Insulin Soluble/ Insulin Isophane

Registered South African indications:

• Diabetes mellitus

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypoglycaemia
• Intravenous administration

Cautions

• Severe renal impairment or ESRD
• Severe hepatic impairment
• Elderly
• Risk factors for cardiac heart failure
• Hyperglycaemia
• Diabetic ketoacidosis
• Untreated hyperglycaemic events
• Conditions masking early warning symptoms of hypoglycaemia (e.g. intensified insulin therapy, long duration of diabetes, diabetic nerve disease)
• Inadequate dosing or discontinuation of therapy
• Concomitant illness, especially infections and feverish conditions
• Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland
• Presence of insulin antibodies
• Patients transferred between different types of insulin products (including strength, brand, and/or species)
• Illness or emotional disturbances
• Change in the level of physical activity or usual diet
• Patient travelling between different time zones
• May impair ability to drive and operate machinery (as a result of hypoglycaemia)

Forms avail. in SA and covered in this monograph: inj

Insulin-dependent diabetes mellitus

• SC (inj): 0.3-1.0 units/kg/day
• See link: General prescribing points on the principles of insulin dosing

The dosage should be determined according to the individual requirement of the patient

Should normally be administered twice daily, usually with two-thirds of the daily requirement given in the morning and the remainder in the evening

Should be administered subcutaneously in the thigh or abdominal wall. The gluteal or deltoid region may also be used

Should not be administered intravenously

Forms avail. in SA and covered in this monograph: inj

Insulin-dependent diabetes mellitus

• SC (inj): Initial: 0.2-0.4 units/kg/day; Maintenance range: 0.5-1.0 unit/kg/day in divided doses
• See link: General prescribing points on the principles of insulin dosing

The dosage should be individualised according to the age and maturity of the patient to achieve glycaemic goals without causing hypoglycaemia

During puberty, requirements may substantially increase to >1.2-2.0 unit/kg/day

The daily doses presented are expressed as the total units/kg/day of all insulin formulations combined

Pregnancy

• Safe
• Patients with diabetes should be advised to inform their doctors if they are pregnant or contemplating pregnancy
• Intensified glucose control and monitoring (for insulin-dependent or gestational diabetes), as well as general health, is essential in pregnant patients with diabetes
• Both hypoglycaemia and hyperglycaemia, which can occur in inadequately controlled diabetes therapy, increase the risk of malformations and death in utero
• Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. After delivery, insulin requirements return rapidly to pre-pregnancy values

Breastfeeding

• Compatible
• Patients with diabetes who are breastfeeding may require adjustments in diet

Renal impairment

• eGFR ≥30-89 ml/min/1.73 m²No dose adjustment recommended
• eGFR ≤29 ml/min/1.73 m or ESRD: Caution; dose adjustment recommended
  Reduced recommended dose by 20-40%. Monitor glucose target and renal function
• Haemodialysis: No dose adjustment recommended 

Hepatic impairment

• Mild to moderate (Child-Pugh Classes A & B): No dose adjustment recommended
• Severe (Child-Pugh Class C): Dose adjustment recommended
  Adjust insulin dose according to blood glucose target

Elderly

• Caution; dose adjustment recommended
  Conservative initial dose is required to avoid risk for hypoglycaemia
  Reduce the initial recommended dose by 10% to 20%
  Avoid intensive glucose control (risk for hypoglycaemia and CVS-related mortality)
  Control of geriatric patient's blood glucose needs to be individualised
  In cases of severe hypoglycaemia, dosage reductions of 25% to 50% have been recommended

Porphyria information

• Not porphyrinogenic (NP)

Drugs in Sport

• Prohibited - At all times

Central Nervous System Disorders

• Peripheral neuropathy (painful neuropathy)

Cardiovascular Disorders

• Heart failure

Endocrine and Metabolic Disorders

• Hypoglycaemia
  - Cold sweats
  - Cool pale skin
  - Fatigue
  - Nervousness or tremor
  - Anxiousness
  - Unusual tiredness or weakness
  - Confusion
  - Difficulty in concentration
  - Drowsiness
  - Excessive hunger
  - Vision changes
  - Headache
  - Nausea
  - Palpitation
• Weight gain
• Insulin resistance

Skin and Subcutaneous Tissue Disorders

• Injection-site reactions
  - Local allergy
  - Redness
  - Swelling
  - Itching
  - Pain
  -Haemotoma
• Lipodystrophy (at injection site)
• Uticaria
• Rash

Immune, Blood and Lymphatic System Disorders

• Systemic allergy/anaphylactic reactions
  - Rash over the whole body
  Itching
  - Shortness of breath
  Palpitation
  Wheezing
  - Fast pulse
  - Sweating
  - Decreased blood pressure
  - Angioneurotic oedema
  - Loss of consciousness
• Oedema

Sensory Disorders

• Refraction disorders
• Diabetic retinopathy

• Agents that may increase or reduce insulin requirements
• Oral contraceptives
• Thiazides
• Glucocorticoids
• Thyroid hormones
• Growth hormone
• Sympathomimetics
• Beta 2-sympatomimetics
• Ritodrine
• Salbutamol
• Terbutaline
• Danazol
• Oral antidiabetic agents
• Antidepressants
• Monoamine oxidase inhibitors (MAOI)
• Non-selective beta-blockers
• Angiotensin converting enzyme (ACE) inhibitors
• Captopril
• Enalapril
• Angiotensin II receptor blockers (ARBs)
• Salicylates
• Acetylsalicylic acid
• Sulpha antibiotics
• Thiazolidinediones (TZDs)
• Pioglitazone
• Somatostatin analogues
• Octreotide
• Lanreotide
• Alcohol

Diabetes mellitus

• Blood glucose
• Electrolytes
• HbA1c
• Lipid profile
• Renal function
• Hepatic function
• Weight

Gestational diabetes mellitus

• Blood glucose 4 times daily (1 fasting and 3 postprandial) until well-controlled

Dosing

• The daily insulin requirement may be higher in patients with insulin resistance (e.g. during puberty or due to obesity) and lower in patients with residual, endogenous insulin production
• In patients with diabetes mellitus, optimised metabolic control delays the onset of late diabetic complications. Close blood glucose monitoring is therefore recommended
• Individual variability will depend on factors such as the size of the dose, site of injection temperature and physical activity of the patient

Transfer from other insulin medicinal products

• Transferring a patient to a new type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type, species (animal insulin, human insulin or insulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in the need for a change in dose
• If dose adjustment is needed, it may be done within the first dose or during the first few weeks or months

Method of administration

• Insulin soluble/ Insulin isophane should not be administered intravenously and is not suitable for use in insulin infusion pumps
• Insulin soluble/ Insulin isophane is administered subcutaneously in the thigh, abdominal wall, gluteal or deltoid region
• Subcutaneous injection into the abdominal wall results in faster absorption than from other injection sites. Use of injection sites should be rotated so that the same site is not used more than approximately once a month
• Injection into a lifted skin fold minimises the risk of intramuscular injection. Keep the needle under the skin got at least 6 seconds to make sure the entire dose is injected
• Care should be taken when injecting any insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged
• Patients must be educated to use proper injection techniques

Incompatibilities

• Insulin soluble/ Insulin isophane is a ready-made mixture designed to avoid the need for mixing insulins by patients
• Insulin soluble/ Insulin isophane preparations should not be mixed with insulins produced by other manufacturers or with animal insulin preparations

Excipients

• Formulations may contain less than 1 mmol sodium (23 mg) per dose, i.e. are essentially “sodium-free”

Special precautions for storage and handling

• When unopened, store in a refrigerator (2°C – 8°C). Do not freeze. Do not expose to excessive heat or direct sunlight
• After the first use, store below 30°C for one month. Do not store in the refrigerator.Do not expose to sunlight or heat
• The pre-filled pen should not be stored with the needle attached
• To prevent the possible transmission of disease, each pen must be used by one patient only, even if the needle is changed
• The product should be resuspended until the insulin appears uniformly cloudy or milky. Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose
• Do not use If clumps of material are present or if solid white particles are evident
• Always follow specific patient information leaflets with instructions on how to inject insulin products

The prime activity of insulin is the regulation of glucose metabolism. Insulin has several anabolic and anti-catabolic actions on a variety of different tissues. Within muscle tissue this includes increasing glycogen, fatty acid, glycerol and protein synthesis and amino acid uptake, while decreasing glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism and amino acid output.

COMBINATION PREPARATIONS

30% Insulin Soluble/ 70% Insulin Isophane 

Injection (per ml) 100u

• Actraphane HM (Novo Nordisk)
• Biosulin 30/70 (Dezzo Trading)
• Diabulyn 30/70 (Ascendis Pharma)
• Humulin 30/70 (Eli-lily)
• Insuman Comb 30/70 (Sanofi)