Usage
- Gliclazide + Rosiglitazone is prescribed for type 2 diabetes mellitus in patients whose blood glucose levels are inadequately controlled by diet, exercise, and lifestyle changes alone, or by monotherapy with either Gliclazide or Rosiglitazone.
- Pharmacological Classification: Gliclazide is a sulfonylurea, and rosiglitazone belongs to the thiazolidinedione class of antidiabetic medications. The combination acts synergistically to improve glycemic control.
- Mechanism of Action: Gliclazide stimulates insulin release from pancreatic beta-cells, while rosiglitazone enhances insulin sensitivity in peripheral tissues (muscle, liver, and adipose tissue) by activating peroxisome proliferator-activated receptor gamma (PPAR-γ).
Alternate Names
- This combination is not typically referred to by alternate generic names. It might be informally called “Gliclazide/Rosiglitazone.”
- Brand Names: Avandaryl is a well-known brand name for the fixed-dose combination of Glimepiride (another sulfonylurea) and Rosiglitazone. Gliclazide and rosiglitazone are also available as individual drugs under various brand names (e.g., Diamicron for gliclazide, Avandia for rosiglitazone), but their combined formulation does not have a widely recognized brand name besides the aforementioned example with glimepiride instead of gliclazide.
How It Works
- Pharmacodynamics: Gliclazide binds to sulfonylurea receptors on pancreatic beta-cells, closing ATP-sensitive potassium channels, depolarizing the cell membrane, opening voltage-gated calcium channels, and triggering insulin release. Rosiglitazone activates PPAR-γ, a nuclear receptor that regulates gene expression related to glucose and lipid metabolism, resulting in increased insulin sensitivity.
- Pharmacokinetics:
- Gliclazide: Well-absorbed orally. Peak plasma concentrations are achieved in 2-6 hours. It is extensively metabolized in the liver, primarily by CYP2C9, and excreted in urine and bile.
- Rosiglitazone: Rapidly absorbed after oral administration. Peak plasma concentrations are reached within 1 hour. Metabolized primarily by CYP2C8 and to a lesser extent by CYP2C9. Excreted primarily in urine, with a smaller fraction in feces.
- Mode of Action: Gliclazide enhances insulin secretion, while rosiglitazone improves insulin action at the cellular level by increasing glucose uptake and utilization.
- Receptor Binding: Gliclazide binds to sulfonylurea receptors (SUR1), a subunit of ATP-sensitive potassium channels on beta-cells. Rosiglitazone binds to and activates PPAR-γ.
- Enzyme Inhibition/Neurotransmitter Modulation: Gliclazide inhibits ATP-sensitive potassium channels. Rosiglitazone indirectly modulates the activity of various enzymes involved in glucose and lipid metabolism through PPAR-γ activation.
- Elimination Pathways: Both drugs are primarily metabolized in the liver and excreted through renal and hepatic pathways.
Dosage
The combination of gliclazide and rosiglitazone is not commonly available as a fixed-dose combination (like glimepiride/rosiglitazone, marketed as Avandaryl). Dosage would involve administering each drug separately, according to their individual recommendations.
Standard Dosage
Adults:
- Gliclazide: Initial: 40-80 mg once daily with breakfast. Maintenance: 80-320 mg daily, possibly divided into two doses if exceeding 160 mg daily. Maximum dose: 320 mg per day.
- Rosiglitazone: Initial: 4 mg once daily or in two divided doses. Maintenance: If response is inadequate after 8-12 weeks, the dose may be increased to a maximum of 8 mg/day, in a single dose or two divided doses.
Children:
- Gliclazide and rosiglitazone are not typically recommended for pediatric populations.
Special Cases:
- Elderly Patients: Initiate at lower doses and titrate cautiously based on blood glucose monitoring.
- Patients with Renal Impairment: Gliclazide dose adjustment may be needed in patients with moderate to severe renal impairment. Rosiglitazone typically does not require dose adjustment for renal impairment.
- Patients with Hepatic Dysfunction: Exercise caution and initiate at lower doses for both drugs. Rosiglitazone is contraindicated in patients with active liver disease.
- Patients with Comorbid Conditions: Patients with heart failure or at risk of heart failure should be monitored closely for fluid retention and worsening heart failure symptoms. Avoid Rosiglitazone in patients with NYHA class III or IV heart failure.
Clinical Use Cases
The combination of gliclazide and rosiglitazone is not generally recommended for these acute settings, and insulin is usually preferred.
Dosage Adjustments
- Dosage adjustments should be made based on renal and hepatic function, patient response (blood glucose monitoring, HbA1c), and other medications.
Side Effects
Common Side Effects
- Gliclazide: Hypoglycemia, gastrointestinal disturbances (nausea, vomiting, diarrhea, constipation), weight gain.
- Rosiglitazone: Upper respiratory tract infections, headache, sinusitis, fluid retention (edema), weight gain.
Rare but Serious Side Effects
- Gliclazide: Severe hypoglycemia, hepatitis, blood disorders (leukopenia, agranulocytosis, thrombocytopenia), skin reactions.
- Rosiglitazone: Congestive heart failure, myocardial infarction, liver dysfunction, macular edema.
Long-Term Effects
- Rosiglitazone: Increased risk of fractures in women, potential for long-term cardiovascular effects.
Adverse Drug Reactions (ADR)
- Severe hypoglycemia, heart failure, hepatic dysfunction, serious hypersensitivity reactions.
Contraindications
- Gliclazide: Type 1 diabetes, diabetic ketoacidosis, severe renal or hepatic impairment, hypersensitivity to sulfonylureas.
- Rosiglitazone: NYHA class III or IV heart failure, active liver disease, hypersensitivity to thiazolidinediones.
Drug Interactions
- Gliclazide: Miconazole, fluconazole, phenylbutazone, alcohol, beta-blockers, NSAIDs, other antidiabetic agents.
- Rosiglitazone: Gemfibrozil, rifampicin, insulin, nitrates, other antidiabetic agents.
Pregnancy and Breastfeeding
- Pregnancy: Gliclazide is generally avoided during pregnancy. Rosiglitazone is contraindicated. Insulin is the preferred treatment for diabetes during pregnancy.
- Breastfeeding: Both gliclazide and rosiglitazone can potentially be excreted in breast milk, though the amount is likely low. Monitor the infant for hypoglycemia if use is necessary. Alternative treatments should be considered.
Drug Profile Summary
- Mechanism of Action: Gliclazide: Stimulates insulin release; Rosiglitazone: Enhances insulin sensitivity.
- Side Effects: Hypoglycemia, fluid retention, weight gain, gastrointestinal disturbances, cardiovascular risks (rosiglitazone).
- Contraindications: Type 1 diabetes, heart failure (rosiglitazone), hepatic impairment.
- Drug Interactions: Numerous; refer to detailed section.
- Pregnancy & Breastfeeding: Generally avoided or contraindicated.
- Dosage: Refer to detailed dosage guidelines.
- Monitoring Parameters: Blood glucose, HbA1c, liver function tests (especially for rosiglitazone), signs and symptoms of heart failure.
Popular Combinations
This combination is not commonly prescribed. Metformin in combination with either Gliclazide or Rosiglitazone (or other anti-diabetic agents) is more frequently used.
Precautions
Refer to special cases and contraindications section.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Gliclazide + Rosiglitazone?
A: This combination is not a standard fixed-dose. Gliclazide usually starts at 40-80 mg/day, max 320mg/day. Rosiglitazone starts at 4 mg/day, max 8 mg/day.
Q2: What are the primary concerns with this combination?
A: Increased risk of hypoglycemia, fluid retention, and cardiovascular events, particularly with rosiglitazone. Close monitoring is crucial.
Q3: What alternatives exist for patients with contraindications?
A: Other antidiabetic agents, such as metformin, DPP-4 inhibitors, SGLT2 inhibitors, or insulin, might be considered depending on the individual patient’s circumstances.
Q4: Can I use this combination in patients with heart failure?
A: Rosiglitazone is contraindicated in moderate to severe heart failure. Gliclazide should be used with extreme caution, if at all, and patients must be closely monitored for signs of fluid overload.
Q5: Are there any dietary restrictions with this combination?
A: Consistent meal timing and carbohydrate intake are important to manage the risk of hypoglycemia, especially with gliclazide. Alcohol should be limited.
Q6: How should I monitor liver function in patients on rosiglitazone?
A: Baseline liver function tests are essential, followed by periodic monitoring, particularly during the first year of treatment.
Q7: Can this combination be used during pregnancy?
A: No. Both gliclazide and rosiglitazone are contraindicated or should be avoided during pregnancy.
A: Rosiglitazone is metabolized primarily by CYP2C8 and to a lesser extent by CYP2C9. Concomitant use of drugs that inhibit or induce these enzymes can affect rosiglitazone levels and require dosage adjustments.
Q9: Is this a first-line therapy for type 2 diabetes?
A: Typically not. Lifestyle modifications and metformin are usually considered first-line treatments. This combination may be an option when these are insufficient or contraindicated.
