Hypurin® Bovine Protamine Zinc

Crystalline Insulin Ph Eur (Bovine) 100 IU/ml.

Protamine Zinc Insulin Injection BP (Bovine)

For excipients, see 6.1

Suspension for injection.

A white suspension

The treatment of insulin dependent diabetes mellitus.

May be used for diabetics requiring a depot insulin of extended duration. It is characteristically slow in onset and is commonly used in conjunction with Hypurin Neutral.

Administered subcutaneously. It is not recommended for intramuscular use and should not be given intravenously. Onset of action occurs after 4-6 hours with an overall duration of 24-36 hours. Maximum effect is exerted between 10-20 hours.

Hypoglycaemia.

Hypersensitivity to insulin or to any of the excipients.

In no circumstances must Hypurin® Bovine Protamine Zinc be given intravenously.

Hypoglycaemia: Susceptibility to hypoglycaemia may be increased by an inaccurate or excessive dosage of insulin, the omission of a meal by the patient or increased physical activity. Correct insulin administration and awareness of the symptoms of hypoglycaemia are essential to reduce the risk of hypoglycaemia (see section 4.9).

Blood or urinary glucose concentrations should be monitored and the urine tested for ketones by patients on insulin therapy.

Newly diagnosed diabetic patients may experience fluctuating insulin requirements during the first weeks, months or even years of treatment (the so-called 'honeymoon period').

Patients transferred to Hypurin® Bovine insulins from other commercially available preparations may require dosage adjustments.

The warning symptoms of hypoglycaemia may be changed, be less pronounced or absent in certain risk groups who should be advised accordingly. These include patients:

- in whom glycaemic control is greatly improved, e.g. by intensified insulin therapy

- with a long history of diabetes

- who are elderly

- receiving concomitant treatment with certain medicinal products e.g. beta blockers or clonidine

- who have experienced repeated episodes of hypoglycaemia.

Elderly diabetic patients are more susceptible to episodes of severe, rapid onset hypoglycaemia.

Combination of Hypurin® insulins with pioglitazone: Cases of cardiac failure have been reported when thiazolidinediones are used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. This should be kept in mind if treatment with the combination of pioglitazone and Hypurin® is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.

Insulin requirements may increase during illness (this includes infection and accidental and surgical trauma), puberty or emotional upset.

Insulin resistance is frequently associated with lipid disorders, hypertension and ischaemic heart disease. Patients with insulin resistance usually require more than 200 units of insulin daily. Insulin resistance of the type manifested by greatly increased insulin requirements may be due to factors including antibody formation although some diseases, such as infections, endocrine hyperfunctional states (e.g. acromegaly, Cushing's syndrome, thyrotoxicosis) or stress can contribute to insulin resistance.

Insulin requirements may decrease with liver disease, disease of the adrenal, pituitary or thyroid glands and coeliac disease. In patients with severe renal impairment, insulin requirements may fall and dosage reduction may be necessary. The compensatory response to hypoglycaemia may also be impaired.

Insulin requirements may be increased in the premenstrual period but may be reduced during or after a menstrual cycle.

Insulin requirements are usually reduced but occasionally increased during periods of increased activity.

Increase in subcutaneous blood flow, brought about by factors such as a hot bath, sunbathing/sunbed or sauna may increase the rate of absorption of insulin and increase the risk of hypoglycaemia occurring.

Drugs that may increase the requirement for insulin

Antipyschotics: chloropromazine

Corticosteroids

Diazoxide

Diuretics: thiazide diuretics or loop diuretics

Sympathomimetic agents

Thyroid hormone replacement therapy

Smoking may also antagonise the hypoglycaemic effect of insulin

Drugs that may decrease the requirement for insulin

ACE inhibitors

Alcohol: moderate or large amounts of alcohol (more than 2 units per day for women and more than 3 units per day for men) can decrease the requirements for insulin and may lead to hypoglycaemic attacks. Episodic heavy drinking ('binge' drinking) carries a particularly high risk of hypoglycaemic episodes.

Anabolic steroids

Analgesics: NSAIDS, or salicylates, particularly large doses of aspirin

Androgens: testosterone may enhance the hypoglycaemic effect of insulin

Anti-arrhythmics: disopyramide.

Concomitant use of insulin with quinidine may increase the risk of hypoglycaemia occurring.

Anti-depressants: monoamine oxidase inhibitors or fluoxetine.

Concomitant use of amitriptyline with insulin may lead to hypoglycaemia.

Antihypertensives: guanethidine

Antimalarials: concomitant use of insulin with antimalarials such as chloroquine or quinine may increase the risk of hypoglycaemia occurring.

Fenfluramine

Hormone antagonists: octreotide

Lipid-regulating drugs: fibrates

Mebendazole

Pentoxifylline: the hypoglycaemic activity of insulin may be potentiated by concomitant administration of high-dose pentoxifylline injection.

Tetracyclines: tetracyclines such as oxytetracycline

Drugs that may increase or decrease the requirements for insulin

Antihypertensives: clonidine. Signs and symptoms of hypoglycaemia may be masked by clonidine.

Beta blockers: beta blockers. Some of the warning signs of insulin-induced hypoglycaemia may be masked.

Calcium channel blockers: nifedipine may occasionally impair glucose tolerance.

Cyclophosphamide

Isoniazid

Lipid-regulating drugs: gemfibrozil

Oral contraceptives

Pregnancy

A decreased requirement for insulin may be observed in the early stages of pregnancy. However, in the second and third trimesters, insulin requirements may increase. Insulin requirements should therefore be assessed frequently by an experienced diabetic physician.

Maternal insulin requirements may decrease after delivery. As this decrease can be at an unpredictable rate, the maternal blood glucose should be closely monitored.

Congenital abnormality is more common in offspring of diabetic than non-diabetic women.

Lactation

Caution should be exercised when prescribing to lactating women. Lactating women may require adjustments in insulin dose and diet.

The patient's 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 whilst 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.

Metabolic disorders:

• Hypoglycaemia is the most common adverse effect associated with insulin therapy. For symptoms of hypoglycaemia, refer to section 4.9, Overdosage.

• Hypokalaemia may occur with insulin therapy.

• Insulin therapy may lead to weight gain.

General disorders and administration site conditions:

Lipodystrophy (atrophy or hypertrophy of the fat tissue) may occur at the injection site. Stinging or sensations of warmth or burning at the site of injection may also occur.

Immune system disorders:

Insulin hypersensitivity can occur with animal insulins, but appears less likely with purified insulins and there is minimal evidence that such effects occur with Hypurin insulins.

Neuropathic pain induced by rapid glycaemic control following insulin administration may occur.

Allergic reactions to phenol and m-cresol contained as preservative and to zinc and protamine may occur.

• Local hypersensitivity: Local allergic reactions to insulin such as pruritus, erythema and oedema may occur at the injection site.

• Generalised hypersensitivity: Generalised hypersensitivity may produce urticaria, rash, nausea, dyspnoea or wheezing and, in rare cases, anaphylactic reactions. Severe, angioedema is a rare adverse effect of insulin treatment occurring most often at the initiation of therapy.

a) Symptoms

Overdosage causes hypoglycaemia. Symptoms include yawning, hunger, pallor, restlessness, weakness, sweating, trembling, confusion, anxiety, nervousness, excitement, irritability, aggression, altered behaviour, deep respiration, cramps, headache, paraesthesia and/or numbness of the nose, mouth, fingers or toes, reduced consciousness, visual disturbance, including blurred vision and double vision, slurred speech, difficulty in finding words, difficulty in concentration, drowsiness, fatigue, convulsions, hemiplegia, paralysis, tachycardia and/or palpitations, myocardial ischaemia and cerebral oedema which, if untreated, will lead to collapse, coma and/or irreversible brain damage.

Hypokalaemia may also occur with insulin overdose.

b) Treatment

Mild hypoglycaemia will respond to oral administration of glucose or sugar and rest.

Moderately severe hypoglycaemia can be treated by intramuscular, intravenous or subcutaneous injection of glucagon followed by oral carbohydrate when the patient is sufficiently recovered.

For patients who are comatose or who have failed to respond to glucagon injection an intravenous injection of strong Dextrose Injection BP should be given.

ATC Code - A10A A

Insulin output from the pancreas of a healthy person is about 50 units per day, which is sufficient to maintain the fasting blood sugar concentration in the range 0.8 + 0.2mg/ml. In diabetes mellitus, the blood sugar rises in an uncontrolled manner. Parenterally administered insulin causes a fall in blood sugar concentration and increased storage of glycogen in the liver. In the diabetic it raises the respiratory quotient after a carbohydrate meal and prevents the formation of ketone bodies. The rise in blood sugar concentration caused by adrenaline and corticosteroids, glucagon and posterior pituitary extract is reversed by insulin.

Insulin is rapidly absorbed from subcutaneous tissue or muscle following injection.

Insulin is metabolised mainly in the liver and a small amount is excreted in the urine.

The plasma half life is 4 to 5 minutes. The half life after subcutaneous injection is about 4 hours and after intramuscular injection about 2 hours.

There are no preclinical data of relevance to the prescriber which are additional to those already included in other sections.

Protamine sulphate

Zinc chloride

Glycerol

Sodium phosphate

Phenol

Water for injections.

None

36 months.

Following injection of the first dose the product should be used within 28 days. Discard any unused material after this time.

Store at 2°C - 8°C.

Do not freeze.

Chemical and physical in-use stability has been demonstrated for 28 days at 25°C.

From a microbiological point of view the opening carries a risk of microbial contamination and aseptic handling is a necessity.

In use storage times and conditions are the responsibility of the user.

10ml neutral glass vial sealed with a rubber bung and metal closure.

The vial must not be used if the contents have been frozen or it contains lumps that do not disperse on mixing.

Prior to use the vial of Hypurin® Bovine Protamine Zinc should be rolled gently between the palms or inverted several times.

Hypurin® Bovine Neutral and Hypurin® Bovine Protamine Zinc should not be mixed together.

The use of each vial should be restricted to a single patient.

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

U.K.

PL 29831/0128

8^th April 2008

15 March 2012