Gliclazide

Gliclazide is an antidiabetic agent belonging to a group of medicines called second-generation sulfonylureas.

Gliclazide is approved for managing hyperglycemia in patients with type 2 diabetes. Promoting the pancreas' secretion of insulin and enhancing cells' sensitivity to the hormone helps regulate and lower high blood sugar levels.

After being taken orally, gliclazide is well-absorbed. It forms active metabolites after a thorough metabolic process in the liver. Urine is where most of these metabolites are eliminated.

Indigestion and upset stomach are the most common side effects of gliclazide. Furthermore, it may result in hypoglycemia or low blood sugar.

Gliclazide is available in the form of oral Tablets.

The molecule is available in India, the United States, Canada, the United Kingdom, Brazil, South Africa, Germany and Australia.

Gliclazide is an Antidiabetic agent belonging to a group of medicines called second-generation sulfonylurea.

The sulfonylurea drug gliclazide works by attaching itself to the pancreatic beta cells' SUR1 sulfonylurea receptor. Potassium efflux is stopped by this binding, which blocks ATP-sensitive potassium channels. The beta cells, therefore, experience depolarization. The beta cells' voltage-dependent calcium channels open in response to this depolarization. An increase in calcium causes the calcium-binding protein calmodulin to become active, which sets off a series of actions that eventually result in the exocytosis of insulin-containing secretory granules. When insulin is released into the bloodstream, cells are more likely to absorb glucose, lowering blood sugar levels in people with diabetes.

Gliclazide is available in oral tablets.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily, generally with or without a meal.

Gliclazide is used to manage high blood sugar in diabetes patients who are not insulin dependent in addition to diet and exercise plans. Heart disease, strokes, kidney disease, circulation issues, and blindness can all be avoided by managing high blood sugar.

In Treatment of Type 2 diabetes mellitus

Gliclazide helps increase the amount of insulin your body produces (in the pancreas). It works by boosting the amount of insulin your body generates following a meal and prevents excessive glucose (sugar) release into the blood. In doing so, it decreases your body's blood glucose levels. It often only causes a single frequent adverse effect and is taken once each day.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of developing any significant consequences of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.

Gliclazide is indicated to manage hyperglycemia in maturity-onset diabetes that is stable, non-ketosis prone, or adult-type diabetes that responds well to the drug. This typically occurs when diet and exercise plans are ineffective and insulin therapy is inappropriate for the patient's condition.

Orally: Gliclazide is available as a tablet that can be taken orally. Gliclazide should be taken on an empty stomach, preferably 30 minutes before a meal. It is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablet: 30mg, 60 mg, 80 mg, 120 mg

Gliclazide is available in the form of Oral Tablets.

Dose Adjustment in Adult Patients:

Type 2 Diabetes Mellitus

Weeks 1 and 2: 40 milligrams once every morning

Depending on blood glucose levels, increase by 40 mg every two weeks if necessary (Weeks 3 & 4: 80 mg PO once daily in the morning).

The recommended dosage is 80 to 160 mg daily (maximum 240 mg daily).

Gliclazide should be used in treating Type 2 Diabetes Mellitus, along with appropriate nutritional limits.

Foods like sugary snacks, pastries, white bread, and cereals can lead to rapid spikes in blood sugar and should be limited.

Fried meals can include a lot of calories and unhealthy fats, making it harder to maintain blood sugar levels and causing weight gain.

Foods that are higher in trans fats and saturated, like fried and fatty foods, should be limited as they can increase the chances of heart disease.

Alcohol can lead to fluctuations in blood sugar levels, and its consumption should be moderated or avoided, especially if taken with gliclazide.

It is advised to stay hydrated, maintain a rich, balanced diet low in saturated fats and cholesterol, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualized as per patient requirements.

Gliclazide may be contraindicated in the following conditions:-

• Known sensitivity or allergy to any of the product's excipients, gliclazide, other sulfonylureas, or sulfonamides
• Diabetes mellitus is unstable and/or insulin-dependent, especially in young people; this includes diabetic ketoacidosis, diabetic pre-coma, and diabetic coma.
• In stressful circumstances like primary infection, trauma, or surgery
• In the event of significant liver damage.
• In the event of significant renal failure.
• Miconazole treatment through oral gel or systemic route
• Pregnancy and lactation

• Gliclazide administration will not prevent the emergence of complications specific to diabetes mellitus.
• Gliclazide use should be considered an adjunct to a healthy diet, not a substitute.
• For many people, gliclazide's effectiveness in bringing blood sugar down to the target level wanes with time. This could be because the patient's diabetes worsens or their body isn't responding well to treatment. The medication should be stopped if gliclazide cannot sufficiently reduce blood glucose.
• Following the administration of sulfonylureas, hypoglycemia can occur. Rarely, there may be severe and prolonged cases. Hospitalization might be necessary, and the glucose infusion might need to last many days.
• To prevent hypoglycemia episodes, patients must be carefully chosen, the dosage must be carefully selected, and the patient must be adequately informed.
• Individuals with adrenal insufficiency or hypopituitarism, as well as those who are elderly, malnourished, or in poor general health, may be especially vulnerable to antidiabetic medications. Identifying hypoglycemia in older patients and those on beta-blockers may provide difficulties.
• Only in cases when the patient is expected to consume food regularly (including breakfast) can this treatment be recommended. Due to the increased risk of hypoglycemia in the event of a delayed meal, insufficient food consumption, or a low-carbohydrate diet, it is imperative to maintain a regular intake of carbohydrates. Hypoglycemia is more likely to happen after extended or intense activity, after consuming alcohol, after being on a low-calorie diet, or when receiving therapy with a mix of hypoglycemic medications.
• Severe renal or hepatic insufficiency can impact gliclazide distribution, and hepatic insufficiency can lower neoglucogenesis capacity. These two outcomes raise the chance of experiencing severe hypoglycemia reactions. In these cases, a hypoglycemic episode could be Long and appropriate monitoring needs to be started.
• Hemolytic anaemia may result after sulfonylurea medication treatment for individuals with G6PD deficiency. Patients with G6PD deficiency should take caution when taking gliclazide because it is a member of the sulfonylurea medication class; instead, non-sulfonylurea alternatives should be considered.

It is unsafe to consume glimepiride with alcohol.

It is not recommended for use during breastfeeding. According to the data, the medicine may be unsafe for the unborn child.

Use during pregnancy is only considered if benefits outweigh fetal risks.

While taking gliclazide, limit or avoid highly processed carbohydrates, sugary beverages, high-sugar fruits, and fried and high-fat foods.

The adverse reactions related to gliclazide can be categorized as

Common Adverse Effects: Hypoglycemia and digestive disorders

Less Common Adverse Effects: Weight gain, Skin reactions like rash, itching, or photosensitivity

Rare Adverse Effects: Allergic Reactions, liver function and blood disorders

Reports on Postmarketing

Hypoglycemia is the most commonly reported adverse medication event in postmarketing experience with gliclazide.

Hypoglycemia coma, pancreatitis, thrombocytopenia, hepatitis, cholestatic jaundice, pyrexia, and skin responses (rash and itching) are the most severe adverse medication events associated with gliclazide.

There have been reports of digestive disorders, including diarrhoea, constipation, dyspepsia, nausea, vomiting, and abdominal discomfort.

There have been reports of bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis), drug rash with eosinophilia and systemic symptoms, rash, pruritus, urticaria, angioedema, erythema, and maculopapular rashes.

Agranulocytosis, hemolytic anaemia, allergic vasculitis, hyponatremia, and elevated liver enzyme levels (AST, ALT, and alkaline phosphatize) have also been reported with gliclazide adverse events. Additionally, there have been a few isolated reports of liver function impairment, including cholestasis and jaundice, which may resolve after the medication is stopped or potentially result in life-threatening liver failure. When cholestatic jaundice manifests, stop the medication.

• Potentiated hypoglycemia: When a sulfonylurea is taken in combination with drugs like long-acting sulfonamides, tuberculostatics, clarithromycin, phenylbutazone, clofibrate, monoamine oxidase inhibitors, coumarin derivatives, salicylates, non-steroidal anti-inflammatory drugs, probenecid, beta-blockers, metronidazole, azole antifungal drugs (oral and parenteral preparations), H2-receptor antagonists, disopyramide, and angiotensin-converting enzyme inhibitors—all of which can cause heightened hypoglycemia. Furthermore, gliclazide increases hypoglycemia when combined with other antidiabetic medications despite not being licensed for use in this manner.
• Some medications tend to cause hyperglycemia, resulting in a loss of blood sugar regulation. Drugs such as thiazides, furosemide, danazol, chlorpromazine, ritodrine/salbutamol/terbutaline (IV), nicotinic acid at pharmacologic quantities, and oral contraceptives (estrogen with progestogen) are among them.
• When administering barbiturates to patients on an oral hypoglycemic medication, caution should be exercised as they may lessen the hypoglycemic effect.
• Gliclazide and fluoroquinolone usage concurrently may result in hypo- or hyperglycemia. Patients who are elderly may be more vulnerable to this interaction. The patient should be informed of the risks of using gliclazide and fluoroquinolone simultaneously, and the significance of blood glucose monitoring should be emphasized.
• Combination with anticoagulant medication (warfarin and others) needs to be considered because sulfonylureas can potentially increase the effects of anticoagulation when used concurrently. It could be required to modify the anticoagulant dosage.
• For individuals receiving sulfonylurea treatment, alcohol intolerance (disulfiram-like reaction: flushing sensation of warmth, giddiness, nausea, and sometimes tachycardia) may develop. One can stop this reaction by abstaining from alcohol. Alcohol can cause a hypoglycemic coma by increasing the hypoglycemic reaction and blocking compensatory mechanisms. Steer clear of alcohol-containing medications.

The most common side effects of Gliclazide include:

• Indigestion is an aching in the stomach.
• Feeling nausea or vomiting
• Feeling unwell (vomiting)
• Weight gain
• Flatulence
• Dizziness
• Diarrhea
• Constipation

• Pregnancy

Pregnancy Category C; Use with caution if the benefits outweigh the risks.

For pregnant women with diabetes, insulin is the recommended treatment; gliclazide is not recommended during pregnancy. Whether or not it is gestational, poorly managed diabetes is linked with a higher risk of perinatal mortality and congenital malformations. Reducing the risk of congenital abnormalities can be achieved by maintaining appropriate blood glucose levels close to conception. During pregnancy, stringent normoglycemia must be attained. Since some oral hypoglycemic medications, such as sulfonylureas, may penetrate the placenta and result in hypoglycemia in newborns, insulin should be used in its place. Gliclazide does not appear to have any teratogenic effects in animal tests, but there is insufficient clinical data to determine how it affects pregnant women.

• Nursing mothers

Breastfeeding mothers should not use gliclazide. Gliclazide may induce hypoglycemia in nursing infants. Therefore, it's essential to use caution even though it's unclear if it is eliminated in human milk, like some sulfonylurea medications are. Breastfeeding is not advised while using gliclazide because of the lack of information regarding this medication's presence in breast milk and the potential risk of newborn hypoglycemia.

• Pediatric Use

As per FDA, safety and effectiveness in the pediatric population have yet to be established.

• Geriatric Use

Gliclazide's effectiveness and tolerance in clinical trials proved valid when the same treatment regimen was administered to patients over 65.

Any sulfonylurea medication can cause acute hypoglycemia; elderly patients are especially vulnerable to this risk.

Dosage adjustment in geriatric patients

For older patients (over 65), an initial dose of 30 mg per day is advised.

The fasting blood glucose response should guide the dosage titration, which should be done in increments of 30 mg. At least two weeks should pass between each phase. Efficient blood glucose control is achieved with a single daily dosage. The daily dosage may include one, three, or even four tablets. One should not take more than 120 mg each day.

Dose Adjustment in Kidney Impairment Patient:

Gliclazide metabolism and excretion may be slowed in individuals with compromised renal function. Sulfonylureas also include other medications. It is recommended to implement adequate care if hypoglycemia occurs in these patients, as it may be prolonged. Thus, in those with significant renal impairment, gliclazide is contraindicated.

Dose Adjustment in Hepatic Impairment Patients:

Patients with moderate hepatic impairment are advised not to change their dosage. Gliclazide should be taken cautiously in individuals with mild to severe hepatic impairment.

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of gliclazide.

Overconsumption of Gliclazide could lead to symptoms such as mild to severe hypoglycaemia.

Management

There is no specific antidote or treatment for excessive intake of Gliclazide. However, immediate medical attention is essential. Gliclazideshould be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

Mild hypoglycemia symptoms (without unconsciousness or neurological symptoms) can be treated with diet changes, dosage adjustments, and/or increased carbohydrate consumption. Strict surveillance should be maintained until the physician states that the patient has no risk.

Severe hypoglycemic reactions should be handled as a medical emergency and require immediate hospitalization. They can occur with coma, convulsions, or other neurological abnormalities.

If hypoglycemic coma is confirmed or suspected, the patient should be administered a rapid intravenous injection of 50 millilitres of a concentrated glucose solution (20 to 30%). After that, a more diluted glucose solution (10%) should be continuously infused at a rate required to keep blood glucose levels above five mmol/L. For a minimum of 48 hours, it is advised that patients be closely observed.

In individuals with liver illness, gliclazide plasma clearance may be extended. However, dialysis is ineffective for these patients because gliclazide binds strongly to proteins.

Pharmacodynamics:

Pharmacological characteristics indicate that gliclazide is a hypoglycemic drug of the second generation of sulphonylureas. It induces insulin release from the pancreatic islet of Langerhans beta cells. Peripheral insulin sensitivity is also improved. Insulin dynamics are generally improved, and insulin release is potentiated.

Pharmacokinetics:

Absorption

Although gliclazide is quickly and effectively absorbed, there can be a significant variation across and within individuals. After oral treatment, peak plasma concentrations usually appear 4-6 hours later.

Distribution

Gliclazide is extensively distributed throughout the body, primarily affecting red blood cells and plasma. With 94–98% bound to albumin, it has a high affinity for plasma proteins, where it binds most of the proteins.

Metabolism

Gliclazide undergoes significant hepatic metabolism. The amount of the oral dosage that remains unaltered in the urine is less than 1%. Metabolites comprise conjugates of glucuronic acid as well as oxidized and hydroxylated derivatives.

Elimination

The kidneys (60–70%) and faeces (10–20%) are the primary systems that eliminate metabolites and conjugates.

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• Leiter, L.A., Shestakova, M.V. & Satman, I. Effectiveness of gliclazide MR 60 mg in managing type 2 diabetes: analyses from the EASYDia trial. Diabetol Metab Syndr 10, 30 (2018). https://doi.org/10.1186/s13098-018-0331-8
• Khunti, K., Hassanein, M., Lee, MK. et al. Role of Gliclazide MR in Managing Type 2 Diabetes: Report of a Symposium on Real-World Evidence and New Perspectives. Diabetes Ther 11 (Suppl 2), 33–48 (2020). https://doi.org/10.1007/s13300-020-00833-x

• Zaccardi F, Jacquot E, etal. Comparative effectiveness of gliclazide modified release versus sitagliptin as second-line treatment after the metformin monotherapy in the patients with uncontrolled type 2 diabetes. Diabetes Obes Metab. 2020 Dec;22(12):2417-2426. doi: 10.1111/dom.14169. Epub 2020 Sep 9. PMID: 32761768.

• Hassanein M, Al Sifri S, et al.; DIA-RAMADAN study investigators. A real-world study in the patients with type 2 diabetes mellitus treated with gliclazide modified-release during the fasting: DIA-RAMADAN. Diabetes Res Clin Pract. 2020 May;163:108154. doi: 10.1016/j.diabres.2020.108154. Epub 2020 Apr 21. PMID: 32330510.

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