Hypurin Bovine Lente

H

1. Name Of The Medicinal Product

Hypurin® Bovine Lente 100 IU/ml injection

2. Qualitative And Quantitative Composition

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

Insulin Zinc Suspension (Mixed) Ph Eur (Bovine)

For excipients, see 6.1

3. Pharmaceutical Form

Suspension for injection.

A white suspension

4. Clinical Particulars 4.1 Therapeutic Indications

The treatment of insulin dependent diabetes mellitus.

Hypurin® Bovine Lente may be used for diabetics requiring a depot insulin of medium to extended duration.

4.2 Posology And Method Of Administration

To be determined by the physician according to the needs of the patient.

Administered subcutaneously. It is not recommended for intramuscular use and should not be given intravenously. Onset of action occurs approximately 2 hours after subcutaneous injection with an overall duration extending up to 30 hours. Maximum effect is exerted between 8-12 hours.

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

4.3 Contraindications

Hypoglycaemia.

Hypersensitivity to insulin or to any of the excipients.

4.4 Special Warnings And Precautions For Use

In no circumstances must Hypurin® Bovine Lente 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.

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, may increase the rate of absorption of insulin.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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

4.6 Pregnancy And Lactation

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.

4.7 Effects On Ability To Drive And Use Machines

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.

4.8 Undesirable Effects

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. 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, 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.

4.9 Overdose

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 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.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

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.

5.2 Pharmacokinetic Properties

Insulin is rapidly absorbed from subcutaneous tissue 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.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium chloride

Sodium acetate

Methylparahydroxybenzoate

Zinc oxide

Water for injections

Hydrochloric acid

Sodium hydroxide

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

Three years.

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

6.4 Special Precautions For Storage

Store at 2oC - 8oC.

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.

6.5 Nature And Contents Of Container

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

6.6 Special Precautions For Disposal And Other Handling

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 Lente should be rolled gently between the palms or inverted several times.

Hypurin® Bovine Lente may be mixed with bovine neutral insulin in the syringe, in which case the bovine neutral insulin should be the first dose to be withdrawn. The injection should then be made immediately upon withdrawal of the contents.

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

7. Marketing Authorisation Holder

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

U.K.

8. Marketing Authorisation Number(S)

PL 29831/0129

9. Date Of First Authorisation/Renewal Of The Authorisation

7th April 2008

10. Date Of Revision Of The Text

23 June 2011

Hypurin Bovine Lente

.