Rosiglitazone

Rosiglitazone is an Antidiabetic Agent belonging to pharmacology class of Thiazolidinedione.

Rosiglitazone can be used in the treatment of Diabetes mellitus, type 2, treatment.

Rosiglitazone is Well absorbed from the GI tract after oral admin with Bioavailability of 99%. It crosses the placenta. Volume of distribution: 17.6 L. Plasma protein binding: 99.8% (mainly albumin)and get extensively metabolised via CYP2C8 isoenzyme and minimally via CYP2C9 isoenzyme which gets excreted Via urine (approx 64%); faeces (approx 23%). Elimination half-life: 3-4 hr.

The common side effects associated with Rosiglitazone include Increased risk of bone fracture in women; wt gain (dose-related), hyperglycemia, GI disturbances, increased appetite, headache, palpitations, muscle cramps, peripheral oedema.

Rosiglitazone is available in the form of Tablets.

The molecule is available in India, USA, Japan, Germany.

Rosiglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). Activation of nuclear PPARgamma receptors influences the production of a number of gene products involved in glucose and lipid metabolism. PPARgamma is abundant in the cells within the renal collecting tubules; fluid retention results from stimulation by thiazolidinediones which increases sodium reabsorption.

Rosiglitazone is available in tablets.

Rosiglitazone can be used in the treatment of Diabetes mellitus, type 2, treatment.

Rosiglitazone is a thiazolidinedione antidiabetic agent which improves insulin sensitivity by lowering blood glucose level w/o increasing pancreatic insulin secretion. It is also a potent peroxisome proliferator-activated receptor-γ agonist, which increases the transcription of insulin-responsive genes involved in the control of glucose production, transport and utilization.

Rosiglitazone is approved for use in the following clinical indications

Diabetes mellitus, type 2, treatment: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Diabetes mellitus, type 2, treatment:

Note: May be used as an adjunctive agent or alternative monotherapy for select patients, including those in whom initial therapy with lifestyle intervention and metformin failed, or cannot take metformin, particularly when avoidance of hypoglycemia is desirable. Rosiglitazone may have a more favorable cardiovascular profile compared to rosiglitazone; use of any thiazolidinedione has been associated with an increased risk of heart failure, and risk is increased with concomitant insulin use.

Oral: Initial: 4 mg/day as a single dose or in 2 divided doses If response is inadequate after 8 to 12 weeks of treatment, the dosage may be increased to 8 mg/day as a single dose or in 2 divided doses daily; maximum dose: 8 mg/day. Per some clinical trial data, 4 mg twice daily may lower fasting plasma glucose and HbA_1c more effectively than 8 mg once daily.

Tablets: 2 mg, 4 mg

Tablets.

• Dose Adjustment in Hepatic Patient:

Hepatic impairment prior to initiation: There are no dosage adjustments provided in the manufacturer's labeling. Clearance is significantly lower in hepatic impairment; therapy should not be initiated if the patient exhibits active liver disease or increased transaminases (ALT >2.5 times the upper limit of normal) at baseline.

Hepatic impairment during therapy: Discontinue therapy if ALT is persistently >3 times ULN or jaundice occurs.

• Dose Adjustment in Pediatric Patient:

Diabetes mellitus, type 2: Limited data available: Note: Rosiglitazone is not recommended for the management of type 2 diabetes mellitus (T2DM) in children and adolescents; if thiazolidinedione therapy is required, other agents are preferred.

Children ≥10 years and Adolescents: Oral: Initial: 2 mg twice daily; then increase to 4 mg twice daily after 8 weeks. Dosing presented was used in 233 pediatric patients as part of a larger multicenter comparative trial of treatments (n=699) in which rosiglitazone in combination with metformin was more effective than metformin alone or metformin and lifestyle changes at maintaining glycemic control.

Rosiglitazone may be contraindicated in the following conditions:

Hypersensitivity to rosiglitazone or any component of the formulation; NYHA Class III/IV heart failure (initiation of therapy).

Concerns related to adverse effects:

• Edema: Dose-related edema may occur. Use with caution in patients with edema; may increase plasma volume and/or cause fluid retention. Monitor for signs/symptoms of heart failure.

• Fractures: Increased incidence of bone fractures in females treated with rosiglitazone was observed during analysis of long-term trial; majority of fractures occurred in the upper arm, hand and foot (differing from the hip or spine fractures usually associated with postmenopausal osteoporosis). Consider risk of fracture prior to initiation and during use.

• Heart failure/cardiac effects: [US Boxed Warning]: Thiazolidinediones, including rosiglitazone, may cause or exacerbate congestive heart failure; closely monitor for signs and symptoms of congestive heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases. If heart failure develops, treat accordingly and consider dose reduction or discontinuation. Not recommended for use in any patient with symptomatic heart failure. Initiation of therapy is contraindicated in patients with NYHA class III or IV heart failure. A higher frequency of cardiovascular events has been noted in patients with NYHA class I or II heart failure treated with rosiglitazone. Use may also be associated with an increased risk of angina and MI. Use with caution in patients at risk for cardiovascular events and monitor closely. Discontinue if any deterioration in cardiac status occurs.

• Hematologic effects: May decrease hemoglobin, hematocrit, and/or WBC count (slight); effects may be related to increased plasma volume and/or dose-related. Changes in hemoglobin and hematocrit generally occurred during the first 3 months after initiation of therapy and after dose increases. Use with caution in patients with anemia.

• Hypoglycemia: The risk of hypoglycemia is increased when rosiglitazone is combined with other hypoglycemic agents; dosage adjustment of concomitant hypoglycemic agents may be necessary.

• Macular edema: Has been reported with thiazolidinedione use, including rosiglitazone; some patients with macular edema presented with blurred vision or decreased visual acuity, and most had peripheral edema at time of diagnosis. In addition to regular ophthalmic exams, diabetic patients with visual symptoms should receive prompt ophthalmic evaluation. Improvement in macular edema may occur with discontinuation of therapy.

• Weight gain: Dose-related weight gain observed with use; mechanism unknown but likely associated with fluid retention and fat accumulation.

There is no sufficient scientific evidence traceable regarding use and safety of Rosiglitazone in concurrent use with alcohol.

It is not known if Rosiglitazone is present in breast milk.

Pregnancy Category (FDA): C

All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Careful monitoring of glucose control is essential in such patients. Most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible.

The adverse reactions related to Rosiglitazone can be categorized as:

Common Adverse effects:

Increased risk of bone fracture in women; wt gain (dose-related), hyperglycemia, GI disturbances, increased appetite, headache, palpitations, muscle cramps, peripheral oedema

Less Common Adverse effects:

Fluid retention, upper resp tract infection, injury, sinusitis, fatigue, diarrhea, dizziness, paranesthesia, back pain, arthralgia, alopecia, dyspnea, leucopenia, thrombocytopenia, decreased haematocrit and hemoglobin (dose-related); increased total cholesterol

Rare Adverse Effects:

Urticaria, rash, pruritus, diabetic macular oedema.

The clinically relevant drug interactions of Rosiglitazone is briefly summarized here:

CYP2C8 Inhibitors and Inducers

An inhibitor of CYP2C8 (e.g., gemfibrozil) may increase the AUC of rosiglitazone and an inducer of CYP2C8 (e.g., rifampin) may decrease the AUC of rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response.

The most common side effects of Rosiglitazone includes: Increased risk of bone fracture in women; wt gain (dose-related), Hyperglycemia, GI disturbances, Increased appetite, Headache, Palpitations, Muscle cramps, Peripheral oedema.

Pregnancy Category (FDA): C

All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Careful monitoring of glucose control is essential in such patients. Most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Labor and Delivery

The effect of rosiglitazone on labor and delivery in humans is not known.

Nursing Mothers

Drug-related material was detected in milk from lactating rats. It is not known whether rosiglitazone is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue rosiglitazone, taking into account the importance of the drug to the mother.

Pediatric Use

After placebo run-in including diet counseling, children with type 2 diabetes mellitus, aged 10 to 17 years and with a baseline mean body mass index (BMI) of 33 kg/m2, were randomized to treatment with 2 mg twice daily of rosiglitazone (n = 99) or 500 mg twice daily of metformin (n = 101) in a 24-week, double-blind clinical trial. As expected, FPG decreased in patients naïve to diabetes medication (n = 104) and increased in patients withdrawn from prior medication (usually metformin) (n = 90) during the run-in period. After at least 8 weeks of treatment, 49% of patients treated with Rosiglitazone and 55% of metformin-treated patients had their dose doubled if FPG >126 mg/dL. For the overall intent-to-treat population, at Week 24, the mean change from baseline in HbA1c was -0.14% with rosiglitazone and -0.49% with metformin. There was an insufficient number of patients in this trial to establish statistically whether these observed mean treatment effects were similar or different.

Geriatric Use

Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of rosiglitazone. Therefore, no dosage adjustments are required for the elderly. In controlled clinical trials, no overall differences in safety and effectiveness between older (≥65 years) and younger (<65 years) patients were observed.

Gender

There is no FDA guidance on the use of Rosiglitazone with respect to specific gender populations.

Race

There is no FDA guidance on the use of Rosiglitazone with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Rosiglitazone in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Rosiglitazone in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Rosiglitazone in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Rosiglitazone in patients who are immunocompromised.

Rosiglitazone has been administered at single oral doses of up to 20 mg and was well tolerated. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status.

Pharmacodynamics:

Rosiglitazone is a thiazolidinedione antidiabetic agent which improves insulin sensitivity by lowering blood glucose level w/o increasing pancreatic insulin secretion. It is also a potent peroxisome proliferator-activated receptor-γ agonist, which increases the transcription of insulin-responsive genes involved in the control of glucose production, transport and utilization.

Pharmacokinetics:

Absorption: Well absorbed from the GI tract after oral admin. Bioavailability: 99%. Time to peak plasma concentration: Approx 1 hr.

Distribution: It crosses the placenta. Volume of distribution: 17.6 L. Plasma protein binding: 99.8% (mainly albumin).

Metabolism: Extensively metabolised via CYP2C8 isoenzyme and minimally via CYP2C9 isoenzyme.

Excretion: Via urine (approx 64%); faeces (approx 23%). Elimination half-life: 3-4 hr.

1. https://www.uptodate.com/contents/ Rosiglitazone -drug-information?search= Rosiglitazone &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Rosiglitazone _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Rosiglitazone ?type=full&mtype=generic#mechanism-of-action