Date of approval.
Date of modification.
Sitagliptin Phosphate Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Sitagliptin Phosphate Tablets
English name: Sitagliptin Phosphate Tablets
Hanyu Pinyin: Linsuan Xigelieting Pian
Ingredients
The main ingredient of this product is sitagliptin phosphate.
Chemical name: 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolone[4,3-a]pyrazine phosphate (1:1) monohydrate
Chemical structure formula.
Molecular formula: C16H15F6N5O-H3PO4-H2O
Molecular weight: 523.32
Properties
This product is white or off-white round film-coated tablets, appear white or off-white after removing the coating.
Indications
Monotherapy
This product is used in combination with diet control and exercise to improve glycemic control in patients with type 2 diabetes.
Combination with metformin
When the glycemic control of metformin hydrochloride alone is not good, it can be used in combination with metformin hydrochloride to improve the glycemic control of type 2 diabetic patients based on diet and exercise.
Combination with sulfonylureas
This product is used in combination with diet control and exercise to improve glycemic control in patients with type 2 diabetes who have been treated with a sulfonylurea alone or with a sulfonylurea in combination with metformin for poor glycemic control.
Combination with insulin
It is used in combination with diet control and exercise to improve blood glucose control in patients with type 2 diabetes mellitus who have poor glycemic control after treatment with insulin monotherapy or insulin combined with metformin.
Specification
(1) 25mg (2) 50mg (3) 100mg (based on selegiline)
Dosage]
The recommended dose of this product is 100 mg once daily as monotherapy or in combination with metformin, or in combination with sulfonylureas (with or without metformin) or in combination with insulin (with or without metformin). This product may be taken with or without food.
When this product is co-administered with a sulfonylurea or insulin, a lower dose of the sulfonylurea or insulin needs to be considered to reduce the risk of hypoglycemia due to the sulfonylurea or insulin. (See Precautions, Hypoglycemia in Combination with a Sulfonylurea or Insulin).
Patients with renal impairment
Renal function should be assessed prior to initiation of therapy with this product and should be evaluated periodically after initiation of therapy.
No dose adjustment is required in patients with mild renal impairment (glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73 m2 and < 90 mL/min/1.73 m2) taking this product.
No dose adjustment is required in patients with moderate renal impairment (eGFR ≥ 45 mL/min/1.73 m2 and < 60 mL/min/1.73 m2).
Patients with moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2
and <45 mL/min/1.73 m2), the dose was adjusted to 50 mg once daily.
For patients with severe renal impairment (eGFR ≥15 mL/min/1.73 m2 and <30 mL/min/1.73 m2) or end-stage renal disease (ESRD) (eGFR <15 mL/min/1.73 m2), including patients requiring hemodialysis or peritoneal dialysis, the dose is adjusted to 25 mg once daily. The duration of dialysis does not need to be taken into account when taking this product.
[Adverse Reactions].
According to foreign literature
Experience from clinical trials
Because clinical trials are conducted under a range of different circumstances, the incidence of adverse reactions in clinical trials for one class of drugs cannot be directly compared with the incidence of adverse reactions in clinical trials for another class of drugs and does not reflect the incidence of adverse reactions in clinical practice.
The overall incidence of adverse reactions, hypoglycemia and discontinuation due to clinical adverse reactions was similar between the treatment and placebo treatment groups in controlled clinical studies of monotherapy with this product and in combination of this product with metformin or pioglitazone. The overall incidence of clinical adverse reactions was higher in the treatment group than in the placebo group when treated with glimepiride in combination with or without metformin, in part because of the higher incidence of hypoglycemia in the treatment group (see Table 1); the incidence of discontinuation due to clinical adverse reactions was similar in the treatment group to that in the placebo treatment group.
In 2 placebo-controlled monotherapy studies lasting 18 and 24 weeks, respectively, patients received Benadryl 100 mg once daily, Benadryl 200 mg once daily, and placebo. In addition, the investigators conducted three 24-week placebo-controlled, combination treatment studies with or without metformin in combination with metformin, pioglitazone and glimepiride. In addition to stable doses of metformin, pioglitazone, glimepiride or glimepiride plus metformin, patients with poorly controlled diabetes were treated with either this product 100 mg once daily or placebo. Excluding the results of the investigator’s assessment of causality, see Table 1 for adverse reactions that occurred at an incidence of ≥5% and were higher than those in the placebo-treated group in the Benadryl 100 mg once-daily monotherapy group, the Benadryl plus pioglitazone combination therapy group, or the Benadryl plus glimepiride with or without the addition of metformin combination therapy group.
Table 1
Placebo-controlled clinical studies on selegiline monotherapy or selegiline in combination with pioglitazone, glimepiride +/- metformin or insulin +/- metformin: adverse reactions occurring at an incidence ≥5% and higher than in the placebo-treated group of patients, regardless of the results of the investigator’s assessment of causality†
Group Number of patients (%) monotherapy selegiline 100 mg placebo N = 443N = 363 nasopharyngitis 23 (5.2)12 (3.3) combination with pioglitazone selegiline 100 mg +
pioglitazone placebo + pioglitazone N = 175N = 178 upper respiratory tract infections11 (6.3)6 (3.4) headache9 (5.1)7 (3.9) in combination with glimepiride
(+/- metformin) Selegiline 100 mg + glimepiride (+/- metformin) Placebo + glimepiride
(+/- metformin) N = 222N = 219 hypoglycemia27 (12.2)4 (1.8)nasopharyngitis14 (6.3)10 (4.6)headache13 (5.9)5 (2.3)combination with insulin
(+/- metformin) Selegiline 100 mg + insulin (+/- metformin) Placebo + insulin
(+/- metformin) N = 322N = 319 hypoglycemia50 (15.5)25 (7.8)†
Intention-to-treat population.
In clinical studies of this product in combination with metformin, there were no adverse reactions that occurred at an incidence ≥ 5% and were higher than those in patients in the placebo-treated group, regardless of the results of the investigator’s assessment of causality.
In a 52-week study, the efficacy and safety of the addition of 100 mg of selegiline once daily or glipizide was compared in patients with poor glycemic control after monotherapy with metformin. The incidence of hypoglycemia was significantly lower in the sitagliptin group (4.9%) than in the glipizide group (32.0%).
In another 24-week study with concomitant insulin intensification (with or without metformin) as add-on therapy, the incidence of hypoglycemia was 25.2% in patients in the group treated with this product and insulin (with or without metformin), compared with 36.8% in patients in the group treated with placebo and insulin (with or without metformin). The main reason for this difference was the higher percentage of patients in the placebo group who had three or more episodes of hypoglycemia (9.4 versus 19.1%). There was no difference in the incidence of severe hypoglycemia.
In a pooled analysis including 2 monotherapy studies, the metformin combination therapy study and the pioglitazone combination therapy study, the overall incidence of hypoglycemic adverse reactions was similar in patients treated with Benadryl 100 mg and placebo (1.2% and 0.9%, respectively). Hypoglycemic adverse reactions were reported from all hypoglycemia reports; concomitant measurement of patients’ blood glucose levels was not required. The incidence of specific gastrointestinal adverse reactions in patients treated with this product is shown below: abdominal pain (2.3% in the 100 mg treatment group; 2.1% in the placebo treatment group), nausea (1.4% in the 100 mg treatment group; 0.6% in the placebo treatment group), and diarrhea (3.0% in the 100 mg treatment group; 2.3% in the placebo treatment group).
In another 24-week, placebo-controlled causality study of the initial combination of selegiline and metformin, adverse reactions with an incidence of ≥5% (not considering the investigator’s assessment of causality) are shown in Table 2. The incidence of hypoglycemia was 0.6%, 0.6%, 0.8%, and 1.6% in patients receiving placebo, selegiline monotherapy, metformin monotherapy, and selegiline plus metformin combination therapy, respectively.
Table 2 Initial combination therapy with selegiline and metformin.
Adverse reactions with an incidence of ≥5% among patients receiving the combination (and higher than among patients receiving metformin monotherapy, selegiline monotherapy, and placebo) (regardless of investigator’s assessment of causality)†
Group Number of patients (%) Placebo Selegiline
100 mg, QD Metformin 500 or
1000 mg, bid ††Selegiline 50 mg, bid + metformin 500 or 1000 mg, bid ††N = 176N = 179N = 364†††N = 372†† Diarrhea7 (4.0)5 (2.8)28 (7.7)28 (7.5) Upper respiratory tract infection9 (5.1)8 (4.5)19 (5.2)23 (6.2) Headache5 (2.8)2 (1.1)14 (3.8)22 (5.9)†
Intention-to-treat population.
††
Pooled data for patients receiving low-dose and high-dose metformin therapy.
Pancreatitis: In a pooled analysis of 19 double-blind clinical trials containing data from 10246 patients randomized to selegiline 100 mg daily (N=5429) or the corresponding (active or placebo) control (N=4817) treatment, the incidence of non-adjudicated acute pancreatitis events in each treatment group was 0.1/100 patient-years (total selegiline treatment group 4708 4 patients with one adverse event in the patient-year; 4 patients with one adverse event in the control group totaling 3942 patient-years). See also the TECOS cardiovascular safety study below. (See Precautions, Pancreatitis).
No clinically meaningful changes in vital signs or electrocardiographic (including QTc interval) parameters occurred in patients treated with this product.
TECOS Cardiovascular Safety Study
In the Selegiline Evaluation of Cardiovascular Clinical Outcomes Trial (TECOS), 7332 patients in the intention-to-treat population received selegiline 100 mg once daily (if baseline estimated glomerular filtration rate (eGFR) was ≥30 and
＜50 mg once daily if the baseline estimated glomerular filtration rate (eGFR) was <50 mL/min/1.73 m2) and 7339 patients in the intention-to-treat population received placebo. Both study treatments were added to conventional treatment aimed at controlling glycated hemoglobin (HbA1c) and cardiovascular (CV) risk factors. The study population consisted of 2004 patients ≥75 years of age (970 treated with sitagliptin and 1034 treated with placebo). The overall incidence of serious adverse events among selegiline treated patients was similar to that of placebo treated patients. A prespecified assessment of diabetes-related complications showed similar rates between treatment groups, including infections (18.4% and 17.7% in selegiline and placebo-treated patients, respectively) and renal failure (1.4% and 1.5% in selegiline and placebo-treated patients, respectively). The characteristics of adverse events among patients ≥75 years of age were broadly similar to the overall population.
In the intention-to-treat population, the incidence of severe hypoglycemia was 2.7% and 2.5% in selegiline and placebo-treated patients, respectively, among patients using insulin and/or sulfonylurea at baseline, and 1.0% and 0.7% among selegiline and placebo-treated patients not using insulin and/or sulfonylurea at baseline. The incidence of adjudicated confirmed pancreatitis events was 0.3% and 0.2% in selegiline and placebo-treated patients, respectively. The incidence of adjudication-confirmed malignancy events was 3.7% and 4.0% in selegiline and placebo-treated patients, respectively.
Laboratory tests
The incidence of laboratory adverse reactions was similar in patients treated with selegiline 100 mg versus placebo in different clinical studies. Patients had a slightly elevated white blood cell count (WBC) due to an elevated neutrophil count. The elevated WBC count (approximately 200/ul in the pooled results of four placebo-controlled clinical studies compared to the placebo-treated group, with a mean baseline WBC count of approximately 6600/ul in patients) was not clinically significant. In a 12-week study enrolling 91 patients with chronic kidney damage, 37 patients with moderate kidney damage were randomized to the selegiline 50 mg once-daily treatment group, while 14 patients with moderate kidney damage were randomized to the placebo treatment group. The mean (standard error) of elevated serum creatinine levels was [0.12 mg/dL (0.04)] in the selegiline group and [0.07 mg/dL (0.07)] in the placebo group, respectively. The clinical significance of the elevated serum creatinine levels in the sitagliptin-treated group compared with the placebo-treated group is unknown.
Postmarketing experience
A number of other adverse reactions have been identified during post-marketing monotherapy and combination therapy with other anti-hyperglycemic agents. Because these adverse reactions have been spontaneously reported from an indeterminate number of people, it is often not possible to reliably estimate the incidence of these adverse reactions or to determine a causal relationship between adverse reactions and drug exposure.
Hypersensitivity reactions, including allergic reactions, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin lesions, including Stevens-Johnson syndrome (see Contraindications and Precautions); acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis (see Precautions, Pancreatitis), elevated liver enzymes, decreased renal function, including acute renal failure (sometimes requiring dialysis), herpetiform aspergillosis (see PRECAUTIONS, herpetiform aspergillosis), upper respiratory tract infection, nasopharyngitis, constipation, vomiting, headache, severe and disabling arthralgia, muscle pain, extremity pain, back pain, pruritus, mouth ulcers, stomatitis.
Contraindication】
Contraindicated in those who are hypersensitive to any of the ingredients in this product (see Precautions, Hypersensitivity Reactions and Adverse Reactions, Postmarketing Experience).
Precautions】
Overview
This product should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Pancreatitis: Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been reported in patients taking selegiline (see ADVERSE REACTIONS). Patients should be informed of the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. There are reports suggesting that symptoms of pancreatitis disappear after discontinuation of selegiline. If pancreatitis is suspected, selegiline and other suspected drugs should be discontinued.
Heart failure: An association between DPP-4 inhibitor therapy and heart failure was found in cardiovascular safety studies of two other DPP-4 inhibitors. These studies evaluated patients with type 2 diabetes and atherosclerotic cardiovascular disease.
In patients at high risk for heart failure, risks and benefits should be assessed prior to initiating therapy, such as a history of prior heart failure and renal impairment, and patients should be observed for signs and symptoms during therapy. Patients should be informed of the typical symptoms of heart failure and reported to the physician immediately upon the onset of appropriate symptoms. If heart failure occurs, treatment should be evaluated according to current treatment criteria and discontinuation should be considered.
The Trial for the Evaluation of Selegiline Cardiovascular Clinical Outcomes (TECOS) was a randomized study conducted in 14,671 patients in the intention-to-treat population with HbA1c ≥6.5 to 8.0% and established CV disease. After a median follow-up of 3 years, supplementing selegiline dosing with conventional therapy did not increase the risk of major adverse cardiovascular events or the risk of hospitalization for heart failure compared to patients with type 2 diabetes who received conventional therapy only and did not receive selegiline dosing.
Dosing in patients with renal impairment: This product is excreted by the kidneys. In order to achieve plasma concentrations of this product in patients with renal impairment similar to those in patients with normal renal function, a dose reduction is recommended in patients with eGFR< 45 mL/min/1.73 m2 and in patients with end-stage renal disease requiring hemodialysis or peritoneal dialysis (see Dosage and Administration, Patients with Renal Impairment).
Hypoglycemia in combination with sulfonylureas or insulin: In clinical trials of this product as monotherapy and in combination with a therapeutic agent known not to cause hypoglycemia (e.g., metformin), the incidence of hypoglycemia reported in the product treatment group was similar to that in the placebo group. As with other hypoglycemic agents, hypoglycemia can be observed when this product is co-administered with insulin or a sulfonylurea (see Adverse Reactions). Therefore, to reduce the risk of hypoglycemia due to sulfonylureas or insulin, lower doses of sulfonylureas or insulin may be considered (see Dosage and Administration).
Hypersensitivity reactions: The following serious hypersensitivity reactions have been identified during the treatment of patients after the marketing of this product. These reactions include allergic reactions, angioedema, and exfoliative skin lesions, including Stevens-Johnson syndrome. Because these reactions were reported spontaneously from a variable number of people, it is usually not possible to reliably estimate the incidence of these reactions or to determine the causal relationship between these adverse reactions and drug exposure. These reactions occurred within the first 3 months of treatment with this product, with some reports occurring after the first dose. If hypersensitivity reactions are suspected, discontinue use of the product, evaluate for other potential causes, and use an alternative regimen for the treatment of diabetes (see the “Postmarketing Experience” section on Contraindications and Adverse Reactions).
Herpetic aspergillosis: Cases of herpetic aspergillosis requiring hospitalization have been reported in the post-marketing period with the use of DPP-4 inhibitors. In such reported cases, patients usually resolved after topical topical or systemic immunosuppressive therapy and discontinuation of DPP-4 inhibitor medication. Patients must be informed to report the presence of blisters or breakouts while receiving this product. If herpetiform aspergillosis is suspected, discontinue the drug and consider referral to a dermatologist for diagnosis and appropriate treatment.
Severe and disabling arthralgia: There have been post-marketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time interval between initiation of drug therapy and the onset of symptoms varies from one day to several years. Patients have experienced relief of symptoms after discontinuation of the drug. Some patients experience a recurrence of symptoms upon re-treatment with the same drug or other DPP-4 inhibitors. If appropriate DPP-4 inhibitors should be considered as the cause of severe joint pain and discontinued.
Macrovascular outcomes: There is no conclusive evidence from clinical studies that the use of this product reduces the risk of macrovascular disease.
Pregnant and lactating women]
During embryonic organogenesis, selegiline did not produce malformations in rats and rabbits given orally at doses up to 250 mg/kg and 125 mg/kg, respectively (32 and 22 times the human exposure based on the recommended adult daily dose of 100 mg, respectively). A mild increase in the incidence of embryonic rib deformities (missing, hypoplastic and corrugated ribs) was observed in rats given orally at doses up to 1000 mg/kg/day (approximately 100 times the human exposure at the recommended adult dose of 100 mg/day). In rats given orally at doses up to 1000 mg/kg per day, a slight decrease in mean body weight was observed in male and female offspring before weaning and an increase in body weight in male offspring after weaning. However, the results of animal reproduction studies are not always predictive of the response in humans.
There are no adequate and well-controlled studies in pregnant women; therefore, the safety of this product for use in pregnant women is unknown. As with other oral antihyperglycemic agents, the use of this product in pregnant women is not recommended.
Sitagliptin is secreted from the milk of lactating rats. It is not known whether selegiline can be secreted in human breast milk. Therefore, this product should not be used in lactating females.
Pediatric Use]
The safety and efficacy of this product in pediatric patients under 18 years of age have not been established.
Geriatric use]
In clinical studies, the safety and efficacy of this product in elderly patients (³ 65 years of age) were comparable to those in younger patients (< 65 years of age). No dose adjustment based on age is required. Older patients are more likely to have renal impairment; as with other ages, dose adjustment is required for severe renal impairment (see Dosage and Administration, “Patients with Renal Impairment” section).
Drug Interactions]
In drug interaction studies, there were no clinically significant effects of selegiline on the pharmacokinetics of metformin, rosiglitazone, glibenclamide, simvastatin, warfarin, and oral contraceptives. Based on these data, selegiline does not inhibit the CYP isoenzymes CYP3A4, 2C8 or 2C9. Based on data from in vitro studies, selegiline also does not inhibit CYP2D6, 1A2, 2C19 or 2B6 or induce CYP3A4.
In patients with type 2 diabetes, twice-daily multi-dose administration of metformin in combination with selegiline does not significantly alter the pharmacokinetics of selegiline.
A population pharmacokinetic analysis in patients with type 2 diabetes showed that the combination did not have a clinically meaningful effect on the pharmacokinetics of selegiline. The drugs evaluated were commonly used in patients with type 2 diabetes and included cholesterol-lowering agents (e.g., statins, fibrates, ezetimibe); antiplatelet agents (e.g., clopidogrel); antihypertensive agents (e.g., ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, hydrochlorothiazide); analgesics and nonsteroidal anti-inflammatory drugs (e.g., naproxen, diclofenac, celecoxib); antidepressants (e.g., bupropion, fluoxetine, sertraline); antihistamines (e.g., cetirizine); proton pump inhibitors (e.g., omeprazole, lansoprazole) and drugs for erectile dysfunction (e.g., cetorphine).
The area under the plasma concentration-time curve (AUC, 11%) as well as the mean peak plasma concentration (Cmax, 18%) of digoxin were slightly increased when the former was combined with selegiline. These changes were not clinically significant. Patients receiving concomitant digoxin therapy should be monitored appropriately. No dose adjustment of digoxin or this product is required.
The AUC and Cmax values of selegiline were elevated by approximately 29% and 68%, respectively, in subjects when a single oral dose of 100 mg of this product and a single oral dose of 600 mg of cyclosporine A, a potent class of p-glycoprotein probe inhibitors, were administered in combination. The pharmacokinetic changes observed with selegiline in the study were not clinically significant. When co-administered with cyclosporine A or other p-glycoprotein inhibitors (e.g., ketoconazole), no dose adjustment of this product is required.
[Drug overdose].
In controlled clinical studies in healthy subjects, this product was well tolerated in single doses up to 800 mg. A slight prolongation of the electrocardiographic QTc interval was observed in only one study with doses up to 800 mg, and these changes were not clinically significant. There is no experience with dosing in clinical trials at doses greater than 800 mg. No dose-related clinical adverse reactions were observed in multi-dose dosing Phase I studies with 10 consecutive days of this product at 600 mg daily and 400 mg daily for up to 28 days.
In the event of overdose, it is reasonable to use the usual supportive measures, such as draining unabsorbed drug from the gastrointestinal tract, using clinical monitoring (including obtaining an electrocardiogram), and supportive therapy if necessary.
Sitagliptin can be cleared by dialysis in small amounts. In clinical studies, approximately 13.5% of the drug was cleared by hemodialysis in 3 to 4 hours. Prolonged hemodialysis time may be considered if clinically indicated. It is not known whether selegiline can be cleared by peritoneal dialysis.
Pharmacology and Toxicology
Pharmacological effects
Sitagliptin dipeptidyl peptidase 4 (DPP-4) inhibitor, enterostatin, which includes glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), is released from the intestine throughout the day and its level increases after meals. Intestinal proinsulin is part of an endogenous system involved in the physiological regulation of glucose endotropic homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic β-cells via an intracellular signaling pathway involving cyclophosphatidyl adenosine. In addition, GLP-1 inhibits the secretion of glucagon by pancreatic α-cells. Decreased glucagon concentrations and increased insulin levels reduce hepatic gluconeogenesis and thus blood glucose levels.The effects of GLP-1 and GIP are glucose-dependent; when blood glucose concentrations are low, GLP-1 does not promote insulin release and does not inhibit glucagon secretion. When glucose levels are higher than normal concentrations, the effects of GLP-1 and GIP in promoting insulin release are enhanced. In addition, GLP-1 does not impair the body’s normal glucagon release response to hypoglycemia. the activity of GLP-1 and GIP is limited by the enzyme DPP-4, which rapidly hydrolyzes enteroglucagon and produces inactive products. Sitagliptin prevents DPP-4 from hydrolyzing enteroglucagon, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By increasing active enteroglucagon levels, selegiline is able to increase insulin release and decrease glucagon levels in a glucose-dependent manner.
Toxicological studies
Repeated administration: Selegiline was administered orally to dogs at 2, 10 and 50 mg/kg daily for 53 weeks, with no adverse effects seen in the trial at a dose of 10 mg/kg, which is approximately 6 times the human exposure based on the recommended adult daily dose of 100 mg. syndrome, vomiting of white foam, ataxia, tremors, reduced activity, and/or an arched back posture. Histological findings in animals in the 50 mg/kg group were suggestive of mild skeletal muscle degeneration at weeks 14-27 of the toxicity test. No skeletal muscle degeneration was observed at week 53 of the toxicity test, suggesting that this change did not recur or progress with increasing duration of administration. Systemic exposure in animals at a daily dose of 50 mg/kg was 26 times greater than human exposure.
Genotoxicity: Sitagliptin did not show genotoxicity.
Reproductive toxicity: No adverse drug effects on fertility were observed in male and female rats given selegiline orally at doses up to 1000 mg/kg/day (approximately 100 times the human exposure based on the recommended adult daily dose of 100 mg) prior to and during mating. A mild increase in the incidence of embryonic rib deformities (absent, hypoplastic and corrugated ribs) associated with drug administration was observed in rats given orally at doses up to 1000 mg/kg/day. No teratogenic effects were observed in rats given selegiline at 250 mg/kg/day (approximately 32 times the human exposure based on the recommended adult daily dose of 100 mg) and rabbits given 125 mg/kg/day (approximately 22 times the human exposure based on the recommended adult daily dose of 100 mg). Sitagliptin is secreted through the milk of lactating rats.
Carcinogenicity: No increase in tumor incidence was observed in mice given sitagliptin 500 mg/kg/day orally for 2 years. In rats given selegiline orally for 2 years at doses of 50, 150 and 500 mg/kg/day, an increased incidence of hepatic adenomas and hepatocellular carcinomas was seen in males in the 500 mg/kg/day group, and in females in the 500 mg/kg/day group. 500 mg/kg/day, based on the recommended adult daily dose of 100 mg, is approximately 58 times the human exposure. Hepatotoxicity was observed in rats at this dose. The dose of selegiline at which no hepatotoxic effects were observed was 150 mg/kg/day (approximately 19 times the human exposure at the recommended adult daily dose of 100 mg). Since the hepatotoxicity of the drug has been found to be associated with the induction of liver tumors in rats, the increased incidence of liver tumors in rats may be secondary to the chronic hepatotoxic effects of high doses of the drug, and the significance of this finding for human clinical use is unknown.
[Pharmacokinetics] According to foreign literature.
Studies on the pharmacokinetic profile of selegiline have been extensively conducted in healthy subjects and in patients with type 2 diabetes mellitus. After oral administration of a 100 mg dose to healthy subjects, selegiline was rapidly absorbed, with peak plasma drug concentrations (median Tmax) 1 to 4 hours after dosing. The blood AUC of selegiline increased in proportion to the dose. After a single oral dose of 100 mg in healthy volunteers, the mean blood AUC of selegiline was 8.52 μM-hr, the Cmax was 950 nM, and the apparent terminal half-life (t1/2) was 12.4 hours. The plasma AUC at steady state with selegiline 100 mg increased by approximately 14% compared to the initial dose. The coefficients of variation for selegiline AUC within and between individuals were small (5.8% and 15.1%). Pharmacokinetic indices of selegiline were broadly similar in healthy subjects and in patients with type 2 diabetes.
Absorption
The absolute bioavailability of selegiline is approximately 87%. Because concomitant administration of this product with a high-fat meal has no effect on pharmacokinetics, this product may be taken with or without food.
Distribution
The mean steady-state volume of distribution for a single intravenous dose of selegiline 100 mg in healthy subjects was approximately 198 liters. The binding rate of selegiline reversibly bound to plasma proteins was low (38%).
Metabolism
Sitagliptin is excreted primarily in the urine as a prototype, with metabolism being only a minor route. Approximately 79% of sitagliptin is excreted in the urine as a prototype.
After oral administration of [14C]-labeled selegiline, approximately 16% of the radioactivity was detected from the metabolites of selegiline. Six trace metabolites were detected and had no effect on the inhibition of plasma DPP-4 activity by selegiline. In vitro tests confirmed that the main enzymes involved in the small amount of selegiline metabolism were CYP3A4, and CYP2C8.
Excretion
Within one week of oral administration of [14C]-labeled selegiline to healthy subjects, approximately 100% of the radioactivity was detected by feces (13%) or by urine (87%). The apparent terminal half-life t1/2 for selegiline administered orally at 100 mg was approximately 12.4 hours, and the renal clearance was approximately 350 mL/min.
Selegiline is excreted primarily through renal clearance and active secretion by the renal tubules. Selegiline is a substrate for the action of human organic anion transporter-3 (hOAT-3), which may be involved in renal clearance of selegiline. hOAT-3 has no known clinical relevance to selegiline transport. Selegiline is also a p-glycoprotein acting substrate, and p-glycoprotein may also be involved in mediating renal clearance of selegiline. However, cyclosporine, an inhibitor of p-glycoprotein, does not reduce the renal clearance of selegiline.
Special Patients
Renal impairment: A single-dose, open study evaluated the pharmacokinetics of this product 50 mg in patients with varying degrees of chronic renal impairment and compared it to normal healthy control subjects. This study included patients with mild, moderate and severe renal impairment, and also patients with end-stage renal disease (ESRD) treated with hemodialysis. In addition, the effect of renal impairment on the pharmacokinetics of selegiline was evaluated by population pharmacokinetic methods in patients with type 2 diabetes mellitus with mild, moderate, and severe renal impairment, including ESRD.
Compared to control normal healthy subjects, selegiline plasma AUC increased approximately 1.2-fold in patients with mild renal impairment (eGFR ≥ 60 mL / min / 1.73 m2 and <90 mL / min / 1.73 m2), and in patients with moderate renal impairment (eGFR ≥ 45 mL / min / 1.73 m2 and <60 mL / min / 1.73 m2), selegiline plasma AUC increased approximately 1.6-fold.
Since this degree of increase was not clinically relevant, no dose adjustment was required for these patients.
Compared with control normal healthy subjects, in patients with moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2
and < 45 mL/min/1.73 m2), selegiline plasma AUC was increased approximately 2-fold; in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2), including patients with end-stage renal disease who were on hemodialysis, an approximately 4-fold increase in selegiline plasma AUC was observed. Sitagliptin can be cleared by hemodialysis in small amounts (approximately 13.5% was cleared by dialysis with a duration of 3 to 4 hours after initiation of dialysis 4 hours after dosing). To achieve plasma concentrations similar to those in patients with normal renal function, a lower dose is recommended for patients with eGFR <45 mL/min/1.73 m2 (see Dosage and Administration, “Patients with Renal Impairment” section).
Hepatic impairment: In patients with moderate hepatic impairment (Child-Pugh scores 7 to 9), mean AUC and Cmax of selegiline increased by approximately 21% and 13%, respectively, following a single dose of 100 mg of this product compared with healthy subjects who served as controls. These differences were not clinically significant. No dose adjustment of this product is required for patients with mild or moderate hepatic impairment.
There is no clinical experience with dosing in patients with severe liver impairment (Child-Pugh score>9). However, since selegiline is primarily cleared renally, severe hepatic impairment is not expected to have an impact on the pharmacokinetics of selegiline.
Geriatric patients: No dose adjustment based on age is required. Based on analysis of phase I and phase II population pharmacokinetic data, age did not have a clinically meaningful effect on the pharmacokinetics of selegiline. Selegiline plasma concentrations were approximately 19% higher in older subjects (65 to 80 years of age) compared to younger subjects.
Children: This product has not been clinically studied in pediatric patients.
Gender: No dose adjustment based on gender is required. Based on analysis of Phase I pharmacokinetic data and Phase I and II population pharmacokinetic data, gender did not have a clinically meaningful effect on selegiline pharmacokinetics.
Race: No race-based dose adjustment was required. Based on analysis of Phase I pharmacokinetic data and Phase I-II population pharmacokinetic data in subjects including Caucasian, Hispanic, Black, Asian, and other ethnic groups, race did not have a clinically meaningful effect on the pharmacokinetics of selegiline.
Body Mass Index (BMI): No dose adjustment based on BMI was required. Based on analysis of Phase I pharmacokinetic data and Phase I and II population pharmacokinetic data, body mass index did not have a clinically meaningful effect on the pharmacokinetics of selegiline.
Type 2 diabetes: The pharmacokinetics of selegiline in patients with type 2 diabetes were similar to those in healthy subjects.
Storage】 Keep under 30℃ and sealed.
Package
Aluminum-plastic plate packaging, 7 tablets/box; 14 tablets/box; 28 tablets/box; 42 tablets/box; 56 tablets/box; 10 tablets/box; 30 tablets/box; 60 tablets/box.
Expiration date】 24 months
【Execution standard
【Approval number】
[Drug Marketing License Holder
Holder’s name: Guangdong East Sunshine Pharmaceutical Co.
Address of the holder: North Industrial Zone, Songshan Lake Science and Technology Industrial Park, Dongguan City, Guangdong Province
Postal Code: 523808
Sales telephone number: 0769-85370280
Fax number: 0769-85370206
Medical consultation telephone number：4006707855
Web
Address: http://pharm.hec.cn/
【Manufacturer】
Company name: Guangdong Dongyang Pharmaceutical Co.
Production Address: North Industrial Zone, Songshan Lake Science and Technology Industrial Park, Dongguan City, Guangdong Province
Postal Code: 523808
Website
Address: http://pharm.hec.cn/
If you have questions, you can contact directly with the drug marketing license holder.