SOLIQUA 33/100

Indications

• Diabetes mellitus (type 1 and type 2)
• Diabetic ketoacidosis
• Hyperglycemia due to other conditions
• Management of blood glucose levels during surgery
• Continuous subcutaneous insulin infusion therapy

Dosage

Children: For children aged 1-17 years, insulin is administered immediately before meals or when necessary shortly after meals, according to individual requirements. Specific dosing should be determined based on blood glucose monitoring and should be referred to the BNF for Children for precise guidance.

Adults: The dosage of insulin varies based on individual needs and is typically guided by blood glucose monitoring. It is recommended to consult local protocols for specific dosing instructions.

Mechanism of action

Insulin has a direct inhibitory effect on lipase, which is involved in the mobilization of fatty acids. In the absence of insulin, there is an abnormally high rate of conversion of protein to glucose, primarily in the liver. Insulin stimulates glycogen synthesis and enhances facilitated diffusion of glucose and the active transport of amino acids, although the exact mechanisms for these actions are not fully understood.

Pharmacodynamics

Insulin's primary pharmacodynamic effect is the reduction of blood glucose levels. It promotes the uptake of glucose by cells, increases glycogen synthesis in the liver, and inhibits gluconeogenesis. Insulin also influences lipid metabolism by inhibiting lipolysis and encouraging fat storage. Additionally, insulin enhances protein synthesis by promoting amino acid uptake into cells.

Pharmacokinetics

Insulin is administered by injection and is rapidly absorbed into the bloodstream. Its onset, peak, and duration of action depend on the formulation used (e.g., rapid-acting, short-acting). The half-life of insulin is typically around 5 to 10 minutes, but its effects can last several hours depending on the formulation. It is metabolized primarily in the liver and kidneys.

Contra-indications

• Hypersensitivity to insulin or any of its excipients
• Hypoglycemia

Adverse effects

• Hypoglycemia
• Injection site reactions
• Weight gain
• Allergic reactions
• Edema
• Lipodystrophy

Interactions

• Metreleptin may increase the risk of hypoglycemia when used with insulin
• Fibrates may increase the risk of hypoglycemia when used with insulin
• Macrolides may increase the risk of severe hypoglycemia when used with insulin
• Clarithromycin may increase the risk of severe hypoglycemia when used with insulin

Precautions

• Monitor blood glucose levels regularly, especially when changing insulin preparations
• Use caution in patients with renal impairment, as insulin clearance may be reduced
• Patients should be advised about the risks of hypoglycemia and how to manage it
• Should be used with caution in patients with cardiovascular disease

Pregnancy

Insulin is generally considered safe for use during pregnancy, but dosages may need to be adjusted.

Breast-feeding

Insulin is compatible with breastfeeding; insulin does not pass into breast milk in significant amounts.

Storage

Store unopened vials or pens in a refrigerator (2-8°C). Once opened, insulin can be stored at room temperature (below 25°C) for up to 28 days, depending on the formulation.

Formulations

• Insulin human 500 units/ml solution for injection
• Insulin human 100 units/ml solution for injection
• Insulin porcine 100 units/ml solution for injection

Indications

• Type 2 diabetes mellitus

Dosage

Adults: Initially, 10 micrograms subcutaneously once daily for 14 days, then increased to 20 micrograms once daily. Administer within 1 hour before a meal.

Mechanism of action

Lixisenatide activates the GLP-1 receptor, leading to the activation of adenylyl cyclase and an increase in cyclic adenosine monophosphate (cAMP) levels within the cell. This activation results in the stimulation of protein kinase A (PKA), Epac1, and Epac2, facilitating the release of calcium ions from the endoplasmic reticulum. This 'amplification' pathway enhances glucose-stimulated insulin secretion from pancreatic beta cells, thereby lowering blood glucose levels.

Pharmacodynamics

As a GLP-1 receptor agonist, lixisenatide increases insulin exocytosis from pancreatic beta cells in response to elevated glucose levels. This results in decreased blood glucose concentrations due to enhanced glucose uptake by peripheral tissues. Additionally, lixisenatide slows gastric emptying, contributing to the reduction of postprandial blood glucose spikes, further supporting glycemic control.

Pharmacokinetics

Lixisenatide is administered via subcutaneous injection and has a half-life of approximately 2.5 hours. It is subject to degradation by dipeptidyl peptidase-4 (DPP-4), which limits its duration of action. The pharmacokinetics may vary based on renal function, with caution advised in patients with moderate to severe renal impairment.

Contra-indications

• Acute pancreatitis
• Severe renal impairment
• Severe hepatic impairment
• Personal or family history of medullary thyroid carcinoma
• Multiple endocrine neoplasia syndrome type 2

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Hypoglycemia
• Headache
• Dyspepsia
• Fatigue
• Injection site reactions
• Angioedema
• Palpitations
• Gastrointestinal disturbances
• Pancreatitis
• Thyroid tumors

Interactions

• Sulfonylureas (risk of hypoglycemia may increase)
• Insulin (dosage adjustment may be necessary)
• Other antidiabetic medications (may require dose adjustments)

Precautions

• Use with caution in patients with a history of pancreatitis
• Monitor for signs of dehydration due to gastrointestinal side effects
• Patients should be informed about the risk of diabetic ketoacidosis when insulin is reduced or discontinued
• Monitor renal function periodically

Pregnancy

Manufacturer advises avoiding use due to potential toxicity in animal studies; insufficient human data available.

Breast-feeding

Manufacturer advises avoiding use; no information available, but animal studies suggest negligible transfer to breast milk.

Storage

Store in a refrigerator (2–8°C). After first use, can be stored below 30°C and used within 1 month. Keep the cap on the pen to protect from light.

Formulations

• Solution for injection: Lixisenatide 6 mg/ml in pre-filled pens (3 ml)

Indications

• Type 1 diabetes mellitus
• Type 2 diabetes mellitus
• Diabetes management in adults and children

Dosage

Adults: The initial dose of insulin glargine is usually individualized based on the patient's blood glucose levels and metabolic needs. Typical starting doses may range from 10 to 20 units once daily, adjusted

Mechanism of action

Insulin glargine binds to the insulin receptor (IR), stimulating the intrinsic tyrosine kinase activity of the receptor's beta subunit. This leads to autophosphorylation of the receptor and phosphorylation of intracellular substrates, activating downstream signaling molecules such as PI3 kinase and Akt. These pathways promote glucose uptake via glucose transporter 4 (GLUT4), enhance glycogenesis, and inhibit catabolism, thereby regulating glucose metabolism. Upon subcutaneous injection, insulin glargine forms microprecipitates, allowing for a sustained release and a stable insulin concentration over 24 hours with no pronounced peak.

Pharmacodynamics

Insulin is a hormone synthesized by pancreatic beta cells, essential for glucose homeostasis. It facilitates the uptake of glucose in muscle and adipose tissues, promotes glycogenesis, and inhibits the breakdown of fat and glycogen. Insulin also stimulates protein synthesis and DNA replication, playing a crucial role in growth and metabolism. Insulin glargine's long-acting properties provide a stable insulin level, which is vital for managing blood glucose levels in diabetic patients.

Pharmacokinetics

Insulin glargine is formulated to be soluble at pH 4, with low solubility at physiological pH 7.4. After subcutaneous injection, it forms microprecipitates that release small amounts of insulin gradually, ensuring a constant concentration of the drug in the bloodstream over a 24-hour period. This results in a prolonged duration of action without peaks, contrasting with regular insulin which has a more rapid onset and shorter duration.

Contra-indications

• Hypersensitivity to insulin glargine or any of its excipients
• Severe hypoglycaemia
• Diabetic ketoacidosis

Adverse effects

• Hypoglycaemia
• Injection site reactions
• Weight gain
• Allergic reactions
• Lipodystrophy at injection sites

Interactions

• Certain medications may affect blood glucose levels, including corticosteroids, oral contraceptives, and thyroid hormones
• Beta-blockers may mask the signs of hypoglycaemia
• Alcohol may potentiate or reduce the hypoglycaemic effect of insulin

Precautions

• Caution in patients with renal or hepatic impairment
• Monitor blood glucose levels regularly
• Adjust dose during periods of stress, illness, or changes in activity
• Educate patients on recognizing and treating hypoglycaemia

Pregnancy

Insulin glargine is generally regarded as safe for use during pregnancy, but blood glucose levels must be carefully monitored.

Breast-feeding

Insulin glargine can be used during breastfeeding, but blood glucose levels should be monitored closely.

Storage

Store in a refrigerator (2-8°C). Do not freeze. Once in use, can be stored at room temperature (up to 25°C) for up to 28 days.

Formulations

• Insulin glargine 100 units/mL solution for injection

Mechanism of action

INSULIN HAS DIRECT INHIBITORY EFFECT ON LIPASE CONCERNED WITH MOBILIZATION OF FATTY ACIDS, WHILE GROWTH HORMONE, GLUCOCORTICOIDS, THYROID HORMONES & CATECHOLAMINES ENHANCE LIPOLYSIS. IN ABSENCE OF INSULIN THERE IS ABNORMALLY HIGH RATE OF CONVERSION OF PROTEIN TO GLUCOSE. ... PROTEINS & AMINO ACIDS ARE CONVERTED TO GLUCOSE @ ABNORMALLY HIGH RATE IN INSULIN DEFICIENCY. THE LIVER IS SITE OF CONVERSION. PROTEIN & AMINO ACIDS ARE MOBILIZED FROM PERIPHERAL TISSUES. INSULIN ACTS TO.../STIMULATE/ GLYCOGEN SYNTHESIS. MECHANISM OF IMPORTANT ACTIONS OF INSULIN TO ENHANCE FACILITATED DIFFUSION OF GLUCOSE & ACTIVE TRANSPORT OF AMINO ACIDS ARE NOT KNOWN.

Mechanism of action

The activation of the GLP-1 receptor by lixisenatide results in the activation of adenylyl cyclase. This increases the concentration of cyclic adenosine monophosphate in the cell leading to the activation of protein kinase A (PKA) as well as Epac1 and Epac2. PKA, Epac1, and Epac2 are involved the in release of Ca2+ from the endoplasmic reticulum which is known as the "amplification" pathway which increases insulin release when the triggering pathway is activated. By activating this amplification pathway lixisenatide increases glucose stimulated insulin secretion.

Pharmacodynamics

Lixisenatide acts as an agonist at the GLP-1 receptor. In the pancreas, this agonism results in increased glucose-stimulated insulin exocytosis by beta islet cells. This produces a reduction in blood glucose due to increased glucose uptake by tissues. GLP-1 receptor activation in the GI tract results in delayed gastric emptying which is thought to mediate the effects of lixisenatide on postprandial blood glucose.

Mechanism of action

Insulin glargine binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signalling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism. Insulin glargine is completely soluble at pH 4, the pH of administered solution, and has low solubility at physiological pH 7.4. Upon subcuteous injection, the solution is neutralized resulting in the formation of microprecipitates. Small amounts of insulin glargine are released from microprecipitates giving the drug a relatively constant concentration over time profile over 24 hours with no pronounced peak. This release mechanism allows the drug to mimic basal insulin levels within the body.

Pharmacodynamics

Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, the pancreas produces a continuous supply of low levels of basal insulin along with spikes of insulin following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin glargine is a long-acting insulin analogue with a flat and predictable action profile. It is used to mimic the basal levels of insulin in diabetic individuals.