ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious or otherwise important adverse reactions for bowel preparations are described elsewhere in the labeling: Serious Fluid and Electrolyte Abnormalities [see Warnings and Precautions 5.1)] Cardiac Arrhythmias [see Warnings and Precautions 5.2)] Seizures [see Warnings and Precautions 5.3)] Use in Patients with Renal Impairment [see Warnings and Precautions 5.4)] Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis [see Warnings and Precautions 5.5)] Use in Patients with Significant Gastrointestinal Disease [see Warnings and Precautions 5.6)] Aspiration [see Warnings and Precautions 5.7)] Risk of Vomiting and Other Gastrointestinal Complications with Ingestion of Undissolved Powder [see Warnings and Precautions 5.8)] Most common adverse reactions are: Adults (>1%): nausea, headache and vomiting. 6.1) Pediatrics to 16 years (>5%): nausea, vomiting, and abdominal pain. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Annora Pharma Private Limited at 1-866-495-1995 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 drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. In randomized, multicenter, controlled clinical trials, nausea, headache, and vomiting were the most common adverse reactions (>1%) following sodium picosulfate, magnesium oxide and anhydrous citric acid administration. The patients were not blinded to the study drug. Since abdominal bloating, distension, pain/cramping, and watery diarrhea are known to occur in response to colon cleansing preparations, these effects were documented as adverse events in the clinical trials only if they required medical intervention (such as change in study drug or led to study discontinuation, therapeutic or diagnostic procedures, met the criteria for serious adverse event), or showed clinically significant worsening during the study that was not in the frame of the usual clinical course, as determined by the investigator. Sodium picosulfate, magnesium oxide and anhydrous citric acid was compared for colon cleansing effectiveness with preparation containing two liters (2L) of polyethylene glycol plus electrolytes solution (PEG E) and two mg bisacodyl tablets, all administered the day before the procedure. Table displays the most common adverse reactions in Study and Study for the sodium picosulfate, magnesium oxide and anhydrous citric acid Split-Dose and Day-Before dosing regimens, respectively, each as compared to the comparator preparation. Table 1: Treatment-Emergent Adverse Reactions observed in at Least (>1%) of Patients using the Split-Dose Regimen and Day-Before Regimen Adverse Reaction tudy 1: Split-Dose Regimen tudy 2: Day-Before Regimen od u picosulfate, magnesium oxide and anhydrous citric acid (N=305) (% n/N) L PEG+E i th x 5-mg bisacodyl tablets (N=298) (% n/N) od u picosulfate, magnesium oxide and anhydrous citric acid (N=296) (% n/N) L PEG+E i th x 5mg bisacodyl tablets (N=302) (% n/N) Nausea (2.6) 11 (3.7) (3.0) 13 (4.3) Headache (1.6) (1.7) (2.7) (1.7) Vomiting (1.0) 10 (3.4) (1.4) (2.0) 2L PEG E two liters polyethylene glycol plus electrolytes solution. abdominal bloating, distension, pain/cramping, and watery diarrhea not requiring an intervention were not collected Electrolyte Abnormalities In general, sodium picosulfate, magnesium oxide and anhydrous citric acid was associated with numerically higher rates of abnormal electrolyte shifts on the day of colonoscopy compared to the preparation containing 2L of PEG E plus two 5-mg bisacodyl tablets (Table 2). These shifts were transient in nature and numerically similar between treatment arms at the Day 30 visit. Table 2: Shifts from Normal Baseline to Outside the Normal Range at Day and Day 30 Laboratory Parameter (direction of change) Visit Study 1: Split-Dose Regimen Study 2: Day-Before Regimen Sodium picosulfate, magnesium oxide and anhydrous citric acid 2L PEG+E with 2x mg bisacodyl tablets Sodium picosulfate, magnesium oxide and anhydrous citric acid 2L PEG+E with 2x mg bisacodyl tablets n/N (%) n/N (%) Potassium (low) Day of Colonoscopy 19/260 (7.3) 11/268 (4.1) 13/274 (4.7) 13/271 (4.8) 24 to 48 hours 3/302 (1.0) 2/294 (0.7) 3/287 (1.0) 5/292 (1.7) Day 11/285 (3.9) 8/279 (2.9) 6/276 (2.2) 14/278 (5.0) Day 30 11/284 (3.9) 8/278 (2.9) 7/275 (2.5) 8/284 (2.8) Sodium (low) Day of Colonoscopy 11/298 (3.7) 3/295 (1.0) 3/286 (1.0) 3/295 (1.0) 24 to 48 hours 1/303 (0.3) 1/295 (0.3) 1/288 (0.3) 1/293 (0.3) Day 2/300 (0.7) 1/292 (0.3) 1/285 (0.4) 1/291 (0.3) Day 30 2/299 (0.7) 3/291 (1.0) 1/284 (0.4) 1/296 (0.3) Chloride (low) Day of Colonoscopy 11/301 (3.7) 1/298 (0.3) 3/287 (1.0) 0/297 (0.0) 24 to 48 hours 1/303 (0.3) 0/295 (0.0) 2/288 (0.7) 0/293 (0.0) Day 1/303 (0.3) 3/295 (1.0) 0/285 (0.0) 0/293 (0.0) Day 30 2/302 (0.7) 3/294 (1.0) 0/285 (0.0) 0/298 (0.0) Magnesium (high) Day of Colonoscopy 34/294 (11.6) 0/294 (0.0) 25/288 (8.7) 1/289 (0.3) 24 to 48 hours 0/303 (0.0) 0/295 (0.0) 0/288 (0.0) 0/293 (0.0) Day 0/297 (0.0) 1/291 (0.3) 1/286 (0.3) 1/285 (0.4) Day 30 1/296 (0.3) 2/290 (0.7) 0/286 (0.0) 0/290 (0.0) Calcium (low) Day of Colonoscopy 2/292 (0.7) 1/286 (0.3) 0/276 (0.0) 2/282 (0.7) 24 to 48 hours 0/303 (0.0) 0/295 (0.0) 0/288 (0.0) 0/293 (0.0) Day 0/293 (0.0) 1/283 (0.4) 0/274 (0.0) 0/278 (0.0) Day 30 0/292 (0.0) 1/282 (0.4) 0/274 (0.0) 1/283 (0.4) Creatinine (high) Day of Colonoscopy 5/260 (1.9) 13/268 (4.9) 12/266 (4.5) 16/270 (5.9) 24 to 48 hours 1/303 (0.3) 0/295 (0.0) 0/288 (0.0) 0/293 (0.0) Day 10/264 (0.4) 13/267 (4.8) 10/264 (3.8) 10/265 (3.8) Day 30 11/264 (4.2) 14/265 (5.3) 18/264 (6.8) 10/272 (3.7) eGFR (low) Day of Colonoscopy 22/221 (10.0) 17/214 (7.9) 26/199 (13.1) 25/224 (11.2) 24 to 48 hours 76/303 (25.1) 72/295 (24.4) 82/288 (28.5) 62/293 (21.2) Day 22/223 (10.0) 17/213 (8.0) 11/198 (5.6) 28/219 (12.8) Day 30 24/223 (10.8) 21/211 (10.0) 21/199 (10.6) 24/224 (10.7) Pediatrics In the pediatric patients aged to 16 years who received sodium picosulfate, magnesium oxide and anhydrous citric acid, the most common adverse reactions (> 5%) were nausea, vomiting, and abdominal pain [see Clinical Trials 14)]. Electrolytes abnormalities were observed in pediatric patients similar to those seen in adults. Three patients had abnormally low glucose levels (40 to 47 mg/dL). Two patients received sodium picosulfate, magnesium oxide and anhydrous citric acid and one received the comparator (PEG). The abnormal values occurred at the colonoscopy visit for one patient (sodium picosulfate, magnesium oxide and anhydrous citric acid) and at the 5-day follow up visit for the other two patients (sodium picosulfate, magnesium oxide and anhydrous citric acid and PEG). All three patients were asymptomatic. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of other oral formulations of sodium picosulfate, magnesium oxide and anhydrous citric acid similar to sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution. 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: rash, urticaria, purpura, and anaphylaxis [see Contraindications 4)] Gastrointestinal: abdominal pain, diarrhea, fecal incontinence, aphthoid ileal ulcers, ischemic colitis [see Warnings and Precautions 5.5)] Neurologic: generalized tonic-clonic seizures with and without hyponatremia in epileptic patients [see Warnings and Precautions 5.3)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Sodium picosulfate is hydrolyzed by colonic bacteria to form an active metabolite: bis-(p-hydroxy-phenyl)-pyridyl-2-methane, BHPM, which acts directly on the colonic mucosa to stimulate colonic peristalsis. Magnesium oxide and citric acid react to create magnesium citrate in solution, which is an osmotic agent that causes water to be retained within the gastrointestinal tract. 12.2 Pharmacodynamics. The stimulant laxative activity of sodium picosulfate together with the osmotic laxative activity of magnesium citrate produces purgative effect which, when ingested with additional fluids, produces watery diarrhea.. 12.3 Pharmacokinetics. Absorption After administration of the first packet of sodium picosulfate, magnesium oxide and anhydrous citric acid in 16 healthy subjects, mean maximum concentration (C max) for picosulfate of 2.3 +- 1.4 ng/mL was reached at hours. After administration of packets of sodium picosulfate, magnesium oxide and anhydrous citric acid separated by hours, picosulfate reached the mean max of 3.2 +- 2.6 ng/mL at approximately hours (T max). In the same study, baseline uncorrected magnesium reached C max of approximately 1.9 mEq/L, which occurred at 10 hours post first packet administration (T max). This represents an approximately 20% increase from the baseline. Distribution The apparent volume of distribution (V/F) for picosulfate was 4,199 liters in healthy adults. Metabolism and Elimination Sodium picosulfate, which is prodrug, is converted to its active metabolite, BHPM, by colonic bacteria. Plasma concentration of the free BHPM were low, and below the lower limit of quantification (0.1 ng/mL) in 13 out of 16 subjects studied. The fraction of the sodium picosulfate dose excreted unchanged in urine was 0.2%. In urine, the majority of excreted BHPM was in the glucuronide- conjugated form. The terminal half-life of sodium picosulfate was 7.4 hours. The apparent clearance (CL/F) of picosulfate was 629 L/h. Use in Specific Populations Pediatric Patients Pharmacokinetics of picosulfate was studied in pediatric patients aged from to 16 years old. For picosulfate, the apparent clearance is from 316 to 409 L/h. The corresponding estimates for apparent volume of distribution are from 2457 to 3935 liters. The derived half-life using these model estimates would be hours. The picosulfate reached the mean max of 3.5 +- 2.1 ng/mL at approximately to hours (T max) The baseline uncorrected mean serum magnesium concentration was 2.02 mEq/L at 10 hours after the first dose of sodium picosulfate, magnesium oxide and anhydrous citric acid and ranged from 1.7 to 2.46 mEq/L in pediatric patients from to 16 years of age. Drug Interaction Studies In an in vitro study using human liver microsomes, sodium picosulfate did not inhibit the major CYP enzymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5) evaluated. Based on an in vitro study using freshly isolated hepatocyte culture, sodium picosulfate is not an inducer of CYP1A2, CYP2B6 or CYP3A4/5.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Adults The colon cleansing efficacy of sodium picosulfate, magnesium oxide and anhydrous citric acid was evaluated for non-inferiority against comparator in two randomized, investigator-blinded, active-controlled, multicenter US trials in adult patients scheduled to have an elective colonoscopy. In all, 1,195 adult patients were included in the primary efficacy analysis: 601 from Study 1, and 594 from Study 2. Patients ranged in age from 18 to 80 years (mean age 56 years); 61% were female and 39% male. Self-identified race was distributed as follows: 90% White, 10% Black, and less than 1% other. Of these, 3% self-identified their ethnicity as Hispanic or Latino. Patients randomized to sodium picosulfate, magnesium oxide and anhydrous citric acid in the two studies were treated with one of two dosing regimens: In Study 1, sodium picosulfate, magnesium oxide and anhydrous citric acid was given by Split-Dose (evening before and day of) dosing, where the first packet was taken the evening before the colonoscopy (between 5:00 and 9:00 PM), followed by five (5) 8-ounce glasses of clear liquid, and the second packet was taken the morning of the colonoscopy (at least hours prior to but no more than hours prior to colonoscopy), followed by three (3) 8-ounce glasses of clear liquid. In Study 2, sodium picosulfate, magnesium oxide and anhydrous citric acid was given by Day-Before (afternoon/evening before only) dosing, where both packets were taken separately on the day before the colonoscopy, with the first packet taken in the afternoon (between 4:00 and 6:00 PM), followed by five (5) 8-ounce glasses of clear liquid, and the second packet taken in the late evening (approximately hours later, between 10:00 PM and 12:00 AM), followed by three (3) 8-ounce glasses of clear liquid. The comparator was preparation containing two liters of polyethylene glycol plus electrolytes solution (PEG E) and two 5-mg bisacodyl tablets, administered the day before the procedure. All patients in both the sodium picosulfate, magnesium oxide and anhydrous citric acid and comparator groups were limited to clear liquid diet on the day before the procedure (24 hours before). The primary efficacy endpoint was the proportion of patients with successful colon cleansing, as assessed by blinded colonoscopists using the Aronchick Scale. The Aronchick scale is tool used to assess overall colon cleansing. Successful colon cleansing was defined as bowel preparations with >90% of the mucosa seen and mostly liquid stool that were graded excellent (minimal suctioning needed for adequate visualization) or good (significant suctioning needed for adequate visualization) by the colonoscopist. In both studies, sodium picosulfate, magnesium oxide and anhydrous citric acid was non-inferior to the comparator. In addition, sodium picosulfate, magnesium oxide and anhydrous citric acid provided by Split-Dose dosing met the pre-specified criteria for superiority to the comparator for colon cleansing in Study 1. The comparator in that study was administered entirely on the day prior to colonoscopy. See Tables and below. Table 3: Proportion of Patients with Successful Colon Cleansing in Study Split-Dose Regimen od u picosulfate, magnesium oxide and anhydrous citric acid Spli -Dose Regimen L PEG+E i th x 5-mg bisacodyl tablets Difference between treatment groups (n/N) (n/N) Difference 95 CI 84 (256/304) 74.4 (221/297) 10% (3.4%, 16.2%) 2L PEG E two liters polyethylene glycol plus electrolytes solution. Non-inferior and superior 2L PEG+E with x mg bisacodyl tablets Table 4: Proportion of Patients with Successful Colon Cleansing in Study Day-Before Regimen od u picosulfate, magnesium oxide and anhydrous citric acid Day-Before Regimen L PEG+E i th x 5mg bisacodyl tablets Difference between treatment groups (n/N) (n/N) Difference 95 CI 83% (244/294) 80% (239/300) % (-2.9%, 9.6%) 2L PEG E two liters polyethylene glycol plus electrolytes solution. Non-inferior Pediatric Patients Years of Age and Older Sodium picosulfate, magnesium oxide and anhydrous citric acid was evaluated for colon cleansing in randomized, assessor-blind, multicenter, dose-ranging, active-controlled study in 78 pediatric patients years to 16 years of age. The majority of patients were female (68%), white (91%), and of non-Hispanic or non-Latino ethnicity (95%). The mean age was 12 years of age. All 78 patients were included in the primary efficacy analysis. Patients aged years to 12 years were randomized into arms (1:1:1): Sodium picosulfate, magnesium oxide and anhydrous citric acid one-half packet administered as two doses Sodium picosulfate, magnesium oxide and anhydrous citric acid one-packet administered as two doses comparator (oral PEG-based solution per local standard of care). Patients aged 13 years to 16 years were randomized into arms (1:1): Sodium picosulfate, magnesium oxide and anhydrous citric acid one-packet administered as two doses comparator (oral PEG-based solution per local standard of care) Patients randomized to sodium picosulfate, magnesium oxide and anhydrous citric acid had two options for dosing, as determined by the investigator. The Split Dose regimen was the preferred method and the Day Before regimen was the alternative method if the Split Dose was not appropriate. Split-Dose Regimen: (evening before and day of) dosing, where the first dose was taken the evening before the colonoscopy (between 5:00 and 9:00 PM), followed by five (5) 8-ounce glasses of clear liquid, and the second dose was taken the morning of the colonoscopy (at least hours prior to but no more than hours prior to colonoscopy), followed by three (3) 8-ounce glasses of clear liquid. Day-Before Regimen: (afternoon/evening before only) dosing, where both doses were taken separately on the day before the colonoscopy, with the first dose taken in the afternoon (between 4:00 and 6:00 PM), followed by five (5) 8-ounce glasses of clear liquid, and the second dose taken in the late evening (approximately hours later, between 10:00 PM and 12:00 AM), followed by three (3) 8-ounce glasses of clear liquid. All patients randomized to sodium picosulfate, magnesium oxide and anhydrous citric acid were limited to clear liquid diet on the day before the procedure. Those who received the comparator were given dietary instructions per the trial sites standard of care. The primary efficacy endpoint was the proportion of patients with successful colon cleansing as defined as rating of either Excellent (> 90% of mucosa seen, mostly liquid stool, minimal suctioning needed for adequate visualization) or Good (> 90% of mucosa seen, mostly liquid stool, significant suctioning needed for adequate visualization) using the Aronchick scale, as assessed by blinded colonoscopists. The sodium picosulfate, magnesium oxide and anhydrous citric acid regimen of one-half packet administered as two doses did not demonstrate comparable efficacy to the comparator, PEG, in patients to 12 years of age and is not recommended dosage regimen [see Dosage and Administration 2)]. The sodium picosulfate, magnesium oxide and anhydrous citric acid regimen of one packet administered as two doses demonstrated successful colon cleansing in both the to 12 year age group and the 13 to 16 year age group. The efficacy rates were similar to those observed in the PEG groups, as shown in Table 5. Table 5. Proportion of Patients to 16 Years of Age with Successful Colon Cleansing S od u picosulfate, magnesium oxide and anhydrous citric acid One Packet Administered as Two Doses either as Split Dose or Day Before Regimen PEG Comparator % (n/N) 95% CI (n/N) 95% CI Age 9-12 88% (14/16) (62, 98) 81% (13/16) (54, 96) Age 13-16 81% (13/16) (54, 96) 86% (12/14) (57, 98) 1Successful colon cleansing as defined by Excellent or Good on the Aronchick scale 2Of the 32 patients, received the Split Dose Regimen and 23 the Day Before Regimen 3Oral PEG-based preparation was used in the study as per standard of care.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Preparation and Administration Each packet of sodium picosulfate, magnesium oxide and anhydrous citric acid must be dissolved with water prior to ingestion and administered according to the dosing regimen. Direct ingestion of the undissolved powder may increase the risk of nausea, vomiting and dehydration. 2.2, 5.8) Two doses (one packet per dose) of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution are required for complete preparation for colonoscopy. The preferred method is the Split-Dose method. The alternative is the Day Before method. 2.1) Additional fluids must be consumed after every dose of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution in both dosing regimens. 2.1, 5.1) Do not take oral medications within hour of start of each dose. 2.1, 7.2) If taking tetracycline or fluoroquinolone antibiotics, iron, digoxin, chlorpromazine, or penicillamine, take these medications at least hours before and not less than hours after administration of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution. 2.1, 7.3) For complete information on preparation before colonoscopy and administration of the dosage regimen, see full prescribing information. 2.1, 2.2, 2.3) Split-Dose Dosage Regimen (Preferred Method) 2.2) First dose: administer during evening before the colonoscopy Second dose: administer the next day, during the morning prior to the colonoscopy. Day-Before Dosage Regimen (Alternative Method), if Split-Dosing is inappropriate 2.3) First dose: administer during afternoon or early evening before the colonoscopy. Second dose: administer hours later during evening before colonoscopy. 2.1 Important Preparation and Administration Instructions. Correct fluid and electrolyte abnormalities before administration of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution [see Warnings and Precautions 5.1)]. Two doses (one packet per dose) of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution are required for complete preparation for colonoscopy either as Split-Dose (preferred) or Day-Before dosing regimen. The preferred method is the Split-Dose method and consists of two separate doses: the first dose during the evening before the colonoscopy and the second dose the next day, the morning of the day of the colonoscopy [see Dosage and Administration 2.2)]. The alternative method is the Day Before method and consists of two separate doses: the first dose during the afternoon or early evening before the colonoscopy and the second dose hours later during the evening before the colonoscopy [see Dosage and Administration 2.3)]. Each packet of sodium picosulfate, magnesium oxide and anhydrous citric acid must be dissolved in ounces of cold water prior to ingestion and administered according to the dosing regimen. Direct ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration and electrolyte disturbances [see Warnings and Precautions 5.8)]. Additional fluids must be consumed after every dose of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution in both dosing regimens [see Dosage and Administration 2.2), Warnings and Precautions 5.1)]. Consume only clear fluids (no solid food) from the start of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution treatment until after the colonoscopy. Do not eat solid food or dairy and do not drink anything colored red or purple. Do not drink alcohol. Do not take other laxatives while taking sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution. Do not take oral medications within one hour before or after starting sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution. If taking tetracycline or fluoroquinolone antibiotics, iron, digoxin, chlorpromazine, or penicillamine, take these medications at least hours before and not less than hours after administration of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution [see Drug Interactions 7.2)]. Stop consumption of all fluids at least hours before the colonoscopy. 2.2 Reconstitution of Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid Powder. 1. Reconstitute the sodium picosulfate, magnesium oxide and anhydrous citric acid powder immediately before each administration. Do not prepare the solution in advance. 2. Fill the supplied dosing cup with cold water up to the lower (5-ounce) line on the cup and pour in the contents of one packet of sodium picosulfate, magnesium oxide and anhydrous citric acid powder. 3. Stir for to minutes. The reconstituted sodium picosulfate, magnesium oxide and anhydrous citric acid solution may become slightly warm as the powder dissolves. 2.3 Split-Dose Dosing Regimen (Preferred Method). The Split-Dose regimen is the preferred dosing method. The recommended dosage in adults and pediatric patients years of age and older is shown below. Instruct patients to take two separate doses (one packet per dose) in conjunction with fluids. Dose - On the day before colonoscopy: Instruct patients to consume only clear liquids (no solid food or dairy) on the day before the colonoscopy up until hours before the time of the colonoscopy. Take the first dose of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution during the evening before the colonoscopy (e.g., 5:00 to 9:00 PM). Follow sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution by drinking at least five 8-ounce cups of clear liquids (40 ounces total), using the upper line on the cup, within hours and before bed. If severe bloating, distention, or abdominal pain occurs, following the first dose, delay the second dose until the symptoms resolve. Dose - Next morning on the day of colonoscopy (start approximately hours prior to colonoscopy): Continue to consume only clear liquids (no solid food or dairy). Take the second dose of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution. Following the sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution dose, drink at least three 8-ounce cups of clear liquids (24 ounces), using the upper line on the cup, at least hours before the colonoscopy. 2.4 Day-Before Dosing Regimen (Alternative Method). The Day-Before regimen is the alternative dosing method for patients for whom the Split-Dosing is inappropriate. The recommended dosage in adults and pediatric patients years of age and older is shown below. Instruct patients to take two separate doses (one packet per dose) in conjunction with fluids Dose - On the day before colonoscopy: Instruct patients to consume only clear liquids (no solid food or dairy) on the day before the colonoscopy up until hours before the time of the colonoscopy. Take the first dose of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution in the afternoon or early evening before the colonoscopy (e.g., 4:00 to 6:00 PM). Following the sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution dose, drink at least five 8-ounce cups of clear liquids (40 ounces total), using the upper line on the cup, within hours and before the next dose. If severe bloating, distention, or abdominal pain occurs, following the first dose, delay the second dose until the symptoms resolve. Dose - Approximately hours later in the evening the night before the colonoscopy (e.g., 10:00 PM to 12:00 AM): Take the second dose of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution. Following the sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution dose, drink at least three 8-ounce cups (24 ounces), using the upper line on the cup, of clear liquids within hours and before bed. Storage Reconstitute immediately before use. Do not prepare the solution in advance or store the solution for later use. Do not refrigerate or add ice to the solution.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Drugs that increase risks due to fluid and electrolyte changes. (7.1) 7.1 Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities. Use caution when prescribing sodium picosulfate, magnesium oxide and anhydrous citric acid for patients with conditions and/or who are taking other drugs that increase the risk for fluid and electrolyte disturbances or may increase the risk of renal impairment, seizures, arrhythmias, or QT prolongation in the setting of fluid and electrolyte abnormalities [see Warnings and Precautions 5.1, 5.2, 5.3, 5.4)]. 7.2 Potential for Reduced Drug Absorption. Sodium picosulfate, magnesium oxide and anhydrous citric acid can reduce the absorption of other co-administered drugs [see Dosage and Administration 2.1)]: Administer oral medications at least one hour before of the start of administration of sodium picosulfate, magnesium oxide and anhydrous citric acid. Administer tetracycline and fluoroquinolone antibiotics [see Drug Interactions 7.3)], iron, digoxin, chlorpromazine, and penicillamine at least hours before and not less than hours after administration of sodium picosulfate, magnesium oxide and anhydrous citric acid. 7.3 Antibiotics. Prior or concomitant use of antibiotics with sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution may reduce efficacy of sodium picosulfate, magnesium oxide and anhydrous citric acid as conversion of sodium picosulfate to its active metabolite BHPM is mediated by colonic bacteria.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Instruct patients: Each packet must be dissolved in ounces of cold water and administered according to the dosing regimen. Direct ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration, and electrolyte disturbances [see Warnings and Precautions 5.8)]. Two doses (one packet per dose) of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution are required for complete preparation for colonoscopy either as Split-Dose (preferred) or Day-Before dosing regimen. Not to take other laxatives while they are taking sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution. Do not eat solid food or dairy and do not drink anything colored red or purple. Do not drink alcohol. Do not take oral medications within one hour of starting sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution. If taking tetracycline or fluoroquinolone antibiotics, iron, digoxin, chlorpromazine, or penicillamine, take these medications at least hours before and not less than hours after administration of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution. To follow the directions in the Instructions for Use, for either the Split-Dose or the Day-Before regimen, as prescribed. To consume additional fluids after each dose of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution. To delay the second dose of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution, if severe bloating, distention, or abdominal pain occurs following the first dose until the symptoms resolve. To contact their healthcare provider if they develop significant vomiting or signs of dehydration after taking sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution or if they experience altered consciousness (e.g. confusion, delirium, loss of consciousness) or seizures [see Warnings and Precautions 5.1, 5.3, 5.4)]. Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854 By: Annora Pharma Pvt. Ltd. Sangareddy 502313, Telangana, India. Revised: 08/2022 sodpicomgoandanhydrouscitricacidcamberlogo1.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption After administration of the first packet of sodium picosulfate, magnesium oxide and anhydrous citric acid in 16 healthy subjects, mean maximum concentration (C max) for picosulfate of 2.3 +- 1.4 ng/mL was reached at hours. After administration of packets of sodium picosulfate, magnesium oxide and anhydrous citric acid separated by hours, picosulfate reached the mean max of 3.2 +- 2.6 ng/mL at approximately hours (T max). In the same study, baseline uncorrected magnesium reached C max of approximately 1.9 mEq/L, which occurred at 10 hours post first packet administration (T max). This represents an approximately 20% increase from the baseline. Distribution The apparent volume of distribution (V/F) for picosulfate was 4,199 liters in healthy adults. Metabolism and Elimination Sodium picosulfate, which is prodrug, is converted to its active metabolite, BHPM, by colonic bacteria. Plasma concentration of the free BHPM were low, and below the lower limit of quantification (0.1 ng/mL) in 13 out of 16 subjects studied. The fraction of the sodium picosulfate dose excreted unchanged in urine was 0.2%. In urine, the majority of excreted BHPM was in the glucuronide- conjugated form. The terminal half-life of sodium picosulfate was 7.4 hours. The apparent clearance (CL/F) of picosulfate was 629 L/h. Use in Specific Populations Pediatric Patients Pharmacokinetics of picosulfate was studied in pediatric patients aged from to 16 years old. For picosulfate, the apparent clearance is from 316 to 409 L/h. The corresponding estimates for apparent volume of distribution are from 2457 to 3935 liters. The derived half-life using these model estimates would be hours. The picosulfate reached the mean max of 3.5 +- 2.1 ng/mL at approximately to hours (T max) The baseline uncorrected mean serum magnesium concentration was 2.02 mEq/L at 10 hours after the first dose of sodium picosulfate, magnesium oxide and anhydrous citric acid and ranged from 1.7 to 2.46 mEq/L in pediatric patients from to 16 years of age. Drug Interaction Studies In an in vitro study using human liver microsomes, sodium picosulfate did not inhibit the major CYP enzymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5) evaluated. Based on an in vitro study using freshly isolated hepatocyte culture, sodium picosulfate is not an inducer of CYP1A2, CYP2B6 or CYP3A4/5.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary There are no data with sodium picosulfate, magnesium oxide and anhydrous citric acid use in pregnant women to determine drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In an animal reproduction study, no adverse developmental effects were observed in pregnant rats when sodium picosulfate, magnesium oxide, and anhydrous citric acid were administered orally at doses 1.2 times the recommended human dose based on body surface area during organogenesis. 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 U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. Data Animal Data reproduction study with sodium picosulfate, magnesium oxide and anhydrous citric acid has been performed in pregnant rats following oral administration of up to 2,000 mg/kg twice daily (about 1.2 times the recommended human dose based on body surface area) during the period of organogenesis. There was no evidence of harm to the fetus due to sodium picosulfate, magnesium oxide and anhydrous citric acid. reproduction study in rabbits was not adequate, as treatment-related mortalities were observed at all doses. pre and postnatal development study with sodium picosulfate, magnesium oxide and anhydrous citric acid in rats showed no evidence of any adverse effect on pre and postnatal development at oral doses up to 2,000 mg/kg twice daily (about 1.2 times the recommended human dose based on body surface area). Published reproduction studies with sodium picosulfate in pregnant rats and rabbits during the period of organogenesis did not show evidence of harm to the fetus at doses up to 100 mg/kg (approximately 49 and 98 times, respectively, the recommended human dose of 10 mg sodium picosulfate based on body surface area).

SPL UNCLASSIFIED SECTION.

2.1 Important Preparation and Administration Instructions. Correct fluid and electrolyte abnormalities before administration of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution [see Warnings and Precautions 5.1)]. Two doses (one packet per dose) of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution are required for complete preparation for colonoscopy either as Split-Dose (preferred) or Day-Before dosing regimen. The preferred method is the Split-Dose method and consists of two separate doses: the first dose during the evening before the colonoscopy and the second dose the next day, the morning of the day of the colonoscopy [see Dosage and Administration 2.2)]. The alternative method is the Day Before method and consists of two separate doses: the first dose during the afternoon or early evening before the colonoscopy and the second dose hours later during the evening before the colonoscopy [see Dosage and Administration 2.3)]. Each packet of sodium picosulfate, magnesium oxide and anhydrous citric acid must be dissolved in ounces of cold water prior to ingestion and administered according to the dosing regimen. Direct ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration and electrolyte disturbances [see Warnings and Precautions 5.8)]. Additional fluids must be consumed after every dose of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution in both dosing regimens [see Dosage and Administration 2.2), Warnings and Precautions 5.1)]. Consume only clear fluids (no solid food) from the start of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution treatment until after the colonoscopy. Do not eat solid food or dairy and do not drink anything colored red or purple. Do not drink alcohol. Do not take other laxatives while taking sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution. Do not take oral medications within one hour before or after starting sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution. If taking tetracycline or fluoroquinolone antibiotics, iron, digoxin, chlorpromazine, or penicillamine, take these medications at least hours before and not less than hours after administration of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution [see Drug Interactions 7.2)]. Stop consumption of all fluids at least hours before the colonoscopy.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk Summary There are no data with sodium picosulfate, magnesium oxide and anhydrous citric acid use in pregnant women to determine drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In an animal reproduction study, no adverse developmental effects were observed in pregnant rats when sodium picosulfate, magnesium oxide, and anhydrous citric acid were administered orally at doses 1.2 times the recommended human dose based on body surface area during organogenesis. 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 U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. Data Animal Data reproduction study with sodium picosulfate, magnesium oxide and anhydrous citric acid has been performed in pregnant rats following oral administration of up to 2,000 mg/kg twice daily (about 1.2 times the recommended human dose based on body surface area) during the period of organogenesis. There was no evidence of harm to the fetus due to sodium picosulfate, magnesium oxide and anhydrous citric acid. reproduction study in rabbits was not adequate, as treatment-related mortalities were observed at all doses. pre and postnatal development study with sodium picosulfate, magnesium oxide and anhydrous citric acid in rats showed no evidence of any adverse effect on pre and postnatal development at oral doses up to 2,000 mg/kg twice daily (about 1.2 times the recommended human dose based on body surface area). Published reproduction studies with sodium picosulfate in pregnant rats and rabbits during the period of organogenesis did not show evidence of harm to the fetus at doses up to 100 mg/kg (approximately 49 and 98 times, respectively, the recommended human dose of 10 mg sodium picosulfate based on body surface area). 8.2 Lactation. Risk Summary There are no data on the presence of magnesium oxide or anhydrous citric acid in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Published data on lactating women indicate that the active metabolite of sodium picosulfate, bis-( p-hydroxyphenyl)-pyridyl-2-methane (BHPM) remained below the limit of detection (1 ng/mL) in breast milk after both single and multiple doses of 10 mg/day. There are no data on the effects of sodium picosulfate on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for sodium picosulfate, magnesium oxide and anhydrous citric acid and any potential adverse effects on the breastfed infant from sodium picosulfate, magnesium oxide and anhydrous citric acid or the underlying maternal condition. 8.4 Pediatric Use. The safety and effectiveness of sodium picosulfate, magnesium oxide and anhydrous citric acid have been established for cleansing of the colon as preparation for colonoscopy in pediatric patients years of age and older. Use of sodium picosulfate, magnesium oxide and anhydrous citric acid in this age group is supported by evidence from adequate and well-controlled trials of sodium picosulfate, magnesium oxide and anhydrous citric acid in adults and single, dose-ranging, controlled trial in 78 pediatric patients to 16 years of age [see Clinical Studies 14)]. The safety profile of sodium picosulfate, magnesium oxide and anhydrous citric acid in this pediatric population was similar to that seen in adults [see Adverse Reactions 6.1)]. Monitor for possible hypoglycemia in pediatric patients, as sodium picosulfate, magnesium oxide and anhydrous citric acid has no caloric substrate. The safety and effectiveness of sodium picosulfate, magnesium oxide and anhydrous citric acid for oral solution in pediatric patients less than years of age have not been established. 8.5 Geriatric Use. Of the 1,201 patients in clinical trials who received sodium picosulfate, magnesium oxide and anhydrous citric acid, 215 (18%) patients were 65 years of age or older. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients. However, elderly patients are more likely to have decreased hepatic, renal or cardiac function and may be more susceptible to adverse reactions resulting from fluid and electrolyte abnormalities [see Warnings and Precautions 5.1)]. 8.6 Renal Impairment. Sodium picosulfate, magnesium oxide and anhydrous citric acid is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min), as accumulation of magnesium in plasma may occur [see Contraindications 4)]. Patients with mild to moderate renal impairment or patients taking concomitant medications that may affect renal function may be at increased risk for renal injury [see Warnings and Precautions 5.4)]. Advise these patients of the importance of adequate hydration before, during and after the use of sodium picosulfate, magnesium oxide and anhydrous citric acid [see Dosage and Administration 2.1)]. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Risk of fluid and electrolyte abnormalities: Encourage adequate hydration, assess concurrent medications, and consider laboratory assessments prior to and after use. 5.1, 5.2, 7.1) Cardiac arrhythmias: Consider pre-dose and post-colonoscopy ECGs in patients at increased risk. 5.2) Seizures: Use caution in patients with history of seizures and patients at increased risk of seizure, including medications that lower the seizure threshold. 5.3, 7.1) Patients with mild to moderate renal impairment or taking concomitant medications that affect renal function: Use caution, ensure adequate hydration and consider testing. 4, 5.4, 7.1) Mucosal ulcerations: Consider potential for mucosal ulcerations when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease. 5.5) Suspected GI obstruction or perforation: Rule out diagnosis before administration. 4, 5.6) Patients at risk for aspiration: Observe during administration. 5.7) Risk of vomiting and other GI complications with ingestion of undissolved powder: Dissolve each packet in ounces of cold water and administered at separate times according to the dosing regimen. 2.3, 2.4, 5.8) 5.1 Serious Fluid and Electrolyte Abnormalities. Advise patients to hydrate adequately before, during, and after the use of sodium picosulfate, magnesium oxide and anhydrous citric acid. Use caution in patients with congestive heart failure when replacing fluids. If patient develops significant vomiting or signs of dehydration including signs of orthostatic hypotension after taking sodium picosulfate, magnesium oxide and anhydrous citric acid, consider performing post-colonoscopy lab tests (electrolytes, creatinine, and BUN) and treat accordingly. Approximately 20% of adult patients in both arms (sodium picosulfate, magnesium oxide and anhydrous citric acid, 2L of PEG E plus two 5 mg bisacodyl tablets) of clinical trials of sodium picosulfate, magnesium oxide and anhydrous citric acid had orthostatic changes (changes in blood pressure and/or heart rate) on the day of colonoscopy. In adult clinical trials orthostatic changes were documented up to seven days post colonoscopy. In single study of patients to 16 years of age, approximately 20% of patients in sodium picosulfate, magnesium oxide and anhydrous citric acid arms had orthostatic changes (changes in blood pressure and/or heart rate) compared with approximately 7% of those who received the comparator (PEG) [see Clinical Studies 14)]. These changes occurred up to five days post colonoscopy. Fluid and electrolyte disturbances can lead to serious adverse reactions including cardiac arrhythmias or seizures and renal impairment. Correct fluid and electrolyte abnormalities before treatment with sodium picosulfate, magnesium oxide and anhydrous citric acid [see Dosage and Administration 2.1)] In addition, use caution when prescribing sodium picosulfate, magnesium oxide and anhydrous citric acid for patients who have conditions or who are using medications that increase the risk for fluid and electrolyte disturbances or that may increase the risk of adverse events of seizure, arrhythmia, and renal impairment [see Drug Interactions 7.1)]. 5.2 Cardiac Arrhythmias. There have been rare reports of serious arrhythmias associated with the use of ionic osmotic laxative products for bowel preparation. Use caution when prescribing sodium picosulfate, magnesium oxide and anhydrous citric acid for patients at increased risk of arrhythmias (e.g., patients with history of prolonged QT, uncontrolled arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy). Consider pre-dose and post-colonoscopy ECGs in patients at increased risk of serious cardiac arrhythmias.. 5.3 Seizures. There have been reports of generalized tonic-clonic seizures with the use of bowel preparation products in patients with no prior history of seizures. The seizure cases were associated with electrolyte abnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality. The neurologic abnormalities resolved with correction of fluid and electrolyte abnormalities. Use caution when prescribing sodium picosulfate, magnesium oxide and anhydrous citric acid for patients with history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, or patients with known or suspected hyponatremia [see Adverse Reactions 6.2)]. 5.4 Use in Patients with Renal Impairment. Sodium picosulfate, magnesium oxide and anhydrous citric acid is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min), accumulation of magnesium in plasma may occur [see Contraindications 4)]. As with other magnesium containing bowel preparations, use caution when prescribing sodium picosulfate, magnesium oxide and anhydrous citric acid for patients with mild to moderate renal impairment or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or non-steroidal anti-inflammatory drugs) [see Drug Interactions 7.1)]. These patients may be at increased risk for renal injury. Advise these patients of the importance of adequate hydration before, during and after the use of sodium picosulfate, magnesium oxide and anhydrous citric acid. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients. 5.5 Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis. Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of additional stimulant laxatives with sodium picosulfate, magnesium oxide and anhydrous citric acid may increase this risk. The potential for mucosal ulcerations should be considered when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease [see Adverse Reactions 6.2)]. 5.6 Use in Patients with Significant Gastrointestinal Disease. If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering sodium picosulfate, magnesium oxide and anhydrous citric acid [see Contraindications 4)]. Use with caution in patients with severe active ulcerative colitis. 5.7 Aspiration. Patients with impaired gag reflex are at risk for regurgitation or aspiration during the administration of sodium picosulfate, magnesium oxide and anhydrous citric acid. Observe these patients during the administration of sodium picosulfate, magnesium oxide and anhydrous citric acid. Use with caution in these patients.. 5.8 Risk of Vomiting and Other Gastrointestinal Complications with Ingestion of Undissolved Powder. Each packet must be dissolved in ounces of cold water and administered at separate times according to the dosing regimen [see Dosage and Administration 2.3, 2.4)] Ingestion of additional water is important to patient tolerance. Direct ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration, and electrolyte disturbances.