BRYNOVIN Sitagliptin Hydrochloride Oral 25 mg/mL Solution — NDC 24338-017-01 (Billing 24338-0017-01)
This is a package of BRYNOVIN Sitagliptin Hydrochloride Oral 25 mg/mL Solution from Azurity Pharmaceuticals, Inc., marketed since Apr 2025 and currently FDA-listed. It is this product's only package size.
Identity & classification
Regulatory identifiers FDA, NLM and CMS codes for this package
Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification
- GSN (GCN sequence number): 087074
- GCN: 56912
- GPI-14 (Medi-Span): 27550070052020
- HICL (First Databank): 048370
- AHFS class code: 68:20.05.00
- RxCUI (RxNorm): 2716485
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
- RxNorm (NLM RxNav) · catalog refreshed Oct 1, 2026
- Medi-Span GPI (licensed)
- First Databank (licensed) · refreshed Oct 1, 2026
RxNorm drug class
This medicine belongs to the Dipeptidyl Peptidase 4 Inhibitor class.
Where does this data come from?
- RxClass (NLM) · catalog refreshed Oct 1, 2026
Clinical
- It helps improve blood sugar control in adults with type 2 diabetes, alongside diet and exercise. It isn't meant for type 1 diabetes.
- Take it by mouth once a day, with or without food. If you use the Brynovin liquid, measure it with an oral syringe or dosing cup marked in mL. Follow your prescriber's instructions...
- The most common are a stuffy nose or sore throat, upper respiratory infections and headache. If you also take insulin or a sulfonylurea, low blood sugar is more likely. Tell your d...
- Call if you have severe stomach pain, swelling of your face or throat, a severe rash, blisters, severe joint pain, or symptoms of heart failure like shortness of breath or swelling...
Patient education
Supplement & herbal interactions
Where does this data come from?
- MedlinePlus (NLM) · refreshed Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Ask a licensed pharmacist directly — free, answered by our team.
Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per mL | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data. | |
| Medicare drug plans payPart D · quarterly | No Part D plan price is available for this NDC in our data. | |
Where does this data come from?
- CMS NADAC weekly file
- CMS ASP pricing files · refreshed Sep 20, 2026
- CMS Medicaid State Drug Utilization Data · refreshed Oct 2, 2026
- CMS Part D plan pricing files · refreshed Sep 24, 2026
- VA National Acquisition Center price file
Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Marketing end | Status |
|---|---|---|---|---|
| 24338-0017-01 You're viewing this Main listing | 1 BOTTLE in 1 CARTON / 120 mL in 1 BOTTLE | 2025-04-01 | — | Active |
Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Brynovin 25 mg/mLthis 24338-0017-01 | Azurity | 1 bottle | — | — | FDA listed | — |
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA Orange Book · refreshed Sep 3, 2026
- CMS NADAC weekly file
Availability & generic status
We did not find an FDA-approved generic match for this exact strength, form and route. Patent/protection dates below may affect future generic timing.
Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.
🛈 What do these terms mean?
- Patent
- Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
- Substance patent
- Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
- Formulation (product) patent
- Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
- Method-of-use patent
- A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
- Skinny label
- A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
- Exclusivity
- FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
- Paragraph IV
- A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
- RLD / RS
- Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
- TE / AB rating
- FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
- LOE (loss of exclusivity)
- The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.
Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.
| Patent | Type | Use code | Expires |
|---|---|---|---|
| US 12295953 ↗ | Drug product | — | Oct 23, 2040 |
| US 11944621 ↗ | Drug product | — | Oct 23, 2040 |
Is there a generic version of BRYNOVIN 25 MG/ML SOLUTION?
The FDA approved a generic — why can’t I get it at my pharmacy yet?
Why do different websites show different generic release dates?
What does “FDA listed” mean?
What does a patent or protection date mean here?
What does “current Orange Book estimate” mean?
Can a generic come out before the last patent expires?
Can a generic come out after the listed dates?
What is the difference between patents and exclusivity?
Why are there multiple patent dates?
Where does this data come from?
- FDA Orange Book · refreshed Sep 3, 2026
Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
Where does this data come from?
IACT rows and label-wide narrative are kept separate; availability and product-level specificity depend on the submitted label.- FDA label on DailyMed · label index refreshed Oct 1, 2026
- FDA openFDA NDC Directory · synced Oct 1, 2026
Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
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Manufacturer & labeler
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- Drugs@FDA
Full prescribing information FDA SPL
🎯 Indications and Usage ▾
1 INDICATIONS & USAGE BRYNOVIN is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use BRYNOVIN is not recommended in patients with type 1 diabetes. BRYNOVIN has not been studied in patients with a history of pancreatitis.
It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using BRYNOVIN. [see Warnings and Precautions ( 5.1 )] . BRYNOVIN is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: • BRYNOVIN is not recommended in patients with type 1 diabetes.
( 1 ) • BRYNOVIN has not been studied in patients with a history of pancreatitis. ( 1 )
⏱️ Dosage and Administration ▾
2 DOSAGE & ADMINISTRATION The recommended dose of BRYNOVIN is 100 mg orally once daily (4 mL). BRYNOVIN can be taken with or without food. ( 2.1 ) Dosage adjustment is recommended for patients with eGFR less than 45 mL/min/1.73 m 2 .
( 2.2 ) Dosage Adjustment in Patients with Renal Impairment ( 2.2 ) eGFR greater than or equal to 30 mL/min/1.73 m 2 to less than 45 mL/min/1.73 m 2 eGFR less than 30 mL/min/1.73 m 2 (including patients with end stage renal disease [ESRD] on dialysis) 50 mg once daily (2 mL) 25 mg once daily (1 mL)
2.1Recommended Dosage and Administration Measure the BRYNOVIN dose using a calibrated oral syringe or oral dosing cup scored using metric units of measurements (i.e., mL). The recommended dosage of BRYNOVIN is 100 mg (4 mL) taken orally once daily. BRYNOVIN can be taken with or without food [see Clinical Pharmacology ( 12.3 )] .
2.2Recommendations for Use in Renal Impairment Assess renal function prior to initiation of BRYNOVIN and periodically thereafter [see Use in Specific Populations ( 8.6 )] . For patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 45 mL/min/1.73 m 2 to less than 90 mL/min/1.73 m 2 , no dosage adjustment for BRYNOVIN is required. For patients with moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73 m 2 to less than 45 mL/min/1.73 m 2 ), the dosage of BRYNOVIN is 50 mg (2 mL) once daily.
For patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dosage of BRYNOVIN is 25 mg (1 mL) once daily. BRYNOVIN may be administered without regard to the timing of dialysis.
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS & STRENGTHS BRYNOVIN oral solution 25 mg/mL is supplied as a clear, colorless to nearly colorless aqueous solution in an amber glass bottle. Oral solution: 25 mg per mL ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS BRYNOVIN is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin or any of the excipients in BRYNOVIN. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported [see Warnings and Precautions ( 5.5 ) and Adverse Reactions ( 6.2 )]. History of a serious hypersensitivity reaction to sitagliptin or any of the excipients in BRYNOVIN, such as anaphylaxis or angioedema.
( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS • Pancreatitis : There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue BRYNOVIN. ( 5.1 ) • Heart failure : Heart failure has been observed with two other members of the DPP-4 inhibitor class.
Consider risks and benefits of BRYNOVIN in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. ( 5.2 ) • Acute Renal Failure : Has been reported postmarketing, sometimes requiring dialysis.
Assessment of renal function is recommended prior to initiating BRYNOVIN and periodically thereafter. ( 5.3 ) • Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues : Increased risk of hypoglycemia when used in combination with insulin or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required.
( 5.4 ) • Hypersensitivity Reactions : There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Promptly stop BRYNOVIN, assess for other potential causes, institute appropriate monitoring and treatment. ( 5.5 ) • Severe and Disabling Arthralgia : Has been reported in patients taking DPP-4 inhibitors.
Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.6 ) • Bullous Pemphigoid : There have been postmarketing reports requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions.
If bullous pemphigoid is suspected, discontinue BRYNOVIN. ( 5.7 )
5.1Pancreatitis There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin. After initiation of BRYNOVIN, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, BRYNOVIN should promptly be discontinued and appropriate management should be initiated.
It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using BRYNOVIN.
5.2Heart Failure An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Consider the risks and benefits of BRYNOVIN prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy.
Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of BRYNOVIN.
5.3Acute Renal Failure There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis with sitagliptin. A subset of these reports involved patients with renal impairment, some of whom were prescribed inappropriate dosages of sitagliptin. A return to baseline levels of renal impairment has been observed with supportive treatment and discontinuation of potentially causative agents.
Consideration can be given to cautiously reinitiating BRYNOVIN if another etiology is deemed likely to have precipitated the acute worsening of renal function. Assessment of renal function is recommended prior to initiating BRYNOVIN and periodically thereafter. A dosage adjustment is recommended in patients with moderate or severe renal impairment and in patients with ESRD requiring hemodialysis or peritoneal dialy… [Excerpted — this section continues on DailyMed.]
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: • Pancreatitis [ see Warnings and Precautions ( 5.1 ) ] • Heart Failure [ see Warnings and Precautions ( 5.2 ) ] • Acute Renal Failure [ see Warnings and Precautions ( 5.3 ) ] • Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [ see Warnings and Precautions ( 5.4 ) ] • Hypersensitivity Reactions [ see Warnings and Precautions ( 5.5 ) ] • Severe and Disabling Arthralgia [ see Warnings and Precautions ( 5.6 ) ] • Bullous Pemphigoid [ see Warnings and Precautions ( 5.7 ) ] Most common adverse reactions (incidence ≥5%) are: upper respiratory tract infection, nasopharyngitis and headache.
In the add-on to sulfonylurea and add-on to insulin trials, hypoglycemia was also more commonly reported in patients treated with sitagliptin compared to placebo. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc., at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of BRYNOVIN has been established for glycemic control in patients with type 2 diabetes mellitus based in adequate and well-controlled trials of sitagliptin tablets, referenced below as “sitagliptin” [see Clinical Studies ( 14 )] .
Common Adverse Reactions In controlled clinical trials as both monotherapy and combination therapy with metformin, pioglitazone, or rosiglitazone and metformin, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with sitagliptin were similar to placebo. In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with sitagliptin was higher than with placebo, in part related to a higher incidence of hypoglycemia (see Table 3); the incidence of discontinuation due to clinical adverse reactions was similar to placebo.
Two placebo-controlled monotherapy trials, one of 18- and one of 24-week duration, included patients treated with sitagliptin 100 mg daily, sitagliptin 200 mg daily, and placebo. Five placebo-controlled add-on combination therapy trials were also conducted: one with metformin; one with pioglitazone; one with metformin and rosiglitazone; one with glimepiride (with or without metformin); and one with insulin (with or without metformin). In these trials, patients with inadequate glycemic control on a stable dosage of the background therapy were randomized to add-on therapy with sitagliptin 100 mg daily or placebo.
The adverse reactions, excluding hypoglycemia, in ≥5% of patients treated with sitagliptin 100 mg daily and more commonly than in patients treated with placebo, are shown in Table 1 for the clinical trials of at least 18 weeks duration. Incidences of hypoglycemia are shown in Table 3. Table 1:Placebo-Controlled Clinical Trials of Sitagliptin Monotherapy or Add-on Combination Therapy with Pioglitazone, Metformin + Rosiglitazone, or Glimepiride +/- Metformin: Adverse Reactions (Excluding Hypoglycemia) Reported in ≥5% of Patients and More Commonly than in Patients Given Placebo* Number of Patients (%) Monotherapy (18 or 24 weeks) Sitagliptin 100 mg Placebo N = 443 N = 363 Nasopharyngitis 23 (5.2) 12 (3.3) Combination with Pioglitazone (24 weeks) Sitagliptin 100 mg + Pioglitazone Placebo + Pioglitazone N = 175 N = 178 Upper Respiratory Tract Infection 11 (6.3) 6 (3.4) Headache 9 (5.1) 7 (3.9) Combination with Metformin + Rosiglitazone (18 weeks) Sitagliptin 100 mg + Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone N = 181 N = 97 Upper Respiratory Tract Infection 10 (5.5) 5 (5.2) Nasopharyngitis 11 (6.1) 4 (4.1) Combination with Glimepiride (+/… [Excerpted — this section continues on DailyMed.]
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS
7.1Concomitant Use with Insulin or Insulin Secretagogues BRYNOVIN lowers blood glucose in patients with type 2 diabetes mellitus. Coadministration of BRYNOVIN with insulin or an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. [See Warnings and Precautions ( 5.4 )].
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS
8.1Pregnancy Risk Summary The limited available data with sitagliptin in pregnant women are not sufficient to inform a drug- associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations] . No adverse developmental effects were observed when sitagliptin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 30-times and 20-times, respectively, the 100 mg clinical dose, based on AUC [see Data].
The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a hemoglobin A1C >7% and has been reported to be as high as 20-25% in women with a hemoglobin A1C >10%. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre- eclampsia, spontaneous abortions, preterm delivery, and delivery complications.
Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Animal Data In embryo-fetal development trials, sitagliptin administered to pregnant rats and rabbits during organogenesis (gestation day 6 to 20) did not adversely affect developmental outcomes at oral doses up to 250 mg/kg (30-times the 100 mg clinical dose) and 125 mg/kg (20-times the 100 mg clinical dose), respectively, based on AUC. Higher doses in rats associated with maternal toxicity increased the incidence of rib malformations in offspring at 1,000 mg/kg, or approximately 100-times the clinical dose, based on AUC.
Placental transfer of sitagliptin was observed in pregnant rats and rabbits. Sitagliptin administered to female rats from gestation day 6 to lactation day 21 caused no functional or behavioral toxicity in offspring of rats at doses up to 1,000 mg/kg.
8.2Lactation Risk Summary There is no information regarding the presence of sitagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Sitagliptin is present in rat milk and therefore possibly present in human milk [ see Data ]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sitagliptin and any potential adverse effects on the breastfed infant from sitagliptin or from the underlying maternal condition.
Data Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1.
8.4Pediatric Use The safety and effectiveness of BRYNOVIN have not been established in pediatric patients. Three 20-week double-blind, placebo-controlled trials each with 34-week extensions were conducted to evaluate the efficacy and safety of sitagliptin in 410 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus, with or without insulin therapy (HbA1C 6.5-10% for patients not on insulin, HbA1C 7-10% for patients on insulin). At trial entry, patients in trial 1 were not treated with oral antihyperglycemic agents; patients in trials 2 and 3 were on maximally tolerated metformin therapy.
The primary efficacy endpoint was the change from baseline in HbA1C after 20 weeks of therapy. The pre-specified primary efficacy analyses included data from trial 1 and pooled data from trials 2 and 3, regardless of glycemic rescue or treatment discontinuation. In both efficacy analyses, the effect of treatment with sitagliptin was not significantly different from placebo.
In trial 1, the mean baseline HbA1C was 7.5%, and 12% of patients were on insulin therapy. At week 20, the change from baseline in HbA1C in patients treated with sitagliptin (N=95) was 0.06% compared to 0.23% in patients treated with placebo (… [Excerpted — this section continues on DailyMed.]
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary The limited available data with sitagliptin in pregnant women are not sufficient to inform a drug- associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations] . No adverse developmental effects were observed when sitagliptin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 30-times and 20-times, respectively, the 100 mg clinical dose, based on AUC [see Data].
The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a hemoglobin A1C >7% and has been reported to be as high as 20-25% in women with a hemoglobin A1C >10%. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre- eclampsia, spontaneous abortions, preterm delivery, and delivery complications.
Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Animal Data In embryo-fetal development trials, sitagliptin administered to pregnant rats and rabbits during organogenesis (gestation day 6 to 20) did not adversely affect developmental outcomes at oral doses up to 250 mg/kg (30-times the 100 mg clinical dose) and 125 mg/kg (20-times the 100 mg clinical dose), respectively, based on AUC. Higher doses in rats associated with maternal toxicity increased the incidence of rib malformations in offspring at 1,000 mg/kg, or approximately 100-times the clinical dose, based on AUC.
Placental transfer of sitagliptin was observed in pregnant rats and rabbits. Sitagliptin administered to female rats from gestation day 6 to lactation day 21 caused no functional or behavioral toxicity in offspring of rats at doses up to 1,000 mg/kg.
🧒 Pediatric Use ▾
8.4Pediatric Use The safety and effectiveness of BRYNOVIN have not been established in pediatric patients. Three 20-week double-blind, placebo-controlled trials each with 34-week extensions were conducted to evaluate the efficacy and safety of sitagliptin in 410 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus, with or without insulin therapy (HbA1C 6.5-10% for patients not on insulin, HbA1C 7-10% for patients on insulin). At trial entry, patients in trial 1 were not treated with oral antihyperglycemic agents; patients in trials 2 and 3 were on maximally tolerated metformin therapy.
The primary efficacy endpoint was the change from baseline in HbA1C after 20 weeks of therapy. The pre-specified primary efficacy analyses included data from trial 1 and pooled data from trials 2 and 3, regardless of glycemic rescue or treatment discontinuation. In both efficacy analyses, the effect of treatment with sitagliptin was not significantly different from placebo.
In trial 1, the mean baseline HbA1C was 7.5%, and 12% of patients were on insulin therapy. At week 20, the change from baseline in HbA1C in patients treated with sitagliptin (N=95) was 0.06% compared to 0.23% in patients treated with placebo (N=95), a difference of -0.17% (95% CI: -0.62, 0.28). In trials 2 and 3, the mean baseline HbA1C was 8%, 15% of patients were on insulin and 72% were on metformin HCl dosages of greater than 1,500 mg daily.
At week 20, the change from baseline in HbA1C in patients treated with sitagliptin (N=107) was -0.23% compared to 0.09% in patients treated with placebo (N=113), a difference of -0.33% (95% CI: -0.70, 0.05).
🧓 Geriatric Use ▾
8.5Geriatric Use Of the total number of subjects (N=3,884) in pre-approval clinical safety and efficacy trials of sitagliptin, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness have been observed between patients 65 years and over and younger patients. Because sitagliptin is substantially excreted by the kidney, and because aging can be associated with reduced renal function, renal function should be assessed more frequently in elderly patients [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 )] .
🆘 Overdosage ▾
10 OVERDOSAGE In the event of an overdose with BRYNOVIN, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Employ the usual supportive measures dictated by the patient’s clinical status. Sitagliptin is modestly dialyzable.
In clinical trials, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes mellitus by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal.
These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP.
GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic dosages.
12.2Pharmacodynamics General In patients with type 2 diabetes mellitus, administration of sitagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
In trials with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia. Sitagliptin and Metformin HCl Coadministration In a two-day trial in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations.
Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear how these findings relate to changes in glycemic control in patients with type 2 diabetes mellitus. Cardiac Electrophysiology In a randomized, placebo-controlled crossover trial, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo.
At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the trial. Following the 800 mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline was observed at 3 hours postdose and was 8 msec. This increase is not considered to be clinically significant.
At the 800 mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100-mg dose. In patients with type 2 diabetes mellitus administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.
12.3Pharmacokinetics The pharmacokinetics of sitagliptin have been extensively characterized in healthy subjects and patients with type 2 diabetes mellitus. Following a single oral 100-mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 µM•hr, C max was 950 nM, and apparent terminal half-life (t 1/2 ) was 12.4 hours. Plasma AUC of sitagliptin in… [Excerpted — this section continues on DailyMed.]
🧬 Mechanism of Action ▾
12.1Mechanism of Action Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes mellitus by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal.
These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP.
GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic dosages.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING BRYNOVIN (sitagliptin) oral solution 25 mg/mL is supplied as a clear colorless, to nearly colorless aqueous solution in an amber glass bottle with a child resistant closure. Each bottle contains 120 mL oral solution, NDC 24338-017-01 Storage Store refrigerated at 2°C to 8°C (36°F to 46°F) [see USP]; Protect from light. Avoid excessive heat and freezing. Discard unused portion 90 days after first opening.
📋 Description ▾
11 DESCRIPTION BRYNOVIN (sitagliptin) oral solution contains sitagliptin hydrochloride (HCl), an orally-active inhibitor of the DPP-4 enzyme. Sitagliptin HCl is described chemically as ((3R)-3-Amino-1-(3-(trifluoromethy1)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1)-4-(2,4,5-trifluorophenyl)butan-l-one HCl monohydrate. The empirical formula is C 16 H 15 F 6 N 5 O•HCl.H 2 O and the molecular weight is 461.79.
The structural formula is: Sitagliptin HCl is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water; very slightly soluble in ethanol; and practically insoluble in n-Heptane. BRYNOVIN oral solution is a clear, colorless to nearly colorless oral solution.
Each mL contains 27.24 mg of sitagliptin HCl, equivalent to 25 mg of sitagliptin. BRYNOVIN contains the following inactive ingredients: butylated hydroxyanisole, citric acid anhydrous, edetate disodium, hydroxyethyl cellulose, methylparaben sodium, polysorbate 80, purified water, sodium citrate dihydrate, and sweetener/flavoring agent. Structure
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Dosage and Administration Instruct patients or caregivers to use an oral dosing syringe or oral dosing cup to correctly measure the prescribed amount of medication. Inform patients that oral dosing syringes and cups may be obtained from their pharmacy [see Dosage and Administration ( 2.1 )] .
Pancreatitis Inform patients that acute pancreatitis has been reported during postmarketing use of sitagliptin. Inform patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to promptly discontinue BRYNOVIN and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions ( 5.1 )] .
Heart Failure Inform patients of the signs and symptoms of heart failure. Before initiating BRYNOVIN, ask patients about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their health care provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions ( 5.2 )] .
Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Inform patients that the incidence of hypoglycemia is increased when BRYNOVIN is added to insulin or a sulfonylurea. Explain to patients receiving BRYNOVIN in combination with these medications the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see Warnings and Precautions ( 5.4 )] . Hypersensitivity Reactions Inform patients that allergic reactions have been reported during postmarketing use of sitagliptin.
If symptoms of allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking BRYNOVIN and seek medical advice promptly [see Warnings and Precautions ( 5.5 )] . Severe and Disabling Arthralgia Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years.
Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions ( 5.6 )] . Bullous Pemphigoid Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions ( 5.7 )] .
Manufactured for: Azurity Pharmaceuticals, Inc. Woburn, MA 01801 BRYNOVIN is a registered trademark of Azurity Pharmaceuticals, Inc. For patent information: https://azurity.com/patents.
This products labeling may have been updated. For current Full Prescribing Information, please visit www.BRYNOVIN.com PN: BRY-PI-00
💬 Medication Guide ▾
SPL MEDGUIDE SECTION Medication Guide BRYNOVIN TM (bri-know-vin) (sitagliptin) oral solution What is the most important information I should know about BRYNOVIN? BRYNOVIN can cause serious side effects, including: • Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis.
Before you start taking BRYNOVIN, tell your healthcare provider if you have ever had: • Pancreatitis • stones in your gallbladder (gallstones) • a history of alcoholism • high blood triglyceride levels • kidney problems Stop taking BRYNOVIN and call your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting.
These may be symptoms of pancreatitis. • Heart failure . Heart failure means your heart does not pump blood well enough. Before you start taking BRYNOVIN , tell your healthcare provider if you have ever had heart failure or have problems with your kidneys.
Contact your healthcare provider right away if you have any of the following symptoms:• increasing shortness of breath or trouble breathing, especially when you lie down • swelling or fluid retention, especially in the feet, ankles or legs • an unusually fast increase in weight • unusual tiredness These may be symptoms of heart failure. What is BRYNOVIN? • BRYNOVIN is a prescription medicine used along with diet and exercise to lower blood sugar in adults with type 2 diabetes. • BRYNOVIN is not for people with type 1 diabetes. • If you have had pancreatitis (inflammation of the pancreas) in the past, it is not known if you have a higher chance of getting pancreatitis while you take BRYNOVIN. • It is not known if BRYNOVIN is safe and effective in children.
Who should not take BRYNOVIN? Do not take BRYNOVIN if: • you are allergic to sitagliptin or any of the ingredients in BRYNOVIN. See the end of this Medication Guide for a complete list of ingredients in BRYNOVIN.
Symptoms of a serious allergic reaction to BRYNOVIN may include rash, raised red patches on your skin (hives), or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing. What should I tell my healthcare provider before taking BRYNOVIN? Before you take BRYNOVIN, tell your healthcare provider about all of your medical conditions, including if you: • have or have had inflammation of your pancreas (pancreatitis). • have kidney problems. • have heart failure. • are pregnant or plan to become pregnant.
It is not known if BRYNOVIN will harm your unborn baby. If you are pregnant, talk with your healthcare provider about the best way to control your blood sugar while you are pregnant. • are breastfeeding or plan to breastfeed. It is not known if BRYNOVIN will pass into your breast milk.
Talk with your healthcare provider about the best way to feed your baby if you are taking BRYNOVIN. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take.
Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take BRYNOVIN? • Use an oral dosing syringe or oral dosing cup to correctly measure your dose of BRYNOVIN. Ask your pharmacist for an oral dosing syringe or oral dosing cup if you do not have one. • Take BRYNOVIN 1 time each day exactly as your healthcare provider tells you. • You can take BRYNOVIN with or without food. • Your healthcare provider will do blood tests to check how well your kidneys are working before and during your treatment with BRYNOVIN. • Your healthcare provider may tell you to take BRYNOVIN along with other diabetes medicines.
Low blood sugar can happen more often when BRYNOVIN is taken with certain other diabetes medicines. See “ What are t… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacokinetics ▾
12.3Pharmacokinetics The pharmacokinetics of sitagliptin have been extensively characterized in healthy subjects and patients with type 2 diabetes mellitus. Following a single oral 100-mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 µM•hr, C max was 950 nM, and apparent terminal half-life (t 1/2 ) was 12.4 hours. Plasma AUC of sitagliptin increased in a dose-proportional manner and increased approximately 14% following 100 mg doses at steady-state compared to the first dose.
The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes mellitus. Absorption After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed with peak plasma concentrations (median T max ) occurring 1 to 4 hours post dose.
The absolute bioavailability of sitagliptin is approximately 87%. Effect of Food Administration of 100 mg sitagliptin oral solution with a high-fat meal resulted in similar AUC, ~28.8% decrease in C max and 2.5 hour delay in T max when compared to the fasted state (T max = 1.5 hour). The difference in C max and T max is not considered clinically meaningful.
Distribution The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%). Elimination Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.
The apparent terminal t 1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min. Metabolism Following a [ 14 C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin.
In vitro trials indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8. Excretion Following administration of an oral [ 14 C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.
Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of P-glycoprotein (P-gp), which may also be involved in mediating the renal elimination of sitagliptin.
However, cyclosporine, a P-gp inhibitor, did not reduce the renal clearance of sitagliptin. Specific Populations Patients with Renal Impairment An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment with eGFR of 30 to less than 45 mL/min/1.73 m 2 , and an approximately 4-fold increase was observed in patients with severe renal impairment, including patients with ESRD on hemodialysis, as compared to normal healthy control subjects. Patients with Hepatic Impairment In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), mean AUC and C max of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100-mg dose of sitagliptin.
These differences are not considered to be clinically meaningful. There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score >9). Effects of Age, Body Mass Index (BMI), Gender, and Race Based on a population pharmacokinetic analysis or a composite analys… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacodynamics ▾
12.2Pharmacodynamics General In patients with type 2 diabetes mellitus, administration of sitagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
In trials with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia. Sitagliptin and Metformin HCl Coadministration In a two-day trial in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations.
Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear how these findings relate to changes in glycemic control in patients with type 2 diabetes mellitus. Cardiac Electrophysiology In a randomized, placebo-controlled crossover trial, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo.
At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the trial. Following the 800 mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline was observed at 3 hours postdose and was 8 msec. This increase is not considered to be clinically significant.
At the 800 mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100-mg dose. In patients with type 2 diabetes mellitus administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.
🔬 Clinical Studies ▾
14 CLINICAL STUDIES Overview of Clinical Trials The effectiveness of BRYNOVIN has been established for glycemic control in patients with type 2 diabetes mellitus based on adequate and well-controlled trials of sitagliptin tablets, referenced below as “sitagliptin”. There were approximately 5,200 patients with type 2 diabetes mellitus randomized in nine double-blind, placebo-controlled clinical safety and efficacy trials conducted to evaluate the effects of sitagliptin on glycemic control. In a pooled analysis of seven of these trials, the ethnic/racial distribution was approximately 59% white, 20% Hispanic or Latino, 10% Asian, 6% Black or African American, and 6% other groups.
Patients had an overall mean age of approximately 55 years (range 18 to 87 years). In addition, an active (glipizide)- controlled trial of 52-weeks duration was conducted in 1,172 patients with type 2 diabetes mellitus who had inadequate glycemic control on metformin. In patients with type 2 diabetes mellitus, treatment with sitagliptin produced clinically significant improvements in hemoglobin A1C, fasting plasma glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to placebo.
14.1Monotherapy A total of 1,262 patients with type 2 diabetes mellitus participated in two double-blind, placebo-controlled trials, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of sitagliptin monotherapy. In both monotherapy trials, patients currently on an antihyperglycemic agent discontinued the agent, and underwent a diet, exercise, and drug washout period of about 7 weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized after completing a 2-week single-blind placebo run-in period; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week single-blind placebo run-in period.
In the 18-week trial, 521 patients were randomized to placebo, sitagliptin 100 mg, or sitagliptin 200 mg, and in the 24-week trial 741 patients were randomized to placebo, sitagliptin 100 mg, or sitagliptin 200 mg. Patients who failed to meet specific glycemic goals during the trials were treated with metformin rescue, added on to placebo or sitagliptin. Treatment with sitagliptin at 100 mg daily provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 6).
In the 18-week trial, 9% of patients receiving sitagliptin 100 mg and 17% who received placebo required rescue therapy. In the 24-week trial, 9% of patients receiving sitagliptin 100 mg and 21% of patients receiving placebo required rescue therapy. The improvement in A1C compared to placebo was not affected by gender, age, race, prior antihyperglycemic therapy, or baseline BMI.
In these 18- and 24-week trials, among patients who were not on an antihyperglycemic agent at trial entry, the reductions from baseline in A1C were -0.7% and -0.8%, respectively, for those given sitagliptin, and -0.1% and -0.2%, respectively, for those given placebo. Overall, the 200 mg daily dosage did not provide greater glycemic efficacy than the 100 mg daily dosage. The effect of sitagliptin on lipid endpoints was similar to placebo.
Body weight did not increase from baseline with sitagliptin therapy in either trial, compared to a small reduction in patients given placebo. Table 6:Glycemic Parameters in 18- and 24-Week Placebo-Controlled Trials of Sitagliptin in Adult Patients with Type 2 Diabetes Mellitus* 18-Week Trial 24-Week Trial Sitagliptin 100 mg Placebo Sitagliptin 100 mg Placebo A1C (%) N = 193 N = 103 N = 229 N = 244 Baseline (mean) 8 8.1 8 8 Change from baseline (adjusted mean†) -0.5 0.1 -0.6
0.2Difference from placebo (adjusted mean†) (95% CI) -0.6 ‡ (-0.8, -0.4) -0.8 ‡ (-1.0, -0.6) Patients (%) achieving A1C <7% 69 (36%) 16 (16%) 93 (41%) 41 (17%) FPG (mg/dL) N = 201 N = 107 N = 234 N = 247 Baseline (mean) 180 184… [Excerpted — this section continues on DailyMed.]
🧪 Nonclinical Toxicology ▾
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment Of Fertility A two-year carcinogenicity trial was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons.
Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity trial was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD.
Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay. In rat fertility trials with oral gavage doses of 125, 250, and 1,000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total) and females were treated 2 weeks prior to mating through gestation day 7.
No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, non-dose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).
📄 Carcinogenesis, Mutagenesis, Impairment of Fertility ▾
13.1Carcinogenesis, Mutagenesis, Impairment Of Fertility A two-year carcinogenicity trial was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons.
Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity trial was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD.
Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay. In rat fertility trials with oral gavage doses of 125, 250, and 1,000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total) and females were treated 2 weeks prior to mating through gestation day 7.
No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, non-dose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).
📄 Package Label / Principal Display Panel ▾
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL BRYNOVIN (Sitagliptin) Oral Solution 25 mg/mL - Carton Label NDC 24338-017-01 120 mL Rx only BRYNOVIN (Sitagliptin) Oral Solution 25 mg/mL - Bottle Label NDC 24338-017-01 120 mL Rx only Sitagliptin Carton Label Sitagliptin bottle label
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