Humalog 100U / ml, solution for injection in vial, Humalog 100U / ml, solution for injection in Cartridge, Humalog Pen 100U / ml, solution for injection

1. Name Of The Medicinal Product

HUMALOG* 100U/ml, solution for injection in vial.

HUMALOG 100U/ml, solution for injection in cartridge.

HUMALOG Pen 100U/ml, solution for injection.

HUMALOG 100U/ml KwikPen, solution for injection.

2. Qualitative And Quantitative Composition

One ml contains 100U (equivalent to 3.5mg) insulin lispro (recombinant DNA origin produced in E. coli).

Vial: Each container includes 10ml equivalent to 1000U insulin lispro.

3 ml cartridge: Each container includes 3ml equivalent to 300U insulin lispro.

HUMALOG Pen 3ml/KwikPen: Each container includes 3ml equivalent to 300U insulin lispro.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection.

HUMALOG, HUMALOG Pen and HUMALOG KwikPen are sterile, clear, colourless, aqueous solutions.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of adults and children with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis. HUMALOG, HUMALOG Pen or HUMALOG KwikPen is also indicated for the initial stabilisation of diabetes mellitus.

4.2 Posology And Method Of Administration

The dosage should be determined by the physician, according to the requirement of the patient.

HUMALOG may be given shortly before meals. When necessary, HUMALOG can be given soon after meals.

HUMALOG preparations should be given by subcutaneous injection or by continuous subcutaneous infusion pump (see section 4.2) and may, although not recommended, also be given by intramuscular injection. If necessary, HUMALOG may also be administered intravenously, for example, for the control of blood glucose levels during ketoacidosis, acute illnesses, or during intraoperative and postoperative periods.

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.

When administered subcutaneously, care should be taken when injecting HUMALOG, HUMALOG Pen or HUMALOG KwikPen to ensure that a blood vessel has not been entered. After injection, the site of injection should not be massaged. Patients must be educated to use the proper injection techniques.

HUMALOG, HUMALOG Pen or HUMALOG KwikPen takes effect rapidly and has a shorter duration of activity (2 to 5 hours) given subcutaneously as compared with soluble insulin. This rapid onset of activity allows a HUMALOG injection (or, in the case of administration by continuous subcutaneous infusion, a HUMALOG bolus) to be given very close to mealtime. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. The faster onset of action compared to soluble human insulin is maintained regardless of injection site. As with all insulin preparations, the duration of action of HUMALOG, HUMALOG Pen or HUMALOG KwikPen is dependent on dose, site of injection, blood supply, temperature, and physical activity.

HUMALOG can be used in conjunction with a longer-acting human insulin or oral sulphonylurea agents, on the advice of a physician.

Use of HUMALOG in an insulin infusion pump:

Only certain CE-marked insulin infusion pumps may be used to infuse insulin lispro. Before infusing insulin lispro, the manufacturer's instructions should be studied to ascertain the suitability or otherwise for the particular pump. Read and follow the instructions that accompany the infusion pump. Use the correct reservoir and catheter for the pump. Change the infusion set every 48 hours. Use aseptic technique when inserting the infusion set. In the event of a hypoglycaemic episode, the infusion should be stopped until the episode is resolved. If repeated or severe low blood glucose levels occur, notify your health care professional and consider the need to reduce or stop your insulin infusion. A pump malfunction or obstruction of the infusion set can result in a rapid rise in glucose levels. If an interruption to insulin flow is suspected, follow the instructions in the product literature and if appropriate, notify your health care professional. When used with an insulin infusion pump, HUMALOG should not be mixed with any other insulin.

Intravenous administration of insulin:

Intravenous injection of insulin lispro should be carried out following normal clinical practice for intravenous injections, for example by an intravenous bolus or by an infusion system. Frequent monitoring of the blood glucose levels is required.

Infusion systems at concentrations from 0.1U/ml to 1.0U/ml insulin lispro in 0.9% sodium chloride or 5% dextrose are stable at room temperature for 48 hours. It is recommended that the system is primed before starting the infusion to the patient.

4.3 Contraindications

Hypersensitivity to insulin lispro or to any of the excipients.

Hypoglycaemia.

4.4 Special Warnings And Precautions For Use

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane, lente, etc.), species (animal, human, human insulin analogue), and/or method of manufacture (recombinant DNA versus animal-source insulin) may result in the need for a change in dosage. For fast-acting insulins, any patient also on basal insulin must optimise dosage of both insulins to obtain glucose control across the whole day, particularly nocturnal/fasting glucose control.

Vials: The shorter-acting HUMALOG should be drawn into the syringe first, to prevent contamination of the vial by the longer-acting insulin. Mixing of the insulins ahead of time or just before the injection should be on advice of the physician. However, a consistent routine must be followed.

Conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, intensified insulin therapy, diabetic nerve disease, or medications such as beta-blockers.

A few patients who have experienced hypoglycaemic reactions after transfer from animal-source insulin to human insulin have reported that the early warning symptoms of hypoglycaemia were less pronounced or different from those experienced with their previous insulin. Uncorrected hypoglycaemic or hyperglycaemic reactions can cause loss of consciousness, coma, or death.

The use of dosages which are inadequate or discontinuation of treatment, especially in insulin-dependent diabetics, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.

Insulin requirements may be reduced in the presence of renal impairment. Insulin requirements may be reduced in patients with hepatic impairment due to reduced capacity for gluconeogenesis and reduced insulin breakdown; however, in patients with chronic hepatic impairment, an increase in insulin resistance may lead to increased insulin requirements.

Insulin requirements may be increased during illness or emotional disturbances.

Adjustment of dosage may also be necessary if patients undertake increased physical activity or change their usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycaemia. A consequence of the pharmacodynamics of rapid-acting insulin analogues is that if hypoglycaemia occurs, it may occur earlier after an injection when compared with soluble human insulin.

If the 40U/ml vial is the product normally prescribed, do not take insulin from a 100U/ml cartridge using a 40U/ml syringe.

HUMALOG should only be used in children in preference to soluble insulin when a fast action of insulin might be beneficial. For example, in the timing of the injection in relation to meals.

Combination of Humalog with pioglitazone:

Cases of cardiac failure have been reported when pioglitazone was 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 Humalog 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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Insulin requirements may be increased by medicinal products with hyperglycaemic activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy, danazol, beta₂ stimulants (such as ritodrine, salbutamol, terbutaline).

Insulin requirements may be reduced in the presence of medicinal products with hypoglycaemic activity, such as oral hypoglycaemics, salicylates (for example, acetylsalicylic acid), sulpha antibiotics, certain antidepressants (monoamine oxidase inhibitors, selective serotonin reuptake inhibitors), certain angiotensin converting enzyme inhibitors (captopril, enalapril), angiotensin II receptor blockers, beta-blockers, octreotide, or alcohol.

The physician should be consulted when using other medications in addition to HUMALOG, HUMALOG Pen or HUMALOG KwikPen.

4.6 Pregnancy And Lactation

Data on a large number of exposed pregnancies do not indicate any adverse effect of insulin lispro on pregnancy or on the health of the foetus/newborn.

It is essential to maintain good control of the insulin-treated (insulin-dependent or gestational diabetes) patient throughout pregnancy. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Patients with diabetes 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.

Patients with diabetes who are breast-feeding may require adjustments in insulin dose, diet or both.

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

Hypoglycaemia is the most frequent undesirable effect of insulin therapy that a patient with diabetes may suffer. Severe hypoglycaemia may lead to loss of consciousness and in extreme cases, death. No specific frequency for hypoglycaemia is presented, since hypoglycaemia is a result of both the insulin dose and other factors, e.g., a patient's level of diet and exercise.

Local allergy in patients is common (1/100 to <1/10). Redness, swelling, and itching can occur at the site of insulin injection. This condition usually resolves in a few days to a few weeks. In some instances, this condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. Systemic allergy, which is rare (1/10,000 to <1/1,000) but potentially more serious, is a generalised allergy to insulin. It may cause a rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalised allergy may be life-threatening.

Lipodystrophy at the injection site is uncommon (1/1,000 to <1/100).

4.9 Overdose

Insulins have no specific overdose definitions because serum glucose concentrations are a result of complex interactions between insulin levels, glucose availability and other metabolic processes. Hypoglycaemia may occur as a result of an excess of insulin activity relative to food intake and energy expenditure.

Hypoglycaemia may be associated with listlessness, confusion, palpitations, headache, sweating and vomiting.

Mild hypoglycaemic episodes will respond to oral administration of glucose or other sugar or saccharated products.

Correction of moderately severe hypoglycaemia can be accomplished by intramuscular or subcutaneous administration of glucagon, followed by oral carbohydrate when the patient recovers sufficiently. Patients who fail to respond to glucagon must be given glucose solution intravenously.

If the patient is comatose, glucagon should be administered intramuscularly or subcutaneously. However, glucose solution must be given intravenously if glucagon is not available or if the patient fails to respond to glucagon. The patient should be given a meal as soon as consciousness is recovered.

Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may recur after apparent clinical recovery.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Fast-acting human insulin analogue. ATC code: A10A B04.

The primary activity of insulin lispro is the regulation of glucose metabolism.

In addition, insulins have 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.

Insulin lispro has a rapid onset of action (approximately 15 minutes), thus allowing it to be given closer to a meal (within zero to 15 minutes of the meal) when compared to soluble insulin (30 to 45 minutes before). Insulin lispro takes effect rapidly and has a shorter duration of activity (2 to 5 hours) when compared to soluble insulin.

Clinical trials in patients with Type 1 and Type 2 diabetes have demonstrated reduced postprandial hyperglycaemia with insulin lispro compared to soluble human insulin.

As with all insulin preparations, the time course of insulin lispro action may vary in different individuals or at different times in the same individual and is dependent on dose, site of injection, blood supply, temperature, and physical activity. The typical activity profile following subcutaneous injection is illustrated below.

The above representation reflects the relative amount of glucose over time required to maintain the subject's whole blood glucose concentrations near fasting levels and is an indicator of the effect of these insulins on glucose metabolism over time.

Clinical trials have been performed in children (61 patients aged 2 to 11) and children and adolescents (481 patients aged 9 to 19 years), comparing insulin lispro to human soluble insulin. The pharmacodynamic profile of insulin lispro in children is similar to that seen in adults.

When used in subcutaneous infusion pumps, treatment with insulin lispro has been shown to result in lower glycosylated haemoglobin levels compared to soluble insulin. In a double-blind, crossover study, the reduction in glycosylated haemoglobin levels after 12 weeks dosing was 0.37 percentage points with insulin lispro compared to 0.03 percentage points for soluble insulin (P = 0.004).

In patients with Type 2 diabetes on maximum doses of sulphonylurea agents, studies have shown that the addition of insulin lispro significantly reduces HbA_1c compared to sulphonylurea alone. The reduction of HbA_1c would also be expected with other insulin products, e.g., soluble or isophane insulins.

Clinical trials in patients with Type 1 and Type 2 diabetes have demonstrated a reduced number of episodes of nocturnal hypoglycaemia with insulin lispro compared to soluble human insulin. In some studies, reduction of nocturnal hypoglycaemia was associated with increased episodes of daytime hypoglycaemia.

The glucodynamic response to insulin lispro is not affected by renal or hepatic function impairment. Glucodynamic differences between insulin lispro and soluble human insulin, as measured during a glucose clamp procedure, were maintained over a wide range of renal function.

Insulin lispro has been shown to be equipotent to human insulin on a molar basis but its effect is more rapid and of a shorter duration.

5.2 Pharmacokinetic Properties

The pharmacokinetics of insulin lispro reflect a compound that is rapidly absorbed and achieves peak blood levels 30 to 70 minutes following subcutaneous injection. When considering the clinical relevance of these kinetics, it is more appropriate to examine the glucose utilisation curves (as discussed in section 5.1).

Insulin lispro maintains more rapid absorption when compared to soluble human insulin in patients with renal impairment. In patients with Type 2 diabetes, over a wide range of renal function, the pharmacokinetic differences between insulin lispro and soluble human insulin were generally maintained and shown to be independent of renal function. Insulin lispro maintains more rapid absorption and elimination when compared to soluble human insulin in patients with hepatic impairment.

5.3 Preclinical Safety Data

In in vitro tests, including binding to insulin receptor sites and effects on growing cells, insulin lispro behaved in a manner that closely resembled human insulin. Studies also demonstrate that the dissociation of binding to the insulin receptor of insulin lispro is equivalent to human insulin. Acute, one-month and twelve-month toxicology studies produced no significant toxicity findings.

Insulin lispro did not induce fertility impairment, embryotoxicity, or teratogenicity in animal studies.

6. Pharmaceutical Particulars

6.1 List Of Excipients

m-cresol (3.15mg/ml), glycerol, dibasic sodium phosphate.7H₂O, zinc oxide, water for injections. Hydrochloric acid and sodium hydroxide may be used to adjust pH to 7.0-7.8.

6.2 Incompatibilities

HUMALOG, HUMALOG Pen or HUMALOG KwikPen preparations should not be mixed with insulin produced by other manufacturers or with animal insulin preparations. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

Unopened vials

2 years

Unused cartridges and unused pre-filled pens

3 years

After cartridge insertion, or after first use (vial and prefilled pen)

28 days

6.4 Special Precautions For Storage

Unused cartridge and unused pre-filled pens

Store in a refrigerator (2°C-8°C). Do not freeze. Do not expose to excessive heat or direct sunlight.

After cartridge insertion or first use (pre-filled pen)

Store below 30°C. Do not refrigerate. The pen with the inserted cartridge and the pre-filled pen should not be stored with the needle attached.

Vials

Do not freeze. Do not expose to excessive heat or direct sunlight.

Unopened vials

Store in a refrigerator (2°C - 8°C).

After first use (vials only)

Store in a refrigerator (2°C - 8°C) or below 30°C.

6.5 Nature And Contents Of Container

Vials: The solution is contained in Type I flint glass vials, sealed with butyl or halobutyl stoppers, and secured with aluminium seals. Dimeticone or silicone emulsion may be used to treat the vial stoppers.

Cartridges/HUMALOG Pens: The solution is contained in Type I flint glass cartridges, sealed with butyl or halobutyl disc seals and plunger heads, and are secured with aluminium seals. Dimeticone or silicone emulsion may be used to treat the cartridge plunger and/or the glass cartridge.

HUMALOG Pens: The 3ml cartridges are sealed in a disposable pen injector. Needles are not included.

HUMALOG KwikPen: The 3ml cartridges are sealed in a disposable pen injector, called the 'KwikPen'. Needles are not included.

Not all packs may be marketed.

1 x 10ml HUMALOG vial.

2 x 10ml HUMALOG vials.

5 x (1 x 10ml) HUMALOG vials.

5 x 3ml HUMALOG cartridges for a 3ml pen.

2 x (5 x 3ml) HUMALOG cartridges for a 3ml pen.

5 x 3ml HUMALOG Pens.

2 x (5 x 3ml) HUMALOG Pens.

5 x 3ml HUMALOG 100 U/ml KwikPens.

2 x (5 x 3ml) HUMALOG 100 U/ml KwikPens.

6.6 Special Precautions For Disposal And Other Handling

Instructions for use and handling

Any unused product or waste material should be disposed of in accordance with local requirements.

HUMALOG Vials

The vial is to be used in conjunction with an appropriate syringe (100 U markings).

a) Preparing a dose

Inspect the HUMALOG solution. It should be clear and colourless. Do not use HUMALOG if it appears cloudy, thickened, or slightly coloured or if solid particles are visible.

i) HUMALOG

1. Wash your hands.

2. If using a new vial, flip off the plastic protective cap, but do not remove the stopper.

3. If the therapeutic regimen requires the injection of basal insulin and HUMALOG at the same time, the two can be mixed in the syringe. If mixing insulins, refer to the instructions for mixing that follow in section (ii) and section 6.2.

4. Draw air into the syringe equal to the prescribed HUMALOG dose. Wipe the top of the vial with an alcohol swab. Put the needle through the rubber top of the HUMALOG vial and inject the air into the vial.

5. Turn the vial and syringe upside down. Hold the vial and syringe firmly in one hand.

6. Making sure the tip of the needle is in the HUMALOG, withdraw the correct dose into the syringe.

7. Before removing the needle from the vial, check the syringe for air bubbles that reduce the amount of HUMALOG in it. If bubbles are present, hold the syringe straight up and tap its side until the bubbles float to the top. Push them out with the plunger and withdraw the correct dose.

8. Remove the needle from the vial and lay the syringe down so that the needle does not touch anything.

ii) Mixing HUMALOG with longer-acting Human Insulins (see section 6.2)

1. HUMALOG should be mixed with longer-acting human insulins only on the advice of a doctor.

2. Draw air into the syringe equal to the amount of longer-acting insulin being taken. Insert the needle into the longer-acting insulin vial and inject the air. Withdraw the needle.

3. Now inject air into the HUMALOG vial in the same manner, but do not withdraw the needle.

4. Turn the vial and syringe upside down.

5. Making sure the tip of the needle is in the HUMALOG, withdraw the correct dose of HUMALOG into the syringe.

6. Before removing the needle from the vial, check the syringe for air bubbles that reduce the amount of HUMALOG in it. If bubbles are present, hold the syringe straight up and tap its side until the bubbles float to the top. Push them out with the plunger and withdraw the correct dose.

7. Remove the needle from the vial of HUMALOG and insert it into the vial of the longer-acting insulin. Turn the vial and syringe upside down. Hold the vial and syringe firmly in one hand and shake gently. Making sure the tip of the needle is in the insulin, withdraw the dose of longer-acting insulin.

8. Withdraw the needle and lay the syringe down so that the needle does not touch anything.

b) Injecting a dose

1. Choose a site for injection.

2. Clean the skin as instructed.

3. Stabilise the skin by spreading it or pinching up a large area. Insert the needle and inject as instructed.

4. Pull the needle out and apply gentle pressure over the injection site for several seconds. Do not rub the area.

5. Dispose of the syringe and needle safely.

6. Use of the injection sites should be rotated so that the same is not used more than approximately once a month.

c) Mixing insulins

Do not mix insulin in vials with insulin in cartridges. See section 6.2.

HUMALOG cartridges

HUMALOG cartridges are to be used with a CE marked pen as recommended in the information provided by the device manufacturer.

a) Preparing a dose

Inspect the HUMALOG solution. It should be clear and colourless. Do not use HUMALOG if it appears cloudy, thickened, or slightly coloured, or if solid particles are visible.

The following is a general description. The manufacturer's instructions with each individual pen must be followed for loading the cartridge, attaching the needle, and administering the insulin injection.

b) Injecting a dose

1. Wash your hands.

2. Choose a site for injection.

3. Clean the skin as instructed.

4. Remove outer needle cap.

5. Stabilise the skin by spreading it or pinching up a large area. Insert the needle as instructed.

6. Press the knob.

7. Pull the needle out and apply gentle pressure over the injection site for several seconds. Do not rub the area.

8. Using the outer needle cap, unscrew the needle and dispose of it safely.

9. Use of injection sites should be rotated so that the same site is not used more than approximately once a month.

c) Mixing insulins

Do not mix insulin in vials with insulin in cartridges. See section 6.2.

HUMALOG Pens (excluding Kwikpen)

a) Preparing a dose

1. Inspect the HUMALOG Pen solution.

It should be clear and colourless. Do not use HUMALOG Pen if it appears cloudy, thickened, or slightly coloured, or if solid particles are visible.

2. Put on the needle.

Wipe the rubber seal with alcohol. Remove the paper tab from the capped needle. Screw the capped needle clockwise onto the pen until it is tight. Hold the pen with needle pointing up and remove the outer needle cap and inner needle cover.

3. Priming the pen (check insulin flow).

(a) The arrow should be visible in the dose window. If the arrow is not present, turn the dose knob clockwise until the arrow appears and notch is felt or visually aligned.

(b) Pull dose knob out (in direction of the arrow) until a '0' appears in the dose window. A dose cannot be dialled until the dose knob is pulled out.

(c) Turn dose knob clockwise until a '2' appears in the dose window.

(d) Hold the pen with needle pointing up and tap the clear cartridge holder gently with your finger so any air bubbles collect near the top. Depress the injection button fully until you feel or hear a click. You should see a drop of insulin at the tip of the needle. If insulin does not appear, repeat the procedure until insulin appears.

(e) Always prime the pen (check the insulin flow) before each injection. Failure to prime the pen may result in an inaccurate dose.

4. Setting the dose.

(a) Turn the dose knob clockwise until the arrow appears in the dose window and a notch is felt or visually aligned.

(b) Pull the dose knob out (in the direction of the arrow) until a '0' appears in the dose window. A dose cannot be dialled until the dose knob is pulled out.

(c) Turn the dose knob clockwise until the dose appears in the dose window. If too high a dose is dialled, turn the dose knob backward (anti-clockwise) until the correct dose appears in the window. A dose greater than the number of units remaining in the cartridge cannot be dialled.

b) Injecting a dose

1. Wash your hands.

2. Choose a site for injection.

3. Clean the skin as instructed.

4. Remove outer needle cap.

5. Stabilise the skin by spreading it or pinching up a large area. Insert the needle as instructed.

6. Press the injection button down with the thumb (until you hear or feel a click); wait 5 seconds.

7. Pull the needle out and apply gentle pressure over the injection site for several seconds. Do not rub the area.

8. Immediately after an injection, use the outer needle cap to unscrew the needle. Remove the needle from the pen. This will ensure sterility, and prevent leakage, re-entry of air, and potential needle clogs. Do not reuse the needle. Dispose of the needle in a responsible manner. Needles and pens must not be shared.

The prefilled pen can be used until it is empty. Please properly discard or recycle.

9. Replace the cap on the pen.

10. Use of injection sites should be rotated so that the same site is not used more than approximately once a month.

11. The injection button should be fully depressed before using the pen again.

c) Mixing insulins

Do not mix insulin in vials with insulin in cartridges. See section 6.2.

HUMALOG KwikPen

Inspect the HUMALOG solution. It should be clear and colourless. Do not use HUMALOG if it appears cloudy, thickened, or slightly coloured or if solid particles are visible.

a) Handling of the pre-filled pen

Before using the KwikPen the user manual included in the package leaflet must be read carefully. The KwikPen has to be used as recommended in the user manual.

b) Mixing insulins

Do not mix insulin in vials with insulin in cartridges. See section 6.2.

7. Marketing Authorisation Holder

Eli Lilly Nederland B.V., Grootslag 1-5, 3991 RA Houten, The Netherlands.

8. Marketing Authorisation Number(S)

HUMALOG vials
1 x 10ml HUMALOG vial:	EU/1/96/007/002
2 x 10ml HUMALOG vials:	EU/1/96/007/020
5 x (1 x 10ml) HUMALOG vials:	EU/1/96/007/021
HUMALOG cartridges
5 x 3ml HUMALOG cartridges for a 3ml pen:	EU/1/96/007/004
2 x (5 x 3ml) HUMALOG cartridges for a 3ml pen:	EU/1/96/007/023
HUMALOG Pens
5 x 3ml HUMALOG Pens:	EU/1/96/007/015
2 x (5 x 3ml) HUMALOG Pens:	EU/1/96/007/026
HUMALOG KwikPen
5 x 3ml HUMALOG 100 U/ml KwikPen:	EU/1/96/007/031
2 x (5 x 3ml) HUMALOG 100 U/ml KwikPen:	EU/1/96/007/032

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 30 April 1996

Date of last renewal: 30 April 2006

10. Date Of Revision Of The Text

17 February 2011

LEGAL CATEGORY

POM (United Kingdom)

*HUMALOG (insulin lispro) and KWIKPEN are trademarks of Eli Lilly and Company. HLG37M

Heparin sodium 25,000 I.U. / ml solution for injection or concentrate for solution for infusion (with preservative)

1. Name Of The Medicinal Product

Multiparin 25,000 I.U./ml solution for injection or concentrate for solution for infusion or Heparin sodium 25,000 I.U./ml solution for injection or concentrate for solution for infusion

2. Qualitative And Quantitative Composition

Heparin sodium 25,000 I.U./ml (125,000 I.U. in 5ml)

For excipients, see 6.1.

3. Pharmaceutical Form

Solution for injection or concentrate for solution for infusion

A colourless or straw-coloured liquid, free from turbidity and from matter that deposits on standing.

4. Clinical Particulars

4.1 Therapeutic Indications

Prophylaxis of deep vein thrombosis and pulmonary embolism

Treatment of deep vein thrombosis, pulmonary embolism, unstable angina pectoris and acute peripheral arterial occlusion.

Prophylaxis of mural thrombosis following myocardial infarction.

In extracorporeal circulation and haemodialysis.

4.2 Posology And Method Of Administration

Route of administration

By continuous intravenous infusion in 5% glucose or 0.9% sodium chloride or by intermittent intravenous injection, or by subcutaneous injection.

The intravenous injection volume of heparin injection should not exceed 15ml.

As the effects of heparin are short-lived, administration by intravenous infusion or subcutaneous injection is preferable to intermittent intravenous injections.

Recommended dosage

Prophylaxis of deep vein thrombosis and pulmonary embolism:

Adults:

2 hours pre-operatively:	5,000 units subcutaneously
followed by:	5,000 units subcutaneously every 8-12 hours, for 7-10 days or until the patient is fully ambulant.

No laboratory monitoring should be necessary during low dose heparin prophylaxis. If monitoring is considered desirable, anti-Xa assays should be used as the activated partial thromboplastin time (APTT) is not significantly prolonged.

During pregnancy:

5,000 - 10,000 units every 12 hours, subcutaneously, adjusted according to APTT or anti-Xa assay.

Elderly:

Dosage reduction and monitoring of APTT may be advisable.

Children:

No dosage recommendations.

Treatment of deep vein thrombosis and pulmonary embolism:

Adults:

Loading dose: 5,000 units intravenously (10,000 units may be required in severe pulmonary embolism)

Maintenance:

1,000-2,000 units/hour by intravenous infusion, or 10,000-20,000 units 12 hourly subcutaneously, or 5,000-10,000 units 4-hourly by intravenous injection.

Elderly:

Dosage reduction may be advisable.

Children and small adults:

Loading dose: 50 units/kg intravenously

Maintenance:

15-25 units/kg/hour by intravenous infusion, or 250 units/kg 12 hourly subcutaneously or 100 units/kg 4-hourly by intravenous injection

Treatment of unstable angina pectoris and acute peripheral arterial occlusion:

Adults:

Loading dose: 5,000 units intravenously

Maintenance:

1,000-2,000 units/hour by intravenous infusion, or 5,000-10,000 units 4-hourly by intravenous injection.

Elderly:

Dosage reduction may be advisable.

Children and small adults:

Loading dose: 50 units/kg intravenously

Maintenance:

15-25 units/kg/hour by intravenous infusion, or 100 units/kg 4-hourly by intravenous injection

Daily laboratory monitoring (ideally at the same time each day, starting 4-6 hours after initiation of treatment) is essential during full-dose heparin treatment, with adjustment of dosage to maintain an APTT value 1.5-2.5 x midpoint of normal range or control value.

Prophylaxis of mural thrombosis following myocardial infarction

Adults:

12,500 units 12 hourly subcutaneously for at least 10 days.

Elderly:

Dosage reduction may be advisable

In extracorporeal circulation and haemodialysis

Adults:

Cardiopulmonary bypass:

Initially 300 units/kg intravenously, adjusted thereafter to maintain the activated clotting time (ACT) in the range 400-500 seconds.

Haemodialysis and haemofiltration:

Initially 1-5,000 units,

Maintenance: 1-2,000 units/hour, adjusted to maintain clotting time >40 minutes.

Heparin resistance

Patients with altered heparin responsiveness or heparin resistance may require disproportionately higher doses of heparin to achieve the desired effect. Also refer to section 4.4, Special warnings and precautions for use.

4.3 Contraindications

Known hypersensitivity to heparin or any of the other ingredients.

Must not be given to premature babies or neonates (contains benzyl alcohol).

Patients who consume large amounts of alcohol, who are sensitive to the drug, who are actively bleeding or who have haemophilia or other bleeding disorders, severe liver disease (including oesophageal varices), purpura, severe hypertension, active tuberculosis or increased capillary permeability.

Patients with present or previous thrombocytopenia. The rare occurrence of skin necrosis in patients receiving heparin contra-indicates the further use of heparin either by subcutaneous or intravenous routes because of the risk of thrombocytopenia. Because of the special hazard of post-operative haemorrhage heparin is contra-indicated during surgery of the brain, spinal cord and eye, in procedures at sites where there is a risk of bleeding, in patients that have had recent surgery, and in patients undergoing lumbar puncture or regional anaesthetic block.

The relative risks and benefits of heparin should be carefully assessed in patients with a bleeding tendency or those patients with an actual or potential bleeding site eg. hiatus hernia, peptic ulcer, neoplasm, bacterial endocarditis, retinopathy, bleeding haemorrhoids, suspected intracranial haemorrhage, cerebral thrombosis or threatened abortion.

Menstruation is not a contra-indication.

4.4 Special Warnings And Precautions For Use

Platelet counts should be measured in patients receiving heparin treatment for longer than 5 days and the treatment should be stopped immediately in those who develop thrombocytopenia.

In patients with advanced renal or hepatic disease, a reduction in dosage may be necessary. The risk of bleeding is increased with severe renal impairment and in the elderly (particularly elderly women).

Although heparin hypersensitivity is rare, it is advisable to give a trial dose of 1,000 I.U. in patients with a history of allergy. Caution should be exercised in patients with known hypersensitivity to low molecular weight heparins.

Heparin injection contains benzyl alcohol (10mg/ml) and methyl parahydroxybenzoate as preservatives. Caution should be used if prescribing Heparin injection to susceptible patients. Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to three years old. Methyl parahydroxybenzoate may cause allergic reactions (possibly delayed) and exceptionally, bronchospasm.

In most patients, the recommended low-dose regimen produces no alteration in clotting time. However, patients show an individual response to heparin, and it is therefore essential that the effect of therapy on coagulation time should be monitored in patients undergoing major surgery.

Caution is recommended in spinal or epidural anaesthesia (risk of spinal haematoma).

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and in all patients treated for more than 7 days.

Heparin resistance

There is considerable variation in individual anticoagulant responses to heparin.

Heparin resistance, defined as an inadequate response to heparin at a standard dose for achieving a therapeutic goal occurs in approximately 5 to 30% of patients.

Factors predisposing to the development of heparin resistance, include:

• Antithrombin III activity less than 60% of normal (antithrombin III-dependent heparin resistance):

Reduced antithrombin III activity may be hereditary or more commonly, acquired (secondary to preoperative heparin therapy in the main, chronic liver disease, nephrotic syndrome, cardiopulmonary bypass, low grade disseminated intravascular coagulation or drug induced, e.g. by aprotinin, oestrogen or possibly nitroglycerin)

• Patients with normal or supranormal antithrombin III levels (antithrombin III-independent heparin resistance)

	• Thromboembolic disorders
	• Increased heparin clearance

• Elevated levels of heparin binding proteins, factor VIII, von Willebrand factor, fibrinogen, platelet factor 4 or histidine-rich glycoprotein

• Active infection (sepsis or endocarditis) • Preoperative intra-aortic balloon counterpulsation • Thrombocytopenia • Thrombocytosis • Advanced age • Plasma albumin concentration • Relative hypovolaemia

Heparin resistance is also often encountered in acutely ill patients,in patients with malignancy and during pregnancy or the post-partum period.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Analgesics: Drugs that interfere with platelet aggregation eg. aspirin and other NSAIDs should be used with care. Increased risk of haemorrhage with ketorolac (avoid concomitant use even with low-dose heparin).

Anticoagulants, platelet inhibitors, etc: Increased risk of bleeding with oral anticoagulants, epoprostenol, clopidogrel, ticlopidine, streptokinase, dipyridamole, dextran solutions, or any other drug which may interfere with coagulation.

Cephalosporins: Some cephalosporins, e.g. cefaclor, cefixime and ceftriaxone, can affect the coagulation process and may therefore increase the risk of haemorrhage when used concurrently with heparin.

ACE inhibitors: Hyperkalaemia may occur with concomitant use.

Nitrates: Reduced activity of heparin has been reported with simultaneous intravenous glyceryl trinitrate infusion.

Probenecid: May increase the anticoagulant effects of heparin.

Tobacco smoke: Nicotine may partially counteract the anticoagulant effect of heparin. Increased heparin dosage may be required in smokers.

Interference with diagnostic tests may be associated with pseudo-hypocalcaemia (in haemodialysis patients), artefactual increases in total thyroxine and triiodothyronine, simulated metabolic acidosis and inhibition of the chromogenic lysate assay for endotoxin. Heparin may interfere with the determination of aminoglycosides by immunoassays.

4.6 Pregnancy And Lactation

Heparin is not contraindicated in pregnancy. Heparin does not cross the placenta or appear in breast milk. The decision to use heparin in pregnancy should be taken after evaluation of the risk/benefit in any particular circumstances.

Reduced bone density has been reported with prolonged heparin treatment during pregnancy.

Haemorrhage may be a problem during pregnancy or after delivery.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Haemorrhage (see also Special Warnings and Precautions and Overdosage Information).

Adrenal insufficiency secondary to adrenal haemorrhage has been associated with heparin (rarely).

Thrombocytopenia has been observed occasionally (see also Special Precautions and Warnings). Two types of heparin-induced thrombocytopenia have been defined. Type I is frequent, mild (usually >50 x 10⁹/L) and transient, occurring within 1-5 days of heparin administration. Type II is less frequent but often associated with severe thrombocytopenia (usually <50 x 10⁹/L). It is immune-mediated and occurs after a week or more (earlier in patients previously exposed to heparin). It is associated with the production of a platelet-aggregating antibody and thromboembolic complications which may precede the onset of thrombocytopenia. Heparin should be discontinued immediately.

There is some evidence that prolonged dosing with heparin (ie. over many months) may cause alopecia and osteoporosis. Significant bone demineralisation has been reported in women taking more than 10,000 I.U. per day of heparin for at least 6 months.

Heparin products can cause hypoaldosteronism which may result in an increase in plasma potassium. Rarely, clinically significant hyperkalemia may occur particularly in patients with chronic renal failure and diabetes mellitus (see Warnings and Precautions).

Hypersensitivity reactions to heparin are rare. They include urticaria, conjunctivitis, rhinitis, asthma, cyanosis, tachypnoea, feeling of oppression, fever, chills, angioneurotic oedema and anaphylactic shock. In some instances the precipitating agent will prove to be the preservative rather than the heparin itself.

Local irritation and skin necrosis may occur but are rare. Erythematous nodules, or infiltrated and sometimes eczema-like plaques, at the site of subcutaneous injections are common, occurring 3-21 days after starting heparin treatment.

Priapism has been reported. Increased serum transaminase values may occur but usually resolve on discontinuation of heparin. Heparin administration is associated with release of lipoprotein lipase into the plasma; rebound hyperlipidaemia may follow heparin withdrawal.

4.9 Overdose

A potential hazard of heparin therapy is haemorrhage, but this is usually due to overdosage and the risk is minimised by strict laboratory control. Slight haemorrhage can usually be treated by withdrawing the drug. If bleeding is more severe, clotting time and platelet count should be determined. Prolonged clotting time will indicate the presence of an excessive anticoagulant effect requiring neutralisation by intravenous protamine sulphate, at a dosage of 1 mg for every 100 I.U. of heparin to be neutralised. The bolus dose of protamine sulphate should be given slowly over about 10 minutes and not exceed 50 mg. If more than 15 minutes have elapsed since the injection of heparin, lower doses of protamine will be necessary.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Heparin is an anticoagulant and acts by inhibiting thrombin and by potentiating the naturally occurring inhibitors of activated Factor X (Xa).

5.2 Pharmacokinetic Properties

As heparin is not absorbed from the gastrointestinal tract and sublingual sites it is administered by injection. After injection heparin extensively binds to plasma proteins.

Heparin is metabolised in the liver and the inactive metabolic products are excreted in the urine.

The half life of heparin is dependent on the dose.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Benzyl alcohol

Methyl parahydroxybenzoate (E218)

Water for injections

Sodium hydroxide solution

Hydrochloric acid

6.2 Incompatibilities

Heparin is incompatible with many injectable preparations e.g. some antibiotics, opioid analgesics and antihistamines.

The following drugs are incompatible with heparin;

Alteplase, amikacin sulphate, amiodarone hydrochloride, ampicillin sodium, aprotinin, benzylpenicillin potassium or sodium, cefalotin sodium, chlorpromazine hydrochloride, ciprofloxacin lactate, cisatracurium besilate, cytarabine, dacarbazine, daunorubicin hydrochloride, diazepam, doxorubicin hydrochloride, droperidol, erythromycin lactobionate, gentamicin sulphate, haloperidol lactate, hyaluronidase, hydrocortisone sodium succinate, kanamycin sulphate, labetolol hydrochloride, meticillin sodium, methotrimeprazine, netilmicin sulphate, nicardipine hydrochloride, oxytetracycline hydrochloride, pethidine hydrochloride, polymyxin B sulphate, promethazine hydrochloride, streptomycin sulphate, tobramycin sulphate, triflupromazine hydrochloride, vancomycin hydrochloride and vinblastine sulphate.

Dobutamine hydrochloride and heparin should not be mixed or infused through the same intravenous line, as this causes precipitation.

Heparin and reteplase are incompatible when combined in solution.

If reteplase and heparin are to be given through the same line this, together with any Y-lines, must be thoroughly flushed with a 0.9% saline or a 5% glucose solution prior to and following the reteplase injection.

6.3 Shelf Life

36 months

Following the withdrawal of the first dose the remainder should be used within 28 days. After this period, any unused material should be discarded.

6.4 Special Precautions For Storage

Do not store above 25°C

Store in the original package

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

From a microbiological point of view, once opened, the product may be stored for a maximum of 28 days at 25°C. Other in use storage times and conditions are the responsibility of the user.

6.5 Nature And Contents Of Container

5ml multidose neutral glass (Type 1, Ph Eur) vial. Carton containing 10 vials.

6.6 Special Precautions For Disposal And Other Handling

Each multidose vial should be restricted to use in a single patient.

7. Marketing Authorisation Holder

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

UK.

8. Marketing Authorisation Number(S)

PL 29831/0108

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 15 October 2007

10. Date Of Revision Of The Text

04 /03/2011

Heparin sodium 1000 IU / ml ampoule, solution for infusion (Leo Laboratories Ltd)

1. Name Of The Medicinal Product

Heparin sodium 1000 IU/ml ampoule, solution for infusion

2. Qualitative And Quantitative Composition

Heparin sodium 1,000 IU/ml

3. Pharmaceutical Form

Solution for infusion.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of thrombo-embolic disorders such as: deep vein thrombosis, acute arterial embolism or thrombosis, thrombophlebitis, pulmonary embolism, fat embolism.

4.2 Posology And Method Of Administration

This product may be used when heparin is being administered intravenously as an alternative to diluting heparin taken from multidose vials.

500 IU/kg bodyweight daily or 5,000 - 10,000 IU every 4 hours as a continuous infusion in sodium chloride injection or dextrose injection. The dose should be individually adjusted according to coagulation tests.

Dosage adjustment: It is recommended that dosages be adjusted to maintain a thrombin clotting time, whole blood clotting time or activated partial thromboplastin time 1.5 to 2 times that of control on blood withdrawn 4-6 hours after commencement of infusion and at similar intervals until the patient is stabilised.

Dosage in the elderly: Lower dosages may be required, however, standard dosages should be given initially and then subsequent dosages and/or dosage intervals should be individually adjusted according to changes in thrombin clotting time, whole blood clotting time and/or activated partial thromboplastin time.

Pregnancy: See Section 4.6, Pregnancy and Lactation. If treatment is considered appropriate, standard dosages should be given initially. Intermittent intravenous injections are not advised. Subsequent dosages and/or dosage intervals should be individually adjusted according to changes in thrombin clotting time, whole blood clotting time and/or activated partial thromboplastin time.

4.3 Contraindications

Known hypersensitivity to constituents.

Current or history of heparin-induced thrombocytopenia.

Generalised or local haemorrhagic tendency, including uncontrolled severe hypertension, severe liver insufficiency, active peptic ulcer, acute or subacute septic endocarditis, intracranial haemorrhage or injuries and operations on the central nervous system, eyes and ears, and in women with abortus imminens.

An epidural anaesthesia during birth in pregnant women treated with heparin is contraindicated (see Section 4.6).

In patients receiving heparin for treatment rather than prophylaxis, locoregional anaesthesia in elective surgical procedures is contra-indicated because the use of heparin may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis.

4.4 Special Warnings And Precautions For Use

Heparin should be used with caution in patients with hypersensitivity to low molecular weight heparin.

Care should be taken when heparin is administered to patients with increased risk of bleeding complications, hypertension, renal or hepatic insufficiency.

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium or taking potassium sparing drugs. The risk of hyperkalaemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and monitored regularly thereafter particularly if treatment is prolonged beyond about 7 days.

Drugs affecting platelet function or the coagulation system should in general not be given concomitantly with heparin (see Section 4.5).

In patients undergoing peridural or spinal anaesthesia or spinal puncture, the prophylactic use of heparin may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis. The risk is increased by the use of a peridural or spinal catheter for anaesthesia, by the concomitant use of drugs affecting haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors or anticoagulants, and by traumatic or repeated puncture.

In decision making on the interval between the last administration of heparin at prophylactic doses and the placement or removal of a peridural or spinal catheter, the product characteristics and the patient profile should be taken into account. Subsequent dose should not take place before at least four hours have elapsed. Re-administration should be delayed until the surgical procedure is completed.

Should a physician decide to administer anti-coagulation in the context of peridural or spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment, such as back pain, sensory and motor deficits and bowel or bladder dysfunction. Patients should be instructed to inform immediately a nurse or a clinician if they experience any of these.

Heparin should not be administered by intramuscular injection due to the risk of haematoma.

Due to increased bleeding risk, care should be taken when giving concomitant intramuscular injections, lumbar puncture and similar procedures.

As there is a risk of antibody-mediated heparin-induced thrombocytopenia, platelet counts should be measured in patients receiving heparin treatment for longer than 5 days and the treatment should be stopped immediately in those who develop thrombocytopenia.

Heparin induced thrombocytopenia and heparin induced thrombocytopenia with thrombosis can occur up to several weeks after discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The anticoagulant effect of heparin may be enhanced by concomitant medication with other drugs affecting platelet function or the coagulation system, e.g. platelet aggregation inhibitors, thrombolytic agents, salicylates, non-steroidal anti-inflammatory drugs, vitamin K antagonists, dextrans, activated protein C. Where such combination cannot be avoided, careful clinical and biological monitoring is required.

Combined use with ACE inhibitors or angiotensin II antagonists may increase the risk of hyperkalaemia.

Use of glyceryl trinitrate infusion may reduce the anticoagulant effect of heparin.

4.6 Pregnancy And Lactation

Because of the known haemorrhagic effect, heparin should be used with caution in pregnant women and only if the benefits outweigh the risks according to the physician's judgement. Precaution is particularly required because of uteroplacental haemorrhage, especially at the time of delivery. If epidural anaesthesia is envisaged, heparin treatment should be suspended, whenever possible.

The use of heparin in women with abortus imminens is contraindicated (see Section 4.3).

Heparin does not cross the placental barrier and is not excreted in breast milk.

4.7 Effects On Ability To Drive And Use Machines

Heparin has no or negligible influence on the ability to drive or use machines.

4.8 Undesirable Effects

Very common	>1/10
Common	>1/100 and <1/10
Uncommon	>1/1,000 and <1/100
Rare	>1/10,000 and <1/1,000
Very rare	<1/10,000

The most frequently reported undesirable effects are bleeding events, reversible increase in liver enzymes, reversible thrombocytopenia and various skin reactions. Isolated reports of generalised allergic reactions, skin necrosis and priapism have been reported.

•Blood and lymphatic system disorders

Heparin can cause thrombocytopenia either through a direct effect or through an immune effect producing a platelet-aggregating antibody (see Section 4.4). Reversible after drug withdrawal.

Common:	Thrombocytopenia type I
Rare:	Thrombocytopenia type II, probably of an immunoallergic nature (see section 4.4)

In some cases thrombocytopenia type II has been accompanied by venous or arterial thrombi.

•Immune system disorders

Rare:	Allergic reactions of all types and severities, with various manifestations
Very rare:	Anaphylactoid reactions and anaphylactic shock

•Metabolism and nutrition disorders

Rare:

Hypoaldosteronism. Heparin products can cause hypoaldosteronism which may result in an increase in plasma potassium. Rarely, clinically significant hyperkalaemia may occur particularly in patients with chronic renal failure and diabetes mellitus (see Section 4.4).

•Vascular disorders

Common:

Haemorrhage. Haemorrhages may affect any organ, particularly in connection with high doses. In some cases haemorrhage has resulted in death or permanent disability.

Very rare cases of epidural and spinal haematoma have been reported in patients receiving heparin for prophylaxis undergoing spinal or epidural anaesthesia or spinal puncture (see Section 4.4).

•Hepatobiliary disorders

Common:

Raised transaminases, gamma-GT, LDH and lipase levels. They are reversible after drug withdrawal.

•Skin and subcutaneous tissue disorder

Uncommon:	Rash (various types of rash such as erythematous and maculopapular), urticaria, pruritus.
Rare:	Skin necrosis. If this occurs treatment must be withdrawn immediately. One case of erythema multiforme was also reported.

•Musculoskeletal and connective tissue disorders

Uncommon:

Osteoporosis has been reported in connection with long-term heparin treatment.

•Reproductive system and breast disorders

Very rare:

Priapism

•General disorders and administration site conditions

Common:

Injection site reactions; local irritation may occur when injected subcutaneously

4.9 Overdose

Bleeding is the main sign of overdose with heparin. As heparin is eliminated quickly, a discontinuation of treatment is sufficient in case of minor haemorrhages. In case of severe haemorrhages heparin may be neutralised with protamine sulphate injected slowly intravenously. One mg of protamine sulphate neutralises approximately 100 IU of heparin. Nevertheless, the required protamine sulphate dose varies according to the time of heparin administration and the dose administered.

It is important to avoid overdosage of protamine sulphate because protamine itself has anticoagulant properties. A single dose of protamine sulphate should never exceed 50 mg. Intravenous injection of protamine may cause a sudden fall in blood pressure, bradycardia, dyspnoea and transitory flushing, but these may be avoided or diminished by slow and careful administration.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Heparin is a naturally occurring anticoagulant which prevents the coagulation of blood in-vivo and in-vitro. It potentiates the inhibition of several activated coagulation factors, including thrombin and factor X.

5.2 Pharmacokinetic Properties

The anticoagulant effect of heparin after intravenous infusion becomes apparent immediately.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride

Sodium citrate

Water for Injections

6.2 Incompatibilities

Heparin has been reported to be incompatible in aqueous solution with certain substances, e.g. some antibiotics, hydrocortisone, phenothiazines, narcotic analgesics and some antihistamines.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store below 25ºC.

6.5 Nature And Contents Of Container

Ph. Eur. Type I glass ampoules

10 x 5ml ampoules

10 x 10ml ampoules

10 x 20ml ampoules

6.6 Special Precautions For Disposal And Other Handling

Contains no preservative, any portion of the contents not used at once should be discarded.

7. Marketing Authorisation Holder

LEO Laboratories Limited

Longwick Road

Princes Risborough

Bucks HP27 9RR

8. Marketing Authorisation Number(S)

PL 0043/0149

9. Date Of First Authorisation/Renewal Of The Authorisation

16 May 1996

10. Date Of Revision Of The Text

April 2007

LEGAL CATEGORY

POM

Haldol 2mg / ml oral liquid

1. Name Of The Medicinal Product

HALDOL 2 mg/ml oral liquid

2. Qualitative And Quantitative Composition

Each ml of liquid contains haloperidol 2mg

3. Pharmaceutical Form

Oral solution

For excipients, see 6.1.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults:

• Schizophrenia: treatment of symptoms and prevention of relapse

• Other psychoses: especially paranoid

• Mania and hypomania

• Mental or behavioural problems such as aggression, hyperactivity and self mutilation in the mentally retarded and in patients with organic brain damage

• As an adjunct to short term management of moderate to severe psychomotor agitation, excitement, violent or dangerously impulsive behaviour

• Intractable hiccup

• Gilles de la Tourette syndrome and severe tics

Children:

• Childhood behavioural disorders, especially when associated with hyperactivity and aggression

• Gilles de la Tourette syndrome

• Childhood schizophrenia.

4.2 Posology And Method Of Administration

For oral administration.

Since this product is not intended for administration in multiples of 5 ml, the quantities given are expressed per ml.

Dosage for all indications should be individually determined and is best initiated and titrated under close clinical supervision. To determine the initial dose, consideration should be given to the patient's age, severity of symptoms and previous response to other neuroleptic drugs.

Patients who are elderly or debilitated or those with previously reported adverse reactions to neuroleptic drugs may require less Haldol. The normal starting dose should be halved, followed by a gradual titration to achieve optimal response.

Haldol liquid should be used at the minimum dose that is clinically effective.

Adults:

Schizophrenia, psychoses, mania and hypomania, mental or behavioural problems, psychomotor agitation, excitement, violent or dangerously impulsive behaviour, organic brain damage

Initial dose:

Moderate symptomatology 1.5-3.0 mg bd or tds

Severe symptomatology/resistant patients 3.0-5.0mg bd or tds

The same starting doses may be employed in adolescents and resitant schizophrenics who may require up to 30 mg/day.

Maintenance dosage:

Once satisfactory control of symptoms has been achieved, dosage should be gradually reduced to the lowest effective maintenance dose, often as low as 5 or 10 mg/day. Too rapid a dosage reduction should be avoided.

Restlessness or agitation in the elderly

Initial dose 1.5-3.0 mg bd or tds. Titrated as required, to attain an effective maintenance dose(1.5 – 30mg daily).

Gilles de la Tourette syndrome, severe tics, intractable hiccup

Starting dose 1.5 mg tds adjusted according to response. A daily maintenance dose of 10 mg may be required in Gilles de la Tourette syndrome.

Children:

Childhood behavioural disorders/schizophrenia

Total daily maintenance dose of 0.025-0.05 mg/kg/day. Half the dose should be given in the morning and the other half in the evening, up to a maximum of 10 mg daily.

Gilles de la Tourette syndrome

Oral maintenance doses of up to 10 mg/day in most patients.

4.3 Contraindications

Comatose states, CNS depression, Parkinson's disease, known hypersensitivity to haloperidol, lesions of basal ganglia.

In common with other neuroleptics, haloperidol has the potential to cause rare prolongation of the QT interval. Use of haloperidol is therefore contra-indicated in patients with clinically significant cardiac disorders e.g. recent acute myocardial infarction, uncompensated heart failure, arrhythmias treated with class IA and III antiarrhythmic medicinal products, QTc interval prolongation, history of ventricular arrhythmia or torsades de pointes clinically significant bradycardia, second or third degree heart block and uncorrected hypokalaemia. Haloperidol should not be used concomitantly with other QT prolonging drugs (see section 4.5, Interactions)

4.4 Special Warnings And Precautions For Use

Cases of sudden death have been reported in psychiatric patients receiving antipsychotic drugs, including haloperidol.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

Haldol is not licensed for the treatment of dementia-related behavioural disturbances.

Cardiovascular effects

Very rare reports of QT prolongation and/or ventricular arrhythmias, in addition to rare reports of sudden death, have been reported with haloperidol. They may occur more frequently with high doses and in predisposed patients.

The risk-benefit of haloperidol treatment should be fully assessed before treatment is commenced and patients with risk factors for ventricular arrhythmias such as cardiac disease, family history of sudden death and/or QT prolongation; uncorrected electrolyte disturbances; subarachnoid haemorrhage, starvation or alcohol abuse should be monitored carefully (ECGs and potassium levels), particularly during the initial phase of treatment to obtain steady plasma levels. The risk of QT prolongation and/or ventricular arrhythmias may be increased with higher doses (see Sections 4.8 and 4.9) or with parenteral use, particularly intravenous administration. ECG monitoring should be performed for QT interval prolongation and for serious cardiac dysrhythmias if Haldol is administered intravenously.

Haloperidol should be used with caution in patients known to be slow metabolisers of CYP2D6, and during use of cytochrome P450 inhibitors. Concomitant use of antipsychotics should be avoided. (See Section 4.5)

Baseline ECG is recommended prior to treatment in all patients, especially in the elderly and patients with a positive personal or family history of cardiac disease or abnormal findings on cardiac clinical examination. During therapy, the need for ECG monitoring (e.g. at dose escalation) should be assessed on an individual basis. Whilst on therapy, the dose should be reduced if QT is prolonged, and haloperidol should be discontinued if the QTc exceeds 500 ms.

Periodic electrolyte monitoring is recommended, especially for patients taking diuretics, or during intercurrent illness.

An approximately 3-fold increase risk of cerebrovascular adverse events have been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Haloperidol should be used with caution in patients with risk factors for stroke.

Neuroleptic malignant syndrome

In common with other antipsychotic drugs, Haldol has been associated with neuroleptic malignant syndrome: a rare idiosyncratic response characterised by hyperthermia, generalised muscle rigidity, autonomic instability, altered consciousness. Hyperthermia is often an early sign of this syndrome. Antipsychotic treatment should be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.

Tardive dyskinesia

As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or after drug discontinuation. The syndrome is mainly characterised by rhythmic involuntary movements of the tongue, face, mouth or jaw. The manifestations may be permanent in some patients. The syndrome may be masked when treatment is reinstituted, when the dosage is increased or when a switch is made to a different antipsychotic drug. Treatment should be discontinued as soon as possible.

Extrapyramidal symptoms

In common with all neuroleptics, extrapyramidal symptoms may occur, e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia.

Antiparkinson drugs of the anticholinergic type may be prescribed as required, but should not be prescribed routinely as a preventive measure. If concomitant antiparkinson medication is required, it may have to be continued after stopping Haldol if its excretion is faster than that of Haldol in order to avoid the development or aggravation of extrapyramidal symptoms. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with Haldol.

Seizures/Convulsions

It has been reported that seizures can be triggered by Haldol. Caution is advised in patients suffering from epilepsy and in conditions predisposing to convulsions (e.g., alcohol withdrawal and brain damage).

Hepatobiliary concerns

As Haldol is metabolised by the liver, caution is advised in patients with liver disease. Isolated cases of liver function abnormalities or hepatitis, most often cholestatic, have been reported.

Endocrine system concerns

Thyroxin may facilitate Haldol toxicity. Antipsychotic therapy in patients with hyperthyroidism should be used only with great caution and must always be accompanied by therapy to achieve a euthyroid state.

Hormonal effects of antipsychotic neuroleptic drugs include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligo- or amenorrhoea. Very rare cases of hypoglycaemia and of Syndrome of Inappropriate ADH Secretion have been reported.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Haldol and preventive measures undertaken.

Additional considerations

In schizophrenia, the response to antipsychotic drug treatment may be delayed. Also, if drugs are withdrawn, recurrence of symptoms may not become apparent for several weeks or months. Acute withdrawal symptoms including nausea, vomiting and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic drugs. Relapse may also occur and gradual withdrawal is advisable.

As with all antipsychotic agents, Haldol should not be used alone where depression is predominant. It may be combined with antidepressants to treat those conditions in which depression and psychosis coexist.

Caution is advised in patients with renal failure and phaeochromocytoma.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of haloperidol with drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias, including torsade de pointes. Therefore concomitant use of these products is not recommended (see section 4.3-Contraindications).

Examples include certain antiarrhythmics, such as those of Class 1A (such as quinidine, disopyramide and procainamide) and class III (such as amiodarone, sotalol and dofetilide), certain antimicrobials (sparfloxacin, moxifloxacin, erythromycin IV), tricyclic antidepressants (such as amitriptyline), certain tetracyclic antidepressants (such as maprotiline), other neuroleptics (e.g. phenothiazines, pimozide and sertindole), certain antihistamines (such as terfenadine), cisapride, bretylium and certain antimalarials such as quinine and mefloquine. This list is not comprehensive.

Concurrent use of drugs causing electrolyte imbalance may increase the risk of ventricular arrhythmias and is not recommended (see section 4.4-Special Warnings and Precautions for Use). Diuretics, in particular those causing hypokalaemia, should be avoided but, if necessary, potassium-sparing diuretics are preferred.

Haloperidol is metabolised by several routes, including glucuronidation and the cytochrome P450 enzyme system (particularly CYP 3A4 or CYP 2D6). Inhibition of these routes of metabolism by another drug or a decrease in CYP 2D6 enzyme activity may result in increased haloperidol concentrations and an increased risk of adverse events, including QT-prolongation. In pharmacokinetic studies, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with drugs characterised as substrates or inhibitors of CYP 3A4 or CYP 2D6 isozymes, such as, itraconazole, buspirone, venlafaxine, alprazolam, fluvoxamine, quinidine, fluoxetine, sertraline, chlorpromazine, and promethazine. A decrease in CYP2D6 enzyme activity may result in increased haloperidol concentrations. Increases in QTc and extrapyramidal symptoms have been observed when haloperidol was given with a combination of the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day). It may be necessary to reduce the haloperidol dosage.

Effect of Other Drugs on Haloperidol

When prolonged treatment with enzyme-inducing drugs such as carbamazepine, phenobarbital, rifampicin is added to Haldol therapy, this results in a significant reduction of haloperidol plasma levels. Therefore, during combination treatment, the Haldol dose should be adjusted, when necessary. After stopping such drugs, it may be necessary to reduce the dosage of Haldol.

Sodium valproate, a drug known to inhibit glucuronidation, does not affect haloperidol plasma concentrations.

Effect of Haloperidol on Other Drugs

In common with all neuroleptics, Haldol can increase the central nervous system depression produced by other CNS-depressant drugs, including alcohol, hypnotics, sedatives or strong analgesics. An enhanced CNS effect, when combined with methyldopa, has also been reported.

Haldol may antagonise the action of adrenaline and other sympathomimetic agents and reverse the blood-pressure-lowering effects of adrenergic-blocking agents such as guanethidine.

Haldol may impair the antiparkinson effects of levodopa.

Haloperidol is an inhibitor of CYP 2D6. Haldol inhibits the metabolism of tricyclic antidepressants, thereby increasing plasma levels of these drugs.

Other Forms of Interaction

In rare cases, an encephalopathy-like syndrome has been reported in combination with lithium and haloperidol. It remains controversial whether these cases represent a distinct clinical entity or whether they are in fact cases of NMS and/or lithium toxicity. Signs of encephalopathy-like syndrome include confusion, disorientation, headache, disturbances of balance and drowsiness. One report showing symptomless EEG abnormalities on the combination has suggested that EEG monitoring might be advisable. When lithium and haloperidol therapy are used concomitantly, haloperidol should be given in the lowest effective dose and lithium levels should be monitored and kept below 1 mmol/l. If symptoms of encephalopathy-like syndrome occur, therapy should be stopped immediately.

Antagonism of the effect of the anticoagulant phenindione has been reported.

The dosage of anticonvulsants may need to be increased to take account of the lowered seizure threshold.

4.6 Pregnancy And Lactation

The safety of haloperidol in pregnancy has not been established. There is some evidence of harmful effects in some but not all animal studies. Neonates exposed to antipsychotic drugs (including haloperidol) during the third trimester of pregnancy are at risk of adverse effects including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

There have been a number of reports of birth defects following foetal exposure to haloperidol for which a causal role for haloperidol cannot be excluded.. Haldol should be used during pregnancy only if the anticipated benefit outweighs the risk and the administered dose and duration of treatment should be as low and as short as possible.

Haloperidol is excreted in breast milk. There have been isolated cases of extrapyramidal symptoms in breast-fed children. If the use of Haldol is essential, the benefits of breast feeding should be balanced against its potential risks.

4.7 Effects On Ability To Drive And Use Machines

Some degree of sedation or impairment of alertness may occur, particularly with higher doses and at the start of treatment, and may be potentiated by alcohol or other CNS depressants. Patients should be advised not to undertake activities requiring alertness such as driving or operating machinery during treatment, until their susceptibility is known.

4.8 Undesirable Effects

The data provided below covers all haloperidol formulations including the Haldol Decanoate formulations.

The safety of Haldol was evaluated in 284 haloperidol-treated subjects who participated in 3 placebo-controlled, and in 1295 haloperidol-treated subjects who participated in sixteen double-blind active comparator-controlled clinical trials. The safety of Haldol decanoate was evaluated in 410 subjects who participated in 3 comparator trials (one comparing haloperidol vs. fluphenazine and two comparing the decanoate formulation to the oral formulation), 9 open label trials and 1 dose responsive trial. Based on pooled safety data from these clinical trials, the most commonly reported (% incidence) Adverse Drug Reactions (ADRs) were: Extrapyramidal disorder (34), Insomnia (19), Agitation (15), Hyperkinesia (13), Headache (12), Psychotic disorder (9), Depression (8), Weight increased (8), Orthostatic hypotension (7) and Somnolence (5).

Including the above mentioned ADRs, the following ADRs have been observed from clinical trials and post-marketing experiences reported with the use of Haldol and Haldol decanoate. Frequencies displayed use the following convention:

Very common (

System Organ Class	Adverse Drug Reactions
Frequency Category
Very Common (	Common (	Uncommon (	Rare (	Not Known
Blood and lymphatic System Disorders			Leukopenia		Agranulocytosis; Neutropenia; Pancytopenia; Thrombocytopenia
Immune System Disorders			Hypersensitivity		Anaphylactic reaction
Endocrine Disorders				Hyperprolactinaemia	Inappropriate antidiuretic hormone secretion
Metabolic and Nutritional Disorders					Hypoglycaemia
Psychiatric Disorders	Agitation; Insomnia	Depression; Psychotic disorder	Confusional state; Libido Decreased; Loss of libido; Restlessness
Nervous System Disorders	Extrapyramidal disorder; Hyperkinesia; Headache	Tardive dyskinesia; Oculogyric Crisis; Dystonia; Dyskinesia; Akathisia; Bradykinesia; Hypokinesia; Hypertonia; Somnolence; Masked Facies, Tremor; Dizziness	Convulsion; Parkinsonism; Akinesia; Cogwheel rigidity; Sedation; Muscle Contractions Involuntary	Motor dysfunction; Neuroleptic malignant syndrome; Nystagmus;
Eye Disorders		Visual disturbance;	Vision blurred
Cardiac Disorders			Tachycardia		Ventricular Fibrillation; Torsade de pointes; Ventricular Tachycardia; Extrasystoles
Vascular Disorders		Orthostatic Hypotension; Hypotension
Respiratory, thoracic and mediastinal Disorders			Dyspnoea	Bronchospasm	Laryngeal Oedema; Laryngospasm
Gastrointestinal Disorders		Constipation; Dry mouth; Salivary hypersecretion; Nausea; Vomiting
Hepatobiliary Disorders		Liver function test abnormal	Hepatitis; Jaundice		Acute Hepatic Failure; Cholestasis
Skin and subcutaneous tissue disorders		Rash	Photosensitivity Reaction; Urticaria; Pruritis; Hyperhidrosis		Leukocytoclastic Vasculitis; Dermatitis Exfoliative
Musculoskeletal and Connective Tissue Disorders			Torticollis; Muscle rigidity; Muscle Spasms; Musculoskeletal stiffness	Trismus; Muscle Twitching
Renal and Urinary Disorders		Urinary retention
Pregnancy, Puerperium and Perinatal Conditions					Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive System and Breast Disorders		Erectile dysfunction	Amenorrhoea; Dysmenorrhoea; Galactorrhoea; Breast Discomfort; Breast Pain;	Menorrhagia; Menstrual Disorder; Sexual Dysfunction	Gynaecomastia, Priapism
General Disorders and Administration Site Conditions			Gait disturbance; Hyperthermia; Oedema		Sudden Death; Face Oedema; Hypothermia
Investigations		Weight increased; Weight decreased		Electrocardiogram QT prolonged

Additional Information

Cardiac effects such as QT-interval prolongation, torsade de pointes, ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia), and cardiac arrest have been reported. These effects may occur more frequently with high doses, and in predisposed patients.

Toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported in patients taking haloperidol. The true incidence of these reports is not known.

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs- Frequency unknown.

4.9 Overdose

Symptoms:

In general, the manifestations of haloperidol overdosage are an extension of its pharmacological actions. The most prominent of which would be severe extrapyramidal symptoms, hypotension and psychic indifference with a transition to sleep. The risk of ventricular arrhythmias possibly associated with QT-prolongation should be considered. The patient may appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. Paradoxically hypertension rather than hypotension may occur. Convulsions may also occur.

Treatment:

There is no specific antidote to haloperidol. A patent airway should be established and maintained with mechanically assisted ventilation if necessary. In view of isolated reports of arrhythmia ECG monitoring is strongly advised. Hypotension and circulatory collapse should be treated by plasma volume expansion and other appropriate measures. Adrenaline should not be used. The patient should be monitored carefully for 24 hours or longer, body temperature and adequate fluid intake should be maintained.

In cases of severe extrapyramidal symptoms, appropriate anti-Parkinson medication should be administered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Haloperidol acts as a central dopamine receptor antagonist. It also has some anticholinergic activity and binds to opiate receptors. It also acts at peripheral dopamine receptors.

5.2 Pharmacokinetic Properties

Haloperidol is absorbed rapidly with a bioavailability of 38-86% (mean 58%) after oral solution. Variable bioavailability is likely to be due to interindividual differences in gastro-intestinal absorption and extent of first-pass metabolism.

Haloperidol is rapidly distributed to extravascular tissues especially liver and adipose tissue. It is approximately 92% bound to plasma proteins.

Haloperidol is extensively metabolised by oxidative dealkylation and ultimately conjugated with glycine. Half-life is approximately 20 hours.

5.3 Preclinical Safety Data

Only limited data are available, however these show no specific hazards apart from decreased fertility, limited teratogenicity as well as embryo-toxic effects in rodents.

Haloperidol has been shown to block the cardiac hERG channel in several published studies in vitro. In a number of in vivo studies intravenous administration of haloperidol in some animal models has caused significant QTc prolongation, at doses around 0.3 mg/kg i.v., giving C_max plasma levels 3 to 7 times higher than the effective human plasma concentrations of 4 to 20 ng/ml. These intravenous doses which prolonged QTc did not cause arrhythmias. In some studies higher intravenous doses of 1 to 5 mg/kg haloperidol i.v. caused QTc prolongation and/or ventricular arrhythmias at C_max plasma levels 19 to 68 times higher than the effective human plasma concentrations.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactic acid

Methyl parahydroxybenzoate

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

Do not refrigerate or freeze

6.5 Nature And Contents Of Container

Bottle:

Amber glass (Type III, Ph.Eur); 100 ml

Closure:

Aluminium screw-cap, tamper resistant, coated on the inner side with polyvinylchloride.

OR

Child resistant, polypropylene screw-cap with low density polyethylene insert.

Dosing Device:

A blunt ended 2.5ml plastic dosing pipette with minor graduations of 0.25ml

6.6 Special Precautions For Disposal And Other Handling

Fig. 1: The 100 ml amber glass bottle comes with a child-resistant cap, and should be opened as follows: - Push the plastic screw cap down while turning it counter clockwise. - Remove the unscrewed cap. Fig. 2: Insert the pipette into the bottle. While holding the bottom ring, pull the top ring up to the mark that corresponds to the number of millilitres or milligrams you need to give. Fig. 3: Holding the bottom ring, remove the entire pipette from the bottle. Empty the pipette into a cup by sliding the upper ring down and drink it immediately. Close the bottle. Rinse the pipette with some water for future use.

7. Marketing Authorisation Holder

Janssen-Cilag Limited

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8. Marketing Authorisation Number(S)

PL 00242/0035R

9. Date Of First Authorisation/Renewal Of The Authorisation

7 June 1989/30 March 2005

10. Date Of Revision Of The Text

16 Nov 2011

LEGAL CATEGORY

POM