Galvus: Glycemic control in type 2 diabetes patients

2021-07-04 06:40 PM

Galvus is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM).

Producer

Novartis Pharma.

Ingredient

Each tablet: Vildagliptin 50mg.

Excipients: Lactose anhydrous, microcrystalline cellulose, sodium starch glycolate, magnesium stearate.

Describe

White to pale yellow, round, white tablet with the word “NVR” engraved on one side and the word “FB” on the other side.

Mechanism of action

Vildagliptin, a drug that enhances islet function, is a potent and selective dipeptidyl-peptidase-4(DPP-4) inhibitor that improves glycemic control. Vildagliptin's inhibition of DPP-4 increases the fasting and postprandial levels of the endogenous incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).

Pharmacodynamic

Administration of vildagliptin resulted in rapid and complete inhibition of DPP-4 activity. In patients with type 2 diabetes, administration of vildagliptin resulted in inhibition of DPP-4 enzyme activity over a 24-hour period.

By increasing endogenous concentrations of these incretin hormones, Vildagliptin increases the sensitivity of beta cells to glucose, leading to improved glucose-dependent insulin secretion. Treatment at a dose of 50-100 mg/day in patients with type 2 diabetes significantly improved markers of beta cell function. The degree of improvement in beta cell function depends on the extent of the initial decline; In non-diabetic (normal glycemic) subjects, vildagliptin did not stimulate insulin secretion or reduce blood glucose concentrations.
 
By increasing levels of endogenous GLP-1 vildagliptin increases the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion. The inappropriate decrease in glucagon secretion during meals in turn reduces insulin resistance.

An increase in the insulin/glucagon ratio in hyperglycemia due to increased levels of the hormone incretin reduces fasting and postprandial hepatic glucose production, resulting in a decrease in blood glucose.

The known effect of increasing GLP-1 concentrations on delayed gastric emptying was not observed with vildagliptin treatment. In addition, a decrease in postprandial lipids unrelated to the incretin-mediated effect of vildagliptin to improve islet function was observed.

Pharmacokinetics

Absorb

Following oral administration in the fasted state, vildagliptin is rapidly absorbed with peak plasma concentrations observed after 1.75 hours. Administration with food slightly decreased the rate of absorption of vildagliptin, which was characterized by a 19% decrease in peak concentrations and a delay in time to peak plasma concentrations of up to 2.5 hours. There was no change in the extent of absorption and food did not change the total exposure (AUC).

Distribution

Vildagliptin is poorly bound to plasma proteins (9.3%) and equally distributed between plasma and erythrocytes. The mean volume of distribution of vildagliptin at steady state following intravenous administration (Vss) of 71 liters suggests extravascular distribution.

Biotransformation/Metabolism

Metabolism is the major route of elimination for vildagliptin in humans, accounting for 69% of the dose. The major metabolite LAY151 is pharmacologically inactive and is the hydrolysis product of the cyano functional group accounting for 57% of the dose, followed by hydrolysis of the amide functional group (4% of the dose). DPP-4 partially contributes to the hydrolysis of vildagliptin as demonstrated in an in vivo study using DPP-4-deficient rats. Vildagliptin is not metabolized by cytochrome P450 enzymes to any quantifiable extent. In vitro studies have shown that vildagliptin does not inhibit or induce cytochrome P450 enzymes.

Elimination

Following oral administration of [14C]-vildagliptin, approximately 85% of the administered dose was excreted in the urine and 15% was recovered in the faeces. The unchanged Vildagliptin is excreted by the kidneys, accounting for 23% of the dose after oral administration. Following intravenous administration to healthy subjects, the total plasma clearance of vildagliptin was 41 l/h and the renal clearance of vildagliptin was 13 l/h. The mean half-life after intravenous administration is about 2 hours. The half-life after oral administration is approximately 3 hours and is independent of dose.

Linearity

Vildagliptin is rapidly absorbed with an absolute oral bioavailability of 85%. Peak plasma concentrations of vildagliptin and area under the plasma concentration-time curve (AUC) are approximately dose proportional over the therapeutic dose range.

Special patient groups

Gender: No differences in the pharmacokinetics of Galvus were observed between male and female subjects with differences in age and body mass index (BMI). Galvus inhibition of DPP-4 was not affected by gender.

Obesity: BMI did not show any effect on the pharmacokinetic parameters of Galvus. Galvus inhibition of DPP-4 was not affected by BMI.

Hepatic impairment: The effect of hepatic impairment on the pharmacokinetics of Galvus was studied in subjects with mild, moderate, and severe hepatic impairment based on the Child-Pugh scale (range 6 being grade). mild to 12 is severe) compared with people with normal liver function. Galvus exposure (100 mg) after a single dose in subjects with mild and moderate hepatic impairment decreased (20% and 8%, respectively), while exposure to Galvus in subjects with severe hepatic impairment 22% increase. The maximum change (increase or decrease) in Galvus exposure is about 30% but is not considered clinically significant. There was no correlation between the degree of hepatic impairment and the change in Galvus exposure.

Vildagliptin is not recommended for patients with hepatic impairment including those with pretreatment ALT or AST >2.5 times the upper limit of normal.

Renal Impairment: Vildagliptin AUC increased on average 1.4, 1.7 and 2-fold in patients with mild, moderate and severe renal impairment, respectively, compared with normal subjects. The AUC of the LAY151 metabolites was increased 1.6, 3.2 and 7.3-fold and the AUC of BQS867 was increased by 1.4, 2.7, and 7.3-fold in patients with mild, moderate, and severe renal impairment, respectively. order, compared with healthy volunteers. Limited data in patients with end-stage renal disease (ESRD) suggest that vildagliptin exposure is similar to that seen in patients with severe renal impairment. Levels of LAY151 in ESRD patients were approximately 2-3 times higher than in patients with severe renal impairment. Dosage adjustment is recommended in patients with moderate or severe renal impairment or end-stage renal disease (ESRD).

Elderly: In healthy elderly subjects (≥ 70 years of age), total exposure to Galvus (100 mg once daily) was increased by 32% with an 18% increase in peak plasma concentrations compared with young subjects. healthy age (18-40 years old). These changes are not considered clinically significant. Galvus inhibition of DPP-4 was not affected by age in the studied age groups.

Children: No pharmacokinetic data are available.

Ethnic Group: There is no evidence that race affects the pharmacokinetics of Galvus.

Indications and uses

Galvus is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM).

Monotherapy for patients inadequately controlled by diet and exercise alone and unable to use metformin because of contraindications or intolerance.

In a two-drug combination:

Metformin in patients with inadequate glycemic control on maximally tolerated metformin monotherapy.

With a sulfonylurea (SU) when diet, exercise and SU alone do not provide adequate glycemic control.

With a thiazolidinedione (TZD) when diet, exercise and thiazolidinedione do not provide adequate glycemic control.

In triple drug combinations: With a sulfonylurea and metformin when diet, exercise, and dual therapy with these agents do not provide adequate glycemic control.

Galvus is also indicated in combination with insulin (with or without metformin) when diet, exercise, and a steady dose of insulin do not provide adequate glycemic control.

Dosage and Administration

Amount

Management of diabetes treatment should be individualized.

The recommended dose of Galvus is 50 mg once or twice daily.

In monotherapy, and in combination with Metformin, with a TZD or with insulin (with or without Metformin), the recommended dose of Galvus is 50 mg or 100 mg daily.

In dual-drug combination therapy with a sulfonylurea, the recommended dose of Vildagliptin is 50 mg once a day. In this patient population, vildagliptin 100 mg/day was no more effective than vildagliptin 50 mg once daily.

In triple combination therapy with metformin and an SU, the recommended dose of Galvus is 100 mg daily.

If tighter glycemic control requires dosing above the maximum recommended daily dose of vildagliptin, the addition of other antidiabetic agents such as metformin, a sulfonylurea, a thiazolidinedione or insulin may be considered.

Doses greater than 100 mg are not recommended.

The safety and efficacy of vildagliptin in an oral triple combination regimen with metformin and a thiazolidinedione derivative have not been established.

Target patient group

Adults 18 years and older.

Special patient group

Renal impairment: No dose adjustment of Galvus is required in patients with mild renal impairment. In patients with moderate or severe renal impairment or end-stage renal disease (ESRD), the recommended dose of Galvus is 50 mg once daily.

Hepatic impairment: Galvus is not recommended for patients with hepatic impairment, including patients with pretreatment ALT or AST > 2.5 times the upper limit of normal.

Elderly patients: In patients ≥65 years of age and ≥75 years of age treated with Galvus, no differences in overall safety, tolerability, or efficacy were observed between this elderly population and younger patients. Therefore, no dose adjustment is required in elderly patients.

Pediatric patients: Galvus has not been studied in patients under 18 years of age, and therefore the use of Galvus in pediatric patients is not recommended.

How to use

Use orally.

Galvus can be taken with or without food.

The 50 mg dose should be taken once a day in the morning. The 100 mg dose should be divided into 2 doses of 50 mg, taken in the morning and in the evening.

If a dose of Galvus is missed, it should be taken as soon as the patient remembers. Do not take a double dose on the same day.

Warning

This medicine is for use only as prescribed by a physician.

General: Galvus is not an insulin substitute in patients requiring insulin. Galvus must not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hepatic impairment: Galvus is not recommended for patients with hepatic impairment, including patients with pretreatment ALT or AST > 2.5 times the upper limit of normal.

Liver enzyme monitoring: Rare cases of liver dysfunction (including hepatitis) have been reported. In these cases, the patient is usually asymptomatic, has no clinical sequelae, and liver function tests return to normal after stopping treatment. Liver function tests should be performed prior to initiating treatment with Galvus. Liver function tests should be monitored during treatment with Galvus every 3 months for the first year and periodically thereafter. Patients with elevated transaminase levels should be monitored with a second liver function reassessment to confirm the results, and then regular liver function testing should be performed until abnormal values ​​return to normal. normal level. If AST or ALT increases to 3 times the upper limit of normal or higher and persists, discontinuation of Galvus therapy is recommended. If a patient develops jaundice or other manifestations indicative of liver dysfunction, Galvus should be discontinued and a physician immediately contacted. Once treatment with Galvus has been discontinued and liver function tests have returned to normal, vildagliptin should not be reintroduced.

Heart Failure: A clinical trial with Vildagliptin in patients with New York Heart Association (NYHA) heart failure class I-III showed that treatment with Vildagliptin was not associated with changes in left ventricular function or exacerbation of pre-existing congestive heart failure (CHF), compared with placebo. Clinical experience in patients with NYHA class III heart failure treated with Vildagliptin is limited and the results are inconclusive.

There is no experience with the use of vildagliptin in clinical trials in patients with NYHA functional class IV heart failure and therefore its use is not recommended in these patients.

Renal impairment: Experience is limited in patients with end-stage renal disease (ESRD) on hemodialysis. Therefore, caution should be exercised when using Galvus in these patients.

Skin disorders: Skin lesions, including blistering and ulceration, have been reported in the extremities of monkeys in nonclinical toxicology studies. Although no increased incidence of skin lesions was observed in clinical trials, there is limited experience in patients with diabetic skin complications.

Furthermore, there have been post-marketing reports of bullous and exfoliative skin lesions. Therefore, to be consistent with routine care in patients with diabetes, monitoring for skin disorders such as blistering or ulceration is recommended.

Acute pancreatitis: In post-marketing experience, there have been some cases of spontaneous pancreatitis reported. Patients should be informed of the characteristic symptoms of acute pancreatitis such as severe and persistent abdominal pain.

If pancreatitis is suspected, vildagliptin should be discontinued; If acute pancreatitis is confirmed, vildagliptin should not be reintroduced. Caution should be exercised in patients with a history of acute pancreatitis.

Hypoglycemia: Sulphonylurea has been known to cause hypoglycemia. Patients receiving vildagliptin in combination with a sulphonylurea may be at risk of hypoglycemia. Therefore, a lower dose of the sulphonylurea may be considered to reduce the risk of hypoglycemia.

Effects on ability to drive and use machines: No studies have been conducted on the effects on the ability to drive and use machines. Therefore, patients who may experience dizziness should avoid driving or operating machinery.

Overdose

Signs and symptoms

In healthy subjects (7-14 subjects per treatment group), Galvus was administered in doses of 25, 50, 100, 200, 400 and 600 mg once daily for 10 consecutive days. Doses up to 200 mg have been well tolerated. At the 400 mg dose, there were 3 cases of myalgia, isolated cases of mild and transient paresthesia, fever, edema, and transient increase in lipase levels (2 times the upper limit of normal). At a dose of 600 mg, one person experienced edema of the feet and hands and elevated creatine phosphokinase (CPK) levels, accompanied by increases in aspartate aminotransferase (AST), C-reactive protein (CRP), and myoglobin. An additional three people in this dose group presented with swelling in both feet, accompanied by paresthesia in 2 cases. All symptoms and laboratory abnormalities disappeared after study drug was discontinued.

To solve

Galvus cannot be removed by dialysis, however the major hydrolytic metabolite (LAY151) can be removed by hemodialysis.

Contraindications

Galvus is contraindicated in patients with known hypersensitivity to vildagliptin or to any of the excipients.

Use in pregnant and lactating women

Pregnancy: Vildagliptin was not teratogenic in both rats and rabbits. There is not enough experience with Galvus in pregnant women. Therefore, Glavus should not be used during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus.

Lactation: Since it is not known whether vildagliptin is excreted in human milk, Galvus should not be used in nursing women.

Fertility: Fertility studies performed in rats at doses up to 200 times the human dose revealed no evidence of impaired fertility or early embryo development due to Vildagliptin. No fertility studies in humans have been performed with Galvus.

Interactive

Vildagliptin has a weak potential for drug interactions. As vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate and neither inhibits nor induces CYP 450 enzymes, it is unlikely to interact with drugs that are co-administered with substrates or inhibitors. or inducers of these enzymes.

Furthermore, vildagliptin did not affect the metabolic clearance of concomitant drugs metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 and CYP 3A4/5. Drug-drug interaction studies have been conducted with drugs commonly prescribed concurrently to patients with type 2 diabetes or those with narrow therapeutic windows. The results of these studies revealed no clinically significant interactions with other oral antidiabetic agents (glibenclamide, pioglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan, or warfarin after when used concomitantly with vildagliptin.

Side effects

Summary of safety record

Safety data were obtained from a total of 3,784 patients receiving vildagliptin at daily doses of 50 mg (1 time/day) or 100 mg (50 mg twice daily or 100 mg once daily) in trials. control for at least 12 weeks. Of these patients, 2,264 received vildagliptin as monotherapy and 1,520 received vildagliptin in combination with another agent. 2,682 patients were treated with vildagliptin 100 mg/day (50 mg twice daily or 100 mg once daily) and 1,102 patients were treated with vildagliptin 50 mg once daily.

The majority of adverse reactions in these trials were mild and transient and did not require discontinuation of treatment. There was no association between these adverse reactions with age, race, duration of dosing or daily dose.

Rare cases of liver dysfunction (including hepatitis) have been reported. In these cases, the patient is usually asymptomatic, has no clinical sequelae, and liver function tests return to normal after stopping treatment. In data from controlled monotherapy and adjuvant therapy trials of up to 24 weeks duration, the incidence of elevations in ALT or AST 3 times the upper limit of normal (ULN) (according to the current classification) (currently based on at least 2 consecutive measurements or at the last visit during treatment) were 0.2% for vildagliptin 50 mg once daily, 0.3% for vildagliptin 50 mg twice daily. /day and 0.2% for all comparator drugs. These elevations of transaminases are usually asymptomatic, non-progressive in nature and are not associated with cholestasis or jaundice.

Rare cases of angioedema have been reported with vildagliptin administration at a similar rate as in the control group. A higher incidence of these cases has been reported when vildagliptin is used in combination with an angiotensin-converting enzyme inhibitor (ACE inhibitor). Most cases were mild and resolved with continued vildagliptin treatment.

List of adverse reactions

Adverse reactions that have been reported in patients receiving Galvus in double-blind studies as monotherapy and as adjunctive therapy are listed below, for each indication, by system organ class and frequency. absolute. Conventional frequencies are: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000), unknown (cannot be estimated from available data). Within each frequency group, adverse reactions are presented in order of decreasing severity.

Combination with metformin:

Description of Selected Adverse Reactions: In controlled clinical trials of the combination of vildagliptin 100 mg/day + metformin, there were no reports of patients discontinuing due to adverse reactions in the vildagliptin 100 mg group. /day + metformin or placebo + metformin.

In clinical trials, the incidence of hypoglycemia was common in patients receiving vildagliptin 100 mg/day in combination with metformin (1%) and was uncommon in patients receiving placebo + metformin (0.4%). No cases of severe hypoglycaemia were reported in the vildagliptin group of patients.

In clinical trials, body weight was unchanged from baseline with vildagliptin 100 mg/day plus metformin (+0.2 kg for vildagliptin and -1.0 kg for placebo).

Clinical trials of up to 2 years duration did not reveal any additional safety profile or unknown risks when vildagliptin was used as an adjunct to metformin.

In combination with a sulphonylurea:

Description of Selected Adverse Reactions: In controlled clinical trials of the combination vildagliptin 50 mg + sulphonylurea, the overall rate of discontinuation due to adverse reactions was 0.6% in the vildagliptin 50 treatment group. mg + sulphonylurea versus 0% in the placebo + sulphonylurea group.

In clinical trials, the incidence of hypoglycaemia in the vildagliptin 50 mg once daily plus glimepiride group was 1.2% compared with 0.6% in the placebo + glimepiride group. No cases of severe hypoglycemia were reported in the vildagliptin group.

In clinical trials, body weight was unchanged from baseline with vildagliptin 50 mg/day plus glimepiride (-0.1 kg for vildagliptin and -0.4 kg for placebo).

In combination with a thiazolidinedione:

Description of Selected Adverse Reactions: In controlled clinical trials of the combination of vildagliptin 100 mg/day with a thiazolidinedione, there were no reports of patients discontinuing due to adverse reactions in the vildagliptin 100 treatment group. mg/day + thiazolidinedione or placebo + thiazolidinedione.

In clinical trials, the incidence of hypoglycemia was uncommon in patients receiving vildagliptin + pioglitazone (0.6%) but was more common in patients receiving placebo + pioglitazone (1.9%). No cases of severe hypoglycaemia were reported in the vildagliptin group of patients.

In the adjunctive study to pioglitazone, the absolute weight gain for placebo was 1.4 kg and for Galvus 100 mg/day was 2.7 kg.

The incidence of peripheral edema with vildagliptin 100 mg/day plus the maximum dose of basal pioglitazone (45 mg once daily) was 7% compared with 2.5% for background pioglitazone alone.

Monotherapy:

Description of Selected Adverse Reactions: In addition, in vildagliptin-controlled monotherapy trials, the overall rate of discontinuation due to adverse reactions was not higher for vildagliptin-treated patients. at a dose of 100 mg/day (0.3%) versus placebo (0.6%) or comparator (0.5%).

In comparative monotherapy studies, hypoglycemia was reported less frequently in 0.4% of patients (7 out of 1,855) treated with vildagliptin 100 mg/day compared with 0.2% of patients. patients (2 out of 1,082) in the group treated with an active comparator or placebo and no severe or serious cases were reported.

In clinical trials, body weight was unchanged from baseline with vildagliptin 100 mg/day as monotherapy (-0.3 kg for vildagliptin and -1.3 kg for placebo).

Clinical trials of up to 2 years did not reveal any additional safety profile or unknown risks with vildagliptin monotherapy.

In combination with metformin and a sulphonylurea:

Description of Selected Adverse Reactions: There were no reports of discontinuation due to adverse reactions in the vildagliptin + metformin + glimepiride group compared with 0.6% in the placebo + metformin + glimepiride group .

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

Combination with insulin:

Description of Selected Adverse Reactions: In controlled clinical trials using vildagliptin 50 mg twice daily in combination with insulin, with or without concomitant metformin, the overall rate of discontinuation was due to Adverse events were 0.3% in the vildagliptin group and there were no discontinuations in the placebo group.

The incidence of hypoglycemia was similar in both treatment groups (14% in the vildagliptin group versus 16.4% in the placebo group). Two patients reported severe hypoglycemic reactions 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 change in weight in the placebo group).

After-sales experience

Reporting of Suspected Adverse Reactions: It is important to report suspected adverse reactions following marketing authorization. This allows continuous monitoring of the benefit-risk balance of the drug.

Preservation

Do not store above 30 degrees Celsius, avoid moisture. Keep the medicine in the original packaging.

Presentation and packaging

Tablets: box of 2 blisters x 14 tablets.