NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. The carcinogenic potential of lactitol was assessed in rats and transgenic mice. In 2-year carcinogenicity study in rats, lactitol was not tumorigenic at daily oral doses up to g/kg/day (about 0.93 times the recommended daily human dose based on body surface area). In 6-month carcinogenicity study in Tg.rasH2 mice at daily oral doses of lactitol up to g/kg/day (about 0.47 times the recommended daily human dose based on body surface area), there were no drug-related neoplasms.Published studies indicated that lactitol was negative in the Ames test, chromosome aberration test with cultured mammalian cells, and in vivo mouse micronucleus test.Published studies indicated that lactitol did not cause any adverse effect on fertility and early embryonic development in rats at doses up to 10 g/kg/day (about 4.6 times the recommended daily human dose based on body surface area).

ADVERSE REACTIONS SECTION.

6. ADVERSE REACTIONS. Most common adverse reactions (>= 3%) are upper respiratory tract infection, flatulence, diarrhea, increased blood creatinine phosphokinase, abdominal distension, and increased blood pressure. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Braintree Laboratories, Inc. at 1-800-874-6756 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described below reflect exposure to PIZENSY in 807 patients with CIC in six-month placebo-controlled trial (Study 1), three-month active-controlled trial (Study 2) [see Clinical Studies (14)] and one-year uncontrolled safety study (NCT02819310). Of the 298 patients in the one-year uncontrolled study, 55 patients were enrolled from Study or Study 2. . Most Common Adverse Reactions:Table provides the incidence of adverse reactions in Study reported in at least 3% of patients in the PIZENSY treatment group and at higher incidence than placebo.Table 1: Common Adverse Reactions Reported in Adult Patients with CIC in Study 1 reported in at least 3% of patients and greater than placebo 74 of 291 patients in the PIZENSY group at least temporarily reduced their dose Upper respiratory tract infection includes the terms viral upper respiratory tract infection and nasopharyngitis. Increased blood creatinine phosphokinase includes the term blood creatinine phosphokinase myocardial band (MB) increased. Increased blood pressure includes the term Hypertension PIZENSY N=291(%)PlaceboN=302(%) Upper Respiratory Tract Infection 96 Flatulence83 Diarrhea43 Increased blood creatinine phosphokinase 43 Abdominal Distension31 Increased blood pressure 31In Study 2, the safety profile of PIZENSY was similar to Study 1.In the 1-year uncontrolled safety study, adverse reactions reported in patients receiving PIZENSY (N=298) with an incidence of at least 3% that are not represented in Table include urinary tract infection (5%) and abdominal pain (3%).. Adverse Reaction of Special Interest Severe DiarrheaIn Study 1, severe diarrhea was reported in (1%) PIZENSY-treated patients compared to no patients in the placebo group.. Adverse Reactions Leading to DiscontinuationIn Study 1, 11/291 (4%) PIZENSY-treated patients discontinued due to adverse reactions, compared to 10/302 (3%) of patients in the placebo group. The most common adverse reactions leading to discontinuation in PIZENSY-treated patients (1% each) were elevated creatinine kinase, flatulence, diarrhea and increased blood pressure.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of lactitol outside of the United States. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.hypersensitivity reactions, including rash and pruritus. hypersensitivity reactions, including rash and pruritus.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Lactitol exerts an osmotic effect, causing the influx of water into the small intestine leading to laxative effect in the colon.. 12.2 Pharmacodynamics. No formal pharmacodynamic studies have been conducted with PIZENSY.. 12.3 Pharmacokinetics. Following single oral dose of 20-gram PIZENSY in healthy adult subjects under fed conditions, the mean +- SD peak serum concentration (C max) is 776 +- 253 ng/mL, and the mean +- SD area under the curve (AUC) is 6,019 +- 1,771 nghr/mL. AbsorptionLactitol is minimally absorbed systemically following oral administration. The mean +- SD time to reach peak serum concentration (T max) is 3.6 +- 1.2 hours following single oral dose of 20-gram PIZENSY in healthy adult subjects under fed conditions. Effect of FoodC max and AUC values increase greater than 2-fold under fasted conditions compared to fed conditions. EliminationThe mean half-life of lactitol is 2.4 hours.ExcretionLactitol is minimally absorbed in the small intestine. Unabsorbed lactitol is expected to be degraded into organic acids in the colon and is minimally excreted in the feces.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. . Study 1PIZENSY was evaluated in double-blind, randomized, placebo-controlled, multicenter clinical study in adult patients with symptoms of CIC (NCT02819297). PIZENSY (20 grams once daily) was compared to placebo in 6-month treatment period. Patients who developed persistent diarrhea or loose stools were allowed to reduce their dosage of study drug to 10 grams once daily. Patients had mean age of 52 years (range 18 to 88 years); 76% were female, 60% were white, and 31% were black.To be eligible for the study, patients were required to meet modified Rome II criteria for at least 12 weeks (which need not be consecutive) in the preceding 12 months. Rome II criteria were modified for the study to allow enrollment of patients having less than defecations per week, rarely having loose stool without the use of laxatives, and not meeting criteria for IBS-C. In addition, patients were required to report at least one of the following symptoms:Straining during at least 25% of defecationsLumpy or hard stool in at least 25% of defecationsSensation of incomplete evacuations for at least 25% of defecationsPatients who met these criteria were also required to demonstrate the following during the 2-week screening period:Average less than complete spontaneous bowel movements (CSBMs) over the 2-week screening period. spontaneous bowel movement (SBM) was defined as bowel movement which had occurred with no rescue laxative use in the prior 24 hours, and CSBM was defined as SMB that is associated with sense of complete evaluation.No more than one SBM with Bristol Stool Form Scale (BSFS) of 6No SBMs with BSFS of 7The efficacy of PIZENSY was assessed using responder analysis and change-from-baseline in the CSBM endpoint. Efficacy was assessed using information provided by patients after each bowel movement using an electronic diary.The primary efficacy analysis was based on the first 12 weeks of the 6-month treatment period for 594 patients. responder was defined as patient who had at least CSBMs in given week and an increase of at least CSBM from baseline in the same week for at least weeks out of the first 12-week treatment period and at least of the last weeks (Weeks 9-12). The responder rates are shown in Table 2.. Straining during at least 25% of defecations. Lumpy or hard stool in at least 25% of defecations. Sensation of incomplete evacuations for at least 25% of defecations. Average less than complete spontaneous bowel movements (CSBMs) over the 2-week screening period. spontaneous bowel movement (SBM) was defined as bowel movement which had occurred with no rescue laxative use in the prior 24 hours, and CSBM was defined as SMB that is associated with sense of complete evaluation.. No more than one SBM with Bristol Stool Form Scale (BSFS) of 6. No SBMs with BSFS of 7. Table 2: Efficacy Responder Rates in Placebo-Controlled Study (Study 1) in Adults with CICCI confidence intervala 74 of 291 patients in the PIZENSY group at least temporarily reduced their dose primary endpoint defined as patient who had at least CSBMs in given week and an increase of at least CSBM from baseline in the same week for at least weeks out of the 12-week treatment period and at least of the last weeks of the study p-value <0.05 for difference from control PIZENSYN=291 PlaceboN=303TreatmentDifference(95% CI) Responder 25%13%12% (6.0, 18.5) . responder analysis based on Weeks 13 to 24 of the treatment period (i.e., the proportion of responders for at least weeks of the last 12 weeks and at least of the last weeks) showed results similar to the responder analysis of the first 12 weeks.Improvements in the mean frequency of CSBMs/week were seen at Week with improvement generally maintained through Week 12. The PIZENSY group had mean increase of 0.8 CSBM/week from baseline to Week 12 over the placebo group.Study 2PIZENSY (20 grams once daily) was compared to an active control (lubiprostone 24 mcg twice daily) in double-blind, double-dummy design study in adult patient with symptoms of CIC (NCT02481947). Patients had mean age of 46 years (range 18 to 87 years); 80% were female, 66% were white, and 29% were black. The primary endpoint was the same as Study 1. The frequency of CSBMs/week for the PIZENSY group was consistent with results from Study 1.Other StudiesStudies of varying design describing the efficacy of lactitol in increasing the frequency of bowel movements during short-term treatment of less than weeks in patients with symptoms of CIC have been published.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. DosageThe recommended adult dosage is 20 grams orally once daily, preferably with meals. (2.1) Reduce the dosage to 10 grams once daily for persistent loose stools. (2.1) Administer oral medications at least hours before or hours after PIZENSY. (2.1, 7.1) Preparation and AdministrationThe multi-dose bottles are equipped with measuring cap marked to contain 10 grams of powder when filled to the top of white section in cap. (2.2) The unit-dose packets contain 10 grams of PIZENSY each. (2.2) See full prescribing information for complete preparation These highlights do not include all the information needed and administration instructions. (2.2) The recommended adult dosage is 20 grams orally once daily, preferably with meals. (2.1) Reduce the dosage to 10 grams once daily for persistent loose stools. (2.1) Administer oral medications at least hours before or hours after PIZENSY. (2.1, 7.1) The multi-dose bottles are equipped with measuring cap marked to contain 10 grams of powder when filled to the top of white section in cap. (2.2) The unit-dose packets contain 10 grams of PIZENSY each. (2.2) See full prescribing information for complete preparation These highlights do not include all the information needed and administration instructions. (2.2) 2.1 Recommended Dosage. The recommended adult dosage of PIZENSY is 20 grams orally once daily, preferably with meals [see Clinical Pharmacology (12.3)]. Reduce the dosage to 10 grams once daily for persistent loose stools.Administer oral medications at least hours before or hours after PIZENSY [see Drug Interactions (7.1)] . The recommended adult dosage of PIZENSY is 20 grams orally once daily, preferably with meals [see Clinical Pharmacology (12.3)]. Reduce the dosage to 10 grams once daily for persistent loose stools.. Administer oral medications at least hours before or hours after PIZENSY [see Drug Interactions (7.1)] . 2.2 Preparation and Administration Instructions. . PIZENSY Multi-dose bottleNOTE: The bottle top is measuring cap marked to contain 10 grams of powder when filled to the top of white section in the cap marked by the arrow.Using the measuring cap, measure the prescribed dose. 20-gram dose: Fill the measuring cap twice to the top of the white section in cap marked by the arrow. 10-gram dose: Fill the measuring cap once to the top of the white section in cap marked by the arrow. Pour the measured dose into an empty 8-ounce glass.Add ounces to ounces of water, juice or other common beverages (coffee, tea, soda) and stir to dissolve.Drink the entire contents of the glass.PIZENSY Unit-dose packetsPour the contents of one or two unit-dose packets, as prescribed, into an empty 8-ounce glass.Add ounces to ounces of water, juice or other common beverages (coffee, tea, soda) to the glass containing the powder and stir thoroughly to dissolve.Drink the entire contents of the glass.. Using the measuring cap, measure the prescribed dose. 20-gram dose: Fill the measuring cap twice to the top of the white section in cap marked by the arrow. 10-gram dose: Fill the measuring cap once to the top of the white section in cap marked by the arrow. Pour the measured dose into an empty 8-ounce glass.. Add ounces to ounces of water, juice or other common beverages (coffee, tea, soda) and stir to dissolve.. Drink the entire contents of the glass.. Pour the contents of one or two unit-dose packets, as prescribed, into an empty 8-ounce glass.. Add ounces to ounces of water, juice or other common beverages (coffee, tea, soda) to the glass containing the powder and stir thoroughly to dissolve.. Drink the entire contents of the glass.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. PIZENSY is supplied in white to off-white crystalline powder form, for oral administration following reconstitution. PIZENSY is available in three sizes:280 grams of lactitol in multi-dose bottles (NDC 52268-600-01)560 grams of lactitol in multi-dose bottles (NDC 52268-600-02)carton of 28 unit-dose packets each containing 10 grams of lactitol (NDC 52268-600-03)The measuring cap on each multi-dose bottle is marked to contain 10 grams of powder when filled to the top of white section in cap and may be used to measure the appropriate PIZENSY dose.Each bottle contains white desiccant packet printed Do Not Eat.StorageStore at 20C to 25C (68 to 77F). Excursions permitted between 15 to 30C (59 to 86F). See USP controlled room temperature. 280 grams of lactitol in multi-dose bottles (NDC 52268-600-01). 560 grams of lactitol in multi-dose bottles (NDC 52268-600-02). carton of 28 unit-dose packets each containing 10 grams of lactitol (NDC 52268-600-03).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Principal Display PanelNDC 52268-600-01Pizensy(TM) (lactitol) for oral solution280 gramsRx ONLY(C)2020 Braintree Laboratories, Inc.Distributed by Braintree LaboratoriesKeep the medication out of the reach of children.Store at 20C to 25C (68 to 77F). Excursions permitted between 15C to 30C (59 to 86F). See USP controlled room temperature. Recommended Dosage: See prescribing information. DIRECTIONSIt is important to follow all of the steps below completely. Step 1: Open the bottle by pushing the cap downward and rotating it to the left until it opens.Step 2: Remove the cap. The cap contains 10 grams of powder when filled to the top of the white section marked by the arrow.Step 3: Measure and pour the prescribed dose into an empty ounce glass.Step 4: Add to ounces of water, juice, or other beverage to the glass containing the measured dose of powder and stir thoroughly with spoon.Step 5: Drink the entire contents of the glass.Step 6: Firmly recap the bottle.. 52268-600-01New.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryLactitol is minimally absorbed systemically following oral administration [see Clinical Pharmacology (12.3)] and it is unknown whether maternal use will result in fetal exposure to the drug. Available data from case reports on lactitol use in pregnant women are insufficient to evaluate for any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal developmental studies, no effects on embryo-fetal development were observed with oral administration of lactitol to rats and rabbits during organogenesis at doses much higher than the maximum recommended human dosage. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal DataReproduction studies have been performed in pregnant rats at oral doses of lactitol up to g/kg/day (about 0.93 times the recommended daily human dose based on body surface area) and in pregnant rabbits at oral doses up to g/kg/day (about 0.93 times the recommended daily human dose based on body surface area) administered during the period of organogenesis. These studies did not reveal any evidence of harm to the fetus due to lactitol.In pre-and postnatal development study in rats, lactitol, administered from gestation day to lactation day 20, did not cause any adverse effect on pre and postnatal development up to g/kg/day (about 0.93 times the recommended daily human dose based on body surface area).. 8.2 Lactation. Risk SummaryThere are no data on the presence of lactitol in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Lactitol is minimally absorbed systemically following oral administration [see Clinical Pharmacology (12.3)] It is unknown whether the minimal systemic absorption of lactitol by adults will result in clinically relevant exposure to breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for PIZENSY and any potential adverse effects on the breastfed infant from PIZENSY or from the underlying maternal condition. 8.4 Pediatric Use. The safety and effectiveness of PIZENSY have not been established in pediatric patients.. 8.5 Geriatric Use. Of the 807 patients who received PIZENSY in clinical trials, 202 (25%) were 65 years of age or older, and 59 (7%) were 75 years of age or older. No overall differences in safety or effectiveness of PIZENSY were observed between geriatric patients and younger patients.