Dificid

DIFICID- fidaxomicin tablet, film coated
DIFICID- fidaxomicin granule, for suspension
Merck Sharp & Dohme LLC

1 INDICATIONS AND USAGE

1.1 Clostridioides difficile -Associated Diarrhea

DIFICID® is indicated in adult and pediatric patients aged 6 months and older for the treatment of C. difficile -associated diarrhea (CDAD).

1.2 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by C. difficile. 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

2.1 Important Administration Instructions

DIFICID is available for oral administration as 200 mg tablets and as granules for oral suspension (40 mg/mL (200 mg/5 mL) when reconstituted). DIFICID is administered orally with or without food.

2.2 Adult Patients

The recommended dosage for adults is one 200 mg DIFICID tablet orally twice daily for 10 days.

2.3 Pediatric Patients (6 Months to Less than 18 Years of Age)

Tablets

The recommended dosage for pediatric patients weighing at least 12.5 kg and able to swallow tablets is one 200 mg DIFICID tablet administered orally twice daily for 10 days. If unable to swallow tablets, pediatric patients may be dosed with DIFICID oral suspension as recommended in Table 1 below.

Oral Suspension

The recommended dosage for pediatric patients based on weight are shown in Table 1. Administer DIFICID oral suspension orally twice daily for 10 days using an oral dosing syringe [see Dosage and Administration (2.4)].

Table 1: Recommended Dosage of DIFICID Oral Suspension in Pediatric Patients, Based on Weight
Body Weight Dose Administered Twice Daily Volume of 40 mg/mL Suspension to be Administered Orally Twice Daily
4 kg to less than 7 kg 80 mg 2 mL
7 kg to less than 9 kg 120 mg 3 mL
9 kg to less than 12.5 kg 160 mg 4 mL
12.5 kg and above 200 mg 5 mL

2.4 Preparation and Administration of DIFICID Oral Suspension

Preparation

  1. Shake the glass bottle to ensure the granules move around freely and no caking has occurred.
  2. Measure 130 mL of purified water, add to the glass bottle, and cap tightly.
  3. Hold bottle in a horizontal position and shake bottle vigorously in that position for at least 2 minutes.
  4. Verify that a homogeneous suspension is obtained. If not, repeat the shaking step.
  5. Once a homogeneous suspension is visually confirmed, shake an additional 30 seconds.
  6. Let bottle stand for 1 minute.
  7. Verify that the suspension is still homogeneous. If not, repeat steps 3 through 6.
  8. Once reconstituted, DIFICID oral suspension is white to yellowish white in color.
  9. Write discard date (current date plus 12 days) on the bottle [see How Supplied/Storage and Handling (16.1, 16.2)].

Storage of Reconstituted Oral Suspension

  • Store the reconstituted oral suspension in a refrigerator [between 36°F-46°F (2°C-8°C)] for up to 12 days. Discard after 12 days.

Administration

  1. Remove bottle from refrigerator 15 minutes prior to each administration.
  2. Shake vigorously until suspension has an even consistency.
  3. Remove cap, then administer orally with or without food using an oral dosing syringe.
  4. Between doses, replace cap and store in a refrigerator.

3 DOSAGE FORMS AND STRENGTHS

DIFICID tablets

200 mg white to off-white film-coated, oblong tablets; each tablet is debossed with “FDX” on one side and “200” on the other side.

DIFICID for oral suspension

White to yellowish white granules; following reconstitution, each mL of white to yellowish white oral suspension contains 40 mg of fidaxomicin (200 mg of fidaxomicin per 5 mL).

4 CONTRAINDICATIONS

DIFICID is contraindicated in patients who have known hypersensitivity to fidaxomicin or any other ingredient in DIFICID [see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS

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

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 (%)
*
Includes abdominal pain, abdominal pain lower, and abdominal pain upper
Includes alanine aminotransferase increased, aspartate aminotransferase increased, and hepatic enzyme increased
Includes rash, rash follicular, rash maculo-papular, and exfoliative rash
Gastrointestinal Disorders
Abdominal pain * 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 5 (5.1) 1 (2.3)
Skin and Subcutaneous Tissue Disorders
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

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