For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Vildagliptin (as Sustained Release), Dapagliflozin, and Metformin Hydrochloride (as Sustained Release) Tablets

GALVUS DM™

BLACK BOX WARNING

Lactic acidosis

Post marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension and resistant bradyarrhythmias. The onset of metformin associated lactic acidosis is often subtle and accompanied by non-specific symptoms such as malaise, myalgias, respiratory distress, somnolence and abdominal pain. Metformin associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increase in lactate/pyruvate ratio, and metformin in plasma levels generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors like topiramate), age 65 years or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g. acute congestive heart failure), excessive alcohol intake and hepatic impairment.

If lactic acidosis is suspected, discontinue this medicine and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

QUALITATIVE AND QUANTITATIVE COMPOSITION

GALVUS DM™ 500

Each film coated bilayered tablet contains:

Vildagliptin IP (as sustained release)…………………………………………100 mg

Dapagliflozin propanediol USP equivalent to dapagliflozin…..…………….10 mg

Metformin hydrochloride IP (as sustained release) ....................................500 mg

Excipients…………………………………………………………………………q.s.

Color: Ferric Oxide USP-NF (Red) (In dapagliflozin layer)

GALVUS DM™ 1000

Each film coated bilayered tablet contains:

Vildagliptin IP (as sustained release)………………………………………..100 mg

Dapagliflozin Propanediol USP equivalent to dapagliflozin…………….... 10 mg

Metformin hydrochloride IP (as sustained release) ..................................1000 mg

Excipients………………………………………………………………………..q.s.

Color: Ferric Oxide USP-NF (Red) (In dapagliflozin layer)

DOSAGE FORMS AND STRENGTHS

GALVUS DM™ 500: Film coated bilayered tablet; vildagliptin (as sustained release) 100 mg, dapagliflozin 10 mg, and Metformin Hydrochloride (as sustained release) 500 mg

GALVUS DM™ 1000: Film coated bilayered tablet; vildagliptin (as sustained release) 100 mg, dapagliflozin 10 mg, and Metformin Hydrochloride (as sustained release) 1000 mg

CLINICAL PARTICULARS

Therapeutic Indication

GALVUS DM™ is indicated for the treatment of patients with type 2 diabetes mellitus.

Posology and Method of Administration

Posology

GALVUS DM™ is to be administered once a day or as directed by registered medical practitioner. The maximum recommended dose for vildagliptin (as sustained release) is 100 mg once daily. The maximum recommended dose for dapagliflozin is 10 mg once daily. The maximum recommended dose for Metformin hydrochloride (as sustained release) is 2000 mg once daily.

Method of Administration

It should be given orally.

Contraindications

History of a serious hypersensitivity reaction to vildagliptin, dapagliflozin or metformin hydrochloride
Severe renal impairment (eGFR below 30 mL/min/1.73 m2).
Patients on dialysis
Patients with severe ketosis, acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
Patients with severe infections, before and after surgery, and with serious trauma

Special Warnings and Precautions for Use

Hypoglycemia: Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. GALVUS DM™ may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination.

Cardiac failure: A clinical trial of vildagliptin in patients with New York Heart Association (NYHA) functional class I-III showed that treatment with vildagliptin was not associated with a change in left-ventricular function or worsening of pre-existing congestive heart failure (CHF) versus placebo. Clinical experience in patients with NYHA functional class III treated with vildagliptin is still limited and results are inconclusive. There is no experience of vildagliptin use in clinical trials in patients with NYHA functional class IV and therefore use is not recommended in these patients.

Skin disorders:Skin lesions, including blistering and ulceration have been reported in extremities of monkeys in non-clinical toxicology studies. Although skin lesions were not observed at an increased incidence in clinical trials, there was limited experience in patients with diabetic skin complications. Furthermore, there have been post-marketing reports of bullous and exfoliative skin lesions. Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering or ulceration, is recommended.

Acute pancreatitis:Use of vildagliptin has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, GALVUS DM™ should be discontinued; if acute pancreatitis is confirmed, vildagliptin should not be restarted. Caution should be exercised in patients with a history of acute pancreatitis.

Arthralgia: Post marketing report shown DPP-4 inhibitors like vildagliptin induced arthralgia.

Volume depletion: Before initiating GALVUS DM™, assess volume status and renal function in the elderly, patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy.

Ketoacidosis in Patients with Diabetes Mellitus: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis regardless of blood glucose level. If suspected, discontinue medication, evaluate and treat promptly. Before initiating, consider risk factors for ketoacidosis. Patients on GALVUS DM™ may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis.

Urosepsis and Pyelonephritis: Evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated.

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in patients with diabetes, both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment.

Genital Mycotic Infections: Monitor and treat if indicated.

Lower limb amputations:An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term, clinical studies in type 2 diabetes mellitus with SGLT2 inhibitors. It is unknown whether this constitutes a class effect. It is important to counsel patients with diabetes on routine preventative foot care.

Vitamin B₁₂: In controlled clinical trials of metformin immediate-release of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂ levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂ intrinsic factor complex may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. Measure hematologic parameters on an annual basis and vitamin B₁₂ measurements at 2- or 3- year intervals in patients on GALVUS DM™.

Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride.

Lactic acidosis: There have been post marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant Brady arrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of Metformin. In Metformin treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue GALVUS DM™ and report these symptoms to their healthcare provider.

General: Vildagliptin is not a substitute for insulin in insulin-requiring patients. Vildagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Drug Interactions

No interaction studies have been performed for GALVUS DM™.

The following statements reflect the information available on the individual active substances.

Vildagliptin

Vildagliptin has a low potential for interactions with co-administered medicinal products. Since vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate and does not inhibit or induce CYP 450 enzymes, it is not likely to interact with active substances that are substrates, inhibitors or inducers of these enzymes.

Combination with pioglitazone, metformin and glyburide

Results from studies conducted with these oral antidiabetics have shown no clinically relevant pharmacokinetic interactions.

Digoxin (Pgp substrate), warfarin (CYP2C9 substrate)

Clinical studies performed with healthy subjects have shown no clinically relevant pharmacokinetic interactions. However, this has not been established in the target population.

Combination with amlodipine, ramipril, valsartan or simvastatin

Drug-drug interaction studies in healthy subjects were conducted with amlodipine, ramipril, valsartan and simvastatin. In these studies, no clinically relevant pharmacokinetic interactions were observed after co-administration with vildagliptin.

Combination with ACE-inhibitors

There may be an increased risk of angioedema in patients concomitantly taking ACE-inhibitors. As with other oral antidiabetic medicinal products the hypoglycaemic effect of vildagliptin may be reduced by certain active substances, including thiazides, corticosteroids, thyroid products and sympathomimetic.

Dapagliflozin

Positive Urine Glucose Test

Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control.

Interference with 1,5-anhydroglucitol (1,5-AG) Assay

Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

Metformin

Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with GALVUS DM™ may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Drugs that Reduce Metformin Clearance

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.

Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving GALVUS DM™.

Others

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These medications include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving this product, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving this product, observe the patient closely for hypoglycemia.

Use in Special Population

Vildagliptin

Patients with Renal Impairment

There is limited experience in patients with ESRD on hemodialysis. Therefore, vildagliptin should be used with caution in these patients.

Patients with Hepatic Impairment

Vildagliptin SR is not recommended in patients with hepatic impairment including patients with a pretreatment ALT or AST >3x the upper limit of normal (ULN).

Pregnant Women

There is insufficient experience with vildagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for humans is unknown. Due to lack of human data, vildagliptin should not be used during pregnancy.

Lactating Women

As it is not known whether vildagliptin is excreted in human milk, Animal studies have shown excretion of vildagliptin in milk. Vildagliptin should not be used during breast-feeding.

Females and Males of Reproductive Potential

No studies on the effect on human fertility have been conducted for vildagliptin.

Pediatric Patients (below 18 years)

Vildagliptin SR is not recommended for use in children and adolescents (< 18 years). The safety and efficacy of vildagliptin in children and adolescents (< 18 years) have not been established.

Geriatric Patients (65 years or above)

In patients treated with vildagliptin ≥65 years of age and ≥75 years of age, no differences were observed in the overall safety, tolerability, or efficacy between this elderly population and younger patients. However, hepatic and renal fuctions should be taken into consideration before initiating therapy with vildagliptin in this age group of patients.

Dapagliflozin

Patients with Renal Impairment

Dapagliflozin was evaluated in two glycemic control studies that included patients with type 2 diabetes mellitus with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m², and an eGFR of 30 to less than 60 mL/min/1.73 m², respectively). The safety profile of Dapagliflozin in the study of patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 was similar to the general population of patients with type 2 diabetes mellitus. Although patients in the Dapagliflozin arm had reduction in eGFR compared to the placebo arm, eGFR generally returned towards baseline after treatment discontinuation. Patients with diabetes and renal impairment using Dapagliflozin may also be more likely to experience hypotension and may be at higher risk for acute kidney injury. In the study of patients with an eGFR 30 to less than 60 mL/min/1.73 m², 13 patients receiving Dapagliflozin experienced bone fractures compared to none receiving placebo.

Use of dapagliflozin for glycemic control in patients without established CV disease or CV risk factors is not recommended when eGFR is less than 45 mL/min/1.73 m² and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²).

In the DAPA-HF study that included patients with eGFR equal to or above 30 mL/min/1.73 m² , there were 1926 (41%) patients with eGFR below 60 mL/min/1.73 m2 and 719 (15%) with eGFR below 45 mL/min/1.73 m² . No overall differences in safety or efficacy were seen in these patients compared to patients with normal renal function. No dose adjustment is recommended for HFrEF patients with eGFR 30 mL/min/1.73 m² and above.

Patients with Hepatic Impairment

No dose adjustment is recommended for patients with mild, moderate, or severe hepatic impairment. However, the benefit-risk for the use of dapagliflozin in patients with severe hepatic impairment should be individually assessed since the safety and efficacy of dapagliflozin have not been specifically studied in this population.

Pregnant Women

Risk Summary

Based on animal data showing adverse renal effects, Dapagliflozin is not recommended during the second and third trimesters of pregnancy.

Limited data with Dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes and untreated heart failure in pregnancy.

In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose.

The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with HbA1c greater than 10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Lactating Women

Risk Summary

There is no information regarding the presence of dapagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Dapagliflozin is present in the milk of lactating rats. However, due to species specific differences in lactation physiology, the clinical relevance of these data are not clear. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.

Because of the potential for serious adverse reactions in breastfed infants, advise women that use of Dapagliflozin is not recommended while breastfeeding.

Pediatric Patients

Use Safety and effectiveness of Dapagliflozin in pediatric patients under 18 years of age have not been established.

Geriatric Patients

No dapagliflozin dosage change is recommended based on age.

A total of 1424 (24%) of the 5936 dapagliflozinA-treated patients were 65 years and older and 207 (3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical studies assessing the efficacy of dapagliflozin in improving glycemic control in type 2 diabetes mellitus. After controlling for level of renal function (eGFR), efficacy was similar for patients under age 65 years and those 65 years and older. In patients ≥65 years of age, a higher proportion of patients treated with dapagliflozin for glycemic control had adverse reactions of hypotension.

In the DAPA-HF study, 2714 (57%) out of 4744 patients with HFrEF were older than 65 years. Safety and efficacy were similar for patients age 65 years and younger and those older than 65.

Metformin HCl

Patients with Renal Impairment

Metformin is substantially excreted by the kidneys and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment. Metformin use is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m².

Patients with Hepatic Impairment

Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of metformin in patients with clinical or laboratory evidence of hepatic disease

Pregnant Women

Teratogenic Effects: Pregnancy Category B

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, which represent 3 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparison for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, Metformin HCl should not be used during pregnancy unless clearly needed.

Labor and Delivery

The safety and effectiveness of Metformin used during labor and delivery has not been evaluated in human studies.

Lactating Women

Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Thus, the potential for hypoglycemia in nursing infants after Metformin HCl Oral Solution may exist.

Pediatric Patient

Safety and effectiveness in pediatric patients have not been established. Metformin is not recommended in pediatric patients below the age of 18 years.

Geriatric Patient

Clinical studies of Metformin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis.

Effects on Ability to Drive and Use Machines

Patients who experience dizziness as an adverse reaction should avoid driving vehicles or using machines.

Undesirable Effects

Vildagliptin

The safety and tolerability of vildagliptin (50 mg qd, 50 mg bid and 100 mg qd) have been assessed by pooling data from more than 11,000 patients from 36 Phase II and III studies (including 3 open label studies) ranging in duration from 12 to more than 104 weeks. The studies used in this pooled analysis have assessed vildagliptin as monotherapy, add-on therapy to other oral anti-diabetic agents (metformin, TZD, SU and insulin) and as an initial combination therapy with metformin or pioglitazone. Patients not receiving vildagliptin (all comparators group) were taking only placebo or metformin, TZD, SU, acarbose or insulin. For the calculation of frequency of adverse drug reactions for the individual indications, safety data from a subset of pivotal controlled trials of at least 12 week’s duration was considered. Safety data were obtained from patients exposed to vildagliptin at a daily dose of 50 mg (once daily) or 100 mg (50 mg twice daily or 100 mg once daily) who received vildagliptin as monotherapy or in combination with another agent.

The majority of adverse reactions in these trials were mild and transient, not requiring treatment discontinuations. No association was found between adverse reactions and age, ethnicity, duration of exposure or daily dose.

Rare cases of angioedema have been reported on vildagliptin at a similar rate to controls. A greater proportion of cases were reported when vildagliptin was administered in combination with an angiotensin converting enzyme inhibitor (ACE-Inhibitor). The majority of events were mild in severity and resolved with ongoing vildagliptin treatment.

Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function tests (LFTs) returned to normal after discontinuation of treatment. In data from controlled monotherapy and add-on therapy trials up to 24 weeks in duration, the incidence of ALT or AST elevations >= 3x ULN (classified as present on at least 2 consecutive measurements or at the final on-treatment visit) was 0.2%, 0.3% and 0.2% for vildagliptin 50 mg daily, vildagliptin 50 mg twice daily and all comparators, respectively. These elevations in transaminases were generally asymptomatic, non-progressive in nature and not associated with cholestasis or jaundice.

Tabulated summary of adverse drug reactions from clinical trials

Adverse reactions reported in patients who received vildagliptin in double-blind studies as monotherapy and add-on therapies, are listed below, for each indication, by MedDRA system organ class and absolute frequency. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Monotherapy

The overall incidence of withdrawal from monotherapy trials due to adverse reactions was no greater for patients treated with vildagliptin at a dose of 50 mg once daily (0.2%) or vildagliptin at a dose of 50 mg twice daily (0.1%) than for placebo (0.6%) or comparators (0.5%).

In monotherapy studies, hypoglycemia was uncommon, reported in 0.5% (2 of 409) of patients treated with vildagliptin 50 mg once daily and 0.3% (4 of 1,373) of patients treated with vildagliptin 50 mg twice daily compared to 0.2% (2 of 1,082) of patients in the groups treated with an active comparator or placebo, with no serious or severe events reported.

Vildagliptin is weight neutral when administered as monotherapy.

Table 1: Adverse reactions reported in patients who received vildagliptin 50 mg once daily (n=409) or 50 mg twice daily (n=1373) as monotherapy in double-blind studies

Nervous system disorders
Common	Dizziness
Uncommon	Headache
Gastrointestinal disorders
Uncommon	Constipation
General disorders and administration site conditions
Uncommon	Edema peripheral

Long term clinical trials of up to 2 years did not show any additional safety signals or unforeseen risks with vildagliptin monotherapy.

Combination with metformin

In clinical trials with the combination of vildagliptin + metformin, 0.4% of patients withdrew due to adverse reactions in the vildagliptin 50 mg once daily + metformin treatment group, and no withdrawal due to adverse reactions was reported in either the vildagliptin 50 mg twice daily + metformin or the placebo + metformin treatment groups.

In clinical trials, the incidence of hypoglycemia was uncommon in patients receiving vildagliptin 50 mg once daily in combination with metformin (0.9%), patients receiving vildagliptin 50 mg twice daily in combination with metformin (0.5%) and in patients receiving placebo + metformin (0.4%). No severe hypoglycemic events were reported in the vildagliptin arms.

Vildagliptin is weight neutral when administered in combination with metformin.

Table 2: Adverse reactions reported in patients who received vildagliptin 50 mg once daily (n=233) or 50 mg twice daily (n=183) in combination with metformin in double-blind studies

Nervous system disorders
Common	Tremor, dizziness, headache

Long-term clinical trials of up to more than 2 years did not show any additional safety signal or unforeseen risks when vildagliptin was added on to metformin.

When vildagliptin was studied as an initial combination therapy with metformin, no additional safety signal or unforeseen risk was observed.

Combination with a sulfonylurea

In clinical trials with the combination of vildagliptin 50 mg + glimepiride, the overall incidence of withdrawals due to adverse reactions was 0.6% in the vildagliptin 50 mg + glimepiride treatment group versus 0% in the placebo + glimepiride treatment group.

In clinical trials, the incidence of hypoglycemia when vildagliptin 50 mg once daily was added to glimepiride was 1.2% versus 0.6% for placebo + glimepiride. No severe hypoglycemic events were reported in the vildagliptin arms.

At the recommended dose of 50 mg, vildagliptin is weight neutral when administered in combination with glimepiride.

Table 3: Adverse reactions reported in patients who received vildagliptin 50 mg once daily in combination with a sulfonylurea in double-blind studies (n=170)

Nervous system disorders
Common	Tremor, headache, dizziness
General disorders and administration site conditions
Common	Asthenia

Combination with a thiazolidinedione

In clinical trials with the combination of vildagliptin and a thiazolidinedione, 0.7% of patients withdrew for adverse reactions in the vildagliptin 50 mg once daily + pioglitazone group, and there were no withdrawals due to adverse reactions reported in either the vildagliptin 50 mg twice daily + pioglitazone or the placebo + pioglitazone treatment groups.

In clinical trials, no hypoglycemia events were reported in patients receiving vildagliptin 50 mg once daily + pioglitazone 45 mg, hypoglycemia was uncommon in patients receiving vildagliptin 50 mg twice daily + pioglitazone 45 mg (0.6%) but common in patients receiving placebo + pioglitazone 45 mg (1.9%). No severe hypoglycemic events were reported in the vildagliptin arms.

In the pioglitazone add-on study, the change in body weight compared to placebo was +0.1 kg and +1.3 kg for vildagliptin 50 mg daily and vildagliptin 50 mg twice daily, respectively.

The incidence of peripheral edema when vildagliptin was added to a maximum dose of background pioglitazone (45 mg once daily) was 8.2% as 50 mg once daily and 7.0%, as 50 mg twice daily compared to 2.5% for background pioglitazone alone. The incidence of edema when vildagliptin was added to pioglitazone as dual initial therapy in drug naïve patients was, however, less than for pioglitazone alone (50 mg once daily 3.5%, 50 mg twice daily 6.1% vs. pioglitazone 30 mg 9.3%).

Table 4: Adverse reactions reported in patients who received vildagliptin 50 mg once daily (n= 146) or 50 mg twice daily (n=158) in combination with a thiazolidinedione in double-blind studies

Investigations
Common	Weight increase
General disorders and administration site conditions
Common	Edema peripheral

Combination with insulin

In controlled clinical trials using vildagliptin 50 mg twice daily in combination with insulin, with or without concomitant metformin, the overall incidence of withdrawal due to adverse reactions was 0.3% in the vildagliptin treatment group and there were no cases of withdrawal in the placebo group.

The incidence of hypoglycemia was similar in both treatment groups (14.0% in the vildagliptin group versus 16.4 % in the placebo group). Two patients reported severe hypoglycemic events in the vildagliptin group, and 6 patients - in the placebo group.

At the end of the study, the effect on mean body weight was neutral (+ 0.6 kg change from baseline in the vildagliptin group and no weight change in the placebo group).

Table 5: Adverse reactions reported in patients who received vildagliptin 50 mg twice daily in combination with insulin (with or without metformin (n=371))

Nervous system disorders
Common	Headache
Gastrointestinal disorders
Common	Nausea, gastroesophageal reflux disease
Uncommon	Diarrhea, flatulence
General disorders and administration site conditions
Common	Chills
Investigations
Common	Blood glucose decreased

Combination with metformin and SU

There were no cases of withdrawal reported due to adverse reactions in the vildagliptin + metformin + glimepiride treatment group versus. 0.6% in the placebo + metformin + glimepiride treatment group.

The incidence of hypoglycemia was common in both treatment groups (5.1% for the vildagliptin + metformin + glimepiride vs. 1.9% for the placebo + metformin + glimepiride). One severe hypoglycemic event was reported in the vildagliptin group.

At the end of the study, the effect on mean body weight was neutral (+ 0.6 kg in the vildagliptin group and -0.1 kg in the placebo group).

Table 6: Adverse reactions reported in patients who received vildagliptin 50 mg twice daily in combination with metformin and SU (n=157)

Nervous system disorders
Common	Dizziness, tremor
General disorders and administration site condition
Common	Asthenia
Metabolism and nutritional disorders
Common	Hypoglycemia
Skin and subcutaneous tissue disorders
Common	Hyperhidrosis

Adverse drug reactions from spontaneous reports and literature cases - Post-marketing Experience (frequency not known)

The following adverse drug reactions have been derived from post-marketing experience with vildagliptin via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency, which is therefore categorized as not known.

Hepatitis reversible upon drug discontinuation
Urticaria, bullous and exfoliative skin lesions, including bullous pemphigoid.
Pancreatitis.
Arthralgia, sometimes severe.

Dapagliflozin

In the clinical studies in type 2 diabetes, more than 15,000 patients have been treated with dapagliflozin. The primary assessment of safety and tolerability was conducted in a pre-specified pooled analysis of 13 short-term (up to 24 weeks) placebo-controlled studies with 2,360 subjects treated with dapagliflozin 10 mg and 2,295 treated with placebo. In the dapagliflozin cardiovascular outcomes study in type 2 diabetes mellitus (DECLARE study), 8,574 patients received dapagliflozin 10 mg and 8,569 received placebo for a median exposure time of 48 months. In total, there were 30,623 patient-years of exposure to dapagliflozin. The most frequently reported adverse reactions across the clinical studies were genital infections.

Table 7: Adverse reactions in placebo-controlled clinical studies and post-marketing experience

System organ class	Very common	Common^*	Uncommon^**	Rare	Very rare
Infections and infestations		Vulvovaginitis, balanitis and related genital infections^,b,c Urinary tract infection^,b,d	Fungal infection^**		Necrotising fasciitis of the perineum (Fournier's gangrene)^b,i
Metabolism and nutrition disorders	Hypoglycaemia (when used with SU or insulin)^b		Volume depletion^b,e Thirst^**	Diabetic ketoacidosis (when used in type 2 diabetes mellitus)^b,i,k
Nervous system disorders		Dizziness
Gastrointestinal disorders			Constipation^ Dry mouth^
Skin and subcutaneous tissue disorders		Rash^j			Angioedema
Musculoskeletal and connective tissue disorders		Back pain^*
Renal and urinary disorders		Dysuria Polyuria^*,f	Nocturia^**
Reproductive system and breast disorders			Vulvovaginal pruritus^ Pruritus genital^
Investigations		Haematocrit increased^g Creatinine renal clearance decreased during initial treatment^b Dyslipidemia^h	Blood creatinine increased during initial treatment^,b Blood urea increased^ Weight decreased^**

^aThe table shows up to 24-week (short-term) data regardless of glycaemic rescue.

^b See corresponding subsection below for additional information.

^c Vulvovaginitis, balanitis and related genital infections includes, e.g. the predefined preferred terms: vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis, vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection, vulvitis, vaginitis bacterial, vulval abscess.

^d Urinary tract infection includes the following preferred terms, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection and prostatitis.

^eVolume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension.

^f Polyuria includes the preferred terms: pollakiuria, polyuria, urine output increased.

^g Mean changes from baseline in haematocrit were 2.30% for dapagliflozin 10 mg versus –0.33% for placebo. Haematocrit values >55% were reported in 1.3% of the subjects treated with dapagliflozin 10 mg versus 0.4% of placebo subjects.

^h Mean percent change from baseline for dapagliflozin 10 mg versus placebo, respectively, was: total cholesterol 2.5% versus 0.0%; HDL cholesterol 6.0% versus 2.7%; LDL cholesterol 2.9% versus -1.0%; triglycerides -2.7% versus -0.7%.

ⁱSee below this section for details

^jAdverse reaction was identified through postmarketing surveillance. Rash includes the following preferred terms, listed in order of frequency in clinical studies:rash pruritic, rash macular, rash maculo-papular, rash pustular, rash vesicular, and rash erythematous. In active- and placebo-controlled clinical studies (dapagliflozin, N=5936, All control, N=3403), the frequency of rash was similar for dapagliflozin (1.4%) and all control (1.4%), respectively

^kReported in the cardiovascular outcomes study in patients with type 2 diabetes (DECLARE). Frequency is based on annual rate.

*Reported in ≥ 2% of subjects and ≥ 1% more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo.

**Reported by the investigator as possibly related, probably related or related to study treatment and reported in ≥ 0.2% of subjects and ≥ 0.1% more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo.

Vulvovaginitis, balanitis and related genital infections

In the 13-study safety pool, vulvovaginitis, balanitis and related genital infections were reported in 5.5% and 0.6% of subjects who received dapagliflozin 10 mg and placebo, respectively. Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females (8.4% and 1.2% for dapagliflozin and placebo, respectively), and subjects with a prior history were more likely to have a recurrent infection. In the DECLARE study, the numbers of patients with serious adverse events of genital infections were few and balanced: 2 patients in each of the dapagliflozin and placebo groups.

Necrotising fasciitis of the perineum (Fournier’s gangrene)

Cases of Fournier’s gangrene have been reported postmarketing in patients taking SGLT2 inhibitors, including dapagliflozin. In the DECLARE study with 17,160 type 2 diabetes mellitus patients and a median exposure time of 48 months, a total of 6 cases of Fournier’s gangrene were reported, one in the dapagliflozin-treated group and 5 in the placebo group.

Hypoglycemia

The frequency of hypoglycemia depended on the type of background therapy used in the clinical studies in diabetes mellitus. For studies of dapagliflozin in monotherapy, as add-on to metformin or as add-on to sitagliptin (with or without metformin), the frequency of minor episodes of hypoglycemia was similar (< 5%) between treatment groups, including placebo up to 102 weeks of treatment. Across all studies, major events of hypoglycemia were uncommon and comparable between the groups treated with dapagliflozin or placebo. Studies with add-on sulphonylurea and add-on insulin therapies had higher rates of hypoglycemia. In an add-on to glimepiride study, at weeks 24 and 48, minor episodes of hypoglycemia were reported more frequently in the group treated with dapagliflozin 10 mg plus glimepiride (6.0% and 7.9%, respectively) than in the placebo plus glimepiride group (2.1% and 2.1%, respectively). In an add-on to insulin study, episodes of major hypoglycemia were reported in 0.5% and 1.0% of subjects treated with dapagliflozin 10 mg plus insulin at weeks 24 and 104, respectively, and in 0.5% of subjects treated with placebo plus insulin groups at weeks 24 and 104. At weeks 24 and 104, minor episodes of hypoglycemia were reported, respectively, in 40.3% and 53.1% of subjects who received dapagliflozin 10 mg plus insulin and in 34.0% and 41.6% of the subjects who received placebo plus insulin. In an add-on to metformin and a sulphonylurea study, up to 24 weeks, no episodes of major hypoglycemia were reported. Minor episodes of hypoglycemia were reported in 12.8% of subjects who received dapagliflozin 10 mg plus metformin and a sulphonylurea and in 3.7% of subjects who received placebo plus metformin and a sulphonylurea. In the DECLARE study, no increased risk of major hypoglycemia was observed with dapagliflozin therapy compared with placebo. Major events of hypoglycemia were reported in 58 (0.7%) patients treated with dapagliflozin and 83 (1.0%) patients treated with placebo.

Volume depletion

In the 13-study safety pool, reactions suggestive of volume depletion (including, reports of dehydration, hypovolemia, or hypotension) were reported in 1.1% and 0.7% of subjects who received dapagliflozin 10 mg and placebo, respectively; serious reactions occurred in < 0.2% of subjects balanced between dapagliflozin 10 mg and placebo. In the DECLARE study, the numbers of patients with events suggestive of volume depletion were balanced between treatment groups: 213 (2.5%) and 207 (2.4%) in the dapagliflozin and placebo groups, respectively. Serious adverse events were reported in 81 (0.9%) and 70 (0.8%) in the dapagliflozin and placebo group, respectively. Events were generally balanced between treatment groups across subgroups of age, diuretic use, blood pressure and angiotensin converting enzyme inhibitors (ACE-I)/angiotensin II type 1 receptor blockers (ARB) use. In patients with eGFR < 60 mL/min/1.73 m² at baseline, there were 19 events of serious adverse events suggestive of volume depletion in the dapagliflozin group and 13 events in the placebo group.

Diabetic ketoacidosis in type 2 diabetes mellitus

In the DECLARE study, with a median exposure time of 48 months, events of DKA were reported in 27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. The events occurred 12 evenly distributed over the study period. Of the 27 patients with DKA events in the dapagliflozin group, 22 had concomitant insulin treatment at the time of the event. Precipitating factors for DKA were as expected in a type 2 diabetes mellitus population.

Urinary tract infections

In the 13-study safety pool, urinary tract infections were more frequently reported for dapagliflozin 10 mg compared to placebo (4.7% versus 3.5%, respectively); most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females, and subjects with a prior history were more likely to have a recurrent infection. In the DECLARE study, serious events of urinary tract infections were reported less frequently for dapagliflozin 10 mg compared with placebo, 79 (0.9%) events versus 109 (1.3%) events, respectively.

Increased creatinine

Adverse reactions related to increased creatinine were grouped (e.g. decreased renal creatinine clearance, renal impairment, increased blood creatinine and decreased glomerular filtration rate). In the 13-study safety pool, this grouping of reactions was reported in 3.2% and 1.8% of patients who received dapagliflozin 10 mg and placebo, respectively. In patients with normal renal function or mild renal impairment (baseline eGFR ≥ 60 mL/min/1.73 m²) this grouping of reactions were reported in 1.3% and 0.8% of patients who received dapagliflozin 10 mg and placebo, respectively. These reactions were more common in patients with baseline eGFR ≥ 30 and < 60 mL/min/1.73 m²(18.5% dapagliflozin 10 mg versus 9.3% placebo). Further evaluation of patients who had renal-related adverse events showed that most had serum creatinine changes of ≤ 0.5 mg/dL from baseline. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment. In the DECLARE study, including elderly patients and patients with renal impairment (eGFR less than 60 mL/min/1.73 m²), eGFR decreased over time in both treatment groups. At 1 year, mean eGFR was slightly lower, and at 4 years, mean eGFR was slightly higher in the dapagliflozin group compared with the placebo group.

Metformin HCl

The following adverse reactions are also discussed earlier in the labeling:

Lactic Acidosis
Vitamin B12 Deficiency
Hypoglycemia

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In placebo-controlled trials, 781 patients were administered metformin hydrochloride sustained-release. Adverse reactions reported in greater than 5% of the metformin hydrochloride sustained-release patients, and those were more common in metformin hydrochloride sustained-release - than placebo-treated patients, are listed in table 8.

Table 8: Most Common Adverse Reactions (>5.0%) in Placebo-Controlled Studies of Metformin Hydrochloride Sustained-Release in Patients with Type 2 Diabetes Mellitus

Adverse Reaction	% of Patients
Adverse Reaction	Metformin Hydrochloride Sustained-Release (N=781)	Placebo (N=195)
Diarrhea	10	3
Nausea/vomiting	7	2

Diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin hydrochloride sustained-release. Additionally, the following adverse reactions were reported in ≥1.0 to ≤5.0% of metformin hydrochloride sustained-release patients and were more commonly reported with metformin hydrochloride sustained-release than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.

Post-marketing Experience

The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

Adverse events observed more than 2% in the clinical trial conducted with combination of vildagliptin SR and dapagliflozin, when given to T2DM patients uncontrolled on metformin were: headache (2.2%), nasopharyngitis (2.7%), urinary tract infections (2.2%), hypoglycemia (4.4%).

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side-effects, write topv@synokempharma.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 By reporting side-effects, you can help provide more information on the safety of this product.

Overdose

Vildagliptin

Information on the likely symptoms of overdose was taken from a rising dose tolerability study in healthy subjects given Vildagliptin for 10 days. At 400 mg, there were three cases of muscle pain, and individual cases of mild and transient paraesthesia, fever, oedema and a transient increase in lipase levels. At 600 mg, one subject experienced oedema of the feet and hands, and increases in creatine phosphokinase (CPK), aspartate aminotransferase (AST), C- reactive protein (CRP) and myoglobin levels. Three other subjects experienced oedema of the feet, with paraesthesia in two cases. All symptoms and laboratory abnormalities resolved without treatment after discontinuation of the study medicinal product.

Dapagliflozin

Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 times the maximum recommended human dose).

Metformin HCl

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

PHARMACOLOGICAL PROPERTIES

Mechanism of Action

Vildagliptin

The effect of vildagliptin results in a rapid and complete inhibition of DPP-4 activity, resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).

Dapagliflozin

Dapagliflozin is a reversible inhibitor of sodium-glucose co-transporter 2 (SGLT2) that improves glycemic control in patients with type 2 diabetes mellitus by reducing renal glucose reabsorption leading to urinary excretion of excess glucose (glucuresis).

SGLT2 is selectively expressed in the kidney. SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary excretion of excess glucose. The amount of glucose removed by the kidney through this mechanism is dependent upon the blood glucose concentration and GFR. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycemia. Dapagliflozin acts independently of insulin secretion and insulin action.

Urinary glucose excretion (glucuresis) induced by Dapagliflozin is associated with caloric loss and reduction in weight. Inhibition of glucose and sodium co-transport by Dapagliflozin is also associated with mild diuresis and transient natriuresis.

Metformin HCl

Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or in healthy subjects, except in unusual circumstances and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

Pharmacodynamic Properties

Vildagliptin

By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the sensitivity of beta cells to glucose, resulting in improved glucose-dependent insulin secretion. Treatment with vildagliptin sustained release tablets 100 mg daily in patients with type 2 diabetes significantly improved markers of beta cell function including HOMA-β (Homeostasis Model Assessment–β), proinsulin to insulin ratio and measures of beta cell responsiveness from the frequently-sampled meal tolerance test. In non-diabetic (normal glycaemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose levels.

By increasing endogenous GLP-1 levels, vildagliptin also enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion.

The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to reduced glycaemia. The known effect of increased GLP-1 levels delaying gastric emptying is not observed with vildagliptin treatment.

Dapagliflozin

Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in subjects with type 2 diabetes mellitus following the administration of dapagliflozin.

Metformin HCl

Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Unlike sulfonylureas, metformin hydrochloride does not cause hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances) and does not cause hyperinsulinemia. With metformin hydrochloride therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

In humans, metformin hydrochloride has favorable effects on lipid metabolism, independent of its action on glycemia. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin hydrochloride reduces total cholesterol, low-density lipoprotein cholesterol (LDLc) and triglyceride levels.

Pharmacokinetic Properties

Vildagliptin

Absorption

Following oral administration in the fasting state, vildagliptin is rapidly absorbed, with peak plasma concentrations observed at 1.7 hours. Food slightly delays the time to peak plasma concentration to 2.5 hours, but does not alter the overall exposure (AUC). Administration of vildagliptin with food resulted in a decreased Cmax (19%). However, the magnitude of change is not clinically significant, so that Vildagliptin can be given with or without food. The absolute bioavailability is 85%.

Distribution

The plasma protein binding of vildagliptin is low (9.3%) and vildagliptin distributes equally between plasma and red blood cells. The mean volume of distribution of vildagliptin at steady-state after intravenous administration (Vss) is 71 litres, suggesting extravascular distribution.

Biotransformation

Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69% of the dose. The major metabolite (LAY 151) is pharmacologically inactive and is the hydrolysis product of the cyano moiety, accounting for 57% of the dose, followed by the glucuronide (BQS867) and the amide hydrolysis products (4% of dose). In vitro data in human kidney microsomes suggest that the kidney may be one of the major organs contributing to the hydrolysis of vildagliptin to its major inactive metabolite, LAY151. DPP-4 contributes partially to the hydrolysis of vildagliptin based on an in vivo study using DPP-4 deficient rats. Vildagliptin is not metabolised by CYP 450 enzymes to any quantifiable extent. Accordingly, the metabolic clearance of vildagliptin is not anticipated to be affected by co-medications that are CYP 450 inhibitors and/or inducers. In vitro studies demonstrated that vildagliptin does not inhibit/induce CYP 450 enzymes. Therefore, vildagliptin is not likely to affect metabolic clearance of co-medications metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4/5.

Elimination

Following oral administration of [14C] vildagliptin, approximately 85% of the dose was excreted into the urine and 15% of the dose is recovered in the faeces. Renal excretion of the unchanged vildagliptin accounted for 23% of the dose after oral administration. After intravenous administration to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 and 13 l/h, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The elimination half-life after oral administration is approximately 3 hours.

Dapagliflozin

Absorption

Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usually attained within 2 hours under fasting state. The Cmax and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its Cmax by up to 50% and prolongs Tmax by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food.

Distribution

Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.

Metabolism

The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.

Elimination

Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t½) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin 10 mg.

Metformin HCl

Absorption

Following a single oral dose of 1000 mg (2x500 mg tablets) Metformin after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7-8 hours. In both single and multiple-dose studies in healthy subjects, once daily 1000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by area-under-the-curve (AUC), and up to 35% higher Cmax, of metformin relative to the immediate release given as 500 mg twice daily. Metformin tablets must be administered immediately after a meal to maximize therapeutic benefit.

Single oral doses of Metformin from 500 mg to 2500 mg resulted in less than proportional increase in both AUC and C_max. Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from Metformin tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin T_maxby approximately 3 hours but C_maxwas not affected.

In a two-way, single-dose crossover study in healthy volunteers, the 1000 mg tablet was found to be bioequivalent to two 500 mg tablets under fed conditions based on equivalent C_max and AUCs for the two formulations.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg immediate release metformin hydrochloride averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally < 1 µg/mL. During controlled clinical trials, which served as the basis of approval for metformin, maximum metformin plasma levels did not exceed 5µg/mL, even at maximum doses.

Metabolism

Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans), nor biliary excretion. Metabolism studies with extended-release metformin tablets have not been conducted.

Elimination

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

NON-CLINICAL PROPERTIES

Animal Toxicology or Pharmacology

Vildagliptin

Vildagliptin is a selective and potent inhibitor of DPP-4. The IC50 value for inhibition of human DPP-4 is about 3 nM and similar activity was observed with the rat enzyme, demonstrating the lack of species selectivity. Vildagliptin showed some activity at the related enzymes DPP-8 and DPP-9 (Ki values of 506 nM and 65 nM respectively). Although these values are 253 and 32 times higher than the Ki for DPP-4, activity at Cmax in humans (2.3 μM) is likely. No assays exist allowing evaluation of DPP-8/DPP-9 inhibition in vivo. The possibility of activity at one or both of these targets is considered a safety concern in relation to the occurrence of skin lesions in monkeys. No, or minimal, inhibition was seen with other related enzymes.

In vivo pharmacodynamic studies were performed in rats and monkeys. These studies demonstrated the in vivo inhibition of DPP-4 and increased plasma levels of GLP-1. Studies in diabetic rats and in insulin-resistant monkeys demonstrated a glucose-lowering effect of Vildagliptin. Chronic effects of Vildagliptin were studied in pre-diabetic and insulin-treated diabetic monkeys. Beneficial effects were observed on HbA1c, fasting insulin, fibrinogen and PAI-1.

Dapagliflozin

In vivo primary pharmacodynamic studies with Dapagliflozin were carried out in single-dose, dose ranging studies in non-diabetic and diabetic rats or mice in order to evaluate the potency, SGLT2-specificity and duration of action in stimulating urinary glucose excretion, and to describe the secondary consequences of urinary glucose excretion, such as changes in urine volume or blood or plasma glucose effects. Subsequently a multiple-dose study was carried out to evaluate the ability of Dapagliflozin to have sustained effects on urinary glucose excretion, urine volume, and fasting plasma glucose in diabetic rats over a two-week dosing period.

Dapagliflozin increased renal glucose excretion in (healthy, non-diabetic) experimental animals. This was accompanied by osmotic diuresis as measured by increased urine flow. An oral glucose tolerance test was also performed showing that Dapagliflozin was able to significantly reduce glucose area under the curve (AUC), compared to vehicle treatment. A study in knock-out mice lacking the gene for SGLT2 revealed that SGLT2 is indeed the main target for Dapagliflozin at least at lower doses. This study also demonstrated the reversibility of Dapagliflozin’s action towards SGLT2.

Metformin HCl

Major target organs of metformin were heart and liver, as evidenced by heart hypertrophy with immune cell infiltration/inflammation and liver hypertrophy with concomitant hepatic injury and elevated LFT biomarkers, starting at approximately 10-times the expected clinical AUC exposures.

Metformin clinical toxicity hallmarks include lactic acidosis and gastrointestinal side effects (e.g., diarrhea, bloating, and discomfort).

A notable new toxicity issue was identified in the nonclinical program suggesting potential metformin-induced teratogenicity. Metformin is not listed as teratogenic at approximate clinical exposures (body surface area estimates) on current labels.

DESCRIPTION

Vildagliptin

Vildagliptin is (S)-1-[N-(3-hydroxy-1-adamantyl) glycyl]pyrrolidine-2- carbonitrile. It has an empirical formula of C₁₇H₂₅N₃O₂ and a molecular weight of 303.40 gm/mole.

Structural formula of Vildagliptin is:

Dapagliflozin

Dapagliflozin Propanediol monohydrate: D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1); It has an empirical formula of C₂₁H₂₅ClO₆•C₃H₈O₂•H₂O and a molecular weight of 502.98 gm/mole.

Structural formula of Dapagliflozin is:

Metformin HCl

Metformin hydrochloride (N, N-dimethylimidodicarbonimidic diamide hydrochloride) is a white to off-white crystalline compound with a molecular formula of C₄H₁₁N₅•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

Structural formula for metformin is:

PHARMACEUTICAL PARTICULARS

Incompatibilities

Not Applicable

Shelf Life

As per the pack label

Packaging Information

10x10, Alu-Alu

Storage and Handling Instruction

Store below 30°C.

Keep the medicine out of reach of children.

PATIENT COUNSELLING INFORMATION

What is GALVUS DM™?

GALVUS DM™ contains three active substances –vildagliptin sustained release, dapagliflozin, and metformin sustained release, all these drugs belong to “oral antidiabetics” class.

Vildagliptin: Vildagliptin is used to treat adult patients with type 2 diabetes. It is used when diabetes cannot be controlled by diet and exercise alone. It helps to control the level of sugar in the blood by having an effect on insulin and glucagon. Type 2 diabetes develops if the body does not make enough insulin or if the insulin that the body makes does not work as well as it should. It can also develop if the body produces too much glucagon. Your doctor will prescribe vildagliptin either alone or together with certain other antidiabetic medicines which you will already be taking if these have not proved sufficiently effective to control diabetes.

Dapagliflozin: Dapagliflozin is a reversible inhibitor of sodium-glucose co-transporter 2 (SGLT2) that improves glycemic control in patients with type 2 diabetes mellitus by reducing renal glucose reabsorption leading to urinary excretion of excess glucose (glucuresis).

Metformin: Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose.

Do not take GALVUS DM™:

If you are allergic to vildagliptin, dapagliflozin and metformin or any of the other ingredients of this medicine. If you think you may be allergic to vildagliptin, dapagliflozin, metformin or any of the other ingredients of this product, do not take this medicine and talk to your doctor.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking GALVUS DM™

if you have type 1 diabetes (i.e. your body does not produce insulin) or if you have a condition called diabetic ketoacidosis.
if you are taking an anti-diabetic medicine known as sulphonylurea (your doctor may want to reduce your dose of the sulphonylurea when you take it together with this medicine.
if you have severe kidney disease.
if you are on dialysis.
if you have liver disease.
if you suffer from heart failure.
if you have or have had a disease of the pancreas.
if you have malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis.
if you have significant renal impairment

If you have previously taken individual components of GALVUS DM™ but had stopped taking it because of any reason, you should not take this combination.

A test to determine your liver function will be performed before the start of treatment with this product, at three-month intervals for the first year and periodically thereafter. This is so that signs of increased liver enzymes can be detected as early as possible.

Diabetic skin lesions are a common complication of diabetes. You are advised to follow the recommendations for skin and foot care that you are given by your doctor or nurse. You are also advised to pay particular attention to new onset of blisters or ulcers while taking this product. Should these occur, you should promptly consult your doctor.

Children and adolescents

The use of this combination product in children and adolescents up to 18 years of age is not recommended.

Interaction between other medicines and GALVUS DM™

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Your doctor may wish to alter your dose if you are taking other medicines such as:

Thiazides or other diuretics (also called water tablets)
Corticosteroid (generally used to treat inflammation)
Thyroid medicines
Certain medicines affecting the nervous system.

Pregnancy, breast feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

If you feel dizzy while taking this medicine, do not drive or use machines.

How should I take GALVUS DM™ ?

Swallow the tablets whole with some water.

If you have taken too many tablets?

Contact your doctor immediately or go to the nearest hospital casualty department taking any remaining medication and this patient information leaflet with you.

If you forget to take GALVUS DM™

If you miss a dose of GALVUS DM™, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular schedule. Do not double the dose.

What are the possible side effects of GALVUS DM™?

Like all medicines, this medicine can cause side effects, although not everybody gets them. Stop taking this medicine and consult your doctor immediately if any of the following occur (hypoglycaemia, serious urinary tract infections, fungal infections, allergic reactions, joint pain) – you may need medical treatment.

DETAILS OF MANUFACTURER

SYNOKEM LIFESCIENCES PVT. LTD.

Plot. No.11, Sector-4, I.I.E, SIDCUL, Ranipur, Haridwar-249403 (Uttarakhand)

MARKETED BY

CIPLA LTD.

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg, Lower Parel,

Mumbai - 400 013 India.

DETAILS OF PERMISSION OR LICENCE NUMBER WITH DATE

10/UA/2022, 20/12/2023

DATE OF REVISION

03/02/2026

GALVUS DM™ Tablets