contains 0.63 mEq potassium.
• Amoxicillin and Clavulanate Potassium for Oral Suspension, 125 mg/31.5 mg per 5mL and 250 mg/62.5 mg per 5mL - Colloidal silicon dioxide, flavorings, xanthan gum, mannitol, succinic acid, silica gel and sodium saccharin.
• Each 5 mL of reconstituted 125 mg/31.5 mg oral suspension of Amoxicillin and Clavulanate Potassium contains 0.16 mEq potassium
• Each 5 mL of reconstituted 250 mg/62.5 mg oral suspension of Amoxicillin and Clavulanate Potassium contains 0.32 mEq potassium
• Amoxicillin and Clavulanate Potassium for Oral Suspension, 200 mg/28.5 mg per 5mL and 400 mg/57 mg per 5mL - Colloidal silicon dioxide, flavorings, xanthan gum, silica gel, hypromellose and aspartame [see Warnings and Precautions ( 5.7 )]
• Each 5 mL of reconstituted 200 mg/28.5 mg oral suspension of Amoxicillin and Clavulanate Potassium contains 0.14 mEq potassium
• Each 5 mL of reconstituted 400 mg/57 mg oral suspension of Amoxicillin and Clavulanate Potassium contains 0.29 mEq potassium
• Amoxicillin and Clavulanate Potassium Chewable Tablets, 125 mg/31.25 mg and 250 mg/62.5 mg - Colloidal silicon dioxide, flavorings, magnesium stearate, mannitol, sodium saccharin, glycine, and D&C Yellow No.10. o Each 125 mg/31.25 mg chewable tablet of Amoxicillin and Clavulanate Potassium contains 0.16 mEq potassium o Each 250 mg/62.5 mg chewable tablet of Amoxicillin and Clavulanate Potassium contains 0.32 mEq potassium
• Amoxicillin and Clavulanate Potassium Chewable Tablets, 200 mg/28.5 mg and 400 mg/57 mg - Colloidal silicon dioxide, flavorings, magnesium stearate, mannitol, FD&C Red No. 40 and aspartame [see Warnings and Precautions ( 5.7 )] o Each 200 mg/28.5 mg chewable tablet of Amoxicillin and Clavulanate Potassium contains 0.14 mEq potassium o Each 400 mg/57 mg chewable tablet of Amoxicillin and Clavulanate Potassium contains 0.29 mEq potassium structure-amoxicillin structure-clav-acid

AND USAGE Adults and Pediatric Patients

• Upper Respiratory Tract Infections of the Ear, Nose, and Throat: Amoxicillin tablets, amoxicillin for oral suspension, amoxicillin tablets (chewable), and amoxicillin capsules are indicated in the treatment of infections due to susceptible (ONLY β-lactamase-negative) isolates of Streptococcus species. (α- and β-hemolytic isolates only), Streptococcus pneumoniae , Staphylococcus spp., or Haemophilus influenzae .
• Infections of the Genitourinary Tract: Amoxicillin tablets, amoxicillin for oral suspension, amoxicillin tablets (chewable), and amoxicillin capsules are indicated in the treatment of infections due to susceptible (ONLY β-lactamase-negative) isolates of Escherichia coli , Proteus mirabilis , or Enterococcus faecalis .
• Infections of the Skin and Skin Structure: Amoxicillin tablets, amoxicillin for oral suspension, amoxicillin tablets (chewable), and amoxicillin capsules are indicated in the treatment of infections due to susceptible (ONLY β-lactamase-negative) isolates of Streptococcus spp. (α- and β-hemolytic isolates only), Staphylococcus spp., or E. coli .
• Infections of the Lower Respiratory Tract: Amoxicillin tablets, amoxicillin for oral suspension, amoxicillin tablets (chewable), and amoxicillin capsules are indicated in the treatment of infections due to susceptible (ONLY β-lactamase-negative) isolates of Streptococcus spp. (α- and β-hemolytic isolates only), S. pneumoniae , Staphylococcus spp., or H. influenzae .

Adult

Patients only

• Helicobacter pylori Infection and Duodenal Ulcer Disease: Triple therapy for Helicobacter pylori (H. pylori) with clarithromycin and lansoprazole: Amoxicillin, in combination with clarithromycin plus lansoprazole as triple therapy, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or 1-year history of a duodenal ulcer) to eradicate H. pylori . Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. Dual therapy for H. pylori with lansoprazole: Amoxicillin, in combination with lansoprazole delayed-release capsules as dual therapy, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or 1-year history of a duodenal ulcer) who are either allergic or intolerant to clarithromycin or in whom resistance to clarithromycin is known or suspected. (See the clarithromycin package insert, MICROBIOLOGY.) Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and other antibacterial drugs, amoxicillin should be used only to treat infections that are proven or strongly suspected to be caused by 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. Amoxicillin is a penicillin-class antibacterial indicated for treatment of infections due to susceptible strains of designated microorganisms. ( 1 ) Adults and Pediatric Patients ( 1 )
• Upper Respiratory Tract Infections of the Ear, Nose, and Throat
• Infections of the Genitourinary Tract
• Infections of the Skin and Skin Structure
• Infections of the Lower Respiratory Tract Adult Patients only ( 1 )
• Helicobacter pylori Infection and Duodenal Ulcer Disease Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin tablets, amoxicillin for oral suspension, amoxicillin tablets (chewable), and amoxicillin capsules and other antibacterial drugs, amoxicillin tablets, amoxicillin for oral suspension, amoxicillin tablets (chewable), and amoxicillin capsules should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1 )

AND ADMINISTRATION

• Adults and Pediatric Patients greater than 40 kg: 500 mg or 875 mg every 12 hours or 250 mg or 500 mg every 8 hours, based on amoxicillin component. ( Error! Hyperlink reference not valid. , 2.3 )
• Pediatric patients aged 12 weeks (3 months) and older: 25 to 45 mg/kg/day every 12 hours or 20 to 40 mg/kg/day every 8 hours, up to the adult dose. ( 2.3 )
• Neonates and infants less than 12 weeks of age: 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. ( 2.3 )

2.1 Important Administration Instructions Amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) are administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) should be taken at the start of a meal.

2.2 Adult Patients See dosing regimens of amoxicillin/clavulanate potassium (based on the amoxicillin component) provided in Table 1 below.

Table

1.

Dosing

Regimens of Amoxicillin/Clavulanate Potassium in Adult Patients TYPE OF INFECTION DOSING REGIMEN OF AMOXICILLIN/CLAVULANATE POTASSIUM Severe infections and infections of the respiratory tract one 875 mg tablet a of amoxicillin/clavulanate potassium every 12 hours or one 500 mg tablet b,c of amoxicillin/clavulanate potassium every 8 hours Less severe infections one 500 mg tablet b,c of amoxicillin/clavulanate potassium every 12 hours or one 250 mg tablet d of amoxicillin/clavulanate potassium every 8 hours a Adults who have difficulty swallowing may be given the amoxicillin and clavulanate potassium 200 mg/28.5 mg per 5 mL for oral suspension or the amoxicillin and clavulanate potassium 400 mg/57 mg per 5 mL for oral suspension may be used in place of the 875 mg/125 mg tablet. b Adults who have difficulty swallowing may be given the amoxicillin and clavulanate potassium 125 mg/31.25 mg per 5 mL for oral suspension or amoxicillin and clavulanate potassium 250 mg/62.5 mg per 5 mL for oral suspension in place of the 500 mg/125 mg tablet. c Two amoxicillin and clavulanate potassium 250 mg/125 mg tablets are NOT substitutable with one 500 mg/125 mg amoxicillin and clavulanate potassium tablet [see Dosage and Administration ( Error! Hyperlink reference not valid. )] . d Amoxicillin and clavulanate potassium 250 mg/125 mg tablet is NOT substitutable with amoxicillin and clavulanate potassium 250 mg/62.5 mg chewable tablet [see Dosage and Administration ( Error! Hyperlink reference not valid. )] .

2.3 Pediatric Patients Based on the amoxicillin component, amoxicillin and clavulanate potassium for oral suspension should be dosed as follows: Neonates and Infants Aged less than 12 Weeks (less than 3 Months) : See dosing regimens of amoxicillin/clavulanate potassium provided in Table 2 below.

Table

2: Dosing Regimens of Amoxicillin and Clavulanate Potassium for Oral Suspension in Neonates and Infants Aged Less than 12 Weeks (Less than 3 Months)

Patient Population Dosing Regimen

Amoxicillin and Clavulanate Potassium 125 mg/31.25 mg per 5 mL for Oral Suspension a Neonates and Infants aged less than 12 weeks (less than 3 months) 30 mg/kg/day every 12 hours a Experience with the amoxicillin and clavulanate potassium for oral suspension 200 mg/28.5 mg per 5 mL formulation in this age group is limited, and thus, use of the amoxicillin and clavulanate potassium 125 mg/31.25 mg per 5 mL for oral suspension is recommended.

Patients Aged

12 Weeks (3 Months) and Older and Weighing Less than 40 kg : See dosing regimens provided in Table 3 below.

• The every 12 hour regimen is recommended as it is associated with significantly less diarrhea [see Clinical Studies ( Error! Hyperlink reference not valid. )] .
• The amoxicillin and clavulanate potassium 200 mg/28.5 mg per 5 mL and amoxicillin and clavulanate potassium 400 mg/57 mg per 5 mL for oral suspension and amoxicillin and clavulanate potassium 200 mg/28.5 mg and amoxicillin and clavulanate tablets (chewable) 400 mg/57 mg contain aspartame and should not be used by phenylketonurics [see Warnings and Precautions ( Error! Hyperlink reference not valid. )] .

Table

3: Dosing in Patients Aged 12 Weeks (3 Months) and Older and Weighing Less than 40 kg INFECTION DOSING REGIMEN Every 12 hours Amoxicillin/Clavulanate Potassium 200 mg/28.5 mg per 5 mL for Oral Suspension or Amoxicillin/Clavulanate Potassium 400 mg/57 mg per 5 mL for Oral Suspension a Otitis media b , sinusitis, lower respiratory tract infections, and more severe infections 45 mg/kg/day every 12 hours Less severe infections 25 mg/kg/day every 12 hours 1. Each strength of amoxicillin and clavulanate potassium for oral suspension is available as a chewable tablet for use by older children. 2. Duration of therapy studied and recommended for acute otitis media is 10 days.

Patients Weighing

40 kg or More: Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations.

• The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium tablets should NOT be used until the child weighs at least 40 kg, due to the different amoxicillin to clavulanic acid ratios in the 250 mg/125 mg tablet of amoxicillin and clavulanate potassium tablets versus the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium tablets (chewable).

2.4 Patients with Renal Impairment Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Renal impairment patients with a glomerular filtration rate (GFR) of less than 30 mL/min should NOT receive the 875 mg dose (based on the amoxicillin component) of amoxicillin and clavulanate potassium tablets. See dosing regimens in patients with severe renal impairment provided in Table 4.

Table

4.

Dosing

Regimens of Amoxicillin and Clavulanate Potassium Tablets in Patients with Severe Renal Impairment Patients with Renal Impairment Dosing Regimen GFR 10 mL/min to 30 mL/min 500 mg or 250 mg every 12 hours, depending on the severity of the infection GFR less than 10 mL/min 500 mg or 250 mg every 24 hours, depending on severity of the infection Hemodialysis 500 mg or 250 mg every 24 hours, depending on severity of the infection Administer an additional dose both during and at the end of dialysis

2.5 Directions for Mixing Amoxicillin and Clavulanate Potassium for Oral Suspension Prepare amoxicillin and clavulanate potassium for oral suspension at time of dispensing as follows: Tap bottle until all powder flows freely. Measure a total (see Table 5 below for total amount of water for reconstitution) OF WATER. Add approximately 2/3 of the water to the powder. Replace cap and shake VIGOROUSLY. Add remaining water. Replace cap and shake VIGOROUSLY.

Table

5: Amount of Water for Mixing Amoxicillin and Clavulanate Potassium for Oral Suspension Strength of Amoxicillin and Clavulanate Potassium for Oral Suspension Bottle Size Amount of Water for Reconstitution Contents of Each Teaspoonful (5 mL) 200 mg/28.5 mg per 5 mL 100 mL 92 mL 200 mg of amoxicillin and 28.5 mg of clavulanic acid as the potassium salt 400 mg/57 mg per 5 mL 100 mL 87 mL 400 mg of amoxicillin and 57 mg of clavulanic acid as the potassium salt Shake oral suspension well before using. Reconstituted suspension must be stored under refrigeration and discarded after 10 days. Some color change is normal during dosing period.

2.6 Switching between Dosage Forms and between Strengths Amoxicillin and Clavulanate Potassium Tablet, 250 mg/125 mg are NOT Substitutable with Amoxicillin and Clavulanate Potassium Chewable Tablet, 250 mg/62.5 mg The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium tablets and the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium tablets (chewable) should NOT be substituted for each other and the tablet of 250 mg/125 mg amoxicillin and clavulanate potassium tablets should NOT be used in pediatric patients weighing less than 40 kg <span class="opacity-50 text-xs">[see Dosage and Administration ( Error! Hyperlink reference not valid. )]</span> .

The

250 mg tablet of amoxicillin and clavulanate potassium tablets and the tablet of 250 mg amoxicillin and clavulanate potassium tablets (chewable) do not contain the same amount of clavulanic acid.

The

250 mg tablet of amoxicillin and clavulanate potassium tablets contain 125 mg of clavulanic acid whereas the 250 mg tablet of amoxicillin and clavulanate potassium tablets (chewable) contain 62.5 mg of clavulanic acid.

Two

Amoxicillin and Clavulanate Potassium Tablets, 250 mg/125 mg are NOT Substitutable with One Amoxicillin and Clavulanate Potassium Tablet, 500 mg/125 mg Two 250 mg/125 mg amoxicillin and clavulanate potassium tablets should NOT be substituted for one 500 mg/125 mg amoxicillin and clavulanate potassium tablet. Since both the 250 mg and 500 mg tablets of amoxicillin and clavulanate potassium tablets contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg tablets of amoxicillin and clavulanate potassium tablets are not equivalent to one 500 mg tablet of amoxicillin and clavulanate potassium tablet.

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

4.1 Hypersensitivity Reactions TALICIA is contraindicated in patients with known hypersensitivity to the components of TALICIA: amoxicillin [or other β-lactam antibacterial drugs (e.g., penicillins and cephalosporins)], omeprazole (or other benzimidazoles [e.g. proton pump inhibitors (PPIs) and anthelmintics]), rifabutin (or any other rifamycins), or to any other component of TALICIA. Hypersensitivity reactions may include anaphylaxis or Stevens Johnson Syndrome, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, rash and urticaria <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 , 5.6 , 5.8 ), Adverse Reactions (6.1) ]</span> .

4.2 Rilpivirine-containing Products Proton pump inhibitors (PPIs), including omeprazole (a component of TALICIA), are contraindicated in patients receiving rilpivirine-containing products <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> .

4.3 Delavirdine The use of rifabutin (a component of TALICIA), is contraindicated in patients receiving delavirdine <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> .

4.4 Voriconazole The use of rifabutin (a component of TALICIA), is contraindicated in patients receiving voriconazole <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> .

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.

AND PRECAUTIONS Hypersensitivity Reactions: Serious and occasionally fatal reactions (e.g., anaphylaxis) have been reported with components of TALICIA. If hypersensitivity reactions occur, discontinue TALICIA and institute immediate therapy (e.g., anaphylaxis management). ( 5.1 )

Severe Cutaneous Adverse

Reactions (SCAR): There have been reports of SCAR with the components of TALICIA. Monitor closely and discontinue TALICIA at the first signs of SCAR. ( 5.2 ) Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of TALICIA. If this occurs, discontinue TALICIA and institute appropriate therapy. ( 5.3 ) Clostridioides difficile -Associated Diarrhea (CDAD): Evaluate if diarrhea occurs. ( 5.4 ) Reduction in the Efficacy of Hormonal Contraceptives: Additional non-hormonal highly effective methods of contraception should be used while taking TALICIA. ( 5.5 )

Acute Tubulointerstitial

Nephritis (TIN): Observed in patients taking Proton Pump Inhibitors (PPIs), including omeprazole and penicillins. Discontinue TALICIA and evaluate patients. ( 5.6 ) Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue TALICIA and evaluate. ( 5.8 )

5.1 Hypersensitivity Reactions Serious and fatal hypersensitivity reactions, e.g., anaphylaxis, angioedema, erythema multiforme, exfoliative dermatitis, hypersensitivity vasculitis, acute tubulointerstitial nephritis, and serum sickness have been reported with the components of TALICIA: omeprazole, amoxicillin and rifabutin. Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with TALICIA, inquire about history of hypersensitivity reactions to penicillins, cephalosporins, rifamycins, or PPIs. Discontinue TALICIA and institute immediate therapy, if hypersensitivity reactions occur.

5.2 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the components of TALICIA: rifabutin, amoxicillin, and omeprazole <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Adverse Reactions (6.3) ]</span> . Monitor closely and discontinue TALICIA at the first signs of SCAR.

5.3 Drug-Induced Enterocolitis Syndrome (DIES) Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of TALICIA <span class="opacity-50 text-xs">[see Adverse Reactions (6.3) ]</span> , with most cases occurring in pediatric patients ≤18 years of age. DIES is a non-IgE mediated hypersensitivity reaction characterized by protracted vomiting occurring 1 to 4 hours after drug ingestion in the absence of skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock, diarrhea within 24 hours after ingesting amoxicillin, and leukocytosis with neutrophilia. If DIES occurs, discontinue TALICIA and institute appropriate therapy.

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

5.5 Reduced Efficacy of Hormonal Contraceptives TALICIA may reduce the efficacy of hormonal contraceptives. Therefore, an additional non-hormonal highly effective method of contraception should be used while taking TALICIA <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> .

5.6 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs including omeprazole, a component of TALICIA. TIN may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions, to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). TIN has also been observed in patients taking penicillins, such as amoxicillin, a component of TALICIA. Discontinue TALICIA and evaluate patients with suspected acute TIN <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.7 Risk of Adverse Reactions or Loss of Efficacy Due to Drug Interactions Components of TALICIA have the potential for clinically important drug interactions <span class="opacity-50 text-xs">[see Contraindications (4) and Drug Interactions (7) ]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>.

5.8 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. If signs or symptoms consistent with CLE or SLE develop in patients receiving TALICIA, discontinue the drug and evaluate as appropriate.

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

5.10 Uveitis Due to the possible occurrence of uveitis, patients should be carefully monitored when rifabutin, a component of TALICIA, is given in combination with clarithromycin (or other macrolides) and/or fluconazole and related compounds. If uveitis is suspected, refer for an ophthalmologic evaluation and, if considered necessary, suspend treatment with rifabutin <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

5.11 Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Assess CgA levels at least 14 days after TALICIA treatment and consider repeating the test if initial CgA levels are high <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> .

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

Precaustions from Manufacturer Package Insert

5.1 Anaphylactic Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy including amoxicillin. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. 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 amoxicillin, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and appropriate therapy instituted.

5.2 Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin, 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. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

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

5.4 Use in Patients With Mononucleosis A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus amoxicillin should not be administered to patients with mononucleosis.

INTERACTIONS Components of TALICIA have the potential for clinically important drug interactions.

See Full Prescribing

Information for important drug interactions with TALICIA. ( 4 , 5.7 )

7.1 Interactions with Other Drugs and Diagnostics Drug interaction studies with TALICIA have not been conducted. The drug interaction information described here is based on the prescribing information of individual TALICIA components: omeprazole, amoxicillin, and rifabutin. Rifabutin is a substrate and inducer of cytochrome P450 (CYP) 3A enzymes. Omeprazole is a substrate and an inhibitor of CYP2C19, and a substrate of CYP3A4. Co-administration of TALICIA and other drugs that are substrates, inhibitors, or inducers of these enzymes may alter concentrations of rifabutin/omeprazole or other co-administered drugs [See Table 2 below and Clinical Pharmacology (12.3) ]. Omeprazole magnesium is a PPI. Refer to the prescribing information of the drugs used concomitantly with TALICIA for further information on their interactions with PPIs.

Table

2: Interactions with TALICIA When Co-Administered with Other Drugs and Diagnostics CYP2C19 or CYP3A4 Inducers Clinical Impact Decreased exposure of omeprazole when used concomitantly with strong inducers. Prevention or Management St. John’s Wort, rifampin : Avoid concomitant use with TALICIA [see Warnings and Precautions (5.7) ]. Ritonavir-containing products : See prescribing information for specific drugs. CYP2C19 or CYP3A4 Inhibitors Clinical Impact Increased blood levels of omeprazole and rifabutin. Prevention or Management Voriconazole : Concomitant use with TALICIA is contraindicated [see Contraindications (4) ] . Fluconazole, posaconazole and itraconazole : Avoid concomitant use with TALICIA. If coadministration cannot be avoided, monitor patients for rifabutin associated adverse events, and lack of anti-fungal efficacy. CYP2C19 Substrates (e.g., Clopidogrel, citalopram, cilostazol, phenytoin, diazepam)

Clinical Impact

Increased plasma concentrations of CYP2C19 substrate drugs or decreased/increased plasma concentrations of its active metabolite(s) [see Clinical Pharmacology (12.3) ] . Prevention or Management Clopidogrel : Consider use of alternative anti-platelet therapy [ see Warnings and Precautions (5.7) ] . Avoid concomitant use with TALICIA.

Antiretrovirals/Protease

Inhibitors Clinical Impact Antiretrovirals/protease inhibitors may increase rifabutin blood levels. The effect of PPIs (such as omeprazole in TALICIA) on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3) ]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3) ] . There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole. Prevention or Management Delavirdine : Combination treatment with TALICIA and delavirdine is contraindicated [see Contraindications (4) ]. Rilpivirine-containing products : Concomitant use with TALICIA is contraindicated [see Contraindications (4) ]. Avoid concomitant use of TALICIA with amprenavir, indinavir, lopinavir/ritonavir, saquinavir/ritonavir, ritonavir, tipranavir/ritonavir, fosamprenavir/ritonavir, or nelfinavir [see Warnings and Precautions (5.7) ] . Other antiretrovirals: See prescribing information for specific antiretroviral drugs.

Probenecid Clinical Impact

Increased and prolonged blood levels of amoxicillin.

Allopurinol Clinical Impact

Increase in the incidence of rashes is reported in patients receiving both allopurinol and amoxicillin together compared to patients receiving amoxicillin alone. It is not known whether 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 [see Warnings and Precautions (5.7) ] . Prevention or Management Avoid concomitant use of TALICIA in patients receiving high-dose methotrexate.

Digoxin Clinical Impact

Potential for increased digoxin blood levels [see Clinical Pharmacology (12.3) ] . 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 Clinical Pharmacology (12.3) ] . 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 [see Warnings and Precautions (5.5) ] . 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 [see Warnings and Precautions (5.11) ] . 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.