Brynovin (sitagliptin HCl)

Sitagliptin is commercially available as the phosphate or hydrochloride salt or free base; dosage is expressed in terms of sitagliptin.

Sitagliptin is commercially available as single-entity tablets (sitagliptin phosphate (Januvia(R)), sitagliptin (Zituvio(R) )) or oral solution (sitagliptin hydrochloride (Brynovin(R))); sitagliptin (as the phosphate salt or free base) is also available as fixed combination tablets with immediate- or extended-release metformin hydrochloride (Janumet(R), Zituvimet(R), Janumet(R) XR, Zituvimet(R) XR) or as fixed combination tablets with ertugliflozin (Steglujan(R)).

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Antidiabetic Agents/Gymnema

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gymnema has been shown to increase the number of insulin-secreting beta cells in animals. It has also been shown to increase the activity of enzymes responsible for glucose uptake and utilization and inhibit peripheral utilization of glucose.(1)

CLINICAL EFFECTS: Use of gymnema may result in decreased requirements of antidiabetic agents.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Diabetic patients should be carefully monitored if gymnema is initiated or discontinued from concurrent therapy. The dosage of the patient's antidiabetic agent(s) may need to be adjusted.(2)

DISCUSSION: In a study in 22 non-insulin-dependent patients, patients had decreased blood glucose, glycosylated hemoglobin, and glycosylated plasma proteins during gymnema therapy. Patients were able to decrease the dosage of their conventional antidiabetic therapy and five patients were able to discontinue their conventional antidiabetic therapy.(3) In a study in 27 insulin-dependent patients, patients had decreased insulin requirements, fasting blood glucose, glycosylated hemoglobin, and glycosylated plasma protein levels.(4)

Dipeptidyl Peptidase-Iv Inhibitors/Ace Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bradykinin can cause vasodilation and increase vascular permeability both directly and by stimulating release of substance P, which also increases vascular permeability.(1) Bradykinin is primarily metabolized by angiotensin-1 converting enzyme (ACE). If ACE is inhibited by ACE inhibitors, other metabolic enzymes become more significant in bradykinin metabolism, including dipeptidyl peptidase-IV (DPP-IV). DPP-IV inhibitors can inhibit both bradykinin and substance P metabolism.(2)

CLINICAL EFFECTS: Concomitant therapy can increase the risk of vasodilation leading to an increase in angioedema risk.(1-3)

PREDISPOSING FACTORS: History of previous angioedema.

PATIENT MANAGEMENT: Patients may be more susceptible to developing angioedema if concomitantly taking an ACE inhibitor and DPP-IV inhibitor. Consider switching the patient to an angiotensin receptor blocker or a different anti-diabetic medication. Use caution in patients receiving concurrent therapy.(3) Monitor closely for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or swollen throat, or trouble breathing). Instruct patients to report angioedema symptoms immediately.

DISCUSSION: A pre-marketing surveillance compared incidence of angioedema in patients on vildagliptin versus a comparator. In all patients combined regardless of ACE inhibitor therapy, there was no association between vildagliptin and angioedema. However among patients taking an ACE inhibitor, vildagliptin was associated with an increased risk of angioedema (odds ratio 9.29 (95% CI 1.22-70.70) from pooled data; odds ratio of 4.57 (95% CI 1.57-13.28) in the meta-analysis). This interaction may be dose-related.(4) In a pooled analysis of data from 19 clinical trials of patients on sitagliptin versus a comparator, there was no difference in the incidence of angioedema between patients on ACE inhibitors and sitagliptin compared to patients on ACE inhibitors alone or patients not on ACE inhibitors.(5) However, events were not adjudicated and encompassed urticaria, anaphylaxis, and hypersensitivity reactions, which may have confounded the results.(6) A disproportionality analysis of the WHO pharmacovigilance database found 340,686 reports of bradykinin-mediated angioedema. Of those, 345 reports involved patients on concomitant ACE inhibitor and DPP-IV inhibitor, with a reporting odds ratio of 42.77 (95% CI 36.93-49.53). There was no association between use of a DPP-IV inhibitor without an ACE inhibitor and angioedema.(7)

*History of serious hypersensitivity (e.g., anaphylaxis, angioedema) to sitagliptin or to any ingredient in the formulation.

• Acute pancreatitis

• Chronic heart failure
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Chronic pancreatitis

• Kidney disease with likely reduction in glomerular filtration rate (GFr)

Adverse effects reported in at least 5% of patients receiving sitagliptin as monotherapy and more commonly than with placebo include upper respiratory tract infection, nasopharyngitis, and headache. In add-on trials with a sulfonylurea or insulin, hypoglycemia was more commonly reported in patients receiving sitagliptin than placebo.

Adverse effects reported in at least 5% of patients receiving sitagliptin concomitantly with metformin and more commonly than with placebo include diarrhea, upper respiratory tract infection, and headache.

Adverse effects reported in clinical trials of sitagliptin given concomitantly with ertugliflozin were similar in type and incidence to those reported with ertugliflozin and sitagliptin alone.

Less Frequent

• Upper respiratory infection

Rare or Very Rare

• Acute pancreatitis
• Acute renal failure
• Anaphylaxis
• Angioedema
• Bullous pemphigoid
• Cutaneous vasculitis
• Exfoliative dermatitis
• Heart failure
• Hypoglycemic disorder
• Interstitial nephritis
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Necrotizing pancreatitis
• Rhabdomyolysis
• Skin rash
• Stevens-johnson syndrome
• Urticaria

Less Frequent

• Headache disorder
• Pharyngitis
• Weight gain

Rare or Very Rare

• Abnormal hepatic function tests
• Acute abdominal pain
• Arthralgia
• Back pain
• Constipation
• Diarrhea
• Myalgia
• Nausea
• Pain in extremities
• Peripheral edema
• Pruritus of skin
• Stomatitis
• Vomiting

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Safety and efficacy of sitagliptin alone or in fixed combination with metformin or ertugliflozin have not been established in children younger than 18 years of age.

Three double-blind, placebo-controlled trials conducted in pediatric patients aged 10--17 years with inadequately controlled type 2 diabetes mellitus (with or without insulin therapy) failed to find a difference in efficacy between those that received sitagliptin versus placebo.

Data are lacking on the use of sitagliptin in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In embryofetal developmental studies, no adverse developmental effects were observed during organogenesis when sitagliptin was administered to pregnant rats and rabbits during organogenesis at doses of 250 and 125 mg/kg, respectively (up to 30 and 20 times, respectively, the 100-mg clinical dosage based on AUC).

Sitagliptin is distributed into milk in rats; data are lacking regarding the presence of the drug in human milk, the effects on the breast-fed infant, or effects on milk production. 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 breast-fed infant from sitagliptin or the underlying maternal condition.

Dosage should be selected with caution because of age-related decreases in renal function. Dosage should be titrated carefully to the minimum dosage necessary for adequate glycemic control. The fixed combination of sitagliptin and ertugliflozin is expected to have diminished efficacy in geriatric patients with renal impairment.

Of the 3884 patients who received sitagliptin in clinical trials, 725 patients were >=65 years of age and 61 patients were >=75 years of age. No substantial differences in safety and efficacy of sitagliptin relative to younger adults, but increased sensitivity cannot be ruled out. Renal function should be assessed more frequently in geriatric patients.