VATAMET 1000

Indications

• Type 2 diabetes mellitus
• Gestational diabetes
• Management of pre-existing diabetes in pregnant women

Dosage

Children: For children aged 10 years and older, the usual starting dose is 500 mg taken with food, with gradual increases based on clinical response. Refer to the BNF for Children for specific dosing recommendations.

Adults: The initial dose is usually 500 mg to 1,000 mg taken orally with food, and the dosage may be gradually increased based on glycemic control and tolerance, with a maximum daily dose typically not exceeding 2,000 mg.

Mechanism of action

Metformin decreases hepatic glucose production and increases peripheral glucose utilization. It does not stimulate insulin release from the pancreas, making it antihyperglycemic rather than hypoglycemic. The drug also interacts with SIRT1, a protein involved in bile acid metabolism, contributing to its effects on glucose homeostasis.

Pharmacodynamics

Metformin improves glycemic control in patients with type 2 diabetes by reducing fasting and postprandial plasma glucose levels. It acts by decreasing intestinal absorption of glucose, increasing insulin sensitivity, and enhancing peripheral glucose uptake and utilization, without causing hypoglycemia.

Pharmacokinetics

Metformin is absorbed from the gastrointestinal tract and is excreted unchanged in the urine. It has a half-life of about 6 hours and does not undergo significant metabolism. The drug's pharmacokinetics can be affected by renal function, and caution is advised in patients with renal impairment.

Contra-indications

• Severe renal impairment (creatinine clearance less than 25 mL/minute)
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis
• Hypersensitivity to metformin or any of its components

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Lactic acidosis (rare)
• Hepatic disorders (rare)
• Oedema (rare)
• Acute generalised exanthematous pustulosis (very rare)
• Thrombocytopenia (very rare)

Interactions

• Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists may require monitoring and adjustments
• Antacids containing magnesium and aluminium salts may reduce the absorption of metformin
• Concomitant use with other antihyperglycemic agents requires careful monitoring for hypoglycemia

Precautions

• Caution in patients with hepatic impairment
• Monitor liver function regularly during treatment
• Patients should be advised to discontinue use in the event of significant illness, especially dehydration or infections

Pregnancy

Avoid use during pregnancy. Women planning to become pregnant should discontinue metformin and consult a healthcare provider for safer alternatives.

Breast-feeding

Avoid use during breastfeeding. Metformin is excreted in breast milk, and its effects on a nursing infant are unknown.

Storage

Store in a cool, dry place, below 25°C. Protect from light.

Formulations

• Metformin hydrochloride 500 mg tablets
• Metformin hydrochloride 850 mg tablets
• Metformin hydrochloride 1000 mg tablets

Indications

• Zinc deficiency
• Wound healing
• Immune support
• Diarrhea in children
• Acne treatment

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines tailored to pediatric patients.

Adults: Refer to the BNF for specific dosing guidelines based on the condition being treated.

Mechanism of action

Clear acts by chelating with biological molecules, facilitating the transfer of electrons and maintaining structural integrity of proteins and enzymes. The zinc component is crucial for various biochemical pathways and is involved in DNA synthesis, immune function, and cell division.

Pharmacodynamics

The pharmacodynamic effects of Clear are primarily attributed to zinc's role in numerous physiological processes. Zinc is a cofactor for over 300 enzymes and is vital for maintaining cellular function, promoting wound healing, and modulating immune response. Its antioxidant properties also help to mitigate oxidative stress in the body.

Pharmacokinetics

Clear is absorbed in the gastrointestinal tract, with bioavailability varying based on the formulation. The distribution of zinc in the body is primarily in muscle and bone, with renal excretion being the main route of elimination. The half-life of zinc can vary based on dietary intake and individual metabolism.

Indications

• Type 2 diabetes mellitus
• Polycystic ovary syndrome (PCOS)

Dosage

Children: The

Adults: The usual starting dose of metformin for adults is 500 mg taken orally twice a day or 850 mg once daily, with gradual increases based on tolerance and blood glucose levels. The maximum recommended daily dose is 2000-3000 mg, depending on the formulation used.

Mechanism of action

Metformin decreases blood glucose levels by decreasing hepatic glucose production (gluconeogenesis), decreasing intestinal absorption of glucose, and increasing insulin sensitivity, which enhances peripheral glucose uptake and utilization. It is known to inhibit mitochondrial complex I activity, leading to increased AMP:ATP ratios that activate AMP-activated protein kinase (AMPK), a key regulator of glucose metabolism. This activation results in reduced hepatic glucose output and improved cellular glucose uptake.

Pharmacodynamics

Metformin exerts its effects primarily by enhancing insulin sensitivity and reducing glucose production by the liver. Unlike sulfonylureas, which increase insulin secretion, metformin does not cause hyperinsulinemia. Its ability to lower fasting plasma glucose and glycosylated hemoglobin (HbA1c) levels makes it a cornerstone in the management of type 2 diabetes. Clinical studies have shown significant reductions in fasting plasma glucose and HbA1c levels in patients treated with metformin.

Pharmacokinetics

Metformin is absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring 2-3 hours after ingestion. It has a bioavailability of approximately 50-60% when administered orally. The drug is primarily eliminated unchanged by the kidneys, and its clearance is proportional to renal function. The half-life of metformin is about 6.5 hours. Accumulation may occur in cases of renal impairment, necessitating caution in patients with reduced renal function.

Adverse effects

• Gastrointestinal disturbances (nausea, vomiting, diarrhea)
• Lactic acidosis
• Vitamin B12 deficiency

Interactions

• dolutegravir+metformin: Moderate (increases exposure)
• cimetidine+metformin: Moderate (increases exposure)
• risdiplam+metformin: Moderate (increases concentration)
• vandetanib+metformin: Moderate (increases exposure)
• bictegravir+metformin: Unknown (increases exposure)
• guanfacine+metformin: Unknown (increases concentration)
• mexiletine+metformin: Unknown (affects exposure)
• pitolisant+metformin: Unknown (increases exposure)
• ribociclib+metformin: Unknown (increases exposure)

Precautions

• Renal impairment
• Dehydration
• Excessive alcohol intake

Pregnancy

Metformin is classified as a Category B medication. It is often used during pregnancy for managing gestational diabetes but should be administered under medical supervision.

Breast-feeding

Metformin is excreted in breast milk, but is generally considered safe for use during breastfeeding. Consult with a healthcare provider for specific guidance.

Storage

Store in a cool, dry place, away from direct light. Keep out of reach of children.

Formulations

• Tablets
• Extended-release tablets
• Oral solution

Indications

• Tablet coating
• Granule coating
• Improvement of drug stability
• Taste masking
• Aesthetic enhancement of pharmaceuticals

Dosage

Children: Dosage will depend on the specific formulation and active ingredients of the medication being coated. Refer to the specific product information for guidance.

Adults: Dosage will depend on the specific formulation and active ingredients of the medication being coated. Refer to the specific product information for guidance.

Mechanism of action

Opadry functions primarily as a coating polymer that adheres to the surface of tablets or granules, creating a protective layer. This layer can control the release of the active ingredient and protect it from environmental factors such as moisture and light. The specific composition of Opadry can vary, but it typically includes film-forming agents, plasticizers, and colorants that work together to achieve the desired coating characteristics.

Pharmacodynamics

The pharmacodynamics of Opadry is largely focused on its physical and chemical properties rather than specific biological interactions. The coating alters the dissolution characteristics of the drug, potentially leading to modified release profiles. This can enhance drug bioavailability or control the release rate of the active ingredient, thereby impacting the therapeutic effect.

Pharmacokinetics

As a coating agent, Opadry itself is not absorbed into the systemic circulation and does not have pharmacokinetic properties related to absorption, distribution, metabolism, or excretion of an active pharmaceutical ingredient. Its impact on pharmacokinetics is indirect, as it affects how the active drug is released and absorbed in the gastrointestinal tract.

Pregnancy

Opadry is a film-coating agent, and specific studies on its effects during pregnancy are not well-documented. Generally, it is advisable to use medications cautiously during pregnancy. Consult a healthcare provider for guidance.

Breast-feeding

Limited data are available regarding the safety of Opadry during breastfeeding. It is recommended to consult a healthcare provider before use.

Storage

Store in a cool, dry place away from direct sunlight and moisture. Keep out of reach of children.

Formulations

• Opadry OY - a coating system for oral solid dosage forms
• Opadry II - a polymer-based coating system for tablet and capsule applications

Indications

• Topical antiseptic for skin disinfection
• Surgical scrubs and hand sanitizers
• Wound care management
• Pharmaceutical excipient in solid and liquid formulations

Dosage

Children: Refer to specific product guidelines for pediatric dosing recommendations, as doses can vary based on formulation and intended use.

Adults: Refer to specific product guidelines for dosing recommendations, as doses can vary based on the formulation and intended use.

Mechanism of action

Povidone acts by forming a complex with iodine when used as an antiseptic, which releases iodine slowly to exert its antimicrobial effect. The iodine disrupts microbial cell walls and interferes with protein synthesis, leading to cell death. Additionally, as a polymer, povidone can enhance drug solubility and stability by forming a hydrophilic matrix.

Pharmacodynamics

Povidone has a broad spectrum of antimicrobial activity against bacteria, viruses, and fungi. Its antiseptic properties are primarily due to the release of iodine, which is effective in reducing microbial load and preventing infection. The polymer's ability to bind to various substances allows it to be utilized in formulations that require improved stability and solubility.

Pharmacokinetics

Povidone is not absorbed systemically when applied topically, as it remains localized at the site of application. Its pharmacokinetics are largely dependent on the formulation and route of administration, with the polymer being metabolized by hydrolysis and excreted in urine as low-molecular-weight compounds. The release and activity of iodine are influenced by the concentration of povidone and the presence of organic matter.

Adverse effects

• Local irritation
• Allergic reactions
• Skin rashes
• Hypersensitivity reactions

Precautions

• Use with caution in patients with known allergies to iodine or povidone-iodine
• Avoid use in deep puncture wounds or serious burns

Pregnancy

Povidone is generally considered safe for use during pregnancy, but it is advisable to consult a healthcare professional before use.

Breast-feeding

Povidone is considered safe during breastfeeding, but it is recommended to consult a healthcare professional.

Storage

Store at room temperature, away from moisture and heat. Keep the container tightly closed.

Formulations

• Topical solution
• Ointment
• Surgical scrub
• Gauze impregnated with povidone-iodine

Dosage

Children: Refer to specific drug formulations and product labels as purified substances can vary widely in their use and dosing.

Adults: Refer to specific drug formulations and product labels as purified substances can vary widely in their use and dosing.

Mechanism of action

The mechanism of action for purified compounds varies widely depending on the specific substance. Generally, purified drugs exert their effects by interacting with specific biological targets, such as receptors, enzymes, or ion channels, leading to a desired therapeutic effect. This interaction can involve binding to receptors to activate or inhibit signaling pathways, modulating enzymatic activity, or altering physiological processes.

Pharmacodynamics

Pharmacodynamics describes the effects of a drug on the body and the relationship between drug concentration and effect. For purified drugs, this can involve dose-response relationships and the time course of their action. The purified form often enhances potency and reduces variability in response among patients, which can lead to more predictable therapeutic outcomes. The overall effect is determined by the drug's affinity for its target, the efficacy of the drug-receptor interaction, and the downstream signaling pathways activated as a result of this interaction.

Pharmacokinetics

Pharmacokinetics involves the absorption, distribution, metabolism, and excretion (ADME) of a drug. For purified substances, absorption can be more efficient due to the absence of impurities that may affect solubility or stability. Distribution may also be enhanced, leading to higher bioavailability. Metabolism can be influenced by the structure of the purified compound, as it may be metabolized more readily by liver enzymes. Excretion typically occurs through the kidneys or liver, depending on the molecular characteristics of the purified drug.

Pregnancy

Consult with a healthcare professional, as the safety of purified forms of medications during pregnancy may vary depending on the specific substance.

Breast-feeding

Consult with a healthcare professional, as the safety of purified forms of medications during breastfeeding may vary depending on the specific substance.

Storage

Store in a cool, dry place, away from light and moisture, and keep out of reach of children.

Mechanism of action

Metformin is widely used to treat hyperglycemia. However, metformin treatment may induce intrahepatic cholestasis and liver injury in a few patients with type II diabetes through an unknown mechanism. Here we show that metformin decreases SIRT1 protein levels in primary hepatocytes and liver. Both metformin-treated wild-type C57 mice and hepatic SIRT1-mutant mice had increased hepatic and serum bile acid levels. However, metformin failed to change systemic bile acid levels in hepatic SIRT1-mutant mice. Molecular mechanism study indicates that SIRT1 directly interacts with and deacetylates Foxa2 to inhibit its transcriptional activity on expression of genes involved in bile acids synthesis and transport. Hepatic SIRT1 mutation elevates Foxa2 acetylation levels, which promotes Foxa2 binding to and activating genes involved in bile acids metabolism, impairing hepatic and systemic bile acid homeostasis. Our data clearly suggest that hepatic SIRT1 mediates metformin effects on systemic bile acid metabolism and modulation of SIRT1 activity in liver may be an attractive approach for treatment of bile acid-related diseases such as cholestasis. Metformin is antihyperglycemic, not hypoglycemic. It does not cause insulin release from the pancreas and does not cause hypoglycemia, even in large doses. Metformin has no significant effects on the secretion of glucagon, cortisol, growth hormone or somatostatin. Metformin reduces glucose levels primarily by decreasing hepatic glucose production and by increasing insulin action in muscle and fat. ... May decrease plasma glucose by reducing the absorption of glucose from the intestine. /Salt not specified/ Metformin potentiates the effect of insulin by mechanisms not fully understood. Metformin does not stimulate pancreatic beta cells to increase secretion of insulin; insulin secretion must be present for metformin to work properly. It is postulated that metformin decreases hepatic glucose production and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. /Salt not specified/ People with Type 2 diabetes mellitus (T2DM) have reduced bone mineral density and an increased risk of fractures due to altered mesenchymal stem cell (MSC) differentiation in the bone marrow. This leads to a shift in the balance of differentiation away from bone formation (osteogenesis) in favour of fat cell development (adipogenesis). The commonly used anti-diabetic drug, metformin, activates the osteogenic transcription factor Runt-related transcription factor 2 (Runx2), which may suppress adipogenesis, leading to improved bone health. Here we investigate the involvement of the metabolic enzyme, AMP-activated protein kinase (AMPK), in these protective actions of metformin. The anti-adipogenic actions of metformin were observed in multipotent C3H10T1/2 MSCs, in which metformin exerted reciprocal control over the activities of Runx2 and the adipogenic transcription factor, PPARgamma, leading to suppression of adipogenesis. These effects appeared to be independent of AMPK activation but rather through the suppression of the mTOR/p70S6K signalling pathway. Basal AMPK and mTOR/p70S6K activity did appear to be required for adipogenesis, as demonstrated by the use of the AMPK inhibitor, compound C. This observation was further supported by using AMPK knockout mouse embryo fibroblasts (MEFs) where adipogenesis, as assessed by reduced lipid accumulation and expression of the adipogeneic transcription factor, C/EBPbeta, was found to display an absolute requirement for AMPK. Further activation of AMPK in wild type MEFS, with either metformin or the AMPK-specific activator, A769662, was also associated with suppression of adipogenesis. It appears, therefore, that basal AMPK activity is required for adipogenesis and that metformin can inhibit adipogenesis through AMPK-dependent or -independent mechanisms, depending on the cellular context.

Mechanism of action

Metformin's mechanisms of action are unique from other classes of oral antihyperglycemic drugs. Metformin decreases blood glucose levels by decreasing hepatic glucose production (also called gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization. It is well established that metformin inhibits mitochondrial complex I activity, and it has since been generally postulated that its potent antidiabetic effects occur through this mechanism. The above processes lead to a decrease in blood glucose, managing type II diabetes and exerting positive effects on glycemic control. After ingestion, the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes (liver cells). As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane. Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios. These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism. Aside from this mechanism, AMPK can be activated by a lysosomal mechanism involving other activators. Following this process, increases in AMP:ATP ratio also inhibit _fructose-1,6-bisphosphatase_ enzyme, resulting in the inhibition of gluconeogenesis, while also inhibiting _adenylate cyclase_ and decreasing the production of cyclic adenosine monophosphate (cAMP), a derivative of ATP used for cell signaling. Activated AMPK phosphorylates two isoforms of acetyl-CoA carboxylase enzyme, thereby inhibiting fat synthesis and leading to fat oxidation, reducing hepatic lipid stores and increasing liver sensitivity to insulin. In the intestines, metformin increases anaerobic glucose metabolism in enterocytes (intestinal cells), leading to reduced net glucose uptake and increased delivery of lactate to the liver. Recent studies have also implicated the gut as a primary site of action of metformin and suggest that the liver may not be as important for metformin action in patients with type 2 diabetes. Some of the ways metformin may play a role on the intestines is by promoting the metabolism of glucose by increasing glucagon-like peptide I (GLP-1) as well as increasing gut utilization of glucose. In addition to the above pathway, the mechanism of action of metformin may be explained by other ways, and its exact mechanism of action has been under extensive study in recent years. Metformin is widely used to treat hyperglycemia. However, metformin treatment may induce intrahepatic cholestasis and liver injury in a few patients with type II diabetes through an unknown mechanism. Here we show that metformin decreases SIRT1 protein levels in primary hepatocytes and liver. Both metformin-treated wild-type C57 mice and hepatic SIRT1-mutant mice had increased hepatic and serum bile acid levels. However, metformin failed to change systemic bile acid levels in hepatic SIRT1-mutant mice. Molecular mechanism study indicates that SIRT1 directly interacts with and deacetylates Foxa2 to inhibit its transcriptional activity on expression of genes involved in bile acids synthesis and transport. Hepatic SIRT1 mutation elevates Foxa2 acetylation levels, which promotes Foxa2 binding to and activating genes involved in bile acids metabolism, impairing hepatic and systemic bile acid homeostasis. Our data clearly suggest that hepatic SIRT1 mediates metformin effects on systemic bile acid metabolism and modulation of SIRT1 activity in liver may be an attractive approach for treatment of bile acid-related diseases such as cholestasis. Metformin is antihyperglycemic, not hypoglycemic. It does not cause insulin release from the pancreas and does not cause hypoglycemia, even in large doses. Me

Pharmacodynamics

**General effects** Insulin is an important hormone that regulates blood glucose levels. Type II diabetes is characterized by a decrease in sensitivity to insulin, resulting in elevations in blood glucose when the pancreas can no longer compensate. In patients diagnosed with type 2 diabetes, insulin is unable to exert adequate effects on tissues and cells (i.e. insulin resistance) and insulin deficiency may also be present. Metformin reduces hepatic production of glucose, decreases the intestinal absorption of glucose, and enhances insulin sensitivity by increasing both peripheral glucose uptake and utilization. In contrast with drugs of the sulfonylurea class, which lead to hyperinsulinemia, the secretion of insulin is unchanged with metformin use. **Effect on fasting plasma glucose (FPG) and Glycosylated hemoglobin (HbA1c)** HbA1c is an important periodic measure of glycemic control used to monitor diabetic patients. Fasting plasma glucose is also a useful and important measure of glycemic control. In a 29-week clinical trial of subjects diagnosed with type II diabetes, metformin decreased the fasting plasma glucose levels by an average of 59 mg/dL from baseline, compared to an average increase of 6.3 mg/dL from baseline in subjects taking a placebo. Glycosylated hemoglobin (HbA1c) was decreased by about 1.4% in subjects receiving metformin, and increased by 0.4% in subjects receiving placebo only.