PRODUCT MONOGRAPH

Hypurin® NPH Insulin, Pork

Insulin Injection, Isophane (Porcine) Ph Eur

Suspension for Injection 100 IU/ml

Anti-Diabetic Agent

Sponsor: Wockhardt UK Ltd 2000 Ellesmere Road, Unit 16 Scarborough, Ontario M1H 2W4

Manufacturer: Wockhardt UK LtdAsh Road NorthWrexham, LL13 9UFUnited Kingdom

Control #: 204997

Date of Approval: June 15, 2017

TABLE OF CONTENTS

PART I: HEALTH PROFESSIONAL INFORMATION ....................................................1

SUMMARY PRODUCT INFORMATION........................................................................1

INDICATIONS AND CLINICAL USE..............................................................................1

CONTRAINDICATIONS ....................................................................................................1

WARNINGS AND PRECAUTIONS ..................................................................................1

ADVSERSE REACTIONS ..................................................................................................5

DRUG INTERACTIONS.....................................................................................................5

DOSAGE AND ADMINISTRATION ................................................................................8

OVERDOSAGE ....................................................................................................................8

ACTION AND CLINICAL PHARMACOLOGY .............................................................8

STORAGE AND STABILITY ............................................................................................9

SPECIAL HANDLING INSTRUCTIONS.........................................................................9

DOSAGE FORMS, COMPOSITION AND PACKAGING ...........................................10

PART II: SCIENTIFIC INFORMATION ..........................................................................11

PHARMACEUTICAL INFORMATION.........................................................................11

CLINICAL TRIALS...........................................................................................................11

DETAILED PHARMACOLOGY.....................................................................................11

MICROBIOLOGY .............................................................................................................11

TOXICOLOGY ..................................................................................................................11

REFERENCES....................................................................................................................11

PART III: CONSUMER INFORMATION.........................................................................12

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PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of Administration Dosage Form / Strength Non-medicinal ingredientsSubcutaneous or intramuscular injection

Suspension for injection, 100 International Units/ml

Glycerol, metacresol, phenol, protamine sulphate, sodium phosphate, water for injection and zinc (as chloride)

INDICATIONS AND CLINICAL USE

Hypurin NPH Insulin, Pork (Insulin Injection, Isophane (Porcine)) is indicated for the following:

treatment of patients with insulin dependent diabetes mellitus who are already using an animal derived insulin

treatment of new patients with insulin dependent diabetes mellitus who are unable to tolerate recombinant human insulin or whose diabetes is inadequately controlled by recombinant human insulin.

May be used for diabetics who fulfil the above criteria and who require a depot of insulin of medium duration.

CONTRAINDICATIONS

Hypurin NPH Insulin, Pork (Insulin Injection, Isophane (Porcine)) should not be used in patients who: have signs of hypoglycaemia. are hypersensitive to the active substance or to any of the excipients (refer to the DOSAGE

FORMS, COMPOSITION AND PACKAGING section for a complete listing of the excipients).

WARNINGS AND PRECAUTIONS

Hypoglycaemia is the most common adverse effect associated with insulin therapy (See OVERDOSAGE for symptoms of hypoglycaemia). Blood or urinary glucose concentrations should be monitored by patients on insulin therapy.

Uncorrected hypoglycaemic or hyperglycaemic reactions can cause loss of consciousness, coma or even death (see Hypoglycaemia and Hyperglycaemia sections under WARNINGS AND PRECAUTIONS).

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

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In no circumstances must Hypurin NPH Insulin, Pork be given intravenously. Hypurin NPH Insulin may be mixed with Hypurin Regular Insulin in the same syringe, in

which case Hypurin Regular Insulin should be the first dose to be withdrawn. The injection should then be made immediately upon withdrawal of the contents.

The vial must not be used if the contents have been frozen or it contains lumps that do not disperse on mixing (see SPECIAL HANDLING INSTRUCTIONS).

General As with all insulin therapies, the duration of action of Hypurin may vary in different

individuals or in the same individual according to dose, injection site, blood flow, temperature and level of physical activity.

Hypokalaemia is among the potential clinical adverse effects associated with the use of all insulin therapies. This potential clinical adverse effect may be relevant in patients who are on potassium lowering drugs or losing potassium through other means (e.g. diarrhoea) (see ADVERSE REACTIONS).

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

To avoid transmission of disease, the use of each vial should be restricted to a single patient.

Patients using Hypurin vials must never share needles or syringes with another person. Thiazolidinediones (TZDs), alone or in combination with other antidiabetic agents

(including Insulin), can cause heart failure and oedema. The combination of Insulin with a TZD is not indicated for the treatment of Type 2 Diabetes Mellitus. Please refer to the respective TZD product monograph Warnings and Precautions information when the use of these drugs in combination with any Insulin, including Hypurin is contemplated.

Endocrine and Metabolism:Hypoglycaemia Hypoglycaemia is the most frequently occurring undesirable effect of insulin therapy (see

ADVERSE REACTIONS). Hypoglycaemia can occur regardless of what type of insulin you take and can cause fatigue,

sweating, heart palpitations, disturbed behaviour, hunger, convulsions, loss of consciousness, or in extreme circumstances even death and can occur without recognizable symptoms.

Some people may not recognize when their blood sugar drops low. 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 OVERDOSAGE for symptoms).

Changes in insulin therapy or changes in life style (i.e. diet, exercise/physical activity) may require a change in dosage to avoid hypoglycaemia.

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.

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

Severe hypoglycaemia can result in temporary or permanent impairment of brain function and death (see OVERDOSAGE).

Blood or urinary glucose concentrations should be monitored by patients on insulin therapy. 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.

Diabetic patients should be instructed to carry glucose tablets or a few lumps of sugar to prevent the progression of a hypoglycaemic reaction, should one occur (refer to the PACKAGE LEAFLET: INFORMATION FOR THE USER).

Hyperglycaemia Inadequate dosing or discontinuation of insulin treatment, especially in type 1 Diabetes

Mellitus, may lead to hyperglycaemia and when untreated, hyperglycaemic events may eventually lead to diabetic ketoacidosis or coma, which are potentially fatal.

Usually the first symptoms of hyperglycaemia develop gradually over a period of hours or days. They included polydipsia; polyurea; nausea; abdominal pain, vomiting; drowsiness; blurred vision, flushed dry skin; loss of appetite, weight loss as well as acetone odour of breath.

Ability to concentrate and react may be impaired as a result of hyperglycaemia or as a result of hyperglycaemia-induced visual impairment. This may constitute a risk in situations where these abilities are of special importance such as driving a car or operating machinery.

Immune:Local allergic reactions Local allergic reactions to insulin such as erythema, pruritus and oedema may occur at the

injection site.

Systemic allergic reactions 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 occuring most often at the initiation of therapy.

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

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

Immune:Antibody productionImmune responses can occur in response to insulin. This may be associated with elevated IgG levels, but the clinical significance is uncertain.

Carcinogenesis and MutagenesisThe carcinogenic and mutagenic potentials of Hypurin insulins have not been established.

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

No adequate and well-controlled studies with Hypurin insulins during pregnancy and lactation have been performed.

Renal / Hepatic / Biliary / Pancreatic impairmentInsulin requirements may decrease with liver 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.

The safety of Hypurin insulins has not been established in patients with biliary or pancreatic impairment.

Drug InteractionsCaution is recommended when administering Hypurin insulins with compounds that may influence insulin requirements (refer to the DRUG INTERACTIONS section).

Transferring Patients from Other Insulins:When patients are transferred between different types of insulin products, including animal insulins, the early warning symptoms of hypoglycaemia may change or become less pronounced than those experienced with their previous insulin. Transferring a patient to a new type or brand of insulin should be done only under strict medical supervision. Changes in insulin strength, timing of administration, manufacturer, type (e.g. regular, NPH, or insulin analogs), species (animal, human) or method of manufacture (recombinant DNA versus animal sourced insulin) may result in the need for a change in dosage. Concomitant oral anti-diabetic treatment may also need to be adjusted. If an adjustment is needed, it may be done with the first doses or during the first few weeks or months and under medical supervision.

Information for patients:Patients should be informed about potential advantages and disadvantages of insulin therapy including the possible side effects. Patients should also be offered continued education and advice on insulin therapies, delivery device options, life-style management, self-monitoring, complications of insulin therapy, timing of dosage, and instructions for use of injection devices, storage of insulin, travelling and others (refer to the PACKAGE LEAFLET: INFORMATION FOR THE USER).

Female patients with diabetes mellitus should be advised to inform their doctor if they are pregnant or are contemplating pregnancy. Careful monitoring of glucose control, as well as general health is essential in pregnant patients with diabetes (refer to WARNINGS AND PRECAUTIONS: Special Populations and the PACKAGE LEAFLET: INFORMATION FOR THE USER).

Mixing of insulins:Hypurin NPH Insulin may be mixed with Hypurin Regular Insulin in the syringe, in which case Hypurin Regular Insulin should be the first dose to be withdrawn. The injection should then be made immediately upon withdrawal of the contents.

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Hypurin NPH Insulin must not be mixed with any other insulin preparations (with the exception of Hypurin Regular Insulin) as this may change the pharmacokinetic/ pharmacodynamic profile of action of one or both insulins in an unpredictable manner.

Other Warnings and Precautions:The urine should be tested for ketones by patients on insulin therapy.

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.

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

Insulin requirements may decrease with disease of the adrenal, pituitary or thyroid glands and coeliac disease.

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 insulin and increase the risk of hypoglycaemia occurring.

Special PopulationsPregnant Women:There are no adequate and well controlled studies in pregnant women. Therefore, Hypurin insulins should be used during pregnancy only under medical supervision.

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.

Nursing Women:It is not known whether Hypurin insulins are excreted in human milk. There are no adequate and well-controlled studies in nursing women. Therefore, Hypurin insulins should be use with caution in nursing women. Lactating women may require adjustments in insulin dose and diet.

Geriatrics (> 65 years of age):

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Elderly diabetic patients are more susceptible to episodes of severe, rapid onset hypoglycaemia and the warning symptoms may be changed, be less pronounced or absent.

Paediatrics (< 6 years of age):There are no evaluated paediatric efficacy and safety data available to support paediatric dosing advice below the age of 6 years. Therefore, Hypurin insulins should be used in this sub-population only if clearly needed and done under medical supervision.

The safety of Hypurin insulins has not been established in this sub-population.

Others:The presence of diseases such as acromegaly, Cushing’s syndrome, hyperthyroidism and pheochromocytoma can complicate the control of diabetes mellitus.

Self-Monitoring of Blood GlucoseBlood glucose concentrations should be monitored by patients on insulin therapy.

ADVERSE REACTIONS

Metabolic disorders: hypoglycaemia is the most common adverse effect associated with insulin therapy (see

WARNINGS AND PRECAUTIONS: Hypoglycaemia and OVERDOSAGE for further information.

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: Refer to WARNINGS AND PRECAUTIONS: Immune for details on immune system disorders.

DRUG INTERACTIONS

To avoid the risk of developing new or worsening heart failure, the use of TZDs in combination therapy with Hypurin is not indicated (refer to WARNINGS AND PRECAUTIONS: General).

Drug-Drug InteractionsDrugs that may increase the requirement for insulin

Antipyschotics: chloropromazine

Corticosteroids

Diazoxide

Diuretics: thiazide diuretics or loop diuretics

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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.

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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

Drug-Food InteractionsInteractions with food have not been established.

Drug-Laboratory InteractionInteractions with laboratory tests have not been established.

Drug-Lifestyle InteractionsSusceptibility 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 (refer to the section on Hypoglycaemia in the WARNINGS AND PRECAUTIONS section).

DOSAGE AND ADMINISTRATION

Dosing ConsiderationsDose adjustment may be required, for example, if the patient’s diet or lifestyle changes or if they suffer from other diseases or illnesses (see WARNINGS AND PRECAUTIONS).

Recommended Dose and Dosage AdjustmentDosage of Hypurin NPH Insulin is individual and determined based on physician’s advice and in accordance to the need of the patient, as determined by glucose monitoring.

AdministrationUsually administered subcutaneously but where necessary it may be given intramuscularly in which case onset is more rapid and overall duration shorter. It should not be given intravenously. Onset of action occurs within 2 hours after subcutaneous injection with an overall duration of 18-24 hours. Maximum effect is exerted between 6-12 hours.

Hypurin NPH Insulin may be mixed with Hypurin Regular Insulin in the syringe (see WARNINGS AND PRECAUTIONS: Mixing of Insulins).

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

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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 with glucagon followed by oral carbohydrate when the patient is sufficiently recovered. Of the two glucagon products authorised for use in Canada, Glucagon (glucagon for injection, rDNA origin) is approved for intramuscular, intravenous, and subcutaneous administration and GlucoGen (glucagon) is approved for intramuscular use only.

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.

ACTION AND CLINICAL PHARMACOLOGY

PharmacodynamicsInsulin 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 3.3 – 5.6 mmol/L. 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.PharmacokineticsInsulin 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.

STORAGE AND STABILITY

Shelf-life (unopened): 36 months.

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

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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.

SPECIAL HANDLING INSTRUCTIONS

Prior to use the vial of Hypurin NPH Insulin, Pork should be rolled gently between the palms or inverted several times.

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

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

DOSAGE FORMS, COMPOSITION AND PACKAGING

Hypurin NPH Insulin is a sterile, white suspension of porcine insulin (100 IU/ml) and is available in a 10ml neutral glass vial sealed with a rubber bung and metal closure.

Full list of excipients:Protamine sulphateZinc chloridem-CresolPhenolSodium phosphateGlycerolWater for injections

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PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Porcine Insulin Ph Eur

Molecular formula and molecular mass: C256H381N65O76S6 5778

Structural formula:

Physiochemical properties: Purified pork insulin is a polypeptide hormone consisting of a 21 amino acid A-chain and a 30 amino acid B-chain linked by 2 disulfide bonds derived from porcine pancreas. Administration of suitable doses of insulin temporarily restores the ability to metabolize carbohydrates, fats and proteins, to store glycogen in the liver, and to convert glucose to fat.

CLINICAL TRIALSNot applicable.

DETAILED PHARMACOLOGYNot applicable.

MICROBIOLOGYNot applicable.

TOXICOLOGYNot applicable.

REFERENCESNot applicable.

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PART III: CONSUMER INFORMATION

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PACKAGE LEAFLET: INFORMATION FOR THE USERHYPURIN® NPH INSULIN, PORK INJECTION

Read all of this leaflet carefully before you inject your insulin.- Keep this leaflet. You may need to read it again while you are receiving your treatment.- As well as reading this leaflet you should ask your doctor to advise you on the use of insulin including delivery device

options, life style management, self monitoring of blood glucose levels, complications of insulin therapy, timing of dosage, instructions on injecting, storage of insulin, and needs if travelling.

- If you have any further questions, please ask your doctor, pharmacist or diabetic nurse.- This medicine has been prescribed for you. It must not be shared with other patients. It may harm them even if their

symptoms are the same as yours.

In this leaflet: 1. What Hypurin® is and what it is used for2. Before you receive Hypurin®3. How to use Hypurin® 4. Possible side effects5. How to store Hypurin®6. Further information

1. WHAT HYPURIN® IS AND WHAT IT IS USED FORThe name of your medicine is Hypurin® NPH Insulin, Pork. Hypurin®, Pork is the brand name for two forms of highly purified porcine (pig) insulin injections – Regular and NPH. These types of insulin differ mainly in the time they take effect and in the length of time their action lasts.

Hypurin® NPH Insulin, Pork is a sterile, white suspension of porcine insulin (100 international units/ml) with protamine sulphate and zinc chloride in water. It is longer acting than Hypurin® Regular Insulin, Pork.

What Hypurin® is used forHypurin® contains insulin which is a natural hormone, made by a gland called the pancreas. Insulin plays a key role in the way the body uses carbohydrate, fat and protein.

Hypurin®, Pork is used for the treatment of insulin-dependent diabetes mellitus. In this type of diabetes, your pancreas does not make enough insulin to control the level of sugar in your blood. It can be treated by controlling your diet and taking insulin. Hypurin®, Pork has been prescribed for you as a substitute for your own insulin.

2. BEFORE YOU RECEIVE HYPURIN®

You should not inject Hypurin® Insulin, Pork if: you have symptoms of hypoglycaemia (low blood sugar or 'hypo' - see the section on hypoglycaemia in

section 4 ‘Possible side effects’) you have ever had an allergic reaction to insulin or any of the other ingredients in Hypurin®, Pork (see ‘What

Hypurin® contains’ in section 6 ‘Further information’).

If any of the above applies to you, you should not inject Hypurin®.

Thiazolidinediones (TZD), such as pioglitazone and rosiglitazone should not be used in combination with Hypurin® because of the risk of oedema and heart failure.

Talk to your doctor before taking this medicine if you suffer from acromegaly, Cushing’s syndrome, hyperthyroidism or pheochromocytoma, as these diseases can complicate the control of your diabetes.

Taking other medicinesTaking another medicine while you are using insulin can affect how it or the other medicine works. Tell your doctor or pharmacist if you are taking any other medicine before you start taking insulin. This includes medicines you may have bought yourself without a prescription.

Medicines that can affect the way insulin works are;

Steroids, used to treat a range of allergic conditions. Thyroxine, used for an underactive thyroid gland. Anti-inflammatory drugs such as aspirin and NSAIDs such as ibuprofen. Cyclophosphamide, used to treat a wide range of tumours. Isoniazid, used to treat tuberculosis (TB). Beta blockers, used to treat high blood pressure and angina. Some drugs such as adrenaline, which are used to treat shock. Some drugs used to treat mental illness such as chlorpromazine, amitriptyline , fluoxetine and MAOIs such as

phenelzine. Thiazide diuretics or loop diuretics, used to control excess water.

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Oral contraceptives (birth control pills). ACE inhibitors, used for high blood pressure. Octreotide, an anti-hormone preparation. Nifedipine, used for angina and high blood pressure. Antimalarial drugs, such as chloroquine or quinine Clonidine or guanethidine, used to treat high blood pressure Diazoxide, used to treat hypoglycaemia Disopyramide or quinidine, used to treat an irregular heartbeat Fenfluramine, used to treat obesity Fibrates or gemfibrozil, used to regulate lipids Mebendazole, used to treat threadworm Oxytetracycline, an antibiotic Testosterone Pentoxifylline, used to treat leg ulcers and problems with blood circulation in the legs Thiazolidinediones (TZD), used to treat diabetes, e.g. pioglitazone and rosiglitazone Alcohol may decrease your insulin requirements Smoking may increase the effect of insulin.

If you have any doubts about your medicine then discuss things more fully with your doctor, pharmacist or diabetic nurse.

Pregnancy and breast-feedingBefore using this medicine you should let your doctor know if you are pregnant or wish to become pregnant or start breast-feeding.

Careful monitoring of your blood glucose control and your general health is important for you and for the health of your baby. Insulin requirements should be assessed frequently by an experienced diabetic physician during pregnancy, after delivery and whilst breast-feeding.

Driving and using machinesYour ability to concentrate or react may be reduced if you have hyperglycaemia (high blood sugar levels) or hypoglycaemia. This might put yourself and others at risk when you are driving a car or operating machinery.

You should contact your doctor about the advisability of driving if you have: frequent episodes of hypoglycaemia reduced or lack of warning signs of hypoglycaemia.

Important information about some of the ingredients of HypurinZinc, protamine and the preservatives m-cresol and phenol may cause allergic reactions.

3. HOW TO USE HYPURIN®

What dose is needed?There is no 'standard' dose of insulin. Each person with diabetes has their own dose calculated according to their needs. Your doctor will decide which dose is best for you and which insulin to use. Always follow your doctor's instructions exactly and also follow any special instructions or warnings that appear on the label that the pharmacist has put on the package.

Use in childrenThere is limited experience with the use of Hypurin® in children less than 6 years old. Therefore, Hypurin should only be used in children below this age under careful medical supervision.

Dosage adjustments of Hypurin®Dosage adjustments may be made as determined by blood glucose monitoring.

Patients with disease of the liver, kidneys, adrenal, pituitary or thyroid glands, or coeliac disease may need lower doses. This dose may alter during illness (including infection and surgery), injury, emotional stress, puberty, around the time of a menstrual period and during pregnancy and after delivery. Lactating women may also require dosage adjustments. The dose may also change with your diet and lifestyle, particularly if you are exercising more.

Patients transferred to Hypurin® Insulin, Pork from other types of insulin may require dosage adjustments.

Newly diagnosed diabetic patients may require dosage adjustments during the first weeks, months or years of treatment.

If you do not understand or are in any doubt ask your doctor, pharmacist or diabetes nurse.

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Advice and checks to be made when using Hypurin® Insulin, Pork Hypoglycaemia is the most common adverse effect of insulin, including Hypurin® Insulin, Pork. You must keep a close watch on your blood sugar by testing your glucose levels regularly in your blood or

urine. Your urine should be tested for ketones at regular intervals. Be aware that insulin resistance can occur, particularly in patients who have lipid disorders, hypertension or

heart disease. Insulin resistance is shown by the need for higher doses of insulin. Stress can also contribute to insulin resistance.

If your doctor has asked you to increase the frequency or dose of your insulin treatment in order to improve your sugar levels, you may at some point lose some of the warning symptoms that usually occur when your blood sugar is falling too low (hypoglycaemia). These symptoms include shakiness, pounding heartbeat, sweating and feeling anxious.

You may also lose some of the warning symptoms of hypoglycaemia if you have had repeated attacks of hypoglycaemia, if control of your blood sugar is greatly improved, if you have a long history of diabetes, or if you are also taking certain other medicines, such as beta blockers (used to treat high blood pressure and angina) or clonidine (used to treat high blood pressure).

If you are elderly, you may have more severe episodes of hypoglycaemia and some of the warning symptoms may change, be weaker or be missing.

Be aware that activities such as taking a hot bath, sunbathing, or using a sunbed or sauna can increase the rate at which insulin is absorbed and increase the risk of hypoglycaemia.

Be aware that the length of time that Hypurin® is effective for may vary depending on the dose taken, temperature, the injection site used and how much exercise you are doing.

If you stop taking Hypurin® or do not inject a high enough dose, your blood sugar may become too high (hyperglycaemia). Usually, the first symptoms of hyperglycaemia develop gradually over a period of hours or days. Symptoms include thirst, increased need to urinate, nausea, vomiting, stomach pain, sleepiness, blurred vision, flushed dry skin, reddening of the face, loss of appetite, weight loss and sweet smelling breath. If untreated, hyperglycaemia can lead to diabetic ketoacidosis (a serious condition, symptoms of which can include deep breathing and confusion) or coma, which can result in death.

Injection sitesRecommended injection sites include the upper arms, thighs, buttocks and lower abdomen. It may be preferable to use those areas that are less visible. Each time you inject your insulin you should use a different spot in the same general area. Change to a different injection area each week.

Hypurin® NPH Insulin, Pork should not be injected into a vein.

Injecting Hypurin®Your doctor or diabetes nurse will advise you on how to inject your insulin.

Check that the vial in the carton has the same label as on the carton and that different types of Hypurin®, Pork have not been mixed up.

Do not use a damaged vial; return to the supplier. Do not use Hypurin®, Pork that has been frozen or contains lumps that do not disappear on mixing. Wash and dry your hands. Clean the rubber plug on the vial, but do not remove it. Roll the vial gently between your hands or invert it several times to mix the contents immediately before use. Before withdrawing your insulin from the vial, draw air into the syringe equal to the amount of insulin to be drawn

up. Push the needle through the rubber plug of the vial and inject the air into the vial. This will make it easier for you to withdraw the insulin.

Leaving the needle in the vial, turn the vial upside down making sure the needle tip stays below the surface of the insulin. Slowly fill the syringe with slightly more than your usual dose of insulin. Push the plunger back to your correct dose, expelling any air bubbles into the vial. Take the needle out of the vial. You are now ready to inject your insulin.

Pinch up the skin at the injection site. Stick the needle in fully at right angles. Do not release the skin. Push the plunger down to empty the syringe keeping the needle in place for a count of five seconds. Release the pinched up skin and take the needle out. There is no need to massage the area.

Once the vial is opened the insulin must only be used by the same patient Always use a new needle for each injection. Never share needles or syringes with another person.

If your doctor recommends it, Hypurin® Regular Insulin, Pork can be mixed with Hypurin® NPH Insulin, Pork in the same syringe. If you need to do this, draw the Hypurin® Regular Insulin, Pork into the syringe before the Hypurin® NPH Insulin, Pork. This should be demonstrated to you before you attempt to do it yourself. Use the injection immediately.

If you think you have received too much Hypurin®

In case of drug overdose, contact a health care practitioner, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms.

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Symptoms of an overdose include weakness, sweating, trembling, nervousness, excitement and irritability which, if untreated, could lead to collapse, coma, even death. For further symptoms of an overdose, see the section on hypoglycaemia in section 4.

4. POSSIBLE SIDE EFFECTS

Like all medicines, insulin may cause side effects in some patients when treatment is first started or if there is a change in the type of insulin used.

These include:

Hypoglycaemia (see section “Treating hypoglycaemia” below) swelling (oedema) redness, itching or swelling around the area of injection stinging, or sensations of warmth or burning at the site of injection thickening or pitting of the skin in the areas used for injection (lipodystrophy) rash pain caused by nerve damage shortness of breath or wheezing low levels of potassium in the blood (hypokalaemia). This is particularly relevant if you are also taking

potassium lowering drugs or if you are losing potassium due to diarrhoea weight gain nausea.

Rarely the following side effects may occur:

generalised swelling (oedema) and allergic reactions severe allergic reactions which causes difficulty in breathing or dizziness.

If you experience any other side effects or feel that your insulin is affecting you badly please contact your doctor, pharmacist or diabetes nurse.

Hypoglycaemia ("hypo" or insulin reaction) symptomsHypoglycaemia means low blood sugar. The symptoms of a "hypo" may involve:

pale face, sweating palpitations, rapid heartbeat hunger cramps deep breathing weakness, drowsiness, yawning, fatigue, reduced consciousness and loss of consciousness altered behaviour, aggression, confusion, irritability, anxiety, nervousness, restlessness, excitement,

trembling difficulty in finding words, difficulty in concentration convulsions blurred vision and/or double vision, slurred speech tingling or numbness of the nose, mouth, fingers, or toes, paralysis headache, excess fluid in the brain, temporary or irreversible brain damage, even death.

Some patients may not recognise when their blood sugar drops.

The symptoms of low blood sugar (hypoglycaemia) may change or become less pronounced following transfer to a different insulin.

Why might hypoglycaemia occur?Hypoglycaemia may occur for the following reasons (or occasionally for no apparent reason):

missing or postponing a meal or eating less than the correct dietary allowance taking more exercise than usual injecting the wrong dose of insulin changing to a different dose of different type of insulin.

Untreated "hypos" can have serious consequences and can result in loss of consciousness, coma or even death. It is important to recognise the symptoms and treat hypoglycaemia early.

Treating hypoglycaemia Always carry glucose tablets or a few sugar lumps with you wherever you go. At the first warning sign of hypoglycaemia, stop what you are doing and take five glucose tablets or three

sugar lumps, preferably with water. You should begin to feel better almost immediately. If you do not feel better in ten minutes repeat the glucose tablets or sugar lumps. If the "hypo" happens shortly before a meal or snack, treat the "hypo" and have your meal as soon as you can.

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If a meal is not due, take the quick-acting glucose tablets or sugar lumps and follow them with some longer-acting carbohydrate food like a sandwich or biscuits.

Because of the risk of a "hypo" you should carry an identification card or wear an identity bracelet or necklace carrying details of your name, address, doctor and insulin treatment. It is also important that relatives, friends and colleagues know that you have diabetes and are taking insulin so that they can recognise symptoms of a "hypo" and help if necessary.

5. HOW TO STORE HYPURIN®

Keep all vials and syringes out of the reach and sight of children.

Hypurin®, Pork vials should be stored in a refrigerator between 2°C - 8°C. Once in use, the vial can be kept at room temperature (up to 25°C) for 28 days after which it should be discarded.

Do not use this medicine if the expiry date on the label has passed or if the insulin has been frozen. The expiry date refers to the last day of the month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

What Hypurin® NPH Insulin, Pork ContainsHypurin® NPH Insulin, Pork is a sterile, white suspension of porcine insulin (100 international units/ml) with protamine sulphate and zinc chloride in water. It also contains m-cresol, phenol, glycerol and sodium phosphate.

Reporting Suspected Side Effects

You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways:

Report online at www.healthcanada.gc.ca/medeffect Call toll-free at 1-866-234-2345 Complete a Canada Vigilance Reporting Form and:

o Fax toll-free to 1-866-678-6789o Mail to:

Canada Vigilance Program Health CanadaPostal Locator 0701DOttawa, OntarioK1A 0K9

Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffectTM Canada Web site at www.healthcanada.gc.ca/medeffect.

NOTE: Should you require information related to the management of side effects, contact your health professional. The Canada Vigilance Program does not provide medical advice.

What Hypurin® looks like and contents of the packHypurin®, Pork is available in glass vials, which contain 10ml of solution or suspension.

Marketing Authorisation holderWockhardt UK Ltd, Ash Road North, Wrexham, LL13 9UF, UK.

ManufacturerCP Pharmaceuticals Ltd, Ash Road North, Wrexham, LL13 9UF, UK.

Leaflet prepared: November 2016.