RYZODEG® FLEXTOUCH® SOLUTION FOR INJECTION IN PRE-FILLED PEN 100 U/ml

Insulin Aspart
Insulin Degludec

Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.

Active Ingredient / Synonyms

Aspart | Aspart Insulin | B28-Aspart-Insulin | Insulin aspart protamine | Insulin aspart protamine recombinant | Insulin aspart recombinant | Insulin X14 | Insulin, aspart protamine, human | Insulin, aspart, human | Insulin,aspart protamine | Insulin Aspart |

Description

Insulin aspart is a recombinant, biosynthetic, fast-acting insulin analogue. It has a single amino acid substitution at position B28 where proline is replaced with aspartic acid. This substitution decreases its propensity to form hexamers and gives it a higher rate of absorption following subcutaneous administration compared to native insulin. Insulin aspart is produced in a genetically modified strain of _Saccharomyces cerevisiae_ and harvested from a bioreactor.

Indication

For the treatment of Type 1 or 2 diabetes mellitus. Should normally be used in conjunction with an intermediate or long-acting insulin.

Mechanism of Action

Insulin aspart 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 signaling 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 and catabolism. In humans, insulin is stored in the form of hexamers; however, only insulin monomers are able to interact with IR. Substitution of the proline residue at B28 with aspartic acid reduces the tendency to form hexamers and results in a faster rate of absorption and onset of action and shorter duration of action.

Pharmacodynamics

Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Postprandial insulin spikes are 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 aspart is a rapid-acting insulin analogue used to mimic postprandial insulin spikes in diabetic individuals. The onset of action of insulin aspart is 10-15 minutes. Its activity peaks 60-90 minutes following subcutaneous injection and its duration of action is 4-5 hours.

Pharmacokinetics

Absorption:

Rapidly absorbed following subcutaneous administration (more so than regular human insulin). Furthermore, insulin aspart has a faster absorption, a faster onset of action, and a shorter duration of action than regular human insulin after subcutaneous injection. It takes 40 - 50 minutes to reach maximum concentration. When a dose of 0.15 U/kg body weight was injected in type 1 diabetes patients, the mean maximum concentration (Cmax) was 82 mU/L. The site of injection has no impact on extent or speed of absorption.

Distribution:

Not Available

Metabolism:

Not Available

Elimination:

Not Available

Half-life

81 minutes (following subcutaneous administration in healthy subjects).

Clearance

* 1.2 L/h/kg [healthy Caucasian male], excreted in the urine

Toxicity

Inappropriately high dosages relative to food intake and/or energy expenditure may result in severe and sometimes prolonged and life-threatening hypoglycemia. 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. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia.

Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.

Active Ingredient / Synonyms

Insulin Degludec | Insulin Degludec |

Description

Insulin Degludec is an ultra-long-acting insulin analogue used for glycemic control in Diabetes Mellitus. Insulin and its analogues lower blood glucose levels by stimulating peripheral glucose uptake and by preventing hepatic glucose production. Compared to endogenous insulin, this product has an added hexadecanedioic acid to lysine at the B29 position which allows for the formation of multi-hexamers. When injected subcutaneously, these multi-hexamers form a drug depot store from which monomers are slowly and continuously absorbed into the circulation. As a result, Insulin Degludec has a protracted time action profile due to the delayed absorption from subcutaneous tissue depots into the systemic circulation. Compared to available long-acting analogues such as insulin glargine and insulin detemir, which have a duration of action of 20-24 hours, insulin degludec provides a consistent level of basal insulin over 42 hours with a low peak:trough ratio. Limitations of shorter acting analogues include more frequent dosing and less stable pharmacokinetics, which may negatively impact patient adherence and glucose control, particularly nocturnal control. Insulin Degludec was approved by the FDA in September 2015 as the product Tresiba, for use in providing glycemic control to adults with diabetes mellitus.

Indication

Insulin degludec is indicated to improve glycemic control in adults with diabetes mellitus.

Mechanism of Action

Insulin and its analogues lower blood glucose levels by stimulating peripheral glucose uptake and by preventing hepatic glucose production. Compared to endogenous insulin, Insulin Degludec has an added hexadecanedioic acid to lysine at the B29 position which allows for the formation of multi-hexamers in subcutaneous tissues. When injected subcutaneously, these multi-hexamers form a drug depot store that slowly release. As a result, Insulin Degludec has a protracted time action profile due to the delayed absorption from subcutaneous tissue depots into the systemic circulation

Pharmacodynamics

Not Available

Pharmacokinetics

Absorption:

In patients with type 1 diabetes, after 8 days of once daily subcutaneous dosing with 0.4 U/kg, maximum degludec concentrations of 4472 pmol/L were attained at a median of 9 hours (tmax). After the first dose of, median onset of appearance was around one hour. The glucose lowering effect lasted at least 42 hours after the last of 8 once-daily injections. Insulin degludec concentration reach steady state levels after 3-4 days.

Distribution:

Not Available

Metabolism:

All insulin degludec metabolites are inactive.

Elimination:

Not Available

Half-life

The half-life after subcutaneous administration is determined primarily by the rate of absorption from the subcutaneous tissue. On average, the half-life at steady state is approximately 25 hours independent of dose.

Clearance

0.03 L/kg

Toxicity

Observe for signs and symptoms of hypoglycemia, hypokalemia, and fluid retention and heart failure with concomitant use of Thiazolidinediones. Pregnancy Category C

References

  1. Health Science Authority of Singapore - Reclassified POM
  2. Drugbank

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Approval Information

RYZODEG FLEXTOUCH SOLUTION FOR INJECTION IN PRE-FILLED PEN 100 U/ML was registered with Health Science Authority of Singapore by NOVO NORDISK PHARMA (SINGAPORE) PTE LTD. It is marketed with the registration number of SIN15706P with effective from 2019-05-31.

This product contains 180nmol/ml of Insulin Aspart, and 420nmol/ml of Insulin Degludec in the form of INJECTION, SOLUTION.

The medicine was manufactured by Novo Nordisk A/S (Bagsvaerd) (Bulk production and Primary Packager) in DENMARK

It is a Presciption Only Medicine which can only be obtained from a doctor or a dentist, or from a pharmacist with a prescription from a Singapore-registered doctor or dentist.

Anatomical Therapeutic Chemical (ATC) Classification

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