Monobasic Sodium Phosphate and Dibasic Sodium Phosphate

Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets are indicated for cleansing of the colon as a preparation for colonoscopy in adults. Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets are an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults.

Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets are supplied as white to off-white uncoated tablet, modified oval shaped, biconvex, bisect on one side and plain on the other. Debossed "N" on the left side of the bisect and "03" on the right side of the bisect. Each Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets contains 1.102 grams of Monobasic Sodium Phosphate, USP and 0.398 grams of Dibasic Sodium Phosphate, USP for a total of 1.5 grams of sodium phosphate per tablet. Inert ingredients include polyethylene glycol 8000, NF; and magnesium stearate, NF. Tablets: 1.5 g of sodium phosphate (3)

Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets are contraindicated in the following conditions: History of acute phosphate nephropathy [see Warnings and Precautions (5.1) ] Gastrointestinal (GI) obstruction [see Warnings and Precautions (5.7) ] Gastric bypass or stapling surgery Bowel perforation Toxic colitis Toxic megacolon Hypersensitivity to sodium phosphate salts or any component of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets [see Warnings and Precautions (5.7) ]. Biopsy-proven acute phosphate nephropathy ( 4 , 5.1 ) Gastrointestinal (GI) obstruction ( 4 , 5.7 ) Gastric bypass or stapling surgery ( 4 ) Bowel perforation ( 4 ) Toxic colitis ( 4 ) Toxic megacolon ( 4 ) Hypersensitivity to sodium phosphate salts or any components of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets ( 4 , 5.7 )

Renal disease and electrolyte disorders : Use caution in severe renal impairment and those taking concurrent medications that increase risk, ensure adequate hydration, and consider laboratory assessments prior to and after use. ( 5.1 , 7.1 ) Cardiac arrhythmias : Consider pre-dose and post-colonoscopy ECGs in patients at increased risk. ( 5.2 ) Seizures : Use caution in patients with a history of seizures and patients at increased risk of seizure, including medications that lower the seizure threshold. ( 5.3 , 7.1 ) Suspected GI obstruction or perforation : Rule out diagnosis before administration. ( 4 , 5.4 ) Colonic mucosal ulceration : Consider potential for mucosal ulcerations when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease. Use with caution in patients with an acute exacerbation of chronic inflammatory bowel disease ( 5.5 ) Patients at risk for aspiration : Observe during administration. ( 5.6 ) Hypersensitivity reactions, including anaphylaxis : Inform patients to seek immediate medical care if symptoms occur. ( 5.7 )

5.1 Renal Disease, Acute Phosphate Nephropathy, and Electrolyte Disorders Renal Disease and Acute Phosphate Nephropathy There have been rare, but serious, reports of renal failure, acute phosphate nephropathy, and nephrocalcinosis in patients who received oral sodium phosphate products, including Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets, for colon cleansing prior to colonoscopy. These cases often resulted in permanent impairment of renal function and several patients required long-term dialysis. The time to onset is typically within days; however, in some cases, the diagnosis of these events has been delayed up to several months after the ingestion of these products. Patients at increased risk of acute phosphate nephropathy may include patients with the following: hypovolemia, baseline kidney disease, increased age, and patients using medicines that affect renal perfusion or function [such as diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and possibly nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.1) ] . Electrolyte Disorders Bowel preparations, including Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tabletscan cause fluid and electrolyte disturbances, which can lead to serious adverse reactions including cardiac arrhythmias, seizures and renal impairment [see Adverse Reactions (6.2) ] . Patient Management Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets are contraindicated in patients with a history of acute phosphate nephropathy [see Contraindications (4) ]. Use Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets with caution in patients with severe renal impairment (creatinine clearance less than 30 mL/minute), with conditions, or who are taking medications, that increase the risk for fluid and electrolyte disturbances or may increase the risk of arrhythmias, seizures, or renal impairment. Consider performing baseline and post-colonoscopy labs (phosphate, calcium, potassium, sodium, creatinine, and BUN) in these patients [see Drug Interactions (7.1) ] . Correct electrolyte abnormalities such as hypernatremia, hyperphosphatemia, hypokalemia, or hypocalcemia before treatment with Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets [see Dosage and Administration (2.1) ] . Avoid additional sodium phosphate-based purgative or enema products [see Drug Interactions (7.1) ] . Advise all patients to hydrate adequately before, during, and after the use of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets [see Dosage and Administration (2.1,2.2) ] . If a patient develops significant vomiting or signs of dehydration while or after taking Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets, consider performing post-colonoscopy lab tests [electrolytes, creatinine, and blood urea nitrogen (BUN)].

5.2 Cardiac Arrhythmias There have been rare reports of serious arrhythmias associated with the use of ionic osmotic laxative products for bowel preparation. QT prolongation with sodium phosphate tablets has been associated with electrolyte imbalances, such as hypokalemia and hypocalcemia. Use caution when prescribing Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged QT, uncontrolled arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy) and those taking medications known to prolong the QT interval, since serious complications may occur. Consider pre-dose and post-colonoscopy ECGs in patients at increased risk of serious cardiac arrhythmias.

5.3 Seizures There have been rare reports of generalized tonic-clonic seizures and/or loss of consciousness associated with use of sodium phosphate osmotic laxative products, such as Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets, 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 Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets with caution in patients with a history of seizures and in patients at higher risk of seizure, such as patients taking medications that lower the seizure threshold (such as tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, or patients with known or suspected hyponatremia [see Drug Interactions (7.1) ] .

5.4 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 Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets [see Contraindications (4) ] . Use with caution in patients with severe active ulcerative colitis.

5.5 Colonic Mucosal Ulceration and Inflammatory Bowel Disease Osmotic laxatives, including Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets, may induce colonic mucosal aphthous ulcerations. In the Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets clinical program, aphthous ulcers were observed in 3% of patients who took the recommended Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets dosing regimen. Consider the potential for mucosal ulcerations resulting from bowel preparation when interpreting colonoscopic finding should in patients with known or suspected inflammatory bowel disease. Use Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets with caution in patients experiencing an acute exacerbation of chronic inflammatory bowel disease as published data suggest that sodium phosphate absorption may be enhanced in such patients.

5.6 Aspiration Patients with impaired gag reflex or other swallowing abnormalities are at risk for regurgitation or aspiration of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets. Observed these patients during administration of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets.

5.7 Hypersensitivity Reactions Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets may cause serious hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, and throat tightness [see Adverse Reactions ( 6.2 )] . Inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care should signs and symptoms occur.

The following serious or otherwise important adverse reactions for bowel preparations are described elsewhere in the labeling: Renal Disease, Acute Phosphate Nephropathy, and Electrolyte Disorders [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 Significant Gastrointestinal Disease [see Warnings and Precautions (5.4) ] Colonic Mucosal Ulceration and Inflammatory Bowel Disease [see Warnings and Precautions (5.5) ] Aspiration [see Warnings and Precautions (5.6) ] Hypersensitivity Reactions [see Warnings and Precautions (5.7) ] Most common adverse reactions (≥3%) are: bloating, nausea, abdominal pain, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals Inc. at 1-866-403-7592 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. The safety of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets was evaluated in two randomized, investigator-blinded, active controlled trials in 931 adult patients undergoing elective colonoscopy. The mean age of the study population was 60 years (range 20 to 89 years), 88% of patients were Caucasian and 55% were female [see Clinical Studies (14) ] . Table 1 shows the most common adverse reactions reported in greater than 3% of patients by treatment group in Study 1 [see Clinical Studies (14) ]. Since diarrhea was considered as a part of the efficacy of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets, diarrhea was not defined as an adverse event in this clinical trial. 1 Reported in more than 3% of patients in at least one treatment group 2 Another oral formulation of monobasic sodium phosphate and dibasic sodium phosphate Table 1: Common Adverse Reactions 1 in Patients Undergoing Colonoscopy in Study 1 Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets 32 tabs (48 g) N=272 Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets 40 tabs (60 g) N=265 Sodium Phosphate2 40 tabs (60 g) N=268 Bloating 31% 39% 41% Nausea 26% 37% 30% Abdominal Pain 23% 24% 25% Vomiting 4% 10% 9% Electrolyte Abnormalities in Study 1 Hyperphosphatemia A total of, 96%, 96%, and 93% of patients who took 60 grams of oral sodium phosphate, 60 grams of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets, and 48 grams of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets, respectively, developed hyperphosphatemia (defined as phosphate level > 5.1 mg/dL) on the day of the colonoscopy. In this study, patients who took 60 grams of oral sodium phosphate, 60 grams of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets, and 48 grams of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets had baseline mean phosphate levels of 3.5, 3.5, and 3.6 mg/dL and subsequently developed mean phosphate levels of 7.6, 7.9, and 7.1 mg/dL, respectively, on the day of the colonoscopy. Hyperkalemia A total of 20%, 22%, and 18% of patients who took 60 grams of oral sodium phosphate, 60 grams of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets, and 48 grams of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets, respectively, developed hypokalemia (defined as a potassium level < 3.4 mEq/L) on the day of the colonoscopy. In this study, patients who took 60 grams of oral sodium phosphate, 60 grams of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets, and 48 grams of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets all had baseline potassium levels of about 4.3 mEq/L and then developed a mean potassium level of 3.7 mEq/L on the day of the colonoscopy. Several patients on all three sodium phosphate regimens developed hypocalcemia and hypernatremia that did not require treatment. The Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets 60-gram dosage regimen was associated with an increased risk of adverse reactions compared to the 48- gram dosage regimen and a similar overall response rate [see Clinical Studies (14) ] . Therefore, the Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets 60-gram dosage is not a recommended regimen [see Dosage and Administration (2.2) ].

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions : anaphylaxis, angioedema (swelling of the lips, tongue and face), rash, pruritus, urticaria, throat tightness, bronchospasm, dyspnea, pharyngeal edema, dysphagia, and paresthesia. Cardiovascular: Arrhythmias Nervous system: Seizures Renal: Renal impairment, increased blood urea nitrogen (BUN), increased creatinine, acute renal failure, acute phosphate nephropathy, nephrocalcinosis, and renal tubular necrosis.

Drugs that increase risks due to fluid and electrolyte changes. ( 7.1 ) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

7.1 Drugs That May Increase Risks due to Fluid and Electrolyte Abnormalities Use caution when prescribing Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets for patients with conditions, or who are using medications, that increase the risk for fluid and electrolyte disturbances or may increase the risk of renal impairment, seizures, arrhythmias, or prolonged QT in the setting of fluid and electrolyte abnormalities. Consider additional patient evaluations as appropriate in patients taking these concomitant medications [see Warnings and Precautions (5.1,5.2,5.3) ] .

7.2 Potential for Reduced Drug Absorption Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets can reduce the absorption of other coadministered oral medications. Administer oral medications at least 1 hour before or 1 hour after starting each Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets dose [see Dosage and Administration (2.1) ] .

7.3 Other Sodium Phosphate-Based Laxatives Administration of additional sodium phosphate-based purgative or enema products with Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets may increase the risk of acute phosphate nephropathy. Avoid concomitant use [see Warnings and Precautions (5.1) ] .

8.1 Pregnancy Risk Summary There are no available data on sodium phosphate use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Animal reproduction studies have not been conducted with sodium phosphate. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 2% to 4% and 15% to 20%, respectively.

8.2 Lactation Risk Summary There are no data available to assess the presence of sodium phosphate in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets to a child during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets and any potential adverse effects on the breastfed child from Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Of the 599 patients in clinical trials receiving at least 48 grams of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets, 134 (22%) were 65 years of age or older, while 27 (5%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients. However, the mean phosphate levels in geriatric patients were greater than the phosphate levels in younger patients after Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets administration. The mean colonoscopy-day phosphate levels in patients 18-64, 65-74, and ≥ 75 years old who received the recommended Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets dosage regimen in Study 1were 7.0, 7.3, and 8.0 mg/dL, respectively. After Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets administration, the mean phosphate levels in patients 18-64, 65-74, and ≥ 75 years old were 7.4, 7.9, and 8.0 mg/dL, respectively. Greater sensitivity of some older individuals cannot be ruled out; therefore, use Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets with caution in geriatric patients. Advise geriatric patients to adequately hydrate before, during, and after the use of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets. Sodium phosphate is known to be substantially excreted by the kidney, and the risk of adverse reactions with sodium phosphate may be greater in patients with impaired renal function. Since geriatric patients are more likely to have impaired renal function, consider performing baseline and post-colonoscopy labs (phosphate, calcium, potassium, sodium, creatinine, and BUN) in these patients [see Warnings and Precautions (5.1) ].

8.6 Renal Impairment Sodium phosphate is substantially excreted by the kidney. Use Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets with caution in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or patients taking concomitant medications that may affect renal function. These patients may be at risk for renal injury. Advise these patients of the importance of adequate hydration before, during and after the use of Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets, and consider performing baseline and post-colonoscopy labs (phosphate, calcium, potassium, sodium, creatinine, and BUN) in these patients [see Warnings and Precautions (5.1) , Drug Interactions (7.1) ] .

The primary mode of action is the osmotic effect of sodium, which induces a laxative effect. The physiological consequence is increased water retention in the lumen of the colon, resulting in loose stools.