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
• Uncorrected hyper- or hypoglycaemic 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
• Omission of a meal, change in diet or unplanned, strenuous physical exercise
• 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

One or several daily injections may be necessary

Can be used alone or, if in intensive insulin therapy, as basal insulin (evening and/or morning injection) with a fast- or rapid-acting insulin given at meal times

Should be administered subcutaneously in the thigh, abdominal wall, gluteal or deltoid region

Should not be given intravenously

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

Insulin-dependent diabetes mellitus 

• SC (inj): Initial: 0.25 units/kg/day; Maintenance range: 0.4-1.0 unit/kg/day in divided doses
• See link: General prescribing points on the principles of insulin dosing

For Type-2 DM in Children ≥10 years and adolescents with ketoacidosis and/or ketonuria 

• SC (inj): Initial: 0.25 to 0.5 units/kg/dose once daily
• Use in combination with lifestyle changes and approved oral agent to achieve glycaemic goals
• See link: General prescribing points on the principles of insulin dosing

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

During puberty, requirements may substantially increase to >1.0-2.0 unit/kg/day

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

Should be administered subcutaneously in the thigh, abdominal wall, gluteal or deltoid region

Should not be given intravenously

Pregnancy

• Safe
• There are no restrictions on the treatment of diabetes with insulin during pregnancy, as insulin does not pass the placental barrier
• If untreated during pregnancy, diabetes mellitus constitutes a risk in intrauterine development. Diabetes therapy must, therefore, be continued during pregnancy
• Both hypoglycaemia and hyperglycaemia, which can occur in inadequately controlled diabetes therapy, increase the risk of malformations and death in utero
• Intensified glucose control and monitoring (for insulin-dependent or gestational diabetes), as well as general health, is essential in pregnant patients with diabetes
• 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
• Patients with diabetes should be advised to inform their doctors if they are pregnant or contemplating pregnancy

Breastfeeding

• Compatible
• There are no restrictions on the treatment of diabetes with insulin isophane during breastfeeding as insulin treatment of nursing mothers presents no risk to the baby
• 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 m² 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): Caution; 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
  Loss of consciousness
• 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
• 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-sympathomimetics
• Ritodrine
• Salbutamol
• Terbutaline
• Danazol
• Oral antidiabetic agents
• Antidepressants
• Monoamine oxidase inhibitors (MAOI)
• Beta-adrenergic 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
• Time action profile of insulin is influenced by several factors including insulin dosage, injection route and site

Excipients

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

Method of administration

• Insulin isophane should not be administered intravenously and is not suitable for use in insulin infusion pumps
• Subcutaneous administration should be in the upper arms, thighs, buttocks or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month
• Care should be taken when injecting any Humulin 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
• Insulin isophane from vials may be administered with short acting insulins when required, usually as a twice a day regimen
• When mixing, the short acting insulin should be drawn into the syringe first to prevent contamination of the vial by the longer-acting preparation. Inject immediately after mixing
• Do not administer the mixture intravenously
• Products should not be mixed with insulins produced by other manufacturers or with animal insulin preparations
• Insulin isophane cartridges are not designed to allow any other insulin to be mixed in the cartridges and disposable pen injectors

Special precautions for storage and handling

• When unused, store in a refrigerator (2°C – 8°C). Do not freeze. Do not expose to excessive heat or direct sunlight
• If refrigeration is not possible or when in use, store below 25°C for up to 28 days and do not expose to sunlight or temperatures above 37°C. Do not refrigerate
• The product should be resuspended until the insulin appears uniformly cloudy or milky. If the product does not become completely homogeneous when agitated it should not be used
• Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose
• The product should be examined frequently and should not be used if clumps of material are present or if solid white particles stick to the bottom or wall of the cartridge, giving a frosted appearance
• After the dose is prepared, the injection should be given promptly to avoid clogging of the needle
• A pen with the inserted cartridge should not be stored with the needle attached
• Do not reuse needles. Dispose of the needle in a responsible manner. Needles and pens must not be shared
• Cartridges should only be used in conjunction with compatible reusable insulin pens as the dosing accuracy has not been established with other pens
• The patient information leaflet with instructions on how to inject insulin using the product should be consulted

The prime activity of insulin is the regulation of glucose metabolism.

Insulin isophane is a long acting insulin that replaces the insufficiency of insulin secretion by the beta-cells of the pancreas. 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.

Injection (per ml) 100u
- Insulin isophane

• Biosulin N (Dezzo Trading)
• Humulin N (Eli Lilly) originator
• Protaphane HM (Novo Nordisk) originator