LEVEMIR FLEXPEN

Insulin detemir is a long-acting form of insulin used for the treatment of hyperglycemia caused by Type and Type 2 Diabetes. 1, 2, 3, 5 Insulin is typically prescribed for the management of diabetes mellitus to mimic the activity of endogenously produced human insulin, a peptide hormone produced by beta cells of the pancreas that promotes glucose metabolism. 1, 2, 3, 5 Insulin is released from the pancreas following a meal to promote the uptake of glucose from the blood into internal organs and tissues such as the liver, fat cells, and skeletal muscle. 1, 2, 3, 5 The absorption of glucose into cells allows for its transformation into glycogen or fat for storage. 1, 2, 3, 5 Insulin also inhibits hepatic glucose production, enhances protein synthesis, and inhibits lipolysis and proteolysis among many other functions. 1, 2, 3, 5 Insulin is an important treatment in the management of Type 1 Diabetes (T1D) which is caused by an autoimmune reaction that destroys the beta cells of the pancreas, resulting in the body not being able to produce or synthesize the insulin needed to manage circulating blood sugar levels. 1, 2, 3, 5 As a result, people with T1D rely primarily on exogenous forms of insulin, such as insulin detemir, to lower glucose levels in the blood. 1, 2, 3, 5 Insulin is also used in the treatment of Type 2 Diabetes (T2D), another form of diabetes mellitus that is a slowly progressing metabolic disorder caused by a combination of genetic and lifestyle factors that promote chronically elevated blood sugar levels. 1, 2, 3, 5 Without treatment or improvement in non-pharmacological measures such as diet and exercise to lower blood glucose, high blood sugar eventually causes cellular resistance to endogenous insulin, and in the long term, damage to pancreatic islet cells. 1, 2, 3, 5 Insulin is typically prescribed later in the course of T2D, after several oral medications such as Metformin, Gliclazide, or Sitagliptin have been tried, when sufficient damage has been caused to pancreatic cells that the body is no longer able to produce insulin on its own. 1, 2, 3, 5 Marketed as the brand name product Levemir, insulin detemir has a duration of action of 16-24 hours allowing for once-daily dosing, typically at bedtime. 1, 2, 3, 5 Due to its duration of action, Levemir is considered "basal insulin" as it provides low concentrations of background insulin that can keep blood sugar stable between meals or overnight. 1, 2, 3, 5 Basal insulin is often combined with short-acting "bolus insulin" such as Insulin lispro, Insulin glulisine, and Insulin aspart to provide higher doses of insulin required following meals. 1, 2, 3, 5 Use of basal and bolus insulin together is intended to mimic the pancreas'production of endogenous insulin, with a goal of avoiding any periods of hypoglycemia. 1, 2, 3, 5 Insulin detemir is produced using recombinant DNA technology in yeast cells. 1, 2, 3, 5 This insulin analogue has a 14-C fatty acid, myristic acid, bound to the lysine amino acid at position B29.

The myristoyl side chain increases self-association and albumin binding. 1, 2, 3, 5 This along with slow systemic absorption from the injection site prolongs distribution of the hormone into tissues and results in a long duration of action. 1, 2, 3, 5 Without an adequate supply of insulin to promote absorption of glucose from the bloodstream, blood sugar levels can climb to dangerously high levels and can result in symptoms such as fatigue, headache, blurred vision, and increased thirst. 1, 2, 3, 5 If left untreated, the body starts to break down fat, instead of glucose, for energy which results in a build-up of ketone acids in the blood and a syndrome called ketoacidosis, which is a life-threatening medical emergency.

In the long term, elevated blood sugar levels increase the risk of heart attack, stroke, and diabetic neuropathy. 1, 2, 3, 5.

Insulin detemir is indicated to improve glycemic control in adults and children with diabetes mellitus.

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. 3, 2 Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. 3, 2 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 the liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. 3, 2 Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). 3, 2 Insulin detemir is a long-acting insulin analogue with a flat and predictable action profile. 3, 2 It is used to mimic the basal levels of insulin in diabetic individuals.

The onset of action of insulin detemir is 1-2 hours and its duration of action is up to 24 hours. 3, 2 Interestingly, it has a lower affinity (30%) for the insulin receptor than human insulin. 3, 2.

After subcutaneous injection of

LEVEMIR in healthy subjects and in patients with diabetes, insulin detemir serum concentrations had a relatively constant concentration/time profile over 24 hours with the maximum serum concentration (Cmax) reached between 6-8 hours post dose.

When single dose of 0.5 units/kg of insulin detemir was given to adult type 1 diabetes patients, the maximum serum concentration (Cmax) was 4,641 ± 2,299 pmol/L. 12, 4 Insulin detemir was more slowly absorbed after subcutaneous administration to the thigh where AUC 0-5h was 30 40% lower and AUC 0-∞ was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and abdominal regions.

Insulin detemir has a slow and prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak.

The median time to maximum serum insulin concentration was 12 hours after injection.

On average, serum insulin concentrations declined to baseline by approximately 24 hours. 12, 1 The absolute bioavailability of insulin detemir is approximately 60%.

Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg.

The liver and kidney play the major role in metabolizing insulin.

However, while the liver predominantly metabolizes endogenous insulin, exogenous insulin is primarily metabolized due to the kidney since it is not directly delivered into the portal system.

30-80% of circulating insulin is removed by the kidney.

After subcutaneous administration in patients with type 1 diabetes, insulin detemir has a terminal half-life of 5-7 hours depending on dose.

The apparent clearance (CL/F) was fairly consistent among different patients population with type 1 diabetes.

It was estimated to be 3.43 ± 1.36 L/min-kg in 6-12 years old patients, 3.74 ± 0.98 L/min-kg in 13-17 years old, and 3.41 ± 1.00 L/min-kg in adult patients (18-65 years old).

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An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia.

Mild episodes of hypoglycemia usually can be treated with oral glucose.

Lowering the insulin dosage, and adjustments in meal patterns, or exercise may be needed.

More severe episodes with coma, seizure, or neurologic impairment may be treated with a glucagon product for emergency use or concentrated intravenous glucose.

Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling.

Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness.

Individuals may become unconscious in severe cases of hypoglycemia.

Injection site reactions may also occur.

Symptoms include: redness, inflammation, bruising, swelling and itching at the injection site.

After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia.