Saxagliptin Tablets Instructions

Date of approval.
Date of revision.    
Saxagliptin Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
 Drug Name]
Generic Name: Shagelieting Tablets
Hanyu Pinyin: Shagelieting Pian
English Name: Saxagliptin Tablets
Ingredients
The active ingredient of this product is saxagliptin.
Chemical name: (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)-1-carbonyl-ethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile monohydrate
Chemical structure formula.
Molecular formula: C18H25N3O2-H2O
Molecular weight: 333.43
【Properties】.
2.5mg: This product is light yellow film-coated tablet, appearing white after removing the coating.
5mg: This product is a pink film-coated tablet, appearing white after removing the coating.
 Indications
For type 2 diabetes mellitus.
Monotherapy
It can be used as monotherapy to improve glycemic control based on diet and exercise.
Combination therapy
When glycemic control is poor with metformin hydrochloride alone, it can be used in combination with metformin hydrochloride to improve glycemic control based on diet and exercise.
Combination insulin therapy (with or without metformin).
Important limitations of use
This product is not intended for use in patients with type 1 diabetes mellitus or diabetic ketoacidosis because effectiveness in type 1 diabetes mellitus and diabetic ketoacidosis has not been established.
This product has not been studied in patients with a history of pancreatitis. Whether the use of this product in patients with a history of pancreatitis increases the risk of pancreatitis has not been determined (see [Precautions]).
【Specifications】.
(1) 2.5mg; (2) 5mg
Dosage]
The recommended dose is 5mg orally, once a day, and the dosing time is not affected by meals.
Saxagliptin tablets should not be cut or broken open.
Patients with renal insufficiency
No dose adjustment is required for patients with eGFR ≥ 45mL/min/1.73 m2. eGFR<45mL/min/1.73 m2 patients (including some patients with moderate or severe renal insufficiency) should have their dose adjusted to 2.5mg once daily (regardless of meals). Saxagliptin should be administered after hemodialysis (see [Precautions] and [Pharmacokinetics]). There have been no studies of saxagliptin in patients on peritoneal dialysis. Experience with the use of saxagliptin in patients with severe renal insufficiency is very limited, so caution should be exercised when using this product in such patients. Depending on renal function, the dose of this product may be limited to 2.5 mg. Therefore, assessment of renal function is recommended prior to treatment with this product and should be performed periodically in conjunction with regular therapy (see [Precautions] and [Pharmacokinetics]).
Patients with impaired hepatic function
No dose adjustment is required in patients with impaired hepatic function (see [Pharmacokinetics]).
Potent cytochrome P450 3A4/5 (CYP3A4/5) inhibitors
When combined with potent CYP3A4/5 inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), the dose of this product should be limited to 2.5 mg/day.
Combined use with insulin
When saxagliptin is combined with insulin, it is required to reduce the dose of insulin so that the risk of hypoglycemia is minimized.
 Adverse reactions】According to foreign literature
Clinical trials
Because the conditions of individual clinical trials vary greatly, the incidence of adverse reactions in clinical trials of one drug cannot be directly compared with the incidence of adverse reactions in clinical trials of another drug, and the incidence does not reflect the incidence of adverse reactions in the actual application of the drug.
The data in Table 1 are from a summary of five placebo-controlled clinical trials [see Clinical Trials]. These data shown in the table reflect saxagliptin exposure in 882 patients with a mean duration of saxagliptin exposure of 21 weeks. The mean age of these patients was 55 years, 1.4% were ≥75 years, and 48.4% were male. The population consisted of 67.5% white, 4.6% black or African American, 17.4% Asian, 10.5% other and 9.8% Hispanic or Latino. At baseline, the population had had diabetes for a mean of 5.2 years and a mean glycated hemoglobin (HbA1c) of 8.2%. 91% of patients had normal or mildly impaired baseline renal function (estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2).
Table 1 shows the common adverse reactions associated with saxagliptin use, excluding hypoglycemia. The incidence of these adverse reactions was higher in the saxagliptin group than in the placebo group and was seen in at least 5% of patients receiving saxagliptin therapy.
Table 1: Adverse reactions reported in placebo-controlled trials* that occurred in ≥5% of patients treated with saxagliptin 5 mg and had a higher incidence than in the placebo group
 Patients % saxagliptin 5 mgN=882 placeboN=799 upper respiratory tract infection 7.77.6 urinary tract infection 6.86.1 headache 6.55.95 placebo-controlled trials, including 2 saxagliptin monotherapy trials and 1 saxagliptin combined with metformin, 1 saxagliptin combined with a thiazolidinedione, and 1 saxagliptin combined with glibenclamide trial. Data from the 24-week trials are shown in the table, including data from patients who required remedial therapy for hyperglycemia.
In patients treated with saxagliptin 2.5 mg, headache (6.5%) was the only adverse effect with an incidence ≥5% and higher than in the placebo group.
In the trial of saxagliptin in combination with thiazolidinediones, the incidence of peripheral edema was higher in the 5 mg treatment group than in the placebo treatment group (8.1% and 4.3%, respectively) and 3.1% in the 2.5 mg treatment group. There were no cases of discontinuation of study drug treatment due to adverse effects of peripheral edema. The incidence of peripheral edema in the saxagliptin monotherapy trials was 3.6%, 2%, and 3% in the 2.5 mg, 5 mg, and placebo treatment groups, respectively; 2.1%, 2.1%, and 2.2% in the metformin combined with saxagliptin treatment trials; and 2.4%, 1.2%, and 2.2% in the glibenclamide combined with saxagliptin treatment trials, respectively.
The incidence of fractures in the saxagliptin (pooled analysis of the 2.5 mg, 5 mg, and 10 mg dose groups) and placebo-treated groups was 1.0 and 0.6 per 100 patient-years, respectively. the 10 mg dose was not an approved dose. There was no increase in the incidence of fractures in patients treated with saxagliptin with increasing duration of treatment. A causal relationship between dosing and fracture has not been defined, and the results of preclinical studies have not shown adverse effects of saxagliptin on bone.
One case of thrombocytopenia was observed in the clinical trial and was diagnosed as idiopathic thrombocytopenic purpura. The relationship of this event to saxagliptin administration has not been clarified.
Treatment was discontinued due to adverse reactions in 2.2%, 3.3%, and 1.8% of subjects receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. The most common adverse reactions associated with early discontinuation (reported in at least 2 subjects treated with saxagliptin 2.5 mg or at least 2 subjects treated with saxagliptin 5 mg) included lymphopenia (0.1%, 0.5%, and 0%, respectively), rash (0.2%, 0.3%, and 0.3%), increased blood creatinine (0.3%, 0%, and 0%), and increased blood creatine phosphokinase increased (0.1%, 0.2% and 0%).
Renal insufficiency
Subjects in a randomized trial looking at cardiovascular outcomes (SAVOR trial) were patients with a confirmed diagnosis of atherosclerotic cardiovascular disease (ASCVD) or with multiple ASCVD risk factors. Adverse reactions related to renal insufficiency, including laboratory changes (i.e., doubling of serum creatinine from baseline and serum creatinine >6 mg/dL), were reported in 5.8% (483/8280) of subjects in the saxagliptin-treated group and 5.1% (422/8212) of subjects in the placebo-treated group. The most commonly reported adverse reactions in the saxagliptin and placebo groups included renal insufficiency (2.1% and 1.9%), acute renal failure (1.4% and 1.2%) and renal failure (0.8% and 0.9%). From baseline to the end of treatment, eGFR decreased by a mean of 2.5 mL/min/1.73m2 in the saxagliptin-treated group and by a mean of 2.4 mL/min/1.73m2 in the placebo-treated group. eGFR decreased from >50 mL/min (i.e., normal or mild renal insufficiency) to ≤50 mL/min (i.e., moderate or severe renal insufficiency) in subjects in the saxagliptin group insufficiency) (421/5227, 8.1%) than subjects in the placebo group (344/5073, 6.8%). The proportion of subjects experiencing renal adverse reactions increased with worsening baseline renal function and age, independent of treatment assignment.
Combination with insulin (with or without metformin)
In clinical trials of saxagliptin in combination with insulin, except for confirmed hypoglycemic events (i.e., symptoms of hypoglycemia with capillary blood glucose values ≤50 mg/dL, see Adverse Reaction Hypoglycemia), the incidence of other adverse events (including serious adverse events and discontinuation of the study due to adverse events) was similar in the saxagliptin and placebo treatment groups.
Adverse reactions to treatment with metformin combined with saxagliptin in patients with type 2 diabetes on initial treatment with the drug
The incidence of adverse reactions with an incidence of ≥5% (not considering investigator-assessed causality) in a 24-week, positive-controlled trial of saxagliptin in combination with metformin in patients on initial drug therapy is shown in Table 2.
Table 2: Adverse reactions with an incidence ≥ 5% in the (saxagliptin 5 mg + metformin) treatment group after combined treatment with saxagliptin and metformin in patients treated with drug priming and higher than in the metformin monotherapy group (without regard to investigator-assessed causality) Number of patients (%) saxagliptin 5 mg + metformin *N=320 metformin *N=328 headache 24(7.5) 17(5.2) Nasopharyngitis22(6.9)13(4.0)* The initial dose of metformin was 500 mg/day, gradually increasing to a maximum dose of 2000 mg/day.
Hypoglycemia
Adverse reactions to hypoglycemia are based on all reports of hypoglycemia. Concomitant glucose testing is not required for further confirmation. In the saxagliptin combined with glibenclamide trial, the overall incidence of hypoglycemia was higher in the saxagliptin 2.5 mg and 5 mg groups than in the control group (13.3%, 14.6%, and 10.1%, respectively), and the incidence of confirmed hypoglycemia (i.e., with symptoms of hypoglycemia and with capillary blood glucose values ≤50 mg/dL), was 2.4%, 0.8%, and 0.7%, respectively. In the saxagliptin monotherapy trial, the reported incidence of hypoglycemia in the saxagliptin 2.5 mg, 5 mg, and control groups was 4.0%, 5.6%, and 4.1%, respectively; in the saxagliptin combined with metformin trial, the incidence of hypoglycemia in the saxagliptin 2.5 mg group, 5 mg group, and control group was 7.8%, 5.8%, and 5%, respectively; in the saxagliptin combined with thiazolidinediones In the trial of saxagliptin combined with thiazolidinediones, the incidence of hypoglycemia was 4.1%, 2.7%, and 3.8% in the saxagliptin 2.5 mg, 5 mg, and control groups, respectively. The incidence of hypoglycemia reported after treatment with saxagliptin 5 mg in combination with metformin was 3.4% in patients on initial treatment with the drug and 4.0% in patients in the metformin monotherapy group.
An active controlled study of saxagliptin versus glipizide in patients with poor glycemic control on metformin monotherapy showed that the incidence of reported hypoglycemia was 3% (13 patients reporting 19 events) and 36.3% (156 patients reporting 750 events) for saxagliptin 5 mg in combination with metformin and glipizide in combination with metformin, respectively. In the saxagliptin and glipizide treatment groups, the incidence of confirmed hypoglycemia was 0% (0 events) and 8.1% (35 events), respectively (p < 0.0001).
In a 12-week treatment period in patients with moderate or severe renal insufficiency or end-stage renal disease (ESRD), the overall incidence of reported hypoglycemia in the saxagliptin 2.5 mg and placebo treatment groups was 20% and 22%, respectively. The incidence of at least one confirmed hypoglycemia in the saxagliptin and placebo treatment groups was 4.7% (4 cases) and 3.5% (3 cases), respectively.
In the saxagliptin-insulin combination therapy trial, the overall incidence of reported hypoglycemia was 18.4% and 19.9% in the saxagliptin 5 mg and placebo treatment groups, respectively. However, the incidence of confirmed hypoglycemia was higher in the saxagliptin 5 mg treatment group (5.3%) than in the placebo treatment group (3.3%) (see [Caution]).
In the trial of saxagliptin combined with metformin in combination with sulfonylurea therapy, the overall incidence of reported hypoglycemia was 10.1% and 6.3% in the saxagliptin 5 mg and placebo treatment groups, respectively. The incidence of confirmed hypoglycemia was 1.6% in the saxagliptin group and no confirmed hypoglycemia in the placebo group (see [Precautions]).
Allergic reactions
In a pooled analysis of five 24-week trials, the incidence of allergy-related events (e.g., urticaria and facial edema) reported in the saxagliptin 2.5 mg, 5 mg, and control groups was 1.5%, 1.5%, and 0.4%, respectively. None of the saxagliptin-treated patients who experienced these events required hospitalization or were considered by the investigators to be life-threatening to the patient. One saxagliptin-treated patient in this pooled analysis discontinued treatment due to generalized urticaria and facial edema.
Infections
In the most recent database of saxagliptin-blinded, controlled clinical trials, 6 cases (0.12%) of tuberculosis were reported in 4,959 saxagliptin-treated patients (1.1/1000 patient-years) and 0 cases were reported in 2,868 patients treated with the control formulation. 2 of the 6 cases of tuberculosis were confirmed by laboratory tests, and the remaining cases had limited information or a presumptive diagnosis of tuberculosis. None of the 6 cases of TB occurred in the United States or Western Europe, and 1 case occurred in Canada in a patient who was originally from Indonesia and had recently visited Indonesia. The duration of saxagliptin treatment before reporting TB ranged from 144 to 929 days. 4 patients had lymphocyte counts within the control range after treatment, and 1 patient had lymphocytopenia before saxagliptin treatment and maintained it stable during saxagliptin treatment. The last 1 patient had a lower than normal lymphocyte count for 4 months prior to reporting tuberculosis. There have been no spontaneous reports of pulmonary TB associated with saxagliptin use. A causal relationship between saxagliptin and tuberculosis has not been assessed, and there are too few cases of tuberculosis to date to determine whether tuberculosis is associated with saxagliptin use.
In the database of blinded, controlled clinical trials, there has been one case of potential opportunistic infection in a saxagliptin-treated patient to date who developed suspected fatal Salmonella septicaemia of foodborne origin approximately 600 days after saxagliptin treatment. There have been no spontaneous reports of opportunistic infections associated with saxagliptin use.
Vital signs
No clinically significant changes in vital signs have been observed in saxagliptin-treated patients.
Laboratory Tests
Absolute lymphocyte count
A dose-related decrease in absolute lymphocyte count was observed in saxagliptin-treated patients. Pooled analysis of observational data from five placebo-controlled, 24-week clinical studies showed that the mean absolute lymphocyte count was approximately 2,200 cells/µL at baseline and that the mean absolute lymphocyte count decreased by approximately 100 and 120 cells/µL after saxagliptin 5 mg and 10 mg treatment, respectively, compared to placebo. The same results could also be observed in the saxagliptin 5mg with metformin initiation combination therapy trial, where the combination treatment resulted in lower absolute lymphocyte counts compared to metformin monotherapy. There was no change in absolute lymphocyte counts with saxagliptin 2.5 mg treatment compared to placebo. The percentage of patients reporting lymphocyte counts ≤750 cells/microliter after saxagliptin 2.5 mg, 5 mg, 10 mg and placebo treatment was 0.5%, 1.5%, 1.4% and 0.4%, respectively. Although some patients had a recurrence of lymphocyte count decline after readministration and eventually led to discontinuation of saxagliptin therapy, the majority of patients did not have a recurrence of lymphocyte count decline after readministration of saxagliptin. The 10 mg dose is not an approved dose.
In the SAVOR trial, a mean decrease of about 84 cells/µL was observed after saxagliptin treatment compared to placebo. The proportion of patients whose lymphocyte counts decreased to ≤750 cells/microliter was 1.6% (136/8280) and 1.0% (78/8212) in the saxagliptin and placebo groups, respectively.
The clinical significance of the reduction in lymphocyte counts after saxagliptin treatment compared with placebo is not known. Lymphocyte counts must be measured when the clinical phenomenon of rare or persistent infection is present. The effect of saxagliptin on lymphocyte counts in patients carrying abnormal lymphocytes (e.g., human immunodeficiency virus) is not known.
Postmarketing Experience.
There have been some reports of adverse reactions during post-marketing use of saxagliptin. Because these adverse reactions were spontaneously reported from populations with uncertain sample sizes, it is not possible to reliably estimate the incidence of these adverse reactions or to determine whether there is a causal relationship between them and drug exposure.
Hypersensitivity reactions (including tachyphylaxis, angioedema, exfoliative skin lesions) (see [Contraindications] and [Precautions]).
Acute pancreatitis (see [Precautions]).
Severe and disabling arthralgia (Disabling Arthralgia) (see [Precautions]).
Herpetiform aspergillosis (see [Precautions]).
 [Contraindication].
Contraindicated in patients with a history of severe hypersensitivity reactions to this product (e.g., rapid onset allergic reactions, angioedema, or exfoliative skin lesions) (see [Precautions] and [Adverse Reactions]).
 [Precautions].
General
Saxagliptin should not be used in patients with type 1 diabetes or diabetic ketoacidosis.
Renal insufficiency
Patients with eGFR <45mL/min/1.73 m2 (including some patients with moderate or severe renal insufficiency) should have their dose adjusted to 2.5mg once daily (without consideration of additional meals). This product should be used with caution in patients with severe renal insufficiency. Assessment of renal function is recommended prior to initiation of this product and should be performed periodically while maintaining conventional therapy (see [Dosage] and [Pharmacokinetics]).
Hypersensitivity reactions.
Serious hypersensitivity reactions have been reported during post-marketing use of saxagliptin, including rapid onset allergic reactions, angioedema, and exfoliative skin lesions. These reactions occur within the first 3 months of treatment, with some reports occurring after the first dose is administered. If a severe hypersensitivity reaction is suspected, discontinue the product, evaluate for other possible causes, and switch to another diabetes treatment regimen (see [Adverse Reactions]).
Caution should be exercised when using this product in patients who develop angioedema with other dipeptidyl peptidase-4 (DPP4) inhibitors. It has not been determined whether such patients are susceptible to angioedema.
Severe and dysfunctional arthralgia
Severe and disabling arthralgia has been reported in post-marketing observations of DPP4 inhibitors. The time from initiation of treatment with the drug to symptom onset ranged from 1 day to several years, with symptom relief after discontinuation of the drug. DPP4 inhibitors are thought to be a possible cause of severe arthralgia and should be discontinued when appropriate.
Skin disease
Ulcerative and necrotizing skin lesions on the extremities of monkeys have been reported in nonclinical toxicology tests (see [Pharmacologic Toxicology]). Although an increased incidence of skin lesions has not been found in clinical practice, there is limited clinical experience with saxagliptin in patients with concomitant skin lesions in diabetes. Post-marketing reports have shown rash in patients using the DPP4 inhibitor class, and therefore rash is listed as an adverse effect of saxagliptin (see [Adverse Reactions]). In the daily management of diabetic patients, it is recommended to observe the skin for blisters, rashes and ulcers.
Herpetiform aspergillosis
There have been post-marketing reports of cases of hospitalization due to herpetiform aspergillosis on DPP-4 inhibitors. In the reported cases, patients usually recovered after local or systemic immunosuppressive therapy and discontinuation of DPP-4 inhibitors. Therefore, when taking saxagliptin, patients should be advised to report any blisters or lesions (erosions) that progress. If herpetiform aspergillosis is suspected, saxagliptin should be discontinued and a dermatologist should be consulted to clarify the diagnosis and obtain appropriate treatment.
Heart Failure
Subjects in the Cardiovascular Outcomes Trial (SAVOR trial) were patients with established ASCVD or with multiple ASCVD risk factors, and the proportion of patients hospitalized for heart failure was higher in the saxagliptin-treated group (289/8280, 3.5%) than in the placebo group (228/8212, 2.8%). Analysis of the time to first event showed that the risk of hospitalization for heart failure was higher in the saxagliptin-treated group (estimated hazard ratio: 1.27; 95% confidence interval (CI): 1.07, 1.51). Subjects with a history of prior heart failure and renal insufficiency had a higher risk of hospitalization for heart failure, independent of treatment assignment.
In patients with a high risk of heart failure, risks and benefits should be assessed before initiating saxagliptin therapy. Signs and symptoms of heart failure need to be observed during treatment. Patients should be informed of the typical symptoms of heart failure and report them to the physician immediately upon onset of the appropriate symptoms. If heart failure occurs, management should be evaluated according to current treatment criteria and discontinuation of saxagliptin should be considered.
Immunocompromised patients
Saxagliptin clinical trials have not been conducted in immunocompromised patients who have undergone organ transplantation or who have a clear diagnosis of immunodeficiency syndrome. Therefore, the efficacy and safety of saxagliptin in such patients has not been obtained.
Lactose
This product contains lactose monohydrate. It should not be administered to patients with rare genetic disorders of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Combination with drugs known to cause hypoglycemia
Insulinotropic agents (e.g., sulfonylureas) and insulin can cause hypoglycemia. Therefore, when combined with saxagliptin, the dose of insulinotropic agents or insulin needs to be reduced to reduce the risk of hypoglycemia.
Studies of macrovascular risk endpoint events
There are no conclusive clinical studies demonstrating that saxagliptin or any other diabetes treatment drug reduces the risk of macrovascular complications.
Pancreatitis
Acute pancreatitis has been reported in post-marketing observations of saxagliptin. 17/8240 (0.2%) and 9/8173 (0.1%) patients in the saxagliptin and placebo arms of the SAVOR trial, respectively, developed acute pancreatitis. Of these, 88% (15/17) of patients in the saxagliptin-treated group and 100% (9/9) of patients in the placebo group had pre-existing risk factors for pancreatitis at baseline.
After initiating treatment with saxagliptin, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, saxagliptin should be discontinued immediately and appropriate therapeutic measures should be given. It is not known whether patients with a history of pancreatitis have an increased risk of developing pancreatitis when treated with saxagliptin.
Do not use if the inner package is opened or broken.
Use in Pregnant and Lactating Women
Adequate and well-controlled studies have not been conducted in pregnant women and are not recommended for use in pregnant women.
As with other diabetes medications, saxagliptin should be used in pregnant women only when indicated and under medical supervision.
It is not known whether saxagliptin is secreted through human breast milk. Since many drugs are secreted through human breast milk, it is not recommended for use in nursing women.
 [Pediatric Use].
Safety and efficacy studies of saxagliptin have not been conducted in pediatric patients, and in addition, pharmacokinetic studies of saxagliptin have not been conducted in pediatric patients. It is not recommended for pediatric patients.
 Geriatric Use】According to foreign literature
In 7 double-blind, controlled design clinical trials on the safety and efficacy of saxagliptin, 4751 (42.0%) of 11,301 randomized patients were ≥65 years of age and 1210 (10.7%) patients were ≥75 years of age. Overall, there were no differences in safety or efficacy between patients ³ 65 years of age and younger patients. This clinical experience has not established differences in drug response between older and younger patients, so the possibility that some older patients are more sensitive to drug response cannot be ruled out.
Saxagliptin and its active metabolites are partially eliminated through the kidneys. Because elderly patients are more likely to have reduced renal function, the dose of saxagliptin should be carefully selected based on renal function when administering the drug to elderly patients.
 Dosing in Patients with Renal Insufficiency
In a 12-week randomized placebo-controlled trial, 85 subjects with moderate (n=48) or severe (n=18) renal insufficiency or ESRD (n=19) received saxagliptin 2.5 mg [see “Clinical Trials”]. The incidence of adverse reactions (including serious adverse events and discontinuations due to adverse events) was similar between the saxagliptin and placebo groups. The overall incidence of reported hypoglycemia was 20% in subjects treated with saxagliptin 2.5 mg and 22% in subjects treated with placebo. 4 subjects treated with saxagliptin (4.7%) and 3 subjects treated with placebo (3.5%) reported at least one confirmed symptomatic hypoglycemia (with capillary blood glucose ≤50 mg/dL from fingertip). .
 Drug interactions]
CYP3A4/5 enzyme inducers
Rifampicin significantly reduced saxagliptin exposure but had no effect on the area under the time-concentration curve (AUC) of its active metabolite, 5-hydroxy-saxagliptin. The inhibition of plasma DPP4 activity was not affected by rifampicin when administered at 24-hour intervals. Therefore, adjustment of saxagliptin dose in combination with rifampicin is not recommended.
CYP3A4/5 enzyme inhibitors
Moderate inhibitors of CYP3A4/5: diltiazem may increase saxagliptin exposure. Application of other moderate CYP3A4/5 inhibitors (e.g., amprenavir, aripitant, erythromycin, fluconazole, furosemide, grapefruit juice, and verapamil) also increased plasma drug concentrations of saxagliptin as expected. Nevertheless, no dose adjustment of saxagliptin is recommended when combined with moderate CYP3A4/5 inhibitors.
CYP3A4/5 strong inhibitors: ketoconazole significantly increased saxagliptin exposure. Application of other CYP3A4/5 strong inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) also increased saxagliptin plasma drug concentrations as expected. When combined with strong inhibitors of CYP3A4/5, saxagliptin dose should be limited to 2.5 mg.
 [Drug overdose].
In a controlled clinical trial, no dose-related clinical adverse reactions and no clinically meaningful changes in QTc interval or heart rate occurred after 2 weeks of oral administration of 400 mg of saxagliptin (80 times the dose of MRHD) once daily in healthy volunteers.
In case of overdose, appropriate supportive therapy should be given according to the clinical status of the patient. Saxagliptin and its active metabolites can be cleared by hemodialysis (23% of the dose is cleared in 4 hours).
 Pharmacology and Toxicology】According to foreign literature
Pharmacological effects
Saxagliptin, a competitive inhibitor of dipeptidyl peptidase 4 (DPP4), decreases the rate of inactivation of enteroglucagon and increases its blood concentration, thereby reducing fasting and postprandial blood glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes. After meals, the concentration of enteric proinsulin hormones released from the small intestine into the blood, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), is increased, promoting the release of insulin from pancreatic beta cells in a glucose-dependent manner, which is inactivated by DPP4. GLP-1 also inhibits glucagon secretion from pancreatic alpha cells, thereby suppressing hepatic glucose production. type 2 GLP-1 concentrations are decreased in patients with diabetes, but the enteric pro-insulin effect of GLP-1 remains.
Pharmacodynamics
The inhibition of DPP4 activity is maintained for 24 hours after saxagliptin administration in type 2 diabetic patients. This inhibitory effect of DPP4 increases circulating levels of active GLP-1 and GIP 2- to 3-fold after an oral sugar load or meal, while decreasing glucagon concentrations and stimulating glucose-dependent release of insulin from pancreatic β-cells. The increase in insulin release and decrease in glucagon leads to a decrease in fasting glucose concentrations and a decrease in glucose drift during or postprandial glucose loading.
Cardiac electrophysiology
In a randomized, double-blind, placebo-controlled, four-way crossover, moxifloxacin-positive control trial involving 40 healthy volunteers, no clinically meaningful QTc interval prolongation or heart rate changes occurred at daily doses of saxagliptin up to 40 mg (8 times the MRHD).
Toxicological studies
Repeated dosing toxicity.
In rats given saxagliptin 2, 20, and 100 mg/kg orally for 6 months, increased spleen weight with lymphoid hyperplasia and pulmonary histiocytosis were seen at doses ≥20 mg/kg; mononuclear cell infiltration of the ocular gland was seen in females.
In dogs given saxagliptin orally at 1, 5 and 10 mg/kg for 12 months, gastrointestinal toxicity was seen at 5 and 10 mg/kg doses, mild mixed hepatic infiltration/inflammation around the central vein (neutrophils, eosinophils, lymphocytes and macrophages), and very mild to mild erosion of the epidermis of the animal’s foot pad. The AUC of saxagliptin and its metabolite (BMS-510849) at a dose of 1 mg/kg was 4-fold and 2-fold higher, respectively, than at MRHD.
In macaques given saxagliptin 0.03, 0.3 and 3 mg/kg orally for 3 months, multifocal lesions/scars on the foot and/or tail, mild multi-tissue mononuclear cell infiltration and mild hyperplasia of the spleen, thymus and/or bone marrow lymphoid tissue were seen at 3 mg/kg dose. Saxagliptin and its metabolite AUC are 1 to 3 times higher than MRHD at a dose of 0.3 mg/kg.
Genotoxicity
The results of Ames test, in vitro human lymphocyte genetics test, in vitro/in vitro chromosomal aberration test of rat peripheral blood lymphocytes, rat micronucleus test and in vivo DNA repair test of saxagliptin were all negative. The Ames test results for the major metabolite BMS-510849 were negative.
Reproductive toxicity
Saxagliptin was administered orally to male rats continuously from 2 weeks before mating and during the mating period until planned execution for approximately 4 weeks, and to female rats continuously from before mating to day 7 of gestation for 2 weeks. No effects on fertility were seen at exposures (in terms of AUC) approximately 603 times (males) and 776 times (females) the maximum recommended human dose of 5 mg (MRHD). At higher doses that caused maternal toxicity (approximately 2069 and 6138 times the MRHD), fetal bone resorption was increased. At doses of 6138 times the MRHD, rats showed prolonged motile cycles, reduced fertility, and decreased luteal and luteal counts.
Incomplete pelvic closure and developmental delay were seen in rats given saxagliptin at 240 mg/kg, a dose approximately 1503 times the MRHD saxagliptin exposure (as AUC) and 66 times the active metabolite exposure. Maternal toxicity and reduced fetal litter weight were seen at doses 7986 times the saxagliptin exposure and 328 times the active metabolite exposure under MRHD. Skeletal variability was seen in rabbits given at doses of 200 mg/kg that showed maternal toxicity, approximately 1432 and 992 times the MRHD exposure. No malformations were seen in rats given a combination of metformin and saxagliptin (21 times the MRHD of saxagliptin). Craniospinal bifida (a rare neural tube defect manifesting as incomplete skull and spinal closure) was seen in two fetuses from the same mother after combined administration of metformin and higher doses of saxagliptin (109 times the MRHD of saxagliptin). The exposure to metformin in the above test was equivalent to four times the exposure in humans at 2000 mg/day.
In female rats given saxagliptin from day 6 of gestation to day 20 of lactation, reduced body weight was seen in female and male offspring at maternal toxic doses (equivalent to ≥1629 times the exposure to saxagliptin at MRHD and 53 times the exposure to the active metabolite), and no functional or behavioral toxicity was seen in the offspring.
Carcinogenicity.
No increase in tumor incidence was seen with saxagliptin 50, 250 and 600 mg/kg/day given orally in a 2-year carcinogenicity test in mice and 25, 75, 150 and 300 mg/kg/day in a 2-year carcinogenicity test in rats. The highest dose in mice was approximately 900 times (male animals) and 1210 times (female animals) the human MRHD exposure (in terms of AUC), and the exposure in rats was approximately 370 times (male animals) and 2300 times (female animals) the human MRHD exposure.
 Pharmacokinetics】According to foreign literature
The pharmacokinetic properties of saxagliptin and its active metabolite 5-hydroxy-saxagliptin were similar in healthy volunteers and type 2 diabetic patients. The peak plasma concentrations (Cmax) and AUC values of saxagliptin and its active metabolite increased proportionally between 2.5 and 400 mg doses. The mean plasma AUC values of saxagliptin and its active metabolite were 78 ng×h/mL and 214 ng×h/mL, corresponding to a Cmax of 24 ng/mL and 47 ng/mL, respectively, after a single oral dose of 5 mg saxagliptin in healthy volunteers. the mean variability (%CV) of AUC and Cmax of saxagliptin and its active metabolite were less than 25%.
No significant accumulation of either saxagliptin or its active metabolite was observed after repeated administration of either test dose once daily. No time- or dose-dependent changes in the clearance of saxagliptin and its active metabolite were observed after 14 days of continuous administration of 2.5 to 400 mg of saxagliptin once daily.
Absorption
After 5 mg administered once daily, the median time to peak (Tmax) of saxagliptin was 2 h and the Tmax of saxagliptin active metabolite was 4 h. Administration after a high-fat diet prolonged the Tmax of saxagliptin by approximately 20 min compared to fasting. saxagliptin postprandial administration increased the AUC value by 27% compared to fasting administration. Saxagliptin can be taken with or without food.
Distribution
The protein binding of saxagliptin and its active metabolites in human plasma in vitro is negligible. Therefore, changes in plasma protein levels due to various disease states (e.g., renal or hepatic insufficiency) do not affect the distribution of saxagliptin.
Metabolism
The metabolism of saxagliptin is mainly mediated by CYP3A4/5. The major metabolite of saxagliptin is also a DPP-4 inhibitor, with one-half the inhibitory activity of saxagliptin. Therefore, strong inhibitors and strong inducers of CYP3A4/5 can alter the pharmacokinetics of saxagliptin and its metabolites.
Excretion
Saxagliptin is excreted through the kidney and liver. After a single administration of 50 mg of 14C saxagliptin, urinary excretion of saxagliptin, saxagliptin active metabolite, and total radioactivity was 24%, 36%, and 75% of the administered dose, respectively. The mean renal clearance of saxagliptin (~230 mL/min) was greater than the mean glomerular filtration rate (~120 mL/min), suggesting the presence of active renal clearance. A total of 22% of the radioactive material was recovered in the feces, suggesting partial excretion of saxagliptin through the bile and/or partial excretion of unabsorbed drug through the gastrointestinal tract. The mean plasma half-lives (t1/2) of saxagliptin and its active metabolites after a single oral dose of saxagliptin 5 mg in healthy volunteers were 2.5 h and 3.1 h, respectively.
Special Populations
Renal insufficiency
A single-dose, open study was conducted to evaluate the pharmacokinetics of oral 10 mg saxagliptin in populations with varying degrees of renal insufficiency and normal renal function. 10 mg was not an approved dose. The degree of renal insufficiency did not affect the Cmax of saxagliptin or its active metabolite. in patients with partial moderate (30 ≤ eGFR< 45 mL/min/1.73m2) or severe (15 ≤ eGFR< 30 mL/min/1.73m2) renal insufficiency and in patients with end-stage renal disease requiring hemodialysis, the AUC values of saxagliptin and its active metabolite were normal. The AUC value of the product is >2 times the AUC value in subjects with normal renal function (see [DOSAGE AND ADMINISTRATION] and [PRECAUTIONS]).
Impaired hepatic function
Patients with mild (ChildPugh Class A), moderate (ChildPugh Class B), or severe (ChildPugh Class C) hepatic impairment had 1.1, 1.4, and 1.8-fold higher exposures to saxagliptin and 22% lower exposures to the metabolite BMS-510849 relative to those with normal hepatic function, respectively. , 7%, and 33%, respectively. These differences were not considered clinically significant. Therefore, dose adjustment in patients with hepatic insufficiency is not recommended.
Body mass index
Dose adjustment based on patient body mass index (BMI) is not recommended. BMI was not a significant covariate for the apparent clearance of saxagliptin or its metabolites in the population pharmacokinetic analysis.
Gender
Dose adjustment based on patient gender is not recommended. There were no significant differences in saxagliptin pharmacokinetics between males and females. Exposure to active metabolites is approximately 25% higher in women compared to men, but this difference may not be clinically significant. Gender was not a significant covariate for the apparent clearance of saxagliptin or its metabolites in the population pharmacokinetic analysis.
Older adults
Dose adjustment based on age alone is not recommended. Geometric mean Cmax and AUC values for saxagliptin were 23% and 59% higher, respectively, in elderly subjects (65 to 80 years of age) compared to younger subjects (18 to 40 years of age). The differences in the pharmacokinetics of the active metabolites between older and younger patients broadly reflect the differences in the pharmacokinetics of saxagliptin between the two. The differences in the pharmacokinetics of saxagliptin and its active metabolites between younger and older patients may be due to a variety of factors, including age-related decline in renal function and metabolic capacity. Age was not a significant covariate for the apparent clearance of saxagliptin or its metabolites in the population pharmacokinetic analysis.
Race
Dosing adjustments based on race are not recommended. Population pharmacokinetic studies compared the pharmacokinetic properties of saxagliptin and its active metabolite in 309 Caucasian and 105 non-Caucasian individuals (including 6 races). The results of the study showed no significant differences in the pharmacokinetics of saxagliptin and its active metabolite between the two populations.
Drug interactions
In vitro drug interaction assay
The metabolism of saxagliptin is mainly mediated through CYP3A4/5.
In in vitro studies, saxagliptin and its major active metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A4 nor induced CYP1A2, 2B6, 2C9 or 3A4. Therefore, saxagliptin and its major metabolite may not alter the metabolic clearance of drugs metabolized by these enzymes when used in combination with these drugs. Saxagliptin is a substrate for P-glycoprotein but is not a significant inhibitor or inducer of P-glycoprotein.
The protein binding of saxagliptin and its active metabolite in human plasma was negligible in in vitro assays. Therefore, protein binding does not have a meaningful effect on the pharmacokinetics of saxagliptin or other drugs.
In vivo drug interactions were measured
Table 3: Effect of combined dosing on systemic exposure of saxagliptin and its active metabolite, 5-hydroxy-saxagliptin
Concomitant drug use Dose of combined drug use * Dose of saxagliptin * Geometric mean ratio
(Ratio with/without combined dosing) No effect = 1.00 AUC†Cmax No dose adjustment required when combined with: metformin 1000 mg100 mg saxagliptin
5-Hydroxy-saxagliptin 0.98
0.990.79
0.88 Digoxin Day 1, 0.25 mg every 6 hours; Day 2, every 12 hours, then once daily for 5 days 10 mg once daily for 7 days
Saxagliptin
5-Hydroxy saxagliptin 1.05
1.060.99
1.02 Simvastatin 40 mg once daily for 8 days 10 mg once daily for 4 days
Saxagliptin
5-Hydroxy-saxagliptin 1.12
1.021.21
1.08 diltiazem 360 mg LA once daily for 9 days 10 mg saxagliptin
5-Hydroxy-saxagliptin 2.09
0.661.63
0.57 Rifampin§ 600 mg once daily for 6 days 5 mg saxagliptin
5-Hydroxy-saxagliptin 0.24
1.030.47
1.39 Omeprazole 40 mg once daily for 5 days 10 mg saxagliptin
5-Hydroxy-saxagliptin 1.13
Not measured 0.98
Not determined Aluminum hydroxide + magnesium hydroxide + dimethylsilicone oil Aluminum hydroxide.
2400 mg Magnesium hydroxide.
2400 mg Dimethylsilicone oil: 240 mg10 mgSaxagliptin
5-Hydroxy saxagliptin 0.97
Not measured 0.74
Not measured Famotidine 40 mg10 mg Saxagliptin
5-Hydroxy-saxagliptin 1.03
Not measured 1.14
Not measured When co-administered with a potent inhibitor of CYP3A4/5, the dose of saxagliptin should be limited to 2.5 mg once daily: ketoconazole 200 mg twice daily for 9 days 100 mg saxagliptin
5-Hydroxy-saxagliptin 2.45
0.121.62
0.05 ketoconazole 200 mg twice daily for 7 days 20 mg saxagliptin
5-Hydroxy-saxagliptin3.67
Not measured 2.44
Not measured* Single dose administration, unless otherwise noted. 10 mg dose is not an approved dose.
† AUC = drug AUC after single-dose administration (INF); AUC = drug AUC after multiple-dose administration (TAU)
§ Plasma dipeptidyl peptidase-4 (DPP4) activity inhibition during the 24-hour dosing interval was not affected by rifampicin.
 Table 4: Effect of saxagliptin on systemic exposure for combined dosing
Combined Dose of Combined Dose * Dose of Saxagliptin * Geometric mean ratio (ratio with/without saxagliptin) No effect = 1.00 AUC†Cmax No dose adjustment required when combined with: metformin 1000 mg 100 mg metformin 1.201.09 digoxin Day 1, 0.25 mg every 6 hours; Day 2, every 12 hours once daily, then once daily for 5 days 10 mg once daily
Digoxin 1.061.09 Simvastatin 40 mg once daily for 7 days and 10 mg once daily for 8 days
for 4 days Simvastatin Simvastatin acid 1.04
1.160.88
1.00 diltiazem 360 mg LA once daily for 9 days 10 mg diltiazem 1.101.16 ketoconazole 200 mg twice daily for 9 days 100 mg ketoconazole 0.870.84 ethinyl estradiol and norgestimate ethinyl estradiol 0.035 mg and norgestimate 0.250 mg
for 21 days 5 mg once daily for
21 days Ethinyl estradiol norgestrel norethindrone 1.07
1.10
1.130.98
1.09
1.17* Single dose administration unless otherwise noted. 10mg and 100mg doses are not approved doses.
† AUC = drug AUC after single dose administration (INF); AUC = drug AUC after multiple dose administration (TAU)
 Storage】Storage below 30℃.
Package】Aluminium/Aluminium blister pack, 10 tablets/plate, 1 plate/box.
Expiration date】18 months
【Execution standard
Approval number】
【Manufacturing enterprise】 【Effective date
Company Name: Jiangsu Aosikang Pharmaceutical Co.
Address: No. 699 Kejian Road, Jiangning Science Park, Nanjing
Postcode：211112
Telephone number: 025-52169999
Fax number: 025-52162777
Web address: http://www.ask-pharm.com