Saxagliptin Hcl (saxagliptin HCl)

Dosage of saxagliptin hydrochloride (anhydrous) is expressed in terms of saxagliptin.

When saxagliptin is administered as monotherapy, the drug should be administered orally once daily without regard to meals. Saxagliptin tablets should be swallowed whole; they should not be cut, chewed, or crushed. If a dose of saxagliptin is missed, resume treatment with the next dose and do not take an extra dose.

When saxagliptin is administered in fixed combination with extended-release metformin, the combination should be administered orally once daily with the evening meal; dosage should be titrated gradually to minimize adverse GI effects of the metformin component. The fixed-combination tablets should be swallowed whole, and not cut, chewed, or crushed. If a dose is missed, resume treatment with the next dose and do not take an extra dose. Patients receiving saxagliptin in fixed combination with extended-release metformin hydrochloride should be advised that occasionally, the inactive ingredients of the fixed-combination tablet will be eliminated in the feces as a soft mass that may resemble the original tablet.

Store saxagliptin tablets alone or in fixed combination with extended-release metformin hydrochloride at 20--25degreesC; excursions permitted to 15--30degreesC.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Saxagliptin (>2.5 Mg)/Strong Cyp3a4 Inhib;Atazanav;Darunavir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of saxagliptin.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of saxagliptin.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of saxagliptin states that the dose of saxagliptin should be limited to 2.5 mg daily in patients taking strong inhibitors of CYP3A4.(1)

DISCUSSION: Pretreatment with ketoconazole (200 mg every 12 hours for 9 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of saxagliptin (100 mg) by 62% and 2.5-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 95% and 91%, respectively. The Cmax and AUC of ketoconazole decreased 16% and 13%, respectively.(1,2) Pretreatment with ketoconazole (200 mg every 12 hours for 7 days) increased the Cmax and AUC of a single dose of saxagliptin (100 mg) by 2.4-fold and 3.7-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 96% and 90%, respectively.(1) Inhibitors of CYP3A4 linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,3,4)

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)

Saxagliptin(<=2.5 Mg)/Strong Cyp3a4 Inhib;Atazanav;Darunavir

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

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of saxagliptin.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of saxagliptin.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of saxagliptin states that the dose of saxagliptin should be limited to 2.5 mg daily in patients taking strong inhibitors of CYP3A4.(1)

DISCUSSION: Pretreatment with ketoconazole (200 mg every 12 hours for 9 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of saxagliptin (100 mg) by 62% and 2.5-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 95% and 91%, respectively. The Cmax and AUC of ketoconazole decreased 16% and 13%, respectively.(1,2) Pretreatment with ketoconazole (200 mg every 12 hours for 7 days) increased the Cmax and AUC of a single dose of saxagliptin (100 mg) by 2.4-fold and 3.7-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 96% and 90%, respectively.(1) Inhibitors of CYP3A4 linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,3,4)

*History of serious hypersensitivity to saxagliptin or 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

• Hypoglycemic disorder
• Lymphopenia

Adverse effects reported in at least 5% of patients in clinical trials receiving saxagliptin and more frequently than with placebo include upper respiratory tract infection, urinary tract infection, and headache.

Adverse effects reported in at least 5% of patients in clinical trials receiving saxagliptin in fixed combination with extended-release metformin and more frequently than placebo include headache and nasopharyngitis.

Less Frequent

• Heart failure

Rare or Very Rare

• Acute pancreatitis
• Anaphylaxis
• Angioedema
• Arthralgia
• Bullous pemphigoid
• Exfoliative dermatitis
• Fracture
• Hypoglycemic disorder
• Infection
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Lymphopenia
• Rhabdomyolysis
• Skin rash
• Urticaria

More Frequent

• Headache disorder
• Upper respiratory infection
• Urinary tract infection

Less Frequent

• Gastroenteritis
• Peripheral edema
• Pharyngitis
• Sinusitis
• Vomiting

Rare or Very Rare

• Facial edema

No enhanced messaging available.

Safety and efficacy of saxagliptin have not been established in patients younger than 18 years of age.

Data on the use of saxagliptin in pregnant women are insufficient to determine a drug-associated risk for major birth defects or miscarriage. Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications. In addition, poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

No adverse developmental effects independent of maternal toxicity were observed when saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis and in pregnant and lactating rats during the prenatal and postnatal period.

Saxagliptin is distributed into milk in rats at a milk-to-plasma ratio of approximately 1:1. Data are lacking regarding the presence of saxagliptin in human milk and on the effects of the drug on the breast-fed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for saxagliptin and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.

The manufacturer states that no specific dosage adjustment of saxagliptin is necessary for age alone. Because geriatric patients are more likely to have decreased renal function, care should be taken in dosage selection based on renal function.

Of the 11,301 patients enrolled in clinical trials with saxagliptin, 4751 (42%) were >=65 years of age and 1210 (10.7%) were >=75 years of age. No substantial differences in safety and efficacy in patients >=65 years of age relative to younger adults have been observed, but increased sensitivity cannot be ruled out.

Saxagliptin and its active metabolite are eliminated in part by the kidneys; renal function should be assessed periodically since geriatric patients are more likely to have decreased renal function.