Usage
- This combination therapy is prescribed for the management of Type 2 Diabetes Mellitus in patients whose blood glucose levels are not adequately controlled by dual therapies or metformin alone. It helps improve glycemic control when lifestyle modifications and other treatments are insufficient.
- Pharmacological Classification: This combination includes drugs from three different classes:
- Gliclazide: Sulfonylurea (Second-generation)
- Metformin: Biguanide
- Rosiglitazone: Thiazolidinedione (TZD)
- Mechanism of Action: This combination targets multiple pathways involved in glucose regulation:
- Gliclazide stimulates insulin release from the pancreas.
- Metformin decreases hepatic glucose production, increases insulin sensitivity, and improves glucose uptake in peripheral tissues.
- Rosiglitazone enhances insulin sensitivity in muscle and fat tissues.
Alternate Names
- There is no single official international non-proprietary name (INN) for this combination product. The individual components each have their respective INNs, as listed above.
- Brand names can vary by region. Avandamet contains rosiglitazone and metformin but does not include gliclazide. This specific triple combination might be available under various brand names in different countries, often combining the names of the individual drugs.
How It Works
- Pharmacodynamics: The triple combination exerts its antihyperglycemic effect by:
- Increasing insulin secretion (Gliclazide)
- Reducing hepatic glucose output (Metformin and Rosiglitazone)
- Enhancing peripheral insulin sensitivity (Metformin and Rosiglitazone)
- Pharmacokinetics:
- Absorption: All three drugs are orally absorbed.
- Metabolism: Gliclazide is primarily metabolized in the liver by CYP2C9. Metformin is not extensively metabolized. Rosiglitazone is metabolized primarily by CYP2C8 and to a lesser extent by CYP2C9.
- Elimination: Gliclazide metabolites are excreted mainly in urine and bile. Metformin is excreted unchanged primarily in the urine. Rosiglitazone metabolites are excreted primarily in urine and feces.
- Mode of Action:
- Gliclazide binds to sulfonylurea receptors on pancreatic beta cells, closing ATP-sensitive potassium channels, depolarizing the cell membrane, opening voltage-gated calcium channels, and leading to increased insulin release.
- Metformin’s mechanism is complex but includes activation of AMP-activated protein kinase (AMPK), leading to reduced hepatic gluconeogenesis.
- Rosiglitazone activates peroxisome proliferator-activated receptor gamma (PPAR-γ), increasing insulin sensitivity in peripheral tissues.
- Elimination Pathways:
- Gliclazide: Renal and hepatic.
- Metformin: Primarily renal.
- Rosiglitazone: Primarily renal and some fecal excretion.
Dosage
The triple combination of Gliclazide, Metformin, and Rosiglitazone isn’t available as a single fixed-dose combination. Therefore, each drug is dosed and titrated individually. It’s crucial to titrate each drug individually based on patient response and tolerance.
Standard Dosage
Adults:
- Gliclazide: Start with 30-40mg daily with breakfast, titrating up to a maximum of 320mg as needed.
- Metformin: Start with 500mg once or twice daily with meals, increasing gradually up to a maximum of 2-3g/day divided into 2-3 doses.
- Rosiglitazone: Start with 4mg daily as a single dose or in divided doses. May increase to 8mg daily after 8-12 weeks if needed.
Children:
This combination is not recommended for pediatric use.
Special Cases:
- Elderly Patients: Start with lower doses and titrate cautiously due to increased risk of hypoglycemia and potential age-related decline in renal function.
- Patients with Renal Impairment: Metformin and Rosiglitazone dosage adjustments are necessary in renal impairment; Gliclazide should be used cautiously. Metformin is contraindicated in severe renal impairment (eGFR < 30 mL/min/1.73 m²).
- Patients with Hepatic Dysfunction: Rosiglitazone and Gliclazide dosage adjustments are necessary in hepatic impairment. Metformin should be used with caution.
- Patients with Comorbid Conditions: Use with caution in patients with heart failure (Rosiglitazone can exacerbate heart failure).
Clinical Use Cases
The dosing in these clinical settings is similar to the standard dosage recommendations but requires closer monitoring:
- Intubation, Surgical Procedures, Mechanical Ventilation, Intensive Care Unit (ICU) Use, and Emergency Situations: Blood glucose monitoring is essential in these situations. Insulin is often preferred for glucose control in these settings due to tighter control and ease of titration.
Dosage Adjustments
- Based on blood glucose levels, renal/hepatic function, and other patient-specific factors. Closely monitor patients for side effects and adjust dosages accordingly.
Side Effects
Common Side Effects
- Hypoglycemia (Gliclazide)
- Gastrointestinal issues: Nausea, vomiting, diarrhea, abdominal pain (Metformin)
- Weight gain, fluid retention, edema (Rosiglitazone)
- Headache
- Upper respiratory tract infection
Rare but Serious Side Effects
- Lactic acidosis (Metformin): Rare but life-threatening, especially in patients with renal impairment.
- Hepatotoxicity
- Heart failure exacerbation (Rosiglitazone)
- Bone fractures (Rosiglitazone, especially in women)
- Anemia
- Blood disorders
Long-Term Effects
- Vitamin B12 deficiency (Metformin)
- Increased risk of bladder cancer (Pioglitazone, a similar TZD; data on Rosiglitazone is less clear).
Adverse Drug Reactions (ADR)
- Severe hypoglycemia
- Lactic acidosis
- Angioedema
- Liver failure
- Severe heart failure
Contraindications
- Type 1 diabetes
- Diabetic ketoacidosis
- Severe renal or hepatic impairment
- Heart failure (NYHA Class III/IV) (Rosiglitazone)
- Hypersensitivity to any of the drug components
Drug Interactions
- Gliclazide: Miconazole, phenylbutazone, sulfonamides, fluconazole, and alcohol can potentiate the hypoglycemic effects.
- Metformin: Cationic drugs (amiloride, digoxin), cimetidine, and alcohol can increase the risk of lactic acidosis. Iodinated contrast media can also interact with Metformin.
- Rosiglitazone: Gemfibrozil increases Rosiglitazone levels, while rifampin decreases them. Combining with insulin or sulfonylureas increases the risk of hypoglycemia.
- Alcohol can increase the risk of both hypoglycemia and lactic acidosis with this combination.
Pregnancy and Breastfeeding
- Pregnancy: This combination is contraindicated in pregnancy. Insulin is the preferred agent for managing diabetes in pregnancy.
- Breastfeeding: This combination is not recommended during breastfeeding. Insulin is the preferred agent for managing diabetes during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Increases insulin secretion, decreases hepatic glucose production, increases peripheral insulin sensitivity.
- Side Effects: Hypoglycemia, GI issues, weight gain, fluid retention, heart failure exacerbation, lactic acidosis.
- Contraindications: Type 1 diabetes, diabetic ketoacidosis, severe renal/hepatic impairment, heart failure.
- Drug Interactions: Multiple drug interactions; see Drug Interactions section.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Titrate individual components based on patient response and tolerability.
- Monitoring Parameters: Blood glucose, HbA1c, renal function, liver function tests, weight, signs and symptoms of heart failure and lactic acidosis, vitamin B12 levels (long-term Metformin use).
Popular Combinations
- This specific triple combination is not commonly used in fixed-dose form. However, the common combination therapies for type 2 diabetes include:
- Metformin + Sulfonylurea
- Metformin + DPP-4 Inhibitor
- Metformin + SGLT2 Inhibitor
- Metformin + GLP-1 Receptor Agonist
Precautions
- General Precautions: Monitor for hypoglycemia, lactic acidosis, fluid retention, heart failure exacerbation. Regularly assess renal and hepatic function.
- Specific Populations (See “Special Cases” under Dosage).
- Lifestyle Considerations: Encourage diet, exercise, and weight management. Alcohol should be avoided or consumed in moderation.
FAQs (Frequently Asked Questions)
A: This combination is not a standard fixed-dose combination, so each component is dosed and titrated individually, based on patient response and tolerability. (See Dosage section).
Q2: What are the most serious side effects to watch for?
A: Lactic acidosis (Metformin), heart failure exacerbation (Rosiglitazone), and severe hypoglycemia (Gliclazide) are the most serious potential adverse effects.
Q3: Can this combination be used during pregnancy or breastfeeding?
A: No, it is contraindicated in both pregnancy and breastfeeding. Insulin is the preferred treatment option.
Q4: What are the key patient monitoring parameters?
A: Blood glucose, HbA1c, renal function, liver function tests, signs and symptoms of heart failure, and lactic acidosis should be monitored regularly.
Q5: What is the role of each drug in this combination?
A: Gliclazide stimulates insulin release. Metformin reduces hepatic glucose production and improves peripheral insulin sensitivity. Rosiglitazone increases insulin sensitivity in muscle and fat tissues.
Q6: What should be done if a patient develops lactic acidosis?
A: Discontinue Metformin immediately and provide supportive care. Hospitalization is usually required.
Q7: What are the potential drug interactions with this combination?
A: Many drugs can interact with this combination. Pay particular attention to interactions with alcohol, gemfibrozil, rifampin, cationic drugs, and other antidiabetic medications. (See Drug Interactions section).
Q8: What are the alternatives to this combination?
A: Other combinations, such as Metformin plus a DPP-4 inhibitor, SGLT2 inhibitor, or GLP-1 receptor agonist, may be considered based on patient characteristics and treatment goals.
Q9: How should this combination be initiated?
A: Start with the lowest recommended dose for each component and titrate individually according to patient response and tolerability. Do not start all three drugs simultaneously at target doses.
A: If Metformin is not tolerated, alternative first-line options include a DPP-4 inhibitor, SGLT2 inhibitor, or GLP-1 receptor agonist.
