Protaphane Hm (Ge) 100 units Suspension for injection

Diabetes Mellitus

Posology
The dosage for each patient is individualised and determined in accordance with the needs of the patient. The individual insulin requirement is usually between 0,3 and 1,0 IU/kg/day. 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. One or several daily injections may be necessary. The preparations may be used alone or mixed with fast- or rapid acting insulin products. In intensive insulin therapy, the insulin suspensions may be used as basal insulin (evening and/or morning injection) with a fast- or rapid acting insulin given at meal times. In patients with diabetes mellitus optimized metabolic control delays the onset of late diabetic complications. Close blood glucose monitoring, is therefore recommended. Protaphane HM (ge) is administered subcutaneously in the thigh or abdominal wall. If convenient the gluteal or deltoid region may also be used. Subcutaneous injection into the abdominal wall ensures a faster absorption than from other injection sites. Injection sites should be rotated within an anatomical region in order to avoid lipodystrophy and cutaneous amyloidosis. Injection into a lifted skin fold minimizes the risk of intramuscular injection. Keep the needle under the skin for at least 6 seconds to make sure the entire dose is injected.
Special populations
Renal or hepatic impairment may reduce insulin requirement.
Method of administration
Avoidance of accidental mix-ups/medication errors
Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between Protaphane u00ae and other insulin products. Use of FlexPen: Instructions for use and handling are reflected in the Patient Information Leaflet (Use of FlexPen). To avoid possible transmission of disease, FlexPen is for single person use only.
Injections using 10 ml vials and conventional syringes: Instructions for use are reflected in the Patient Information Leaflet. Protaphane HM (ge) vials are for use with insulin syringes with a corresponding unit scale. Injections using Protaphane HM (ge) Penfill: Protaphane HM (ge) Penfill cartridges are designed to be used with Novo Nordisk insulin delivery system and NovoFine or NovoTwist needles. General instructions for use of Penfill (cartridges) See patient instructions for use in the Patient Information Leaflet enclosed with the Penfill (cartridges). Always ensure that the injection device is assembled according to manufacturer's directions. Please refer to the instructions included with the relevant devices.

• Hypoglycaemia
• Hypersensitivity to human insulin or any of the excipients.

Protaphane HM (ge) is not to be administered intravenously. Before traveling between different time zones, the patient should be advised to consult the doctor, since this may mean that the patient has to take insulin and meals at different times. Concomitant illness, especially infections and feverish conditions, usually increases the patientu2019s insulin requirement.
Hyperglycaemia
Inadequate dosing or discontinuation of treatment, especially in Type 1 diabetes (insulin dependent diabetes mellitus), may lead to hyperglycaemia. The first symptoms of hyperglycaemia usually comes on gradually, over a period of hours or days. They include increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath. In Type 1 diabetes, untreated hyperglycaemic events eventually lead to diabetic ketoacidosis, which is potentially lethal.
Hypoglycaemia
Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia. The symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiety, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. Patients, whose blood glucose control is greatly improved by e.g. intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia and should be advised accordingly.
Transfer from other insulin products
Transferring a patient to a new type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, species (animal, human, human insulin, insulin analogue) and/or method of manufacture may result in a change in dosage from that used with their usual insulins. If an adjustment is needed, it may be done with the first dose or during the first few weeks or months. A few patients who have experienced hypoglycaemic reactions after transfer from animal source insulin have reported that early warning symptoms of hypoglycaemia were less pronounced or different from those experienced with their previous insulin.
Skin and subcutaneous tissue disorder
Lipodsytrophy may occur at the injection site as a consequence of failure to rotate injection sites within the same area. Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site from an affected to an unaffected area, and dose adjustment of antidiabetic medicines may be considered.
Combination of Protaphane with pioglitazone
Cases of congestive heart failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of congestive heart failure. This should be kept in mind if treatment with the combination of pioglitazone and insulin medicinal products is considered. If the combination is used, patients should be observed for signs and symptoms of congestive heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.

A number of medicines are known to interact with glucose metabolism.
The following medicines may reduce the patientu2019s insulin requirements: Oral hypoglycaemic agents (OHAs), monoamine oxidase inhibitors (MAOI), non-selective beta-blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates and alcohol.
The following medicines may increase the patientu2019s insulin requirements: Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol. Beta blocking medicines may mask the symptoms of hypoglycaemia and delay recovery from hypoglycaemia. Ocreotide may either decrease or increase the insulin requirements. Alcohol may intensify and prolong the hypoglycaemic effect of insulin.

Pregnancy
There are no restrictions on 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 intra-uterine 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 deaths in utero. Intensified blood glucose control and monitoring of pregnant women with diabetes is recommended throughout pregnancy and when contemplating a pregnancy. Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimesters. After delivery, insulin requirements return rapidly to pre-pregnancy values.
Breastfeeding
There are no restrictions on the treatment of diabetes with Protaphane HM (ge) during lactation. Insulin treatment of nursing mother presents no risk to the baby. However the dosage, diet or both may need to be adjusted.

The patientu2019s ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery). Patients should be advised to take precautions to avoid hypoglycaemia while driving. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.

(a) Summary of the safety profile
Side effects observed in patient using Protaphane are mainly dose-dependent and due to the pharmacological effect of insulin. Hypoglycaemia is the most frequent side effect. It may occur if the insulin dose is too high in relation to the insulin requirement. In clinical trials and during marketed use, the frequency varied with the patient population and dose regimens.
(b) Tabulated list of adverse reactions
Frequencies of side effects from clinical trials, which by an overall judgment are considered related to Protaphane are listed below. The frequencies are defined as: Very Common (u2265 1/10), Common (u2265 1/100, u02c2 1/10); Uncommon (u2265 1/1 000, < 1/100); rare (u2265 1/10 000, u02c2 1/1000. Isolated spontaneous cases are presented as very rare defined as: < 1/10 000.
System organ class Side effect and frequency
Immune system disorders Uncommon - Urticaria, rash Very rare - Anaphylactic reactions
Metabolism and nutrition disorders Very common - Hypoglycaemia
Nervous system disorders Very rare - Peripheral neuropathy (painful neuropathy)
Eye disorders Very rare - Refraction disorders Uncommon - Diabetic retinopathy
Skin and subcutaneous disorders Uncommon u2013 Lipodystrophy Not known: Cutaneous amyloidosis* u03ee
General disorders and administration site conditions Uncommon - Injection site reactions, oedema
*see description of selected adverse reactions u03ee Adverse reactions from post marketing sources
(c) Description of selected adverse reactions
Anaphylactic reactions Symptoms of generalised hypersensitivity may include generalised skin rash, itching, sweating, gastrointestinal upset, and angio-oedema, difficulties in breathing, palpitation, reduction in blood pressure and fainting /loss of consciousness. Generalised hypersensitivity reactions are potentially life threatening.
Peripheral neuropathy (painful neuropathy) Fast improvement in blood glucose control may be associated with a condition termed u201cacute painful neuropathyu201d which is usually reversible.
Skin and subcutaneous tissue disorders Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis may occur at the injection site and delay insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions
Injection site reactions Injection site reactions (redness, swelling, itching, pain and haematoma at the injection site) may occur during treatment with insulin. Most reactions are transitory and disappear during continued treatment.
Oedema Oedema may occur upon initiation of insulin treatment. These symptoms are usually of transitory nature.
Eye disorders Refraction disorders: Refraction anomalies may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature. Diabetic retinopathy Long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy. However, intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications https://www.sahpra.org.za/Publications/Index/8

A specific overdose of insulin cannot be defined, however hypoglycaemia may develop over sequential stages if too high doses relative to the patientu2019s requirements are administered:
u2022 Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient constantly carries sugary containing products.
u2022 Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated with glucagon (0,5 to 1 mg) given intramuscularly or subcutaneously by a trained person or with glucose given intravenously by a healthcare professional. Glucose must be given intravenously, if the patient does not respond to glucagon within 10 to 15 minutes. Upon regaining consciousness, administration of oral carbohydrate is recommended for the patient in order to prevent relapse.