Kombiglyze (Saxagliptin and Metformin) is a prescription medicine that contains a combination of two drugs. Saxagliptin increases the half-life of natural incretin while metformin acts as a sensitizer. It is recommended in patients with diabetes mellitus type 2 in addition to diet and exercise who are not controlled on monotherapy.

Kombiglyze (Saxagliptin and Metformin) Uses:

• Diabetes mellitus, type 2:

  • Management of type 2 diabetes mellitus in adults as an adjunct to diet and exercise when treatment with both saxagliptin and metformin is needed.

Kombiglyze (Saxagliptin and Metformin) Dose in Adults

Kombiglyze (Saxagliptin and Metformin) Dose in the treatment of type 2 Diabetes mellitus: Oral:

• Extended-release (ER) formulation:

Note:

• Initial doses should be based on the current daily dose of saxagliptin and metformin.
• The daily dose should usually be administered once daily.
• Maximum: Saxagliptin 5 mg/metformin 2 g ER per day.

• Patients inadequately controlled on metformin alone:

  • Initial: Saxagliptin 2.5 to 5 mg once daily in addition to the current daily dose of metformin.
  • Patients who need saxagliptin 2.5 mg and metformin >1 g/day should not be started on combination products.

• Patients inadequately controlled on saxagliptin 5 mg alone:

  • Initial dose: Saxagliptin 5 mg/metformin 500 mg ER once daily.
  • Patients who need saxagliptin 2.5 mg and are metformin-naive or require metformin >1 g/day should not be switched to the combination product.

• Concomitant use with strong CYP3A4/5 inhibitors:

  • Maximum: Saxagliptin 2.5 mg/metformin 1 g once daily

• Concomitant use with insulin or insulin secretagogues:

  • A decreased dose of insulin or insulin secretagogues (eg, sulfonylureas) may be required.

• Immediate release formulation [Canadian product]:

  • Starting doses should be based on the current dose of saxagliptin and metformin; daily dose should be divided into 2 equal doses taken with food.
  • Maximum: Saxagliptin 5 mg/metformin 2 g per day
  • Patients inadequately controlled on metformin alone:
    • starting dose: Saxagliptin 2.5 mg twice daily plus a current dose of metformin.

  • Concomitant use with insulin:

    • A decreased dose of insulin may be required.

Use in Children:

Not indicated.

Pregnancy Risk Category: B

• Metformin crosses over to the placenta. Refer to the individual monographs.

Use of metformin and saxagliptin during breastfeeding

• Breast milk contains metformin; excretion is unknown.
• The manufacturer suggests that you consider the risks of infant exposure, the benefits to breastfeeding and the treatment options for the mother before beginning to breastfeed.

Kombiglyze (Saxagliptin and Metformin) Dose in Kidney Disease:

• eGFR >45 mL/minute/1.73 m²:
  • No dosage adjustment needed;
  • monitor renal function at least yearly.
• eGFR 30 to 45 mL/minute/1.73 m²:
  • Use is not recommended for beginning therapy; if eGFR falls to <45 mL/minute/1.73 m² during therapy, take into account benefits/risks of continuing therapy and limit saxagliptin dose to 2.5 mg once daily.
  • A metformin dosage reduction of 50% (maximum: 1 g/day) and monitoring of renal function every 3 months is advised.
• eGFR <30 mL/minute/1.73 m²:
  • contraindicated use.

Kombiglyze (Saxagliptin and Metformin) Dose in Liver disease:

The manufacturer's advice is to avoid metformin as liver disease is a risk factor for the development of lactic acidosis during metformin therapy. However, continued use of metformin in diabetics with liver dysfunction, including cirrhosis, has been used successfully and may be associated with a survival benefit in certain patients; use cautiously in patients at risk for lactic acidosis (eg, renal impairment, alcohol use).

Side Effects of Kombiglyze (Saxagliptin and Metformin)

See individual agents (metformin and saxagliptin)

Contraindications to Kombiglyze (Saxagliptin and Metformin):

US Labeling

• History of severe hypersensitivity reactions (eg anaphylaxis or angioedema, exfoliative conditions) to saxagliptin or metformin or any component thereof;
• Grave renal impairment (eGFR 30mL/minute/1.73m2)
• acute or chronic metabolic acidosis including diabetic ketoacidosis

Canadian labeling:

• Hypersensitivity to saxagliptin or another dipeptidylpeptidase-4 inhibitor, metformin, and any component of the formulation
• Type 1 diabetes mellitus: Instability and/or insulin-dependent
• Acute or chronic metabolic acidosis including diabetic ketoacidosis and history of ketoacidosis without or with coma.
• Patients with elevated serum creatinine (60mL/minute) or abnormal creatinine clearance (>60mL/minute) may have renal disease.
• This could also be due to conditions like cardiovascular collapse, acute coronary infarction, septicemia, or when the renal function is not known.
• Excessive ethanol consumption (acute and chronic).
• Moderate and severe hepatic impairment.
• Hyperlactatemia is often linked to cases of cardiac collapse and other diseases associated with hypoxemia, such as cardiorespiratory failure.
• During stressful conditions (e.g. severe infection, trauma and surgery, as well as the postoperative recovery phase).
• severe dehydration.
• pregnancy.
• Breastfeeding

Warnings and precautions

• Arthralgia

  • DPP-IV inhibitors have been linked to severe and disabling arthritis. It can occur from one day to several years after treatment began.
  • The symptoms may resolve after discontinuing therapy.
  • Patients may experience a recurrence if the DPPIV inhibitor therapy is stopped.

• Bullous pemphigoid:

  • Bullous pemphigoid has been linked to DPP-4 inhibitor treatment.
  • These cases are usually treated with systemic or topical immunosuppressive therapy, and then the DPP-4 inhibitor therapy is stopped.
  • Patients should be advised to notify you if they develop blisters or emphysies.
  • If bullous pemphigoid symptoms are suspected, discontinue treatment and consult a dermatologist.

• Hematologic:

  • Saxagliptin has been associated with a decrease in the number of lymphocytes. The clinical significance of this finding is not known.
  • Patients with persistent or unusual infections may require monitoring of their lymphocyte count.

• Hypersensitivity reactions

  • Use of saxagliptin has been associated with rare hypersensitivity reactions.
  • These reactions include anaphylaxis, exfoliative dermatologic reactions and angioedema.
  • If you experience signs/symptoms that indicate a severe hypersensitivity reaction, stop using saxagliptin.
  • Generally, events are noted within the first three months of therapy. They may also occur after the first dose.
  • If the patient is experiencing angioedema due to DPP-IV inhibitions, be cautious.

• Lactic acidosis: [US Boxed Warning]:

  • Metformin-associated lactosis has been linked to deaths, hypothermia and hypotension after metformin was approved for marketing.
  • The symptoms include malaise, myalgias and respiratory distress.
  • Patients with renal impairment, concurrent use of certain drugs (eg carbonic anhydrase inhibiters such as topiramate), >=65, having a radiologic scan with contrast, surgery, and other procedures, hypoxic conditions (eg acute heart failure), excessive alcohol consumption, and hepatic impairment are all risk factors for lactic acidosis.
  • If you suspect lactic acidosis, immediately stop; prompt hemodialysis recommended.
  • Any patient on metformin who has evidence of acidosis, but not ketoacidosis, should be tested for lactic acidosis.
  • Patients with hypoperfusion, hypohydration, sepsis or hypoxemia should be stopped using this medication.
  • Patients with restricted fluid and food intake may be temporarily withheld from receiving treatment.
  • With renal dysfunction, the risk of lactic acidosis and accumulation increases.

• Pancreatitis

  • Saxagliptin has been shown to cause acute pancreatitis in some cases.
  • You should monitor for pancreatitis signs and symptoms. If you suspect pancreatitis, stop using the medication immediately.
  • Patients with a history or pancreatitis should be cautious. It is not known if they are at higher risk.

• Concentrations of Vitamin B:

  • Metformin long-term use can lead to vitamin B deficiency. Long-term therapy should monitor vitamin B serum levels regularly.
  • Patients receiving metformin should monitor their B serum levels, especially those suffering from peripheral neuropathy or anemia.

• Bariatric surgery

  • Absorption altered:

    • After surgery, you can use other agents.
    • Gastric bypass and Sleeve Gastrectomy can cause changes in absorption.
    • ER tablets can have a decreased effect after gastric bypass. This is due to the direct bypassing of the stomach and proximal bowel with gastric bypass, or a faster gastric emptying and proximal bowel transit with sleeve gastrectomy.
    • The administration of IR tablets after gastric bypass (Rouxen-Y gastric bypass [RYGB]) led to an increase in absorption (AUC increased 21%) and bioavailability (50%).
    • After gastric bypass (RYGB), weight loss is not affected by metformin.
    • As long as normal renal function remains intact, it is not necessary to reduce metformin doses after gastric bypass.

  • Exposure to Glucagon-like peptide-1 and its therapeutic efficacy

    • Monitor closely for symptoms of pancreatitis. Gastric bypass and Sleeve Gastrectomy can increase endogenous secretion glucagon-like Peptide-1.
    • One placebo-controlled, single-dose study evaluated short-term sitagliptin therapy in patients with gastric bypass who had persistent or recurrent type 2. It was found to be well-tolerated, and it provided a modest, but significant, drop in blood glucose postprandially (Shah 2018).

• Heart failure:

  • Metformin can be used for patients with stable or inpatient heart failure.
  • Hypoperfusion may increase the risk of developing lactic acidosis.
  • Metformin may reduce mortality in patients with heart disease and decrease hospital readmissions.
  • In a multi-center, randomized, double-blind placebo-controlled trial, heart failure in patients with type II diabetes has been reported. The risk was higher in patients who had a history of or are at high risk of cardiovascular events.
  • In an ambulatory setting, with lower baseline cardiovascular risk factors, a population-based retrospective study did not show any increased risk for patients taking saxagliptin.
  • If you notice any signs or symptoms of heart disease, discontinue therapy immediately.
  • The American Heart Association has stated that metformin and saxagliptin may be agents that can exacerbate myocardial dysfunction.
  • The ADA recommends that patients with heart disease should not use saxagliptin.

• Hepatic impairment

  • Because of the possibility for lactic acidosis, the manufacturer suggests that patients with hepatic dysfunction avoid metformin.
  • Metformin may provide a survival benefit for patients with diabetes and liver dysfunction.

• Renal impairment

  • Metformin is mostly excreted by your kidneys. Before starting treatment, assess your renal function and then periodically use eGFR.
  • With increasing renal dysfunction, the risk of metformin accumulation or lactic acidosis is higher.
  • Patients with eGFR 30 mL/minute/1.73 m2.
  • Metformin is recommended for patients with an eGFR of 30 to 45 mL/minute/1.73m2. If metformin is used, it should be reduced.
  • It is also necessary to reduce the dosage of Saxagliptin.
  • Metformin disposition may be affected by concurrent medication that can affect renal function (ie tubular secretion).
  • Patients with prerenal azotemia and dehydration should stop taking Metformin.

• Stress-related disorders:

  • In stressful situations such as fever, trauma, infection, or surgery, it may be necessary to switch to insulin instead of metformin.

Saxagliptin and metformin: Drug Interaction

Monitoring parameters:

• Urine for glucose and ketones.
• plasma glucose.
• HbA1C (at least twice yearly in patients who have stable glycemic control and are achieving treatment goals; every 3 months in patients not meeting treatment goals or with alteration in therapy.
• initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices, and lymphocyte counts if unusual or persistent infection).
• hepatic function.
• renal function (eGFR) should be done before starting therapy and at least yearly (more often in patients at risk of developing renal impairment; every 3 to 6 months if eGFR 45 to <60 mL/minute/1.73 m²; every 3 months if eGFR 30 to <45 mL/minute/1.73 m².
• vitamin B-12 serum concentrations every 2 to 3 years.
• folate levels (if megaloblastic anemia is suspected);
• signs/symptoms of pancreatitis and/or heart failure

How to administer Kombiglyze (Saxagliptin and Metformin)?

• Oral: Administer extended-release (ER) tablets once daily with dinner.
• Swallow whole; do not crush, cut, or chew tablets.
• Immediate release formulation [Canadian product] should be taken twice daily with meals (eg, breakfast and dinner).

Mechanism of action of Kombiglyze (Saxagliptin and Metformin):

• Saxagliptin blocks the dipeptidylpeptidase IV enzyme (DPP-IV), resulting in prolonged active incretin levels.
• Incretin hormones, such as glucagon-like protein-1 [GLP-1] or glucose-dependent insulinotropic peptide [GIP], regulate glucose homeostasis.
• They increase insulin synthesis and release by pancreatic beta cells and decrease pancreatic alpha cell glucagon production.
• A decreased secretion of glucagon results in a lower hepatic glucose level.
• Normal physiology states that incretin hormones, which are released throughout the day by the intestine and increase with meals, are quickly inactivated by DPP-IV enzyme.
• Metformin lowers hepatic glucose and intestinal absorption, and increases insulin sensitivity (increases peripheral sugar uptake and use).

Also, see individual drug details.

International Brands of Saxagliptin and metformin:

• Kombiglyze XR
• Kombiglyze
• Comboglyze
• Diasaxin
• Duoglyze
• Saxavam

Saxagliptin and metformin Brand Names in Pakistan:

No Brands Available in Pakistan.