Saxagliptin

315.414

315.41

1308068-626-2

DTXSID7048580

A10BD|A10BD21|A10BH03|A - Alimentary tract and metabolism

2933990090

90.35000

1.79618

1.35

548.7ºC at 760mmHg

548.7℃

1.640

In water, 791.8 mg/L at 25 °C (est)

Store at 20 deg - 25 °C (68 deg - 77 °F); excursions permitted to 15 deg - 30 °C (59 deg - 86 °F).

4.19X10-11 mm Hg at 25 °C (est)

Henry's Law constant = 1.11X10-18 atm-cu m/mol at 25 °C (est)

pKa = 7.90 (est)

White to yellow or light brown, non-hygroscopic, crystalline powder; sparingly soluble in water at 24 °C; slightly soluble in ethyl acetate; soluble in methanol, ethanol, isopropyl alcohol; acetonitrile, acetone, and polyethylene glycol 400 /Saxagliptin monohydrate/|Hydroxyl radical reaction rate constant = 6.46X10-11 cu cm/molec-sec at 25 °C (est)

3077

28-38-41-48

24/25-26-28-36/37/39

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including saxagliptin hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Saxagliptin hydrochloride/

IDENTIFICATION AND USE: Saxagliptin is a dipeptidyl peptidase-4(DPP-4) inihibitor used in the treatment of type-2 diabetes. It has been indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. HUMAN EXPOSURE AND TOXICITY: Treatment with saxagliptin provided significant improvements in A1C versus placebo. Cases of overdose have been reported but most were accidental. The majority of gliptin-exposed adult and pediatric/adolescent patients were safely managed at home and when evaluated in a healthcare facility, did not require hospitalization. Intentional self-harm-adult gliptin exposures were managed in a healthcare facility but rarely resulted in hospitalization or serious morbidity at doses up to 18 times the adult therapeutic dose. Saxagliptin in healthy subjects at doses up to 400 mg daily for 2 weeks, or 80 times the maximum recommended human dose (MRHD) had no dose-related clinical adverse reactions and no clinically meaningful effect on corrected QT interval (QTc) or heart rate. ANIMAL STUDIES: Saxagliptin produced adverse skin changes in the extremities of cynomolgus monkeys (scabs and/or ulceration of tail, digits, scrotum, and/or nose). Skin lesions were reversible at doses 20 times the MRHD but in some cases were irreversible and necrotizing at higher exposures. In developmental studies, higher doses of saxagliptin that elicited maternal toxicity also increased fetal resorptions (approximately 2069 and 6138 times the MRHD). Additional effects on estrous cycling, fertility, ovulation, and implantation were observed at approximately 6138 times the MRHD. Saxagliptin was not mutagenic or clastogenic with or without metabolic activation in an in vitro Ames bacterial assay, an in vitro cytogenetics assay in primary human lymphocytes, an in vivo oral micronucleus assay in rats, an in vivo oral DNA repair study in rats, and an oral in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes. The active metabolite was not mutagenic in an in vitro Ames bacterial assay.

In large clinical trials, rates of serum enzyme elevations were similar with saxagliptin therapy (

Concomitant administration of single doses of saxagliptin (10 mg) and glyburide (5 mg) increased peak plasma concentrations of glyburide and saxagliptin by 16 and 8%, respectively; the AUC of glyburide was increased by 6% and that of saxagliptin was decreased by 2%. The manufacturer states that no dosage adjustments are required because of changes in systemic exposures when saxagliptin and glyburide are given concomitantly. However, in patients receiving saxagliptin concomitantly with a sulfonylurea antidiabetic agent, a reduced dosage of the sulfonylurea may be required to reduce the risk of hypoglycemia.|Concomitant administration of a single dose of saxagliptin (100 mg) and metformin hydrochloride (1 g) decreased the peak plasma concentration of saxagliptin by 21% and the AUC by 2%; metformin AUC and peak plasma concentration were increased by 20 and 9%, respectively.|Concurrent administration of saxagliptin (5 mg once daily for 21 days) and an estrogen-progestin combination contraceptive (ethinyl estradiol 35 mcg in fixed combination with norgestimate 0.25 mg once daily for 21 days) did not appreciably alter the steady-state pharmacokinetics of ethinyl estradiol or the primary active progestin component, norelgestromin.|Administration of a single dose of saxagliptin (10 mg) concurrently with a single dose of famotidine (40 mg) increased the peak plasma concentration of saxagliptin by 14% and AUC by 3%.|For more Interactions (Complete) data for Saxagliptin (8 total), please visit the HSDB record page.

A dose-related mean decrease in absolute lymphocyte count was observed with ONGLYZA. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of Onglyza on lymphocyte counts in patients with lymphocyte abnormalities (e.g. human immunodeficiency virus) is unknown. Immunocompromised patients, such as patients who have undergone organ transplantation or patients diagnosed with human immunodeficiency syndrome, have not been studied in the Onglyza clinical program. Therefore, the efficacy and safety profile of saxagliptin in these patients has not been established.|Onglyza should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.|Onglyza tablets contain lactose monohydrate. Patients with hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this product.|Safety and efficacy of saxagliptin have not been established in patients younger than 18 years of age.|For more Populations at Special Risk (Complete) data for Saxagliptin (7 total), please visit the HSDB record page.

Saxagliptin's production and use as an antidiabetic drug(1) may result in its release to the environment through various waste streams(SRC). Antidiabetic compounds are among the most prescribed pharmaceuticals(2).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 440(SRC), determined from a structure estimation method(2), indicates that saxagliptin is expected to have moderate mobility in soil(SRC). The estimated pKa of saxagliptin is 7.90(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of saxagliptin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.1X10-18 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Saxagliptin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.2X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2014).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 440(SRC), determined from a structure estimation method(2), indicates that saxagliptin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces iis not expected(3) based upon an estimated Henry's Law constant of 1.1X10-18 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from an estimated log Kow of 0.98(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2014).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), saxagliptin, which has an estimated vapor pressure of 4.2X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase saxagliptin may be removed from the air by wet and dry deposition(SRC). Saxagliptin contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Saxagliptin is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Saxagliptin contains chromophores that absorb at wavelengths >290 nm(1) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 3 was calculated in fish for saxagliptin(SRC), using a/n estimated/ log Kow of 0.98(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of saxagliptin can be estimated to be 400(SRC). According to a classification scheme(2), this estimated Koc value suggests that saxagliptin is expected to have moderate mobility in soil. The estimated pKa of saxagliptin is 7.90(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

The Henry's Law constant for saxagliptin is estimated as 1.1X10-18 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that saxagliptin is expected to be essentially nonvolatile from water and moist soil surfaces(2). Saxagliptin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.2X10-11 mm Hg(SRC), determined from a fragment constant method(3).

While data specific to saxagliptin were not located(SRC, 2014), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are, therefore, discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Saxagliptin is distributed into milk in rats at a milk-to-plasma ratio of approximately 1:1; it is not known whether saxagliptin is distributed into human milk. Caution is advised if the drug is administered in nursing women.

Occupational exposure to saxagliptin may occur through inhalation and dermal contact with this compound at workplaces where saxagliptin is produced or used. Exposure to saxagliptin among the general population may be among those administered the drug, an antidiabetic. (SRC)

Qtrilmet is indicated in adults aged 18 years and older with type 2 diabetes mellitus:to improve glycaemic control when metformin with or without sulphonylurea (SU) and either saxagliptin or dapagliflozin does not provide adequate glycaemic control.when already being treated with metformin and saxagliptin and dapagliflozin.|Qtern, fixed dose combination of saxagliptin and dapagliflozin, is indicated in adults aged 18 years and older with type 2 diabetes mellitus:to improve glycaemic control when metformin and/or sulphonylurea (SU) and one of the monocomponents of Qtern do not provide adequate glycaemic control,when already being treated with the free combination of dapagliflozin and saxagliptin.(See sections 4.2, 4.4, 4.5 and 5.1 for available data on combinations studied.)|Add-on combination therapyOnglyza is indicated in adult patients aged 18 years and older with type-2 diabetes mellitus to improve glycaemic control:as monotherapy:in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance;as dual oral therapy:in combination with metformin, when metformin alone, with diet and exercise, does not provide adequate glycaemic control;in combination with a sulphonylurea, when the sulphonylurea alone, with diet and exercise, does not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate;in combination with a thiazolidinedione, when the thiazolidinedione alone with diet and exercise, does not provide adequate glycaemic control in patients for whom use of a thiazolidinedione is considered appropriate;as triple oral therapy:in combination with metformin plus a sulphonylurea when this regimen alone, with diet and exercise, does not provide adequate glycaemic control;as combination therapy with insulin (with or without metformin), when this regimen alone, with diet and exercise, does not provide adequate glycaemic control.|Treatment of type II diabetes mellitus

Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor which is used in combination with diet and exercise in the therapy of type 2 diabetes, either alone or in combination with other oral hypoglycemic agents. Saxagliptin is a relatively new medication and has yet to be implicated in causing clinically apparent liver injury.

Antidiabetic Agents

Onglyza is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. /Included in US product label/|Onglyza should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

/BOXED WARNING/ WARNING: LACTIC ACIDOSIS. Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, Kombiglyze XR should be discontinued and the patient hospitalized immediately. /Saxagliptin and metformin hydrochloride combination product/|FDA is evaluating unpublished new findings by a group of academic researchers that suggest an increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients with type 2 diabetes treated with a class of drugs called incretin mimetics. These findings were based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes. FDA has asked the researchers to provide the methodology used to collect and study these specimens and to provide the tissue samples so the Agency can further investigate potential pancreatic toxicity associated with the incretin mimetics. Drugs in the incretin mimetic class include exenatide (Byetta, Bydureon), liraglutide (Victoza), sitagliptin (Januvia, Janumet, Janumet XR, Juvisync), saxagliptin (Onglyza, Kombiglyze XR), alogliptin (Nesina, Kazano, Oseni), and linagliptin (Tradjenta, Jentadueto). These drugs work by mimicking the incretin hormones that the body usually produces naturally to stimulate the release of insulin in response to a meal. They are used along with diet and exercise to lower blood sugar in adults with type 2 diabetes. FDA has not reached any new conclusions about safety risks with incretin mimetic drugs. This early communication is intended only to inform the public and health care professionals that the Agency intends to obtain and evaluate this new information. ... FDA will communicate its final conclusions and recommendations when its review is complete or when the Agency has additional information to report. The Warnings and Precautions section of drug labels and patient Medication Guides for incretin mimetics contain warnings about the risk of acute pancreatitis. FDA has not previously communicated about the potential risk of pre-cancerous findings of the pancreas with incretin mimetics. FDA has not concluded these drugs may cause or contribute to the development of pancreatic cancer. At this time, patients should continue to take their medicine as directed until they talk to their health care professional, and health care professionals should continue to follow the prescribing recommendations in the drug labels. ...|Acute pancreatitis has been reported during postmarketing experience in patients receiving saxagliptin therapy. The US Food and Drug Administration (FDA) is evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous cellular changes (pancreatic duct metaplasia) in patients with type 2 diabetes mellitus receiving incretin mimetics (exenatide, liraglutide, sitagliptin, saxagliptin, alogliptin, or linagliptin). These findings are based on examination of a small number of pancreatic tissue specimens taken from patients who died from unspecified causes while receiving an incretin mimetic. FDA has not yet reached any new conclusions about safety risks with incretin mimetics. FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete or when the agency has additional information to report. FDA states that at this time clinicians should continue to follow the recommendations in the prescribing information for incretin mimetics. The manufacturer states that patients receiving saxagliptin-containing therapy should be monitored for manifestations of pancreatitis. If pancreatitis is suspected, saxagliptin should be promptly discontinued and appropriate management instituted. Saxagliptin has not been studied in patients with a history of pancreatitis and it is not known whether such patients are at increased risk for pancreatitis with saxagliptin therapy.|... There have been postmarketing reports of serious allergic and hypersensitivity reactions (e.g., anaphylaxis, angioedema, exfoliative skin conditions). The onset of such reactions usually was within the first 3 months following treatment initiation; some reactions occurred after the first dose.|For more Drug Warnings (Complete) data for Saxagliptin (19 total), please visit the HSDB record page.

Compounds that suppress the degradation of INCRETINS by blocking the action of DIPEPTIDYL-PEPTIDASE IV. This helps to correct the defective INSULIN and GLUCAGON secretion characteristic of TYPE 2 DIABETES MELLITUS by stimulating insulin secretion and suppressing glucagon release. (See all compounds classified as Dipeptidyl-Peptidase IV Inhibitors.)|Peptides which stimulate INSULIN release from the PANCREATIC BETA CELLS following oral nutrient ingestion, or postprandially. (See all compounds classified as Incretins.)

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment (N=8 per group) compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The study included patients with renal impairment classified on the basis of creatinine clearance as mild (>50 to =80 mL/min), moderate (30 to =50 mL/min), and severe (<30 mL/min), as well as patients with end-stage renal disease on hemodialysis. ... The degree of renal impairment did not affect the Cmax of saxagliptin or its active metabolite. In subjects with mild renal impairment, the AUC values of saxagliptin and its active metabolite were 20% and 70% higher, respectively, than AUC values in subjects with normal renal function. Because increases of this magnitude are not considered to be clinically relevant, dosage adjustment in patients with mild renal impairment is not recommended. In subjects with moderate or severe renal impairment, the AUC values of saxagliptin and its active metabolite were up to 2.1- and 4.5-fold higher, respectively, than AUC values in subjects with normal renal function. To achieve plasma exposures of saxagliptin and its active metabolite similar to those in patients with normal renal function, the recommended dose is 2.5 mg once daily in patients with moderate and severe renal impairment, as well as in patients with end-stage renal disease requiring hemodialysis. Saxagliptin is removed by hemodialysis.|Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of (14)-C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (approximately 120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract.|Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasma concentrations (Cmax) of saxagliptin and its major metabolite attained within 2 and 4 hours (Tmax), respectively. The Cmax and AUC values of saxagliptin and its major metabolite increased proportionally with the increment in the saxagliptin dose, and this dose-proportionality was observed in doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its major metabolite were 78 ng*hr/mL and 214 ng*hr/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The intra-subject coefficients of variation for saxagliptin Cmax and AUC were less than 12%.

The metabolism of saxagliptin is primarily mediated by CYP3A4/5. In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Saxagliptin is a P-glycoprotein (P-gp) substrate but is not a significant inhibitor or inducer of P-gp. ... The major metabolite of saxagliptin is also a DPP4 inhibitor, which is one-half as potent as saxagliptin.

Following a single oral dose of Onglyza 5 mg to healthy subjects, the mean plasma terminal half-life for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.

Type 2 diabetes (T2D) is one of the major risk factors associated with Alzheimer's disease (AD). Recent studies have found similarities in molecular mechanisms that underlie the respective degenerative developments in the two diseases. Pharmacological agents, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, which increase the level of glucagon-like peptide-1 (GLP-1) and ameliorate T2D, have become valuable candidates as disease modifying agents in the treatment of AD. In addition, endogenous GLP-1 levels decrease amyloid beta (Abeta) peptide and tau phosphorylation in AD. The present study examines the efficacy of Saxagliptin, a DPP-4 inhibitor in a streptozotocin (STZ) induced rat model of AD. Three months following induction of AD by intracerebral administration of streptozotocin, animals were orally administered Saxagliptin (0.25, 0.5 and 1 mg/kg) for 60 days. The effect of the DPP-4 inhibitor on hippocampal GLP-1 levels, Abeta burden, tau phosphorylation, inflammatory markers and memory retention were evaluated. The results reveal an attenuation of Abeta, tau phosphorylation and inflammatory markers and an improvement in hippocampal GLP-1 and memory retention following treatment. This remarkable therapeutic effect of Saxagliptin mediated through DPP-4 inhibition demonstrates a unique mechanism for Abeta and tau clearance by increasing GLP-1 levels and reverses the behavioural deficits and pathology observed in AD.|Saxagliptin inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that inactivates incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both saxagliptin and its active metabolite (5-hydroxy saxagliptin) are more selective for inhibition of DPP-4 than for DPP-8 or DPP-9. Saxagliptin increases circulating levels of GLP-1 and GIP in a glucose-dependent manner. GLP-1 and GIP stimulate insulin secretion from pancreatic beta-cells in a glucose-dependent manner (i.e., when glucose concentrations are normal or elevated). GLP-1 also decreases glucagon secretion from pancreatic alpha-cells, leading to reduced hepatic glucose production. Saxagliptin lowers fasting plasma glucose concentrations and reduces glucose excursions following a glucose load or meal in patients with type 2 diabetes mellitus.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status. Saxagliptin and its active metabolite are removed by hemodialysis (23% of dose over 4 hours).|For more Antidote and Emergency Treatment (Complete) data for Saxagliptin (7 total), please visit the HSDB record page.

/HUMAN EXPOSURE STUDIES/ The cardiovascular safety and efficacy of many current antihyperglycemic agents, including saxagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, are unclear. ... 16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events /were randomly assigned/ to receive saxagliptin or placebo and followed them for a median of 2.1 years. Physicians were permitted to adjust other medications, including antihyperglycemic agents. The primary end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. A primary end-point event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3% and 7.2%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio with saxagliptin, 1.00; 95% confidence interval (CI), 0.89 to 1.12; P=0.99 for superiority; P<0.001 for noninferiority); the results were similar in the "on-treatment" analysis (hazard ratio, 1.03; 95% CI, 0.91 to 1.17). The major secondary end point of a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1059 patients in the saxagliptin group and in 1034 patients in the placebo group (12.8% and 12.4%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio, 1.02; 95% CI, 0.94 to 1.11; P=0.66). More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; P=0.007). Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two groups (acute pancreatitis, 0.3% in the saxagliptin group and 0.2% in the placebo group; chronic pancreatitis, <0.1% and 0.1% in the two groups, respectively). DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes.|/HUMAN EXPOSURE STUDIES/ A single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment (N=8 per group) compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The study included patients with renal impairment classified on the basis of creatinine clearance as mild (>50 to =80 mL/min), moderate (30 to =50 mL/min), and severe (<30 mL/min), as well as patients with end-stage renal disease on hemodialysis. ... The degree of renal impairment did not affect the Cmax of saxagliptin or its active metabolite. In subjects with mild renal impairment, the AUC values of saxagliptin and its active metabolite were 20% and 70% higher, respectively, than AUC values in subjects with normal renal function. Because increases of this magnitude are not considered to be clinically relevant, dosage adjustment in patients with mild renal impairment is not recommended. In subjects with moderate or severe renal impairment, the AUC values of saxagliptin and its active metabolite were up to 2.1- and 4.5-fold higher, respectively, than AUC values in subjects with normal renal function. To achieve plasma exposures of saxagliptin and its active metabolite similar to those in patients with normal renal function, the recommended dose is 2.5 mg once daily in patients with moderate and severe renal impairment, as well as in patients with end-stage renal disease requiring hemodialysis. Saxagliptin is removed by hemodialysis.|/HUMAN EXPOSURE STUDIES/ In a controlled clinical trial, once-daily, orally-administered Onglyza in healthy subjects at doses up to 400 mg daily for 2 weeks (80 times the MRHD) had no dose-related clinical adverse reactions and no clinically meaningful effect on QTc interval or heart rate.|/SIGNS AND SYMPTOMS/ In a pooled analysis of data from 5 studies, hypersensitivity reactions (e.g., urticaria, facial edema) were reported in 1.5% of patients receiving saxagliptin 2.5 or 5 mg daily. In addition, there have been postmarketing reports of serious allergic and hypersensitivity reactions (e.g., anaphylaxis, angioedema, exfoliative skin conditions). The onset of such reactions usually was within the first 3 months following treatment initiation; some reactions occurred after the first dose.|For more Human Toxicity Excerpts (Complete) data for Saxagliptin (10 total), please visit the HSDB record page.

3-hydroxyadamantylglycine-4,5-methanoprolinenitrile hydrate

Table: Saxagliptin Hydrochloride Preparations [Table#8192]|Table: Saxagliptin Hydrochloride Combinations Preparations [Table#8193]

Simple, accurate and precise spectrophotometric methods have been developed for the determination of saxagliptin in bulk and dosage forms. The proposed methods are based on the charge transfer complexes of saxagliptin with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and 7,7,8,8-tetracyanoquinodimethane (TCNQ). All the variables were studied to optimize the reactions' conditions. Beer's law was obeyed in the concentration ranges of 50-300 ug/mL and 10-110 ug/mL with DDQ and TCNQ, respectively. The developed methods were validated and proved to be precise and accurate for the quality control of the saxagliptinin its pharmaceutical dosage form.

A liquid chromatography and tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determine the concentrations of saxagliptin ... and its major active metabolite, 5-hydroxy saxagliptin to support pharmacokinetic analyses in clinical studies. The dynamic range of the assay was 0.1-50 ng/mL for saxagliptin and 0.2-100 ng/mL for 5-hydroxy saxagliptin. Protein precipitation (PPT) with acetonitrile was used to extract the analytes from plasma matrix before injecting on an Atlantis dC18 column (50 mm x 2.1 mm, 5 um) for LC-MS/MS analysis. ... The recoveries for both analytes were >90%. ... Under these chromatographic conditions, the isomers of saxagliptin and 5-hydroxy saxagliptin were chromatographically separated from saxagliptin and 5-hydroxy saxagliptin. The assay has been used to support multiple clinical studies and regulatory approvals.|... A simple, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay method for the simultaneous determination of saxagliptin and its active metabolite 5-hydroxy saxagliptin in human plasma /was proposed/. ... Analytes and the internal standards were extracted from human plasma by a single step solid-phase extraction technique without drying, evaporation and reconstitution steps. The optimized mobile phase was composed of 0.1% acetic acid in 5 mM ammonium acetate and acetonitrile (30:70, v/v) and delivered at a flow rate of 0.85 mL/min. The method exhibits the linear calibration range of 0.05-100?ng/mL for both the analytes. The precision and accuracy results for both the analytes were well within the acceptance limits. The different stability experiments conducted in aqueous samples and in matrix samples are meeting the acceptance criteria. The chromatographic run time was set at 1.8 min; hence more than 400 samples can be analyzed in a single day.

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