FDA label 01c5599b-745a-4860-b87f-24dfd41cd170

5. WARNINGS AND PRECAUTIONS Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should also be administered as indicated. ( 5.1 ) Clostridium difficile associated diarrhea (ranging from mild diarrhea to fatal colitis): Evaluate if diarrhea occurs. ( 5.2 ) 5.1 Anaphylaxis and Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. 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 MOXATAG, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, MOXATAG should be discontinued and appropriate therapy instituted. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should also be administered as indicated. 5.2 Clostridium difficile Associated Diarrhea (CDAD) Clostridium difficile Associated Diarrhea (CDAD) has been reported with 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 antibiotic 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 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 Superinfection s The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur, amoxicillin should be discontinued and appropriate therapy instituted. 5.4 Mononucleosis Rash A high percentage of patients with mononucleosis who receive ampicillin develop an erythematous skin rash. Thus, ampicillin-class antibiotics should not be administered to patients with mononucleosis. 5.5 Development of Drug-Resistant Bacteria Prescribing amoxicillin in the absence of proven or strongly suspected bacterial infection or treating prophylactically is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. 5.6 False-Positive Urinary Glucose Tests High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using Clinitest®, Benedict's Solution or Fehling's Solution. Since this effect may also occur with amoxicillin, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix®) be used.

6. ADVERSE REACTIONS 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 most common drug-related adverse reactions (incidence ≥1.0 %) are vulvovaginal mycotic infection, diarrhea, nausea, vomiting and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Shionogi Inc. at 1-800-849-9707 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Stud y Experience Tonsillitis and/or Pharyngitis In a controlled Phase 3 trial, 302 adult and pediatric patients (≥12 years) were treated with MOXATAG 775 mg once-daily for 10 days and 306 adult and pediatric patients (≥12 years) were treated with penicillin VK 250 mg QID for 10 days. In this clinical trial, the majority of treatment-emergent adverse reactions were of a mild and transient nature with similar frequency reported in both treatment groups. Discontinuation due to drug-related treatment-emergent adverse reactions occurred in 1.3% of the MOXATAG-treated patients and 3.3% of the penicillin VK-treated patients. The most frequently reported adverse reactions (≥1%) which were suspected or probably drug-related are shown in Table 1. Table 1. Drug-Related Treatment-Emergent Adverse Reactions by System Organ Class Experienced by ≥1% of Patients in Either Treatment Group – ITT/Safety Population Number (%) of patients System Organ Class/Preferred Term* MOXATAG (N =302) Penicillin VK (N = 306 ) Patients with at least one drug-related treatment-emergent adverse event 32 (10.6) 45 (14.7) Infections and infestations Vulvovaginal mycotic infection 6 (2.0) 8 (2.6) Gastrointestinal disorders Diarrhea 5 (1.7) 6 (2.0) Nausea 4 (1.3) 2 (0.7) Vomiting 2 (0.7) 5 (1.6) Abdominal pain 1 (0.3) 3 (1.0) Nervous system disorders Headache 3 (1.0) 3 (1.0) *Presented in decreasing order of frequency in the MOXATAG column within each system organ class. 6.2 Adverse Reactions for Other Amoxicillin Products The following adverse reactions have been reported for other products containing amoxicillin: Infections and Infestations : Mucocutaneous candidiasis. Gastrointestinal : Nausea, vomiting, diarrhea, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. Hypersensitivity Reactions : Anaphylaxis (See Warnings and Precautions). Serum sickness like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens-Johnson Syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis and urticaria have been reported. (NOTE: These hypersensitivity reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, amoxicillin should be discontinued unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to amoxicillin therapy.) Liver: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis have been reported. Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Central Nervous System: Reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness have been reported rarely. Renal: Crystalluria has also been reported Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been rarely reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases.

<table> <caption>Table 1. Drug-Related Treatment-Emergent Adverse Reactions by System Organ Class Experienced by &#x2265;1% of Patients in Either Treatment Group &#x2013; ITT/Safety Population</caption> <col width="205"/> <col width="74"/> <col width="80"/> <tbody> <tr> <td align="center"/> <td colspan="2" align="center">Number (%) of patients </td> </tr> <tr> <td align="center"> System Organ Class/Preferred Term*</td> <td styleCode="Toprule " align="center">MOXATAG (N =302)</td> <td styleCode="Toprule " align="center">Penicillin VK (N = 306 )</td> </tr> <tr> <td>Patients with at least one drug-related treatment-emergent adverse event</td> <td align="center">32 (10.6)</td> <td align="center">45 (14.7)</td> </tr> <tr> <td>Infections and infestations</td> <td align="center"/> <td align="center"/> </tr> <tr> <td> Vulvovaginal mycotic infection</td> <td align="center">6 (2.0)</td> <td align="center">8 (2.6)</td> </tr> <tr> <td>Gastrointestinal disorders</td> <td align="center"/> <td align="center"/> </tr> <tr> <td> Diarrhea </td> <td align="center">5 (1.7)</td> <td align="center">6 (2.0)</td> </tr> <tr> <td> Nausea </td> <td align="center">4 (1.3)</td> <td align="center">2 (0.7)</td> </tr> <tr> <td> Vomiting</td> <td align="center">2 (0.7)</td> <td align="center">5 (1.6)</td> </tr> <tr> <td> Abdominal pain</td> <td align="center">1 (0.3)</td> <td align="center">3 (1.0)</td> </tr> <tr> <td>Nervous system disorders</td> <td align="center"/> <td align="center"/> </tr> <tr> <td> Headache</td> <td align="center">3 (1.0)</td> <td align="center">3 (1.0)</td> </tr> <tr> <td styleCode="Toprule " colspan="3">*Presented in decreasing order of frequency in the MOXATAG column within each system organ class.</td> </tr> </tbody> </table>