Saxagliptin + Metformin
Drug Related WarningSaxagliptin + Metformin
Metformin accumulation-induced lactic acidosis (plasma concentration >5 mcg/mL) is an uncommon but potentially severe side effect; mortality is approximately 50% if it materializes.
With 0.015 fatal cases per 100 patient years, the incidence is relatively low at ~0.03 cases/per 1000 patient years.
Lactic acidosis is more common in patients with CHF who need pharmacologic therapy, especially those with unstable or severe CHF who risk hypoperfusion and hypoxemia.
The degree of renal impairment and age are associated with an higher risk of lactic acidosis.
Patients 80 or older are more likely to develop lactic acidosis, so do not begin treatment until CrCl shows that renal function is not diminished.
Refrain from Metformin promptly if one has sepsis, dehydration, or hypoxemia.
Avoided in cases where there is laboratory or clinical evidence of liver disease.
Avoid excessive alcohol consumption, acute or chronic, while taking Metformin, as it can intensify the medication's effects on lactate metabolism.
Before any intravascular radiocontrast scan and any surgical procedure, it should be temporarily stopped.
The symptoms of lactic acidosis, such as malaise, myalgias, respiratory difficulty, increasing somnolence, and nonspecific stomach distress, are generally nonspecific and appear gradually at first.
When DPP-4 inhibitors are stopped, joint discomfort that was previously severe and incapacitating usually goes away in a month.
GI symptoms, which are typical during the start of therapy, are unlikely to be drug-related once stable on any dose level of Metformin; further occurrences of Gastrointestinal symptoms could be due to lactic acidosis or other severe disease.
Medicine Type :
Allopathy
Allopathy
Prescription Type:
Prescription Required
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Schedule H
Pharmacological Class:
Dipeptidyl Peptidase 4 (DPP-4) Inhibitor, Biguanide, Therapy Class:
Antidiabetic Agent, Approved Countries
The United States, Canada, the United Kingdom, Australia, Germany, and India.
Saxagliptin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Dipeptyl Peptidase-IV Inhibitors and biguanide.
Saxagliptin + Metformin is approved for treating type 2 diabetes mellitus in adults. It is an oral medication that helps control the blood sugar levels by increasing insulin release, lowering the production of glucose in the liver and improving insulin sensitivity.
Saxagliptin + Metformin is absorbed into the bloodstream, with peak plasma concentrations (Cmax) achieved around 2 hours after dosing. Metformin has an elimination half-life of about 6.2 hours, while Saxagliptin's half-life is approximately 2.5 hours, indicating their durations of action in the body.
The common side effects of Saxagliptin + Metformin are diarrhoea, nausea, vomiting, upset stomach, headache, and sore throat.
Saxagliptin + Metformin is available as tablets for convenient administration.
Saxagliptin + Metformin is available in the United States, Canada, the United Kingdom, Australia, Germany, and India.
Saxagliptin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Dipeptyl Peptidase-IV Inhibitors and biguanide.
Saxagliptin: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), two incretin hormones, are released at increased concentrations into the bloodstream in response to meals by the small intestine. Although the DPP4 enzyme immediately inactivates them, these hormones stimulate insulin release from pancreatic beta cells in a glucose-dependent manner. Additionally, GLP-1 reduces hepatic glucose synthesis by decreasing glucagon release from pancreatic alpha cells. GLP-1 concentrations are lower; however, the insulin response to GLP-1 still exists in type 2 diabetic individuals. In patients with type 2 diabetes mellitus, Saxagliptin, a competitive DPP4 inhibitor, delays the inactivation of incretin hormones by raising their blood levels and lowering fasting and postprandial glucose concentrations in a glucose-dependent manner.
Metformin: Metformin decreases hepatic glucose production, reduces glucose absorption in the intestine and improves insulin sensitivity (increases peripheral glucose uptake and utilization).
Synergistic Benefits: Patients with type 2 diabetes can benefit synergistically from the combination of Saxagliptin and Metformin. Metformin, a biguanide, lowers hepatic glucose synthesis and increases insulin sensitivity, while saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, increases insulin secretion and glucagon levels. Taken as a whole, they enable complete blood glucose regulation, supporting weight loss and protecting the heart. Through improved general health and diabetes management, as well as reduced side effects and convenience and customized therapy, this combination improves patients' quality of life.
Data Onset of action of Saxagliptin + Metformin is typically within a few hours after taking the medication.
Data duration of action of Saxagliptin + Metformin effects can last throughout the day.
The Data of Tmax (time to peak concentration) of Saxagliptin + Metformin typically occurs within 2 hours after administration.
The Data of Cmax of Saxagliptin + Metformin is generally reached within few hours after oral administration.
Saxagliptin + Metformin is available in oral tablets.
Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.
As the physician recommends, take the medication orally once daily, generally with a meal.
Saxagliptin + Metformin combination helps control blood sugar levels by improving insulin sensitivity and reducing excessive glucose production by the liver. It is used as an adjunct to diet and exercise in patients whose diabetes is inadequately controlled with Metformin or pioglitazone alone.
Saxagliptin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Dipeptyl Peptidase-IV Inhibitors and biguanide.
Saxagliptin: Saxagliptin can be used to treat Diabetes mellitus type 2 treatment. Saxagliptin helps increase the amount of insulin produced after a meal and stops the body from releasing too much glucose (sugar) into the blood. This way, it lowers the blood glucose levels in the body. It often only causes a single frequent adverse effect and is taken once each day.
Metformin: Metformin improves glucose tolerance by lowering basal and postprandial plasma glucose. It exerts its effect by decreasing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis, delaying intestinal glucose absorption, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization.
Saxagliptin + Metformin is a combination medication used to manage type 2 diabetes. Enhanced blood sugar regulation through several modes of action is one of the benefits of this combination medication. Metformin lowers the amount of glucose produced in the liver and raises insulin sensitivity in peripheral tissues, whereas Saxagliptin increases insulin synthesis and decreases glucagon release. Combining these strategies allows for a more comprehensive approach to diabetic pathology, improving glucose control, lowering HbA1c levels, and possibly reducing the risk of long-term consequences from uncontrolled diabetes, including neuropathy and cardiovascular problems.
Indicated as an adjunct to diet and exercise in individuals with type 2 diabetes mellitus who are currently receiving treatment with Metformin or sitagliptin and who do not achieve adequate glycemic control with these medications alone.
Orally: Saxagliptin + Metformin is available as a tablet that can be taken orally. Saxagliptin + Metformin should be taken qDay with evening food, and it is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Saxagliptin + Metformin has various strengths, such as 5mg+500mg, 2.5mg+1000mg or 5mg+1000mg.
Saxagliptin + Metformin is available in the form of Oral tablets.
Dosage Adjustment for Adult Patients
Type 2 Diabetes Mellitus
Start each individual at a different dose according to their existing regimen.
Dosage should be adjusted based on effectiveness and tolerance; daily doses of 5 mg/2000 mg should not be exceeded.
Insufficiently managed with Metformin alone; 2.5–5 mg/day of saxagliptin PO in addition to the existing metformin dosage.
Not well enough under Saxagliptin alone
Metformin PO 500 mg/day plus 5 mg/day Enzagliptin
Saxagliptin + Metformin should be used in treating type 2 diabetes mellitus, along with appropriate dietary restrictions.
Limit alcohol consumption, which may increase the risk of lactic acidosis when taking Metformin.
Taking Saxagliptin + Metformin with food is usually recommended to lower the risk of gastrointestinal (GI) side effects associated with Metformin.
While taking this combination, it is advised to stay hydrated, consume a rich-balanced diet low in saturated fats and cholesterol—and drink plenty of vegetables, whole grains, fruits, and lean proteins in meals.
Avoid excessive grapefruit and juice, as it may interact with the medication.
The dietary restriction should be individualized as per patient requirements.
Saxagliptin + Metformin may be contraindicated in the following conditions: -
- A history of severe hypersensitivity, such as exfoliative skin disorders, angioedema, or anaphylaxis
- eGFR <30 ml/min/1.73 m² indicates severe renal illness.
- Metabolic acidosis, both acute and chronic, including diabetic ketoacidosis (which requires insulin treatment)
- Lactic acidosis: Advise patients not to drink too much alcohol. Saxagliptin + metformin is not recommended in cases of renal impairment and not advised in cases of hepatic impairment. Verify proper kidney function before starting and at least once a year afterwards. Patients undergoing intravascular iodinated contrast material administration for radiologic tests or any surgical procedure requiring restricted food and fluid intake should temporarily stop taking Saxagliptin + Metformin.
- Acute pancreatitis in people on Saxagliptin has been reported postmarketing. If pancreatitis is thought to be present, stop using Metformin plus Saxagliptin
- Lack of vitamin B12: Vitamin B12 levels may be lowered by metformin. Every year, measure the haematological parameters.
- Hypoglycemia: A lower insulin dose or an insulin secretagogue (such as sulfonylurea) may be necessary to administer insulin to reduce the risk of hypoglycemia.
- Macrovascular outcomes: Neither Saxagliptin, Metformin nor any other anti-diabetic medication has significantly reduced macrovascular risk.
- Severe hypersensitivity reactions, including anaphylaxis, angioedema, and exfoliative skin disorders, have been reported in postmarketing reports involving individuals using Saxagliptin. In such circumstances, stop taking Saxagliptin + Metformin immediately, look for additional possible reasons, set up suitable monitoring and therapy, and start a different diabetes regimen.
Alcohol Warning
It is unsafe to consume Saxagliptin + Metformin with alcohol.
Breast Feeding Warning
There is insufficient scientific evidence regarding the use and safety of Saxagliptin + Metformin in breastfeeding.
Pregnancy Warning
It is generally considered safe to use Saxagliptin + metformin during pregnancy.
Food Warning
Increase intake of fibre-rich foods and minimize the carbohydrate or sugary intake.
The adverse reactions related to Saxagliptin + Metformin can be categorized as:-
- Common Adverse Effects: Nasopharyngitis, upper respiratory tract infection
- Less Common Adverse Effects: Diarrhea, nausea/vomiting, headache, hypoglycemia (Saxagliptin)
- Rare Adverse Effects: Rash and lymphopenia
Reports on Postmarketing
Saxagliptin
Hypersensitivity responses, such as angioedema, anaphylaxis, and skin problems requiring exfoliation
Pancreatitis
Severe and disabling arthralgia
The pemphigoid bullous
Rhabdomyolysis
Metformin
Hepatocellular, mixed hepatocellular, and cholestatic liver damage
The clinically relevant drug interactions of Saxagliptin + Metformin are briefly summarized here:
- Iodinated Contrast Agents: Saxagliptin and Metformin should be temporarily discontinued before an iodinated contrast imaging procedure, especially in patients with kidney issues. This reduces the risk of acute kidney injury.
- Cationic Drugs: The combination may interact with cationic drugs, potentially affecting their absorption. It's essential to monitor the use of such medications.
- Alcohol: Alcohol consumption can increase the risk of lactic acidosis associated with Metformin, so caution and moderation are advised.
- Sulfonamides: Some sulfa-containing drugs may interact with Metformin. These interactions can affect blood sugar control and should be monitored.
- Liver Enzyme Inducers/Inhibitors: Drugs that affect liver enzymes, such as CYP3A4 inducers or inhibitors, can alter the metabolism of Saxagliptin, potentially affecting its efficacy.
The most common side effects of Saxagliptin + Metformin include:
- Nausea
- Vomiting
- Low blood glucose, or hypoglycemia
- Loss of appetite
- Diarrhea
- intra-auricular infection
- Nasopharyngitis is an inflammation of the nasal passages and throat.
Saxagliptin + Metformin should be prudent in the following group of special populations.
- Pregnancy
Pregnancy Category B: Could be acceptable. Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been shown by animal studies but not by human studies.
Published studies with metformin use during pregnancy have not found a clear link between Metformin and significant congenital disabilities or miscarriage risk. The little data on pregnant women is insufficient to evaluate the drug-associated risk for significant congenital disabilities and miscarriage.
Clinical Considerations
When Saxagliptin and Metformin were given to pregnant rats and rabbits during the organogenesis phase, independently or in combination, no negative developmental consequences were seen that were unrelated to maternal toxicity.
Maternal risks for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm birth, stillbirth, and delivery problems are increased in cases with poorly controlled diabetes during pregnancy. Uncontrolled diabetes raises the risk of severe congenital disabilities, macrosomia-related morbidity, and stillbirth in fetuses.
- Nursing Mothers
There is no evidence available about the presence of Metformin or alogliptin in human milk, how they affect breastfed infants, or how they affect milk production. Metformin is found in human milk, according to a small number of published studies; however, there is not enough information to determine how Metformin affects breastfed infants or milk production. The benefits of breastfeeding for development and health should be considered, along with the mother's clinical need for therapy and any potential adverse effects on the breastfed child from treatment or an underlying maternal condition.
- Pediatric Use
As per FDA, safety and effectiveness in the pediatric population have yet to be established.
- Geriatric Use
Saxagliptin + Metformin is usually adequate and safe in managing type 2 diabetes in older adults. It poses a small risk of hypoglycemia and adverse effects and aids in improving glycemic control. Depending on each patient's unique features and renal function level, dosage modifications can be required. In such a population, routine observation and medical supervision are crucial.
Dosage adjustment in geriatric patients
Type 2 Diabetes Mellitus
Saxagliptin PO 2.5–5 mg/day in addition to the existing metformin dosage; inadequately managed on Metformin alone
Before determining whether a patient's renal function is normal, do not administer it to those older than 80.
Inadequate control on Saxagliptin alone, 500 mg/day metformin PO with 5 mg/day saxagliptin
Before determining a patient's normal renal function, do not administer it to those older than 80.
Dose Adjustment in Kidney Impairment Patient:
Assess eGFR before initiating Metformin.
An eGFR of less than 30 mL/min/1.73 m² is not recommended. 1.73 m² at 30-45 mL/min: Not advised to start therapy right away
For people at risk for renal impairment (such as the elderly), the eGFR should be checked at least once a year or more frequently.
The hazards and benefits of continued treatment should be assessed if eGFR drops below 45 mL/min/1.73 m² while on Metformin.
When taking Metformin, stop the medication if the eGFR drops below 30 mL/min/1.73 m².
Dose Adjustment in Hepatic Impairment Patients:
Hepatic impairment: Do not administer
Signs and Symptoms
The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Saxagliptin + Metformin.
Overconsumption of Saxagliptin + Metformin could lead to hypoglycemia, gastrointestinal distress, lactic acidosis, and, in severe cases, organ failure.
Management
There is no specific antidote or treatment for excessive intake of Saxagliptin + Metformin. However, immediate medical attention is essential. Saxagliptin + Metformin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Activated charcoal or gastric lavage may also be considered if the overdose is detected shortly after ingestion to reduce absorption.
Mild episodes of hypoglycemia can be effectively treated with oral glucose, whereas severe hypoglycemia with seizure, coma, or neurological impairment can be treated with glucagon or intravenous (IV) glucose. In severe metformin overdosage with lactic acidosis, bicarbonate and renal replacement therapy (hemodialysis) might be necessary to clear Metformin and correct the acid-base imbalance.
Management typically involves supportive measures like maintaining vital signs, correcting electrolyte imbalances, and treating symptoms. The patient will also continue to be monitored for several hours to ensure that blood sugar levels remain stable and that there are no further complications.
Pharmacodynamics
- Saxagliptin: Saxagliptin causes GLP-1 and GIP levels to increase two to three times after treatment. Less systemic adverse effects are experienced due to its particular DPP-4 inhibition. For a total 24-hour period, Saxagliptin blocks the DPP-4 enzyme. Additionally, it reduced glucagon levels and raised pancreatic beta cell release of glucose-dependent insulin. It has an IC50 of 0.5 nmol/L or half the maximum inhibitory concentration, and it has shown that there was no clinically significant prolongation of the QTc interval by Saxagliptin.
- Metformin: Metformin is an antihyperglycemic medication that lowers basal and postprandial plasma glucose levels in people with type 2 diabetes, improving their glucose tolerance. Its pharmacologic modes of action are distinct from those of other oral antihyperglycemic medication groups. Metformin increases peripheral glucose uptake and utilization, which lowers intestinal glucose absorption, reduces hepatic glucose synthesis, and enhances insulin sensitivity. Metformin, unlike sulfonylureas, does not result in hyperinsulinemia or hypoglycemia in either type 2 diabetes patients or healthy persons. Metformin medication does not alter insulin secretion, although it may reduce the plasma insulin response throughout the day and insulin levels while fasting.
Pharmacokinetics
Absorption
Saxagliptin: After a 5 mg once-daily dosing, Saxagliptin's median time to maximum concentration (Tmax) was 2 hours, but its active metabolites were 4 hours. Saxagliptin's Tmax increased by around 20 minutes after administration with a high-fat meal compared to when it was given under fasting settings. Compared to fasted settings, Saxagliptin's AUC increased by 27% when administered with a meal. With or without meals, Saxagliptin can be issued.Peak plasma time: 2hr (Saxagliptin); 4 hr (5-hydroxy Saxagliptin)
Metformin: Slowly and incompletely absorbed from the gastrointestinal tract. Food slightly delays and decreases the extent of absorption. Absolute bioavailability: 50-60%. Time to peak plasma concentration: 2-3 hours (immediate-release); 7 hours, range: 4-8 hours (extended-release).
Bioavailability: 50-60% (Metformin [fasted])
Distribution
Saxagliptin: Saxagliptin and its active metabolite are limited regarding in vitro protein binding in human serum. The distribution of Saxagliptin is thus not anticipated to be affected by variations in blood protein levels in various disease conditions (such as renal or hepatic impairment).
Metformin: Concentrates in the liver, kidney and gastrointestinal tract. It crosses the placenta and then enters breast milk (small amounts). Volume of distribution: 654 ± 358 L.
Protein-bound: Negligible (Metformin)
Metabolism
Saxagliptin: Cytochrome P450 3A4/5 (CYP3A4/5) is primarily responsible for the metabolism of Saxagliptin. A DPP4 inhibitor that is also Saxagliptin's primary metabolite has half the potency of the original drug. As a result, Saxagliptin and its active metabolite's pharmacokinetics will be affected by potent CYP3A4/5 inducers and inhibitors.
Metformin: Excreted unchanged in the urine and did not undergo specific hepatic metabolism (no metabolites have been found in humans) or biliary excretion.
Elimination
Saxagliptin: Saxagliptin is eliminated via the hepatic and renal pathways. A single 50 mg dosage of 14C-saxagliptin excreted 24%, 36%, and 75% of the dose as Saxagliptin, its active metabolite, and total radioactivity, respectively, in the urine. The percentage of the saxagliptin dosage excreted in bile and/or unabsorbed medication from the gastrointestinal system was 22% of the supplied radioactivity in the faeces.
Metformin: With a plasma elimination half-life of roughly 6.2 hours, 90% of the absorbed medication is excreted via the renal pathway during the first 24 hours following oral administration. The elimination half-life of blood is roughly 17.6 hours, indicating that the erythrocyte bulk could constitute a distribution compartment.
Therapeutic benefits of a combination of Saxagliptin + Metformin
- Improved Glycemic Control: Saxagliptin + Metformin helps regulate blood sugar levels, reducing hyperglycemia, and its associated symptoms.
- Cardiovascular Protection: Studies indicate that Saxagliptin could have cardiovascular benefits, and when paired with Metformin, it may provide heart and blood vessel protection.
- Weight control: Saxagliptin and Metformin may help some individuals control their weight or avoid uncontrollably gaining weight, which is crucial for maintaining general health and managing diabetes.
- Jadzinsky M, et al; CV181-039 Investigators. Saxagliptin given in combination with Metformin as initial therapy improves the glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab. 2009 Jun;11(6):611-22. doi: 10.1111/j.1463-1326.2009.01056.x. PMID: 19515181.
- Minze MG, Klein MS, Terrell BT. Saxagliptin and Metformin in fixed combination for the treatment of type 2 diabetes in adults. Clin Med Insights Endocrinol Diabetes. 2013 Jul 31;6:15-24. doi: 10.4137/CMED.S8510. PMID: 23966808; PMCID: PMC3738378.
- Pfützner A, et al; CV181039 Investigators. Initial combination therapy with Saxagliptin and Metformin provides a sustained glycaemic control and is well tolerated for up to 76 weeks. Diabetes Obes Metab. 2011 Jun;13(6):567-76. doi: 10.1111/j.1463-1326.2011.01385.x. PMID: 21342412.
- Matthaei S, Aggarwal N, et al. One-year efficacy and safety of saxagliptin add-on in the patients receiving dapagliflozin and Metformin. Diabetes Obes Metab. 2016 Nov;18(11):1128-1133. Doi: 10.1111/dom.12741. Epub 2016 Aug 19. PMID: 27403645.
- Rosenstock J, et al. Long-term 4-year safety of Saxagliptin in the drug-naive and metformin-treated patients with Type 2 diabetes. Diabet Med. 2013 Dec;30(12):1472-6. doi: 10.1111/dme.12267. Epub 2013 Jul 19. PMID: 23802840.
- https://www.ncbi.nlm.nih.gov/books/NBK518983/
- https://dailymed.nlm.nih.gov/dailymed/drugInfo.
- https://www.ncbi.nlm.nih.gov/books/NBK195495/
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/200678s003s004lbl.pdf
Published on: 26 Oct 2023 9:15 AM GMT