Saxagliptin and dapagliflozin

Uses

Dapagliflozin is used for an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Monotherapy And Combination Therapy: Saxagliptin is used for an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Limitation Of Use: Saxagliptin is not used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

Saxagliptin and dapagliflozin is also used to associated treatment for these conditions: Type 2 Diabetes MellitusType 2 Diabetes Mellitus

How Saxagliptin and dapagliflozin works

Dapagliflozin inhibits the sodium-glucose contransporter 2(SGLT2) which is primarily located in the proximal tubule of the nephron. SGLT2 facilitates 90% of glucose resorption in the kidneys and so its inhibition allows for glucose to be excreted in the urine. This excretion allows for better glycemic control and potentially weight loss in patients with type 2 diabetes mellitus.

Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor antidiabetic for the treatment of type 2 diabetes. DPP-4 inhibitors are a class of compounds that work by affecting the action of natural hormones in the body called incretins. Incretins decrease blood sugar by increasing consumption of sugar by the body, mainly through increasing insulin production in the pancreas, and by reducing production of sugar by the liver. [Bristol-Myers Squibb Press Release] DPP-4 is a membrane associated peptidase which is found in many tissues, lymphocytes and plasma. DPP-4 has two main mechanisms of action, an enzymatic function and another mechanism where DPP-4 binds adenosine deaminase, which conveys intracellular signals via dimerization when activated. Saxagliptin forms a reversible, histidine-assisted covalent bond between its nitrile group and the S630 hydroxyl oxygen on DPP-4. The inhibition of DPP-4 increases levels active of glucagon like peptide 1 (GLP-1), which inhibits glucagon production from pancreatic alpha cells and increases production of insulin from pancreatic beta cells.

Dosage

Saxagliptin and dapagliflozin dosage

5 mg orally once a day.May increase to 10 mg orally once a day in patients tolerating therapy with 5 mg and requiring additional glycemic control

Recommended Dosage: The recommended dosage of Saxagliptin is 2.5 mg or 5 mg once daily taken regardless of meals. Saxagliptin tablets must not be split or cut.

Dosage In Patients With Renal Impairment: No dosage adjustment for Saxagliptin is recommended for patients with mild renal impairment (CrCl >50 mL/min).

The dosage of Saxagliptin is 2.5 mg once daily (regardless of meals) for patients with moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis (CrCl ≤ 50 mL/min). Saxagliptin should be administered following hemodialysis. Saxagliptin has not been studied in patients undergoingperitoneal dialysis.

Because the dosage of Saxagliptin should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of Saxagliptin and periodically thereafter. Renal function can be estimated from serum creatinine using the Cockcroft-Gault formula or Modification of Diet in Renal Disease formula.

Dosage Adjustment With Concomitant Use Of Strong CYP3A4/5 Inhibitors: The dosage of Saxagliptin is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin)

Concomitant Use With An Insulin Secretagogue (e.g., Sulfonylurea) Or With Insulin When Saxagliptin is used in combination with aninsulinsecretagogue (e.g.,sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk ofhypoglycemia

May be taken with or without food.

Side Effects

Renal impairment, Female genital mycotic infections, Urinary tract infection, Increased urination, Male genital mycotic infections, Dyslipidemia, Constipation, Discomfort with urination, Extremity pain, Volume depletion, Hypersensitivity

The following serious adverse reactions are described below or elsewhere in the prescribing information: Pancreatitis, Heart Failure, Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin, Hypersensitivity Reactions, Severe and disabling arthralgia, Bullous pemphigoid

Toxicity

Age, gender, race, and body weight do not affect dapagliflozin dosing requirements. Although age does not affect dosing requirements, safety has not been established in pediatric populations and patients at an especially advanced age may be more susceptible to adverse effects. Animal studies in pregnancy showed no fetal toxicity in the first trimester but exposure later in pregnancy was associated with renal pelvic dilatation and maternal toxicity at much higher doses than the maximum recommended human dose. Due to this data, dapagliflozin is not recommended in the second and third trimester of pregnancy. Dapagliflozin is excreted in milk from rats, though this may not necessarily be the case in humans. Children under 2 years old who are exposed to dapagliflozin may be at risk of improper kidney development. Dapagliflozin is not recommended in patients with a creatinine clearance below 45mL/min and is contraindicated in patients with creatinine clearance below 30mL/min. Dose adjustments are not necessary in patients with hepatic impairment at any stage, although the risk and benefit to the patient must be assessed as there is limited data on dapagliflozin use in this population.

Adverse reactions reported in ≥5% of patients treated with saxagliptin and more commonly than in patients treated with placebo are: upper respiratory tract infection, urinary tract infection, and headache.

Precaution

CV disease, history of hypotension, UTI, Children, Elderly. Unknown whether distributed in human breast milk; breastfeeding women should discontinue dapagliflozin or nursing taking into account the importance of the drug to the mother

Moderate and severe renal impairment. Pregnancy and lactation.

Interaction

Hypoglycemia may occur with concomitant use with insulin & insulin secretagogues eg sulfonylureas. Decrease in Cmax & AUC with rifampin. Increase in Cmax & AUC with mefenamic acid. Increased thiazide & loop diuretic effects; may increase risk of dehydration & hypotension. Pioglitazone.

Increased risk of hypoglycaemia with concomitant sulfonylureas, dose reduction may be necessary. Increased serum levels with CYP3A4/5 inhibitors (e.g. atazanavir, ketoconazole, nefazodone, ritonavir). Concomitant CYP3A4 inducers (e.g. carbamazepine, phenobarbital) may reduce the glycaemic lowering effect of saxagliptin.

Volume of Distribution

118L.

151 L

Elimination Route

Oral dapagliflozin reaches a maximum concentration within 1 hour of administration when patients have been fasting. When patients have consumed a high fat meal, the time to maximum concentration increases to 2 hours and the maximum concentration decreases by half though a dose adjustment is not necessary. Oral dapagliflozin is 78% bioavailable.

Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. Saxagliptin did not accumulate following repeated doses. The median time to maximum concentration (Tmax) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite. Bioavailability, 2.5 - 50 mg dose = 67%

Half Life

13.8h.

Saxagliptin = 2.5 hours; 5-hydroxy saxagliptin = 3.1 hours;

Clearance

Oral plasma clearance was 4.9 mL/min/kg, and renal clearance was 5.6 mL/min.

Renal clearance, single 50 mg dose = 14 L/h

Elimination Route

75.2% of dapagliflozin is recovered in the urine with 1.6% of the dose unchanged by metabolism. 21% of the dose is excreted in the feces with 15% of the dose unchanged by metabolism.

Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract.

Pregnancy & Breastfeeding use

Pregnancy Category-C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks

Category B: Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).

Contraindication

Hypersensitivity to dapagliflozin propanediol or to any of the excipients. Moderate to severe renal impairment; end-stage renal disease; active bladder cancer. Pregnancy (2nd & 3rd trimester) & lactation.

Type 1 diabetes, diabetic ketoacidosis.

Special Warning

Renal Impairment: No dosage adjustment is indicated based on renal function. The efficacy is dependent on renal function. lt is not recommended for use in patients with moderate to severe renal impairment (patients with CrCI <60 mL/min or eGFR <60 mL/min/1.73 m2).

Mild Renal Impairment: No dosage adjustment needed.

Moderate to Severe including with ESRD requiring hemodialysis: 2.5 mg once daily.

Hepatic Impairment No dosage adjustment.

Storage Condition

Store between 20-25° C.

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