DONOR HUMAN STOOL: 211 Adverse Event Reports & Safety Profile

REBYOTA (fecal microbiota, live – jslm) is an opaque fecal microbiota suspension for rectal administration. REBYOTA is manufactured from human fecal matter sourced from qualified donors. The human fecal matter is tested for a panel of transmissible pathogens. Donors do not have dietary restrictions with respect to potential food allergens. The fecal microbiota suspension is the filtrate generated by processing the fecal matter in a pre-defined ratio with a solution of polyethylene glycol (PEG) 3350 and saline.

Each

150mL dose of REBYOTA contains between 1×10 8 and 5×10 10 colony forming units (CFU) per mL of fecal microbes including >1×10 5 CFU/mL of Bacteroides , and contains not greater than 5.97 grams of PEG3350 in saline.

AND USAGE REBYOTA is indicated for the prevention of recurrence of Clostridioides difficile infection (CDI) in individuals 18 years of age and older following antibiotic treatment for recurrent CDI. REBYOTA is indicated for the prevention of recurrence of Clostridioides difficile infection (CDI) in individuals 18 years of age and older, following antibiotic treatment for recurrent CDI. ( 1 ) Limitation of Use: REBYOTA is not indicated for treatment of CDI. Limitation of Use: REBYOTA is not indicated for treatment of CDI.

AND ADMINISTRATION For rectal administration only. For rectal administration only. Administer REBYOTA 24 to 72 hours after the last dose of antibiotics for CDI. ( 2 ) Administer a single dose of 150 mL rectally of REBYOTA. ( 2 )

2.1 Dose A single dose is 150 mL.

2.2 Preparation Prior to use, thaw REBYOTA completely by placing the carton in a refrigerator, 2°C to 8°C (36°F to 46°F), for approximately 24 hours. REBYOTA carton may be stored in the refrigerator at 2°C to 8°C (36°F to 46°F) and used within 5 days, including thawing time. DO NOT thaw using a heat source such as a microwave or hot water. Condensation is normal after thawing. Remove the thawed REBYOTA carton from the refrigerator. Remove the bag containing thawed REBYOTA from the outer carton and the inner carton insert. DO NOT remove the bag containing thawed REBYOTA from the sealed outer bag. Locate an Administration Set (supplied), water-soluble lubricant (not included) and a disposable underpad (not included) (See Figure 1 ). 1. Open the administration set and close the pinch clamp by pushing the clamp until it is fully closed (see Figure 2 ). 2. Remove the tab from the spike port of the bag containing thawed REBYOTA and remove the cap from the administration tube spike. Insert the administration tube spike through the spike port of the bag containing thawed REBYOTA (see Figure 3 ). DO NOT remove air from the administration tube prior to insertion to avoid loss of REBYOTA.

Figure

1 Figure 2 Figure 3

2.3 Administration Administer REBYOTA 24 to 72 hours after the last dose of antibiotics for CDI. 1. Prepare the patient for administration by requesting they empty their bladder and bowel, if possible. Place the patient in the left-side position or the knee-chest position with a disposable underpad beneath the patient (see Figures 4 and 5 ). 2. Apply water-soluble lubricant to the administration tube tip. Gently insert the administration tube tip into the rectum about 12 cm (5 inches) in a direction pointed slightly toward the navel (umbilicus) (see Figure 6 ). 3. Hold the administration tube in place with one hand for the entire procedure to maintain the tube position in the rectum. With the other hand, open the pinch clamp on the administration tube, and then gradually raise the bag to allow delivery of REBYOTA via gravity flow (see Figure 7 and 8 ). DO NOT allow the administration tube to sag or loop as this will prevent the entire dose from being delivered. DO NOT squeeze the bag to deliver REBYOTA as this could be uncomfortable for the patient. DO NOT hang the bag from an IV stand. 4. When the entire dose has been delivered, close the pinch clamp and then slowly withdraw the tube. Take care to prevent any residual REBYOTA remaining in the tube from leaking out. NOTE: Some REBYOTA will remain in the tube after administration. 5. Keep the patient in the left-side position or the knee-chest position for up to 15 minutes to minimize any cramping that may occur (see Figure 9 and 10 ). There are no restrictions on the patient's use of the restroom. Dispose of all components in medical waste.

Figure

4 and Figure 5 Figure 6 Figure 7 and Figure 8 Figure 9 and Figure 10

Do not administer REBYOTA to individuals with a history of a severe allergic reaction (e.g. anaphylaxis) to any of the known product components [see Description 11 ] . Severe allergic reactions (e.g. anaphylaxis) to any component of REBYOTA. ( 4 )

REACTIONS The most commonly reported (≥ 3%) adverse reactions occurring in adults following a single dose of REBYOTA were abdominal pain, (8.9%), diarrhea (7.2%), abdominal distention (3.9%), flatulence (3.3%), and nausea (3.3%). The most commonly reported (≥ 3%) adverse reactions occurring in adults following a single dose of REBYOTA were abdominal pain, (8.9%), diarrhea (7.2%), abdominal distention (3.9%), flatulence (3.3%), and nausea (3.3%) ( Table 1 ). To report SUSPECTED ADVERSE REACTIONS, contact Ferring Pharmaceuticals Inc. at 1-888-FERRING (1-888-337-7464) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . ( 6 )

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. The safety of REBYOTA was evaluated in 2 randomized, double-blind clinical studies (Study 1: NCT03244644 and Study 2: NCT02299570) and 3 open-label clinical studies (NCT01925417, NCT02589847, NCT03931941) conducted in the United States and Canada. A total of 978 adults 18 years of age and older with a history of 1 or more recurrences of Clostridioides difficile (CDI) infection and whose symptoms were controlled 24 – 72 hours post-antibiotic treatment were enrolled and received 1 or more doses of REBYOTA; 595 of whom received a single dose of REBYOTA. In the 2 randomized, double-blind clinical studies, 131 adults were originally randomized to receive placebo and 48 crossed over to receive an open-label dose of REBYOTA after additional CDI recurrence. Overall, across the 5 studies, the median age of participants was 64 years and 67.2 % were female. The racial and ethnic distribution was as follows: 93.8% were white, and 2.4% were of Hispanic or Latino ethnicity. No meaningful differences in demographic characteristics occurred across the treatment groups.

Study

1 and Study 2 excluded individuals with celiac disease, Inflammatory Bowel Disease, Irritable Bowel Syndrome, and chronic diarrhea. Individuals with these conditions were not excluded from one of the open-label studies (NCT03931941), and individuals with food allergies were not excluded from any of the 5 clinical studies.

Adverse Reactions

Across the 5 clinical studies, participants recorded solicited adverse events in a diary for the first 7 days after each dose of REBYOTA or placebo. Participants were monitored for all other adverse events by queries during scheduled visits, with duration of follow-up ranging from 6 to 24 months after the last dose.

In Study

1, a multi-center, double-blind randomized (2:1), placebo-controlled trial conducted in the United States and Canada, 180 adults 18 years of age and older received a single dose of REBYOTA and 87 received placebo. Participants with a recurrence of CDI (rCDI) during the first 8 weeks after receipt of REBYOTA or placebo were censored from analysis at the time of rCDI . During the first two weeks following a dose of REBYOTA or placebo, 34 participants (18.9%) and 24 participants (27.6%) respectively, were censored. Overall, during the 8 week follow up period, 47 REBYOTA recipients (26.1%) and 30 placebo recipients (34.5%) were censored from analysis. In an analysis of solicited and unsolicited adverse events reported in Study 1, the most common adverse reactions (defined as adverse events assessed as definitely, possibly, or probably related to Investigational Product by the investigator) reported by ≥3% of REBYOTA recipients, and at a rate greater than that reported by placebo recipients, were abdominal pain, (8.9%), diarrhea (7.2%), abdominal distention (3.9%), flatulence (3.3%), and nausea (3.3%) (Table 1).

Table

1: Adverse Reactions Adverse reactions were defined as solicited and unsolicited adverse events that were assessed as definitely, possibly or probably related to treatment by the study investigator. reported by ≥3% of REBYOTA recipients, and at a rate greater than that reported by placebo recipients, within 8 weeks after receipt of REBYOTA or placebo (Study 1).

Adverse

Reaction REBYOTA N=180 n (%) Placebo N=87 n (%)

Abdominal Pain

16 (8.9) 6 (6.9)

Diarrhea

13 (7.2) 3 (3.4) Abdominal distension 7 (3.9) 2 (2.3)

Flatulence

6 (3.3) 0 Nausea 6 (3.3) 1 (1.1) Most adverse reactions occurred during the first 2 weeks after treatment. After this, the proportion of patients with adverse reactions declined in subsequent 2-week intervals.

Beyond

2 weeks after treatment only a few single adverse reactions were reported. Most adverse drug reactions were mild to moderate in severity. No life-threatening adverse reaction was reported.

Serious Adverse

Reactions In a pooled analysis of the 5 clinical studies, 10.1% (60/595) of REBYOTA recipients (1 dose only) and 7.2% (6/83) of placebo recipients reported a serious adverse event within 6 months post last dose of investigational product. None of these events were considered related to the investigational product.

AND PRECAUTIONS

5.1 Transmissible infectious agents Because REBYOTA is manufactured from human fecal matter it may carry a risk of transmitting infectious agents. Any infection suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Ferring Pharmaceuticals Inc.

5.2 Management of acute allergic reactions Appropriate medical treatment must be immediately available in the event an acute anaphylactic reaction occurs following administration of REBYOTA.

5.3 Potential presence of food allergens REBYOTA is manufactured from human fecal matter and may contain food allergens. The potential for REBYOTA to cause adverse reactions due to food allergens is unknown.