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warnings and cautions
5 WARNINGS AND PRECAUTIONS Acute hypersensitivity reactions (angioedema, dyspnea, pruritus, and rash) have been reported. If a severe hypersensitivity reaction occurs, discontinue DIFICID. ( 5.1 ) DIFICID is not expected to be effective for the treatment of other types of infections due to minimal systemic absorption of fidaxomicin. DIFICID should only be used for the treatment of C. difficile -associated diarrhea. ( 5.2 ) Development of drug-resistant bacteria: Only use DIFICID for infection proven or strongly suspected to be caused by C. difficile . ( 5.3 ) 5.1 Hypersensitivity Reactions Acute hypersensitivity reactions, including dyspnea, rash, pruritus, and angioedema of the mouth, throat, and face have been reported with DIFICID. If a severe hypersensitivity reaction occurs, DIFICID should be discontinued and appropriate therapy should be instituted. Some patients with hypersensitivity reactions to DIFICID also reported a history of allergy to other macrolides. Physicians prescribing DIFICID to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions. 5.2 Not for Use in Infections Other than C. difficile -Associated Diarrhea DIFICID is not expected to be effective for the treatment of other types of infections due to minimal systemic absorption of fidaxomicin [see Clinical Pharmacology (12.3) ] . DIFICID has not been studied for the treatment of infections other than CDAD. DIFICID should only be used for the treatment of CDAD. 5.3 Development of Drug-Resistant Bacteria Prescribing DIFICID in the absence of proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
6 ADVERSE REACTIONS The most common adverse reactions in adults (incidence ≥2%) are nausea, vomiting, abdominal pain, gastrointestinal hemorrhage, anemia, and neutropenia. ( 6 ) The most common adverse reactions in pediatric patients (incidence ≥5%) treated with DIFICID are pyrexia, abdominal pain, vomiting, diarrhea, constipation, increased aminotransferases, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. Adults The safety of DIFICID 200 mg tablets taken twice a day for 10 days was evaluated in 564 adult patients with CDAD in two active-controlled trials with 86.7% of patients receiving a full course of treatment. Thirty-three adult patients receiving DIFICID (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the DIFICID and vancomycin patients in Phase 3 trials. The most common selected adverse reactions occurring in ≥2% of adult patients treated with DIFICID are listed in Table 2. Table 2: Selected Adverse Reactions with an Incidence of ≥2% Reported in DIFICID-Treated Adult Patients in Controlled Trials System Organ Class DIFICID (N=564) Vancomycin (N=583) Adverse Reaction n (%) n (%) Blood and Lymphatic System Disorders Anemia 14 (2%) 12 (2%) Neutropenia 14 (2%) 6 (1%) Gastrointestinal Disorders Nausea 62 (11%) 66 (11%) Vomiting 41 (7%) 37 (6%) Abdominal Pain 33 (6%) 23 (4%) Gastrointestinal Hemorrhage 20 (4%) 12 (2%) The following adverse reactions were reported in <2% of adult patients taking DIFICID tablets in controlled trials: Gastrointestinal Disorders: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, flatulence, intestinal obstruction, megacolon Investigations: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet count Metabolism and Nutrition Disorders: hyperglycemia, metabolic acidosis Skin and Subcutaneous Tissue Disorders: drug eruption, pruritus, rash Pediatrics The safety of DIFICID in pediatric patients 6 months to less than 18 years of age was evaluated in a Phase 2 single-arm trial in 38 patients and a Phase 3 randomized, active-controlled trial in 98 patients treated with DIFICID and 44 patients treated with vancomycin [see Clinical Studies (14.2) ] . In both studies, patients received DIFICID orally twice daily for 10 days. Patients <2 years of age, or weighing <12.5 kg, or unable to swallow tablets received weight-based doses of DIFICID oral suspension. Patients weighing at least 12.5 kg and able to swallow tablets received the 200 mg DIFICID tablet. The age range in the Phase 2 trial was 11 months to 17 years and in the Phase 3 trial was 1 month to 17 years (one patient was less than 6 months of age). One death occurred in the Phase 2 single-arm trial. In the Phase 3 trial, there were 3 deaths in DIFICID-treated patients and no deaths in vancomycin-treated patients during the study period (40 days). All deaths occurred in patients less than 2 years of age and appeared to be related to underlying comorbidities [see Clinical Studies (14.2) ]. Treatment discontinuation due to adverse reactions occurred in 7.9% (3/38) of patients in the Phase 2 trial, and in 1% (1/98) and 2.3% (1/44) of DIFICID- and vancomycin-treated patients, respectively, in the Phase 3 trial. The most common selected adverse reactions occurring in ≥5% of pediatric patients treated with DIFICID in the Phase 3 trial are listed in Table 3. Table 3: Selected Adverse Reactions with an Incidence of ≥5% Reported in DIFICID-Treated Pediatric Patients in the Controlled Trial System Organ Class DIFICID (N=98) Vancomycin (N=44) Adverse Reaction n (%) n (%) Gastrointestinal Disorders Abdominal pain Includes abdominal pain, abdominal pain lower, and abdominal pain upper 8 (8.2) 9 (20.5) Vomiting 7 (7.1) 6 (13.6) Diarrhea 7 (7.1) 5 (11.4) Constipation 5 (5.1) 1 (2.3) General Disorders and Administration Site Conditions Pyrexia 13 (13.3) 10 (22.7) Investigations Aminotransferases increased Includes alanine aminotransferase increased, aspartate aminotransferase increased, and hepatic enzyme increased 5 (5.1) 1 (2.3) Skin and Subcutaneous Tissue Disorders Rash Includes rash, rash follicular, rash maculo-papular, and exfoliative rash 5 (5.1) 1 (2.3) The following adverse reactions were reported in <5% of pediatric patients taking DIFICID in clinical trials: Skin and Subcutaneous Tissue Disorders: urticaria, pruritus 6.2 Post Marketing Experience The following adverse reactions have been identified during post-approval use of DIFICID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions (dyspnea, angioedema, rash, pruritus)