Dapagliflozin + Metformin
Drug Related WarningDapagliflozin + Metformin
Lactic acidosis
- Metformin accumulation-induced lactic acidosis (plasma concentration >5 mcg/mL) is an uncommon but potentially serious side effect; if it materializes, mortality is approximately 50%.
- Risk factors include being 65 years of age or older, having a radiological study with contrast, surgery and other procedures, hypoxic states (such as acute congestive heart failure), concomitant use of certain drugs (such as carbonic anhydrase inhibitors like topiramate), and certain conditions (such as renal impairment, sepsis, dehydration, excess alcohol intake, and hepatic impairment).
- The only nonspecific symptoms present at the onset are malaise, myalgias, respiratory difficulty, growing somnolence, and nonspecific stomach distress.
- Low pH, an increased anion gap, and high blood lactate are examples of anomalies in the laboratory.
- If lactic acidosis is suspected, stop the medication promptly and check the patient into a hospital.
- When a patient has an estimated glomerular filling rate (eGFR) of 30-60 mL/minute/1.73 m², has a past history of liver disease, alcoholism, or heart failure, or is scheduled to receive intra-arterial iodinate contrast, stop taking metformin. 48 hours after the imaging procedure, reevaluate the patient's eGFR and restart therapy if renal function is stable.
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:
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, Biguanide, Therapy Class:
Antidiabetic Agent, Approved Countries
The United States, Canada, the United Kingdom, Germany, France and Australia.
Dapagliflozin+ Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Sodium-glucose transport protein 2 (SGLT2) Inhibitors and biguanides.
The combination of Dapagliflozin and metformin is approved for treating type 2 diabetes mellitus to enhance the glycemic control in adults when diet and exercise alone do not provide adequate control.
Dapagliflozin is absorbed rapidly in the gastrointestinal tract. It is primarily distributed to the systemic circulation and undergoes metabolism in the liver, mainly through the UGT1A9 enzyme. It is eliminated mostly via the renal route, with approximately 75% of the dose excreted unchanged in the urine. Metformin is also absorbed in the gastrointestinal tract and is excreted mostly unchanged in the urine.
Most common side effects of Dapagliflozin+ Metformin include sore throat, nasal congestion, runny nose, headache, nausea, vomiting, and diarrhoea.
Dapagliflozin+ Metformin is available as a tablet for convenient administration.
Dapagliflozin+ Metformin is available in the United States, Canada, the United Kingdom, Germany, France and Australia.
Dapagliflozin+ Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Sodium-glucose transport protein 2 (SGLT2) Inhibitors and biguanides.
Dapagliflozin: The sodium-glucose cotransporter 2 (SGLT2), primarily found in the proximal tubule of the nephron, is inhibited by Dapagliflozin. Because SGLT2 supports 90% of the kidneys' reabsorption of glucose, its blockage permits the excretion of glucose in the urine. Patients with type 2 diabetes mellitus may greatly benefit from improved glycemic control and possible weight loss due to this excretion.
Metformin: Metformin decreases hepatic glucose production, reduces glucose absorption in the intestine and improves insulin sensitivity (increases peripheral glucose uptake and utilization).
Synergistic Benefits: Metformin and Dapagliflozin work synergistically to manage type 2 diabetes. Dapagliflozin lowers blood sugar levels by promoting the elimination of excess glucose through urine. Metformin reduces the liver's synthesis of glucose and increases insulin sensitivity. When combined, they manage several diabetes-related issues and improve glycemic control. Compared to monotherapy, this combination might help achieve more notable reductions in HbA1c, body weight, and blood pressure while lowering the risk of hypoglycemia and promoting excellent cardiovascular health.
Data Onset of action of Dapagliflozin+ Metformin typically occurs within a few hours after administration.
Data duration of action of Dapagliflozin+ Metformin effects generally lasts throughout the day.
The Data of Tmax (time to peak concentration) of Dapagliflozin+ Metformin generally reached within 2-4 hours after oral administration.
The Data of Cmax of Dapagliflozin+ Metformin is achieved within 2 hours following administration.
Dapagliflozin+ 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.
Dapagliflozin+ Metformin is used to treat type 2 diabetes. By combining two distinct methods of action, it helps in the regulation of adult blood glucose levels. While metformin improves insulin sensitivity and reduces the liver's synthesis of glucose, Dapagliflozin promotes glucose excretion in the urine, leading to better glycemic control.
This combination is used to improve glycemic control and manage the blood sugar levels in people with type 2 diabetes, potentially lowering the risk of complications associated with uncontrolled diabetes.
Dapagliflozin: For people with type 2 diabetes, the drug Dapagliflozin provides several benefits. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors like Dapagliflozin promote the excretion of extra glucose through the urine, which might improve blood sugar regulation and perhaps result in weight loss. To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of any of the severe complications of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.
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.
Dapagliflozin+ Metformin combination provides several therapeutic advantages to patients with type 2 diabetes. It utilizes a number of methods to help lower blood glucose levels. Dapagliflozin decreases hyperglycemia by encouraging the elimination of extra glucose in the urine. Metformin reduces the amount of glucose produced by the liver and increases insulin sensitivity. When taken as a whole, they promote weight loss, lower the risk of cardiovascular events, improve glycemic control, and improve metabolic health overall.
When treatment with the combination of Dapagliflozin and metformin is appropriate, metformin, a combination of the sodium-glucose cotransporter 2 (SGLT2) inhibitor, and Dapagliflozin is indicated as an adjunct to diet and exercise to enhance glycemic control in the adults with type 2 diabetes mellitus.
Limitation of use:
Not for the management of diabetic ketoacidosis or type 1 diabetes mellitus.
Orally: Dapagliflozin+ Metformin is a tablet that can be taken orally. Take once daily in the morning with food. Swallow the tablet whole; do not crush, cut, or chew it. Sometimes, the inactive ingredients in the extended-release tablet may appear in the faeces as a soft, hydrated mass resembling the original tablet.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Dapagliflozin+ Metformin has various strengths, such as 2.5mg+1000mg, 5mg+500mg or 5 mg+1000mg, 10mg+500mg or 10mg+1000mg.
Dapagliflozin+ Metformin is available in the form of Oral tablets.
Dosage Adjustment for Adult Patients
Type 2 Diabetes Mellitus
Individualized beginning dosage according to existing treatment plan
Not using dapagliflozin currently: Start dapagliflozin at 5 mg PO once every day.
Dosage should be adjusted based on effectiveness and tolerance; 2,000 mg of metformin plus 10 mg of dapagliflozin is the maximum.
Heart Failure and/or Chronic Kidney Disease
Dapagliflozin has been shown to lower the risk of
- Adults with type 2 diabetes (T2DM) who have established cardiovascular disease (CVD) or numerous CV risk factors are at risk of hospitalization for heart failure (HF).
- Adults with T2DM who have HF (NYHA class II–IV) with lower ejection fraction are at risk for CV death and hospitalization.
- End-stage renal disease (ESRD), hospitalization for heart failure (HF), CV mortality, and persistent fall in eGFR rates in persons with chronic kidney disease who are at risk of progression.
Dose
- Adjust the initial dosage according to the existing regimen.
Dapagliflozin+ Metformin should be used in treating type 2 diabetes mellitus, along with appropriate dietary restrictions.
Maintain adequate fluid intake to reduce the risk of dehydration and hypotension, especially in hot weather or during vigorous physical activity.
Excessive alcohol intake can increase the chance of lactic acidosis, a rare but severe side effect of 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.
The dietary restriction should be individualized as per patient requirements.
Dapagliflozin+ Metformin may be contraindicated in the following conditions:
- Patients undergoing dialysis, end-stage renal disease, or severe renal impairment (e.g., eGFR <30 ml/min/1.73 m2) can also be carried by illnesses including shock, acute MI, and septicemia.
- The metabolic acidosis, either acute or chronic, encompassing diabetic ketoacidosis
- Excessive sensitivity
- Lactic acidosis: See black boxed warning
- Hypotension: When starting Dapagliflozin+ Metformin, check volume status and treat hypovolemia in individuals who are old, have low systolic blood pressure, have renal impairment, or are using diuretics. As you receive therapy, monitor for any symptoms.
- Ketoacidosis: Regardless of blood glucose level, patients with metabolic acidosis signs and symptoms should be evaluated for ketoacidosis. Stop using Dapagliflozin+ Metformin if there is a suspicion; consult a physician immediately. Consider into account the risk factors for ketoacidosis before starting Dapagliflozin+ Metformin. In clinical settings where ketoacidosis is known to be predisposed, patients taking Dapagliflozin plus Metformin may need to be closely monitored and temporarily stop their medication.
- Acute Kidney Injury and Impairment in Renal Function: In situations where, oral intake is decreased, or fluid losses occur, you may want to stop temporarily. If acute renal injury develops, discontinue promptly and seek medical attention. Monitor renal function while receiving treatment.
- Pyelonephritis and Urosepsis: Assess patients for urinary tract infection symptoms and signs, and if necessary, treat them immediately.
- Hypoglycemia: Patients using insulin or an insulin secretagogue who have hypoglycemia. For people using Dapagliflozin plus metformin, lowering the insulin dosage or using an insulin secretagogue can help lessen the risk of hypoglycemia.
- Every year, measure the hematological parameters.
- Infections with genital mycotic: watch for these infections and treat if necessary.
- Elevated LDL-C: treat and monitor in accordance with the standard of care.
- Bladder Cancer: Clinical research revealed an imbalance in bladder cancer cases. Patients with an active bladder cancer should not take Dapagliflozin; those with a history of bladder cancer should use it cautiously.
- Macrovascular outcomes: There needs to be solid proof from clinical trials that using Dapagliflozin plus Metformin lowers macrovascular risk.
- Lack of vitamin B12: Metformin may cause a reduction in vitamin B12 levels.
Alcohol Warning
It is unsafe to consume Dapagliflozin+ Metformin with alcohol.
Breast Feeding Warning
There is insufficient scientific evidence regarding the use and safety of Dapagliflozin+ Metformin in breastfeeding.
Pregnancy Warning
Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus.
Food Warning
Avoid excessive intake of high-sugar or high-fat foods.
The adverse reactions related to Dapagliflozin+ Metformin can be categorized as:-
- Common Adverse Effects: Genital mycotic infections, urinary tract infections or increased urination, elevated levels of blood lactate, decreased vitamin B12 absorption
- Less Common Adverse Effects: Hypotension (low blood pressure), dehydration, dizziness, abdominal pain or discomfort or dyspepsia (indigestion)
- Rare Adverse Effects: Hypersensitivity reactions
Reports on post-marketing
Lactic acidosis
Acute kidney injury and impairment in the renal function
Dapagliflozin
Ketoacidosis
Acute kidney injury
Impairment in renal function
Urosepsis
Pyelonephritis rash
Individuals with type 1 diabetes mellitus, diabetic ketoacidosis
Metformin hydrochloride
Hepatocellular, cholestatic, and mixed hepatocellular liver damage
The clinically relevant drug interactions of Dapagliflozin+ Metformin are briefly summarized here:
Inhibitors of carbonic anhydrase may make lactic acidosis more likely. Consider monitoring more often. Drugs, including ranolazine, vandetanib, dolutegravir, and cimetidine that decrease metformin clearance may cause more metformin to accumulate. Examine the advantages and disadvantages of using concurrently. Metformin's effects on lactate metabolism can be amplified by alcohol. Advise patients not to consume alcohol in excess.
The most common side effects of Dapagliflozin+ Metformin include:
Low blood glucose, or hypoglycemia
Flatulence
Skin rash
Nausea
Vomiting
Diarrhea
Genital fungal infection
Infection of the nasal passages and throat, or nasopharyngitis
Dizziness
Back pain
Increased hematocrit
Decreased creatinine clearance
Dyslipidemia
Urinary tract infection
Polyuria
Difficulty in urination
Tremors
Dapagliflozin+ Metformin should be prudent in the following group of special populations.
- Pregnancy
Pregnancy Category C: Use with caution if the benefits outweigh the risks.
It is not advised to become pregnant during the second or third trimester due to animal studies that demonstrate detrimental effects on the kidneys.
Pregnancy-related medication use is not well enough studied to identify the risk of severe birth abnormalities or miscarriages.
There hasn't been any conclusive evidence in published studies linking metformin use during pregnancy to a higher risk of severe congenital disabilities or miscarriages.
When diabetes is not well controlled during pregnancy, there are dangers to both the mother and the fetus.
Discuss the possibility of an unplanned pregnancy with premenopausal women because metformin medication may cause ovulation in certain anovulatory women.
Maternal risks of diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm birth, and delivery problems are increased in cases with poorly controlled diabetes during pregnancy. Severe hyperglycemia increases the chance of serious birth abnormalities, stillbirth and morbidity associated with macrosomia in fetuses.
Reproductive potential
Discuss with premenopausal women about the possibility of an unplanned pregnancy because metformin medication may cause ovulation in certain anovulatory women.
Animal data
During a phase of renal development that corresponds to the late second and third trimesters of human pregnancy, rats were exposed to Dapagliflozin at all tested doses, which resulted in unfavorable renal pelvis and tubule dilatations. The lowest dose resulted in an exposure that was fifteen times higher than the clinical dose of 10 mg. It wasn't possible to totally reverse these dilations.
- Nursing Mothers
No information is available about its presence in human milk, how it affects breastfed infants, or how it affects milk production.
There is metformin in human milk, according to a small number of published research.
On the other hand, there is no evidence currently available on the effects of metformin on milk production and insufficient information regarding the medication's effects on breastfed infants.
The milk of nursing rats contains Dapagliflozin.
Inform mothers that using is not advised while nursing since it may cause significant adverse reactions in breastfed infants.
- Pediatric Use
As per FDA, safety and effectiveness in the pediatric population have yet to be established.
Dose Adjustment in Kidney Impairment Patient:
Measure eGFR before beginning metformin.
For eGFR ≥45 mL/min/1.73 m², there is no need to change the dosage.
3.74 m³/1.73 mL/min eGFR: Not advised
Reduced eGFR <30 mL/min/1.73 m²: Not recommended
Check the eGFR once a year or more frequently if you are at risk of renal impairment, such as the elderly.
Iodinated contrast imaging operations should be discontinued.
Patients who have a past history of liver disease, alcoholism, or heart failure or who will be receiving intra-arterial iodinated contrast should stop taking Dapagliflozin or metformin at the time of, or before, an iodinated contrast imaging procedure.
Reassess eGFR 48 hours following the imaging procedure, and if renal function remains stable, continue.
Dose Adjustment in Hepatic Impairment Patient:
Metformin use in hepatic impairment patients has been linked to lactic acidosis in certain circumstances. Patients with hepatic impairment should not use Dapagliflozin + Metformin.
Signs and Symptoms
The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Dapagliflozin+ Metformin.
Overconsumption of Dapagliflozin+ Metformin could lead to severe dehydration, electrolyte imbalances, hypoglycemia, and lactic acidosis.
Management
There is no specific antidote or treatment for excessive intake of Dapagliflozin+ Metformin. However, immediate medical attention is essential. Dapagliflozin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.
In cases of recent overdose, activated charcoal may be administered to limit further absorption of the drugs in the gastrointestinal tract.
Management typically involves supportive measures like intravenous fluids, fluid replacement to prevent dehydration, and symptomatic treatment such as antiemetic medications for nausea and vomiting.
Maintain a healthy lifestyle through proper nutritional diet, regular physical activity, and stress management. These factors can help improve blood sugar control and reduce the risk of Hypoglycemia.
In cases of severe overdose with Metformin or acute kidney injury, hemodialysis may be considered to remove excess Metformin from the bloodstream.
Pharmacodynamics
Dapagliflozin: Dapagliflozin increases the amount of sodium delivered to the distal tubule while decreasing its reabsorption. After receiving Dapagliflozin, both healthy individuals and patients with type 2 diabetes mellitus showed increases in the amount of glucose expelled in their urine, and in the patients with type 2 diabetes mellitus, dapagliflozin dosages of 5 or 10 mg per day for 12 weeks led to an excretion of about 70 grams of glucose per day in the urine by Week 12. At a daily dose of 20 mg of Dapagliflozin, a near-maximum glucose excretion was noted. Dapagliflozin-induced increases in urine volume are also a consequence of this glucose excretion in the urine. The rise in urine glucose excretion for the 10 mg dose often returns to baseline three days after stopping Dapagliflozin. Dapagliflozin was not associated with a clinically significant lengthening of the QTc interval in a trial of healthy subjects at daily doses up to 150 mg (15 times the maximum amount advised). Moreover, in healthy individuals, a single amount of Dapagliflozin up to 500 mg (50 times the recommended maximum dose) did not cause a change in the QTc interval that was clinically significant.
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
Dapagliflozin: When Dapagliflozin is taken orally, maximal concentration is attained during fasting for around two hours. AUC and Cmax grow in direct proportion to dosage. At 10 mg, the bioavailability is 78%. When taken with a high-fat meal, the AUC is unaffected, but Cmax and Tmax are slightly lowered. People can take Dapagliflozin with or without food.
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
Dapagliflozin: Roughly 91% of Dapagliflozin is linked to proteins. Patients with hepatic or renal impairment do not have altered protein binding.
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
Dapagliflozin: UGT1A9 is the main enzyme involved in dapagliflozin metabolism, with CYP-mediated metabolism as a minor human clearance mechanism. Dapagliflozin undergoes much metabolism, primarily producing the inactive metabolite dapagliflozin 3-O-glucuronide. Dapagliflozin 3-O-glucuronide is the main drug-related component in human plasma, accounting for 61% of a 50 mg [14C]-dapagliflozin dosage.
Metformin: Excreted unchanged in the urine and did not undergo specific hepatic metabolism (no metabolites have been found in humans) or biliary excretion.
Elimination
Dapagliflozin: Renal elimination is the primary method to eliminate dapagliflozin and its associated metabolites. After a single 50 mg dose of [14C]-Dapagliflozin, the amount of radioactivity excreted in the urine is 75%, whereas the amount in the faeces is 21%. Less than 2% of the dosage is eliminated as a parent drug in the urine. About 15% of the dosage is destroyed as a parent drug in stools. After taking 10 mg of Dapagliflozin, the mean plasma terminal half-life (t¬) for Dapagliflozin is about 12.9 hours.
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 Dapagliflozin+ Metformin
Metformin and Dapagliflozin combine to lower blood glucose levels. Better glycemic control is achieved with metformin, which reduces hepatic glucose synthesis and increases insulin sensitivity, and Dapagliflozin, which increases glucose excretion through urine.
Metformin is weight-neutral, while Dapagliflozin may cause mild weight loss because it increases the excretion of glucose in the urine, which burns calories. For people with diabetes who need to control their weight, this combination may be beneficial.
According to clinical trials, Dapagliflozin and Metformin use may improve cardiovascular results and lower the chance of heart failure in people with type 2 diabetes, as well as improve cardiovascular outcomes overall.
- Ferreira-Hermosillo A, Molina-Ayala MA, Molina-Guerrero D, Garrido-Mendoza AP, RamÃrez-RenterÃa C, Mendoza-Zubieta V, Espinosa E, Mercado M. Efficacy of the treatment with Dapagliflozin and metformin compared to metformin monotherapy for weight loss in the patients with class III obesity: a randomized controlled trial. Trials. 2020 Feb 14;21(1):186. doi: 10.1186/s13063-020-4121-x. PMID: 32059692; PMCID: PMC7023779.
- Bailey CJ, et al. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med. 2013 Feb 20;11:43. Doi: 10.1186/1741-7015-11-43. Erratum in: BMC Med. 2013;11:193. PMID: 23425012; PMCID: PMC3606470.
- Tan X, Hu J. Combination therapy for type 2 diabetes: Dapagliflozin plus metformin. Expert Opin Pharmacother. 2016;17(1):117-26. doi: 10.1517/14656566.2016.1121235. Epub 2015 Dec 8. PMID: 26567559.
- Kuecker CM, Vivian EM. Patient considerations in type 2 diabetes - the role of combination dapagliflozin-metformin XR. Diabetes Metab Syndr Obes. 2016 Feb 23;9:25-35. Doi: 10.2147/DMSO.S81565. PMID: 26966383; PMCID: PMC4770010.
- https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205649s008lbl.pdf
- https://www.ema.europa.eu/en/documents/product-information/xigduo-epar-product-information_en.pdf
- https://www.medicines.org.uk/emc/product/5293/smpc
Published on: 1 Nov 2023 11:35 AM GMT