ROSIZ-4 4MG TABLET

Indications

• Type 2 diabetes mellitus
• Insulin resistance

Dosage

Children: The safety and efficacy of rosiglitazone in children and adolescents under 18 years have not been established. Refer to the BNF for Children for specific guidance.

Adults: The usual starting dose of rosiglitazone is 4 mg once daily, which may be increased to a maximum dose of 8 mg once daily based on glycemic control.

Mechanism of action

Rosiglitazone acts as a highly selective and potent agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization, thereby enhancing tissue sensitivity to insulin.

Pharmacodynamics

When used as monotherapy, rosiglitazone is associated with increases in total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels. It also leads to a decrease in free fatty acids. LDL levels typically increase during the first 1 to 2 months of therapy, while HDL levels continue to rise over time, resulting in a peak LDL/HDL ratio followed by a decrease.

Pharmacokinetics

Rosiglitazone is well-absorbed after oral administration, with peak plasma concentrations occurring within 1 hour. It has a half-life of approximately 3 to 4 hours, and is primarily metabolized in the liver through cytochrome P450 enzymes. The drug is excreted mainly in the urine as metabolites, with less than 1% excreted unchanged. Its pharmacokinetics can be influenced by factors such as hepatic function and concomitant medications.

Contra-indications

• Heart failure
• Severe hepatic impairment
• Hypersensitivity to rosiglitazone or any of its components

Adverse effects

• Weight gain
• Edema
• Increased risk of heart failure
• Bone fractures
• Hypoglycemia
• Cardiovascular events

Interactions

• May interact with insulin and other antidiabetic medications, increasing the risk of hypoglycemia
• Caution with drugs that may affect liver enzymes, as they can alter rosiglitazone metabolism
• Use with caution in patients taking drugs that may exacerbate heart failure

Precautions

• Monitor patients for signs of heart failure
• Periodic monitoring of liver function tests is recommended
• Assess for risk of bone fractures, especially in postmenopausal women
• Use with caution in patients with a history of bladder cancer

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Rosiglitazone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether rosiglitazone is excreted in human milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets: 2 mg, 4 mg, 8 mg

Mechanism of action

Rosiglitazone acts as a highly selective and potent agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, rosiglitazone enhances tissue sensitivity to insulin. Because osteoblasts and marrow adipocytes are derived from a common mesenchymal progenitor, increased adipogenesis may occur at the expense of osteoblasts, leading to bone loss. Our previous in vitro studies indicated that activation of the proadipogenic transcription factor peroxisome proliferator-activated receptor isoform gamma 2 with rosiglitazone suppressed osteoblast differentiation. Here, we show that 5-month-old Swiss-Webster mice receiving rosiglitazone for 28 day exhibited bone loss associated with an increase in marrow adipocytes, a decrease in the ratio of osteoblasts to osteoclasts, a reduction in bone formation rate, and a reduction in wall width--an index of the amount of bone formed by each team of osteoblasts. Rosiglitazone had no effect on the number of early osteoblast or osteoclast progenitors, or on osteoblast life span, but decreased the expression of the key osteoblastogenic transcription factors Runx2 and Osterix in cultures of marrow-derived mesenchymal progenitors. These effects were associated with diversion of bipotential progenitors from the osteoblast to the adipocyte lineage, and suppression of the differentiation of monopotential osteoblast progenitors. However, rosiglitazone had no effect on osteoblastic cells at later stages of differentiation. Hence, rosiglitazone attenuates osteoblast differentiation and thereby reduces bone formation rate in vivo, leading to bone loss. These findings provide a mechanistic explanation for the recent evidence that peroxisome proliferator-activated receptor isoform gamma activation is a negative regulator of bone mass and suggest that the increased production of oxidized fatty acids with age may indeed be an important mechanism for age-related osteoporosis in humans. Brain peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, is involved in neuroprotection. It is activated by the drug rosiglitazone, which then can increase the pro-survival protein B-cell lymphoma 2 (BCL-2), to mediate neuroprotection. However, the mechanism underlying this molecular cascade remains unknown. Here, we show that the neuroprotective protein neurotrophic factor-a1 (NF-a1), which also induces the expression of BCL-2, has a promoter that contains PPARgamma-binding sites that are activated by rosiglitazone. Treatment of Neuro2a cells and primary hippocampal neurons with rosiglitazone increased endogenous NF-a1 expression and prevented H2 O2 -induced cytotoxicity. Concomitant with the increase in NF-a1, BCL-2 was also increased in these cells. When siRNA against NF-a1 was used, the induction of BCL-2 by rosiglitazone was prevented, and the neuroprotective effect of rosiglitazone was reduced. These results demonstrate that rosiglitazone-activated PPARgamma directly induces the transcription of NF-a1, contributing to neuroprotection in neurons. We proposed the following cascade for neuroprotection against oxidative stress by rosiglitazone: Rosiglitazone enters the neuron and binds to peroxisome proliferator-activated receptor gamma (PPARgamma) in the nucleus. The PPARgamma-rosiglitazone complex binds to the neurotrophic factor-a1 (NF-a1) promoter and activates the transcription of NF-a1 mRNA which is then translated to the protein. NF-a1 is the secreted, binds to a cognate receptor and activates the extracellular signal-regulated kinases (ERK) pathway. This in turn enhances the expression of the pro-survival protein, B-cell lymphoma 2 (BCL-2) and inhibition of caspa

Pharmacodynamics

When rosiglitazone is used as monotherapy, it is associated with increases in total cholesterol, LDL, and HDL. It is also associated with decreases in free fatty acids. Increases in LDL occurred primarily during the first 1 to 2 months of therapy with AVANDIA and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL ratio peaked after 2 months of therapy and then appeared to decrease over time.