Humulin Vials, Cartridges and Pens

1. Name Of The Medicinal Product

HUMULIN* S (Soluble) 100IU/ml solution for injection in vial

HUMULIN S (Soluble) 100IU/ml solution for injection in cartridge

HUMULIN I (Isophane) 100IU/ml suspension for injection in vial

HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge

HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection

HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in vial

HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge

HUMULIN M3 KwikPen (Mixture 3) 100IU/ml suspension for injection

2. Qualitative And Quantitative Composition

1ml contains 100IU human insulin (produced in E. coli by recombinant DNA technology).

HUMULIN S:	One vial contains 10ml equivalent to 1000IU of soluble insulin. One cartridge contains 3ml equivalent to 300IU of soluble insulin.
HUMULIN I:	One vial contains 10ml equivalent to 1000IU of isophane insulin. One cartridge contains 3ml equivalent to 300IU of isophane insulin.
HUMULIN I KwikPen:	One pre-filled pen contains 3ml equivalent to 300IU of isophane insulin.
HUMULIN M3:	One vial contains 10ml equivalent to 1000IU of biphasic isophane insulin - 30% soluble insulin/70% isophane insulin. One cartridge contains 3ml equivalent to 300IU of biphasic isophane insulin - 30% soluble insulin/70% isophane insulin.
HUMULIN M3 KwikPen:	One pre-filled pen contains 3ml equivalent to 300IU of biphasic isophane insulin - 30% soluble insulin/70% isophane insulin.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

HUMULIN S: A solution for injection in a cartridge or vial. HUMULIN S is a sterile, clear, colourless, aqueous solution of human insulin.

HUMULIN I: A suspension for injection in a cartridge, vial or pre-filled pen. HUMULIN I is a sterile suspension of a white, crystalline precipitate of isophane human insulin in an isotonic phosphate buffer.

HUMULIN M3: A suspension for injection in a cartridge, vial or pre-filled pen. HUMULIN M3 is a sterile suspension of human insulin in the proportion of 30% soluble insulin to 70% isophane insulin.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of patients with diabetes mellitus who require insulin for the maintenance of glucose homeostasis.

4.2 Posology And Method Of Administration

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

HUMULIN S should be given by subcutaneous injection but may, although not recommended, also be given by intramuscular injection. It may also be administered intravenously.

HUMULIN I and HUMULIN M3 should be given by subcutaneous injection but may, although not recommended, also be given by intramuscular injection. This formulation should not be administered intravenously.

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.

Care should be taken when injecting any HUMULIN insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques.

HUMULIN I (Isophane) may be administered in combination with HUMULIN S (Soluble). (See 'Instructions for use and handling' for 'Mixing of insulins'.)

HUMULIN Mixture formulation is a ready-made defined mixture of soluble and isophane insulin designed to avoid the need for the patient to mix insulin preparations. A patient's treatment regimen should be based on their individual metabolic requirements.

Each pack contains a patient information leaflet with instructions on how to inject insulin.

4.3 Contraindications

Hypoglycaemia.

Hypersensitivity to HUMULIN or to the formulation excipients, unless used as part of a desensitisation programme.

Under no circumstances should any HUMULIN formulation, other than HUMULIN S (Soluble), be given intravenously.

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, mixture), 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.

Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months.

A few patients who experienced hypoglycaemic reactions after transfer to human insulin have reported that the early warning symptoms were less pronounced or different from those experienced with their previous animal insulin. Patients whose blood glucose is greatly improved, e.g., by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycaemia and should be advised accordingly. Other conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, diabetic nerve disease, or medications such as beta-blockers. Uncorrected hypoglycaemic and 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.

Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin.

Insulin requirements may change significantly in diseases of the adrenal, pituitary, or thyroid glands, and in the presence of renal or hepatic impairment.

Insulin requirements may be increased during illness or emotional disturbances.

Adjustment of insulin dosage may also be necessary if patients change their level of physical activity or change their usual diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Some medicinal products are known to interact with glucose metabolism. The physician should take possible interactions into account and ask patients about their other medications in addition to human insulin.

Insulin requirements may be increased by substances with hyperglycaemic activity, such as glucocorticoids, thyroid hormones, growth hormone, danazol, beta₂-sympatomimetics (such as ritodrine, salbutamol, terbutaline), thiazides.

Insulin requirements may be reduced in the presence of substances with hypoglycaemic activity, such as oral hypoglycaemics (OHA), salicylates (for example, acetylsalicylic acid), certain antidepressants (monoamine oxidase inhibitors), certain angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril), angiotensin II receptor blockers, non-selective beta-blocking agents, and alcohol.

Somatostatin analogues (octreotide, lanreotide) may both decrease or increase insulin dose requirements.

4.6 Pregnancy And Lactation

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 doctors 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 lactating may require adjustments in insulin dose and/or diet.

4.7 Effects On Ability To Drive And Use Machines

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g., driving a car or operating machinery).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving; this is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.

4.8 Undesirable Effects

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, local reactions may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique.

Systemic allergy, which is very rare (<1/10,000) but potentially more serious, is a generalised allergy to insulin. It may cause 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. In the rare event of a severe allergy to HUMULIN, treatment is required immediately. A change of insulin or desensitisation may be required.

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

4.9 Overdose

Insulin has 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 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 sugar 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 occur after apparent clinical recovery.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmaco-therapeutic group:

HUMULIN S: ATC code, A10A B01

HUMULIN I: ATC code, A10A C01

HUMULIN M3: ATC code, A10A D01

HUMULIN S is a rapidly-acting insulin preparation.

HUMULIN I is an intermediate-acting insulin preparation.

HUMULIN M3 (Mixture 3) is an intermediate-acting insulin preparation.

The prime activity of insulin is the regulation of glucose metabolism.

In addition, insulin has 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.

The typical activity profile (glucose utilisation curve) following subcutaneous injection is illustrated below by the heavy line. Variations that a patient may experience in timing and/or intensity of insulin activity are illustrated by the shaded area. Individual variability will depend on factors such as size of dose, site of injection temperature and physical activity of the patient.

5.2 Pharmacokinetic Properties

The pharmacokinetics of insulin do not reflect the metabolic action of that hormone. Therefore, it is more appropriate to examine glucose utilisation curves (as discussed above) when considering the activity of insulin.

5.3 Preclinical Safety Data

HUMULIN is human insulin produced by recombinant technology. No serious events have been reported in subchronic toxicology studies. Human insulin was not mutagenic in a series of in vitro and in vivo genetic toxicity assays.

6. Pharmaceutical Particulars

6.1 List Of Excipients

For HUMULIN S preparations:

m-cresol

Glycerol

Water for injections

The following may be used to adjust pH:

Hydrochloric acid and/or

Sodium hydroxide

For HUMULIN I and HUMULIN M3 preparations:

m-cresol

Glycerol

Phenol

Protamine sulphate

Dibasic sodium phosphate 7H₂O

Zinc oxide

Water for injections

The following may be used to adjust pH:

Hydrochloric acid and/or

Sodium hydroxide

6.2 Incompatibilities

HUMULIN preparations should not be mixed with insulins produced by other manufacturers or with animal insulin preparations.

6.3 Shelf Life

Vials: The shelf-life for HUMULIN S, HUMULIN I and HUMULIN M3 presentations is two years.

Once in use the vials may be used for up to 28 days. Do not use beyond this period. When in use the vials should not be stored above 30°C.

Cartridges: The shelf-life for the HUMULIN S presentation is two years. The shelf-life for HUMULIN I and HUMULIN M3 presentations is 3 years.

After insertion of the cartridge in the pen, the solution or suspension should be used in 28 days. Do not use beyond this period. When in use the cartridges should not be stored above 30°C.

Pre-filled pens: The shelf-life for HUMULIN I- and M3 KwikPen presentations is 3 years.

Once in use HUMULIN I- and M3 KwikPen may be used for up to 28 days. Do not use beyond this period. When in use HUMULIN I- and M3 KwikPen should not be stored above 30°C.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C-8°C).

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

Keep the container in the outer carton.

6.5 Nature And Contents Of Container

Vials: 10ml of solution or suspension in a vial (Type I glass) with a stopper (rubber) sealed with a seal (aluminium) combined with a flip top (plastic).

Pack size 1 or 2.

Cartridges: 3ml solution or suspension in a cartridge (Type I glass) with a plunger head at the bottom (rubber) and disc seal at the top (rubber).

Pack size of 5.

Pre-filled pens: 3ml suspension in a cartridge (Type I glass) with a plunger head at the bottom (rubber) and disc seal at the top (rubber) in a pre-filled pen.

HUMULIN I- and M3 KwikPen: Pack size of 5, or 2 x 5 x 3ml.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Do not reuse needles. Dispose of the needle in a responsible manner. Needles and pens must not be shared. Vials, cartridges and HUMULIN I- and M3 KwikPen can be used until empty, then properly discard. Any unused product or waste material should be disposed of in accordance with local requirements.

Instructions for use and handling

A Vials

A solution or suspension for injection in a 10ml vial to be used in conjunction with an appropriate syringe (100 IU/ml markings).

B Cartridges

A solution or suspension for injection in a 3ml cartridge to be used with a CE marked pen as recommended in the information provided by the device manufacturer.

C Pre-filled pens

A suspension for injection in a pre-filled /disposable pen injector containing a 3ml cartridge. HUMULIN I- and M3 KwikPen delivers up to 60 units per dose in single unit increments.

a) Preparing a dose

Vials or cartridges containing HUMULIN S formulation do not require resuspension and should only be used if it is clear, colourless, with no solid particles visible and if it is of water-like appearance.

Vials containing HUMULIN I or the HUMULIN M3 formulations should be rotated several times in the palms of the hands before use to completely resuspend the insulin, until it appears uniformly cloudy or milky. Cartridges and pre-filled pens containing HUMULIN I and HUMULIN M3 formulations should be rolled in the palms of the hands ten times and inverted 180° ten times immediately before use to resuspend the insulin until it appears uniformly cloudy or milky. If not, repeat the above procedure until contents are mixed. Cartridges contain a small glass bead to assist mixing. Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose.

The vials, cartridges, and pre-filled pens should be examined frequently and should not be used if clumps of material are present or if solid white particles stick to the bottom or wall of the vial or cartridge, giving a frosted appearance.

HUMULIN S and I Vials: Mixing of insulins - The shorter-acting insulin should be drawn into the syringe first, to prevent contamination of the vial by the longer-acting preparation. It is advisable to inject directly after mixing. However, if a delay is necessary, a consistent routine must be followed.

Alternatively, a separate syringe or, separate cartridges of HUMULIN S and I, can be used for administration of the correct amount of each formulation.

Vials:

Prepare your syringe prior to injection, as directed by your doctor or diabetes specialist nurse.

Use an insulin syringe marked for the strength of insulin being administered.

Cartridges and pre-filled pens:

The cartridges are not designed to allow any other insulin to be mixed in the cartridge. Cartridges are not designed to be refilled.

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

Follow the instructions with HUMULIN I- and M3 KwikPen for attaching the needle and administering the insulin injection.

For HUMULIN I- and M3 KwikPen, a needle must always be attached before priming, dialling, and injecting an insulin dose. HUMULIN I- and M3 KwikPen should always be primed before each injection. Failure to prime HUMULIN I- and M3 KwikPen may result in an inaccurate dose.

b) Injecting a dose

Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse.

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

Each pack contains a patient information leaflet with instructions on how to inject insulin.

7. Marketing Authorisation Holder

Eli Lilly and Company Limited

Lilly House

Priestley Road

Basingstoke

Hampshire, RG24 9NL

8. Marketing Authorisation Number(S)

HUMULIN S vial:	PL 00006/0216
HUMULIN I vial:	PL 00006/0228
HUMULIN M3 vial:	PL 00006/0233
HUMULIN S cartridge:	PL 00006/0242
HUMULIN I cartridge:	PL 00006/0257
HUMULIN M3 cartridge:	PL 00006/0260
HUMULIN I KwikPen:	PL 00006/0338
HUMULIN M3 KwikPen:	PL 00006/0341

9. Date Of First Authorisation/Renewal Of The Authorisation

HUMULIN S vial:	Date of first authorisation: Date of last renewal:	16 February 1987 24 April 2006
HUMULIN I vial:	Date of first authorisation: Date of last renewal:	16 February 1987 24 April 2006
HUMULIN M3 vial:	Date of first authorisation: Date of last renewal:	28 April 1987 24 April 2006
HUMULIN S cartridge:	Date of first authorisation: Date of last renewal:	23 November 1990 24 April 2006
HUMULIN I cartridge:	Date of first authorisation: Date of last renewal:	23 November 1990 24 April 2006
HUMULIN M3 cartridge:	Date of first authorisation: Date of last renewal:	16 November 1990 24 April 2006
HUMULIN I KwikPen:	Date of first authorisation: Date of last renewal:	19 September 1997 24 April 2006
HUMULIN M3 KwikPen:	Date of first authorisation: Date of last renewal:	19 September 1997 24 April 2006

10. Date Of Revision Of The Text

02 June 2010

LEGAL CATEGORY

POM

HUMULIN* (human insulin [prb]) is a trademark of Eli Lilly and Company. HU29M

EpiPen Auto-Injector 0.3mg

EpiPen
Auto-Injector 0.3 mg Adrenaline

Read all of this leaflet carefully before you start using this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What EpiPen is and what it is used for


• 2. Before you use EpiPen


• 3. How to use EpiPen


• 4. Possible side effects


• 5. How to store EpiPen


• 6. Further information

What EpiPen is and what it is used for

EpiPen contains a sterile solution for emergency injection into the muscle (intramuscular injection).

EpiPen is to be used for the emergency treatment of sudden life threatening allergic reactions (anaphylactic shock) to insect stings or bites, foods or drugs or exercise. The reaction is the result of the body trying to protect itself from the allergen (the foreign substance that causes the allergy) by releasing chemicals into the blood stream. Sometimes the cause of the allergic reaction is not known.

Symptoms that signal the onset of an anaphylactic shock occur within minutes of exposure to the allergen and include: itching of the skin; raised rash (like a nettle rash); flushing; swelling of the lips, throat, tongue, hands and feet; wheezing; hoarseness; shortness of breath; nausea; vomiting; stomach cramps and in some cases, loss of consciousness.

The medicine in the Auto-injector (the pen) is adrenaline which is an adrenergic drug.

It works directly on the cardiovascular (heart and circulation) system and respiratory (lung) system, to stop the possible fatal effects of anaphylactic shock by very quickly making the blood vessels smaller, relaxing muscles in the lungs to improve breathing, reducing swelling and stimulating heartbeat.

The EpiPen is intended for immediate self administration by a person with a history or recognised risk of going into anaphylactic shock. If you are at risk, you should always keep your EpiPen with you. It is designed as an emergency rescue therapy but you must get medical attention as soon as possible after its use.

Before you use EpiPen

There is no known reason why anyone should not use EpiPen during an allergic emergency.

Take special care with EpiPen

Adrenaline is essential for the treatment of anaphylaxis. However, take special care with EpiPen

• particularly if you have heart disease as it may affect the medicines that you are taking and may bring on an attack of chest pain (angina)


• if you have an overactive thyroid


• if you have high blood pressure


• if you have diabetes


• if you are elderly, pregnant or the child weighs less than 30 kg (4 stone 9lbs)

as there is a greater risk of getting side effects.

Make sure you have discussed this with your doctor if any of these apply to you.

Patients with these conditions, or anyone who may be in the position to administer EpiPen to a patient having an allergic reaction, should be properly instructed on how and when to give it.

The instructions for use must be carefully followed in order to avoid accidental injection.

EpiPen should only be injected into the outer thigh. It should not be injected into the buttock due to the risk of accidental injection into a vein.

Warning

Accidental injection into the hands or fingers may result in reduced blood supply to these areas. If there is an accidental injection into these areas, you should go immediately to the nearest hospital casualty department for treatment.

Taking other medicines

When being prescribed EpiPen, please tell your doctor or pharmacist if you are taking, or have recently taken, any other medicines, including medicines obtained without a prescription as they may affect how the adrenaline works.

This is especially important if you take any of the following:

• Antidepressants such as tricyclic antidepressants or monoamine oxidase inhibitors (MAO inhibitors), since the effects of adrenaline may be increased.


• Medicines that may make the heart sensitive to uneven beats (arrhythmias), such as digitalis, mercurial diuretics or quinidine.

Diabetic patients should carefully monitor their glucose levels after use of EpiPen as adrenaline can reduce the amount of insulin made by the body, thus increasing the blood glucose level.

Pregnancy

Ask your doctor or pharmacist for advice before taking any medicine.

There is limited experience of the use of adrenaline during pregnancy. If you are pregnant, do not hesitate to use EpiPen in an emergency, since your and your baby’s lives may be in danger. Discuss this with your doctor if you are pregnant.

Driving and using machines

The ability to drive and use machines is unlikely to be affected by the administration of an adrenaline injection, but may be affected by an anaphylactic reaction. If affected, do not drive.

Important information about some of the ingredients of EpiPen

EpiPen contains sodium metabisulphite, which may rarely cause severe allergic reactions (hypersensitivity) or breathing difficulty (bronchospasm). However, you should still use the EpiPen as there are no satisfactory alternatives.

How to use EpiPen

When your doctor prescribes EpiPen, you must make sure you understand the reason it has been prescribed for you. You should be confident that you know exactly how and when to use it. Always use EpiPen exactly as your doctor has told you. If you are at all unsure about how to use it, ask to have the instructions repeated by your doctor, nurse or pharmacist.

If you have been stung by an insect, try to remove the stinger with your fingernails – do not squeeze, pinch or push it deeper into the skin. If possible, put an ice pack on the area of the sting. Keep warm and avoid exercise. For allergic reactions caused by foods make sure you remove any remaining food from the mouth immediately.

EpiPen is intended to be used by people with a body weight above 30Kg. For persons weighing less than 30 kg (4 stone 9lbs), EpiPen Jr. may be more appropriate for use.

Dosage

The dose will be decided by your doctor, who will adjust it individually for you. The usual adult dose for allergic emergencies is 0.3 mg adrenaline for injection into the muscle (intramuscular use).

If you notice the signs of an acute allergic reaction, use EpiPen immediately, through your clothing if necessary.

Each EpiPen Auto-injector delivers one single dose of 0.3 ml liquid which is equal to 0.3 mg (300 micrograms) adrenaline. After use a volume of 1.7 ml will remain in the Auto-injector but this cannot be reused.

Sometimes a single dose of adrenaline may not be sufficient to completely reverse the effects of an allergic reaction. For this reason, your doctor may prescribe more than one EpiPen for you. Repeated injections may be administered after 5-15 minutes if the symptoms are still there and the doctor has told you that you can do this. For this reason it may be a good idea to carry more than one EpiPen with you at all times.

Method of administration

The EpiPen is designed to be used easily by people without medical training. EpiPen should simply be jabbed firmly against the outer portion of the thigh from a distance of approximately 10 cm (4 inches). There is no need for precise placement in the outer portion of the thigh. When you jab the EpiPen firmly into your thigh, a spring activated plunger will be released, which pushes the hidden needle into the thigh muscle and administers a dose of adrenaline. If you are wearing clothes the EpiPen can be injected through the clothes.

The instructions for use of the EpiPen given below must be carefully followed.

EpiPen should only be injected into the outer thigh. It should not be injected into the buttock (your bottom).

Directions for use

Before you ever need to use it, fully familiarise yourself with the EpiPen, when and how it should be used (refer to diagram 1).

Follow these directions only when ready to use.

Hold the EpiPen by the middle, never by the ends.

For proper administration, look at the diagrams and follow these steps:

• Never put thumb, fingers or hand over the black tip.


• Do not remove grey safety cap until ready to use.

Diagram 1

• 1. Grasp EpiPen in dominant hand (the hand you use to write), with thumb nearest grey cap and form fist around unit (black tip down).


• 2. With other hand pull off grey safety cap.


• 3. Hold the EpiPen at a distance of approximately 10 cm (4 inches) away from the outer thigh, as shown in diagram 2a. The black tip should point towards the outer thigh.


• 4. Jab the EpiPen firmly into outer thigh at a right angle (90 degree angle) as shown in diagram 2b. (listen for click)


• 5. Hold firmly in thigh for 10 seconds. EpiPen should be removed and safely discarded.


• 6. Massage the injection area for 10 seconds.

Diagram 2

A small air bubble may be present in the EpiPen Auto-injector. It does not affect the way the product works.

Even though most of the liquid (about 90%) remains in the EpiPen after use, it cannot be reused. After use, place the EpiPen safely in the tube provided and bring it with you when you visit your doctor, hospital or pharmacy.

As the EpiPen is designed as emergency treatment only, you should always seek medical help immediately after using EpiPen, by reporting to your doctor, nearest hospital or by calling an ambulance. Make sure that you inform the healthcare professional that you have received an intramuscular injection of adrenaline or show them the container and/or leaflet.

If you use more EpiPen than you should

In case of overdose or accidental injection of the adrenaline, you should always seek immediate medical help. Your blood pressure may rise sharply and it will need to be monitored.

Possible side effects

Like all medicines EpiPen can cause side effects, although not everybody gets them.

Usual side effects include: irregular heartbeat (including palpitations and rapid heartbeats), high blood pressure, sweating, nausea, vomiting, difficulty breathing, paleness, headache, dizziness, weakness, tremor and apprehension, nervousness or anxiety.

Accidental injection of the pens in hands or fingers have been reported and may result in lack of blood supply to these areas. In case of accidental injection, always seek immediate medical help.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store EpiPen

Keep out of the reach and sight of children.

Do not use EpiPen after the expiry date which is stated on the label.

Do not store above 25°C. Do not refrigerate or freeze.

Keep container in the outer carton in order to protect from light. When exposed to air or light, adrenaline deteriorates rapidly and will become pink or brown. Please remember to check the contents of the glass cartridge in the EpiPen Auto-injector from time to time to make sure the liquid is still clear and colourless. Replace the Auto-injector by the expiry date or earlier if the solution is discoloured or contains a precipitate (solid particles).

Medicines should not be disposed of via drains or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. See also section 3 - Directions for use.

Further information

What EpiPen contains

The active substance is adrenaline 0.3 mg (300 microgram).

The other ingredients are: Sodium Chloride, Sodium Metabisulphite, Hydrochloric Acid, Water for Injections.

What EpiPen looks like and contents of the pack

Clear and colourless solution in a pre-filled pen (Auto-injector).

The Auto-injector (single-dose) contains 2 ml solution for injection.

Marketing Authorisation Holder and Manufacturer

Marketing authorisation holder:

ALK-Abelló A/S

Bøge Allé 6-8

2970 Hørsholm

Denmark

Manufacturer:

Meridian Medical Techn. Inc.

St. Louis

USA

Distributor:

ALK-Abelló Ltd.

1 Tealgate

Hungerford

Berkshire

RG17 0YT

UK

This leaflet was last approved on May 2009.

For information in large print, tape, CD or Braille, telephone 01488 686016

EpiPen
Expiry Date Alert Service

It is important that your EpiPen should be replaced before the expiry date marked on the label. For your safety and convenience, ALK-Abelló offers all patients prescribed EpiPen an Expiry Date Alert Service. We will contact you by mail to remind you when you need to replace your EpiPen. Please fill in the form below and return it to:

ALK-Abelló Ltd.

Freepost (RG3630)

Hungerford

Berkshire

RG17 0YT

UK

EpiPen
Expiry Date Alert Form

Please print clearly in capital letters.

Lot No.:

(see label)

Your Full Name:

Your Mailing Address:

Postal Code:

Please remember to inform us if you change address.

Expiry Date:

(see label)

Your Doctor’s Name:

Your Doctor’s Address:

Postal Code:

Tel No.:

1039913

Ipratropium Bromide

Class: Antimuscarinics/Antispasmodics
Molecular Formula: C₂₀H₃₀BrNO₃•H₂O
CAS Number: 66985-17- 9
Brands: Atrovent, Combivent, DuoNeb

Introduction

Bronchodilator; a nonselective, competitive antagonist at muscarinic receptors.^{2 224 225 232}

Uses for Ipratropium Bromide

Bronchospasm in COPD

Long-term treatment of reversible bronchospasm associated with COPD,^{1 2 4 58 76 114 115 118 120 121 122 123 124 127 128 130 228 230 244 245 253 254 255 256 257 258 259 260 261 262 263 267 278 281 285 292 293 294} including chronic bronchitis^{1 2 4 36 55 61 76 90 116 117 119 120 121 124 125 129 131 281} and emphysema.^{1 2 4 90 91 119 120 125 281 343 344 345 347}

Fixed combination with albuterol sulfate is used for the symptomatic management of bronchospasm associated with COPD in patients who continue to have evidence of bronchospasm despite the regular use of an orally inhaled bronchodilator and who require a second bronchodilator.^{320 347}

Bronchospasm in Asthma

Has been used for symptomatic treatment of acute or chronic bronchial asthma†;^{36 55 56 76 91 92 115 124 125 129 153 161 162 164 180 181 211 225 228 268 302 303 331 336 337} β₂-adrenergic agonist bronchodilators generally preferred initially for relief of bronchospasm in asthmatic patients.^{161 164 225 257 268 302 303 331 337}

May be useful as alternative therapy in adults experiencing adverse effects (e.g., tachycardia, arrhythmia, tremor) with a β-adrenergic agonist†.^{331 336 337}

Some clinicians consider ipratropium as adjunctive therapy in patients with moderate or severe exacerbations (peak expiratory flow rate ≤80% of predicted) of asthma† who fail to respond adequately to β-adrenergic agonists and corticosteroids.^{331 337}

May be useful for prevention or reversal of bronchospasm induced by β-adrenergic blocking agents† (e.g., propranolol) in asthmatic patients; β-adrenergic bronchodilators generally ineffective for this indication in such patients.^{31 191 194 225 268}

Ipratropium Bromide Dosage and Administration

Administration

Administer by oral inhalation using an oral aerosol inhaler^{1 10 320} or via nebulization.^{4 281 329}

Oral Inhalation via Metered-dose Aerosol

Ipratropium Bromide

Aerosol delivers ≥200 metered sprays per canister.¹

Patient should be instructed to clear excessive sputum from chest before inhalation.¹⁰

Shake well immediately prior to use.^{1 10 320} Actuate aerosol inhaler 3 times prior to the initial use or if it has not been used for >24 hours.¹

Do not use mouthpiece for other aerosol drugs.¹

Exhale slowly and completely and place the mouthpiece of the inhaler well into the mouth with the lips closed around it.^{10 348} To avoid contact of the drug with the eyes and subsequent adverse effects, close eyes during inhalation of aerosol.^{1 10 348} Inhale slowly and deeply through the mouth while actuating the inhaler.^{1 10} Hold the breath for 10 seconds, withdraw the mouthpiece, and exhale slowly.^{1 10}

Allow ≥15 seconds to elapse between subsequent inhalations from the aerosol inhaler.^{10 348}

Wash the mouthpiece in hot running water as needed.^{10 348} If soap is used, rinse mouthpiece thoroughly with plain water.^{10 348}

Ipratropium Bromide and Albuterol Sulfate

Aerosol delivers ≥200 metered sprays per canister.³⁴⁶

Shake well immediately prior to use.³⁴⁶ Actuate 3 times prior to the initial use or if it has not been used for >24 hours.³⁴⁶ Do not use actuator provided for other aerosol drugs.³⁴⁶ To avoid contact of the drug with the eyes and subsequent adverse effects, close eyes during inhalation of aerosol.³⁴⁶

Exhale deeply and place mouthpiece of the inhaler into the mouth.³⁴⁶ Inhale slowly and deeply through the mouth while actuating the inhaler.³⁴⁶ Hold the breath for 10 seconds, withdraw the mouthpiece, and exhale slowly.³⁴⁶ Allow approximately 2 minutes to elapse and repeat the procedure.³⁴⁶ Rinse the mouthpiece in hot water as needed.³⁴⁶ If soap is used, rinse the mouthpiece thoroughly with plain water.³⁴⁶ When dry, replace the cap on the mouthpiece when the inhaler is not in use.³⁴⁶

Oral Inhalation via Nebulization

Ipratropium Bromide

Empty entire contents of the single-use vial of solution into the nebulizer reservoir and attach reservoir to the mouthpiece or face mask and to the compressor according to the manufacturer’s instructions.^{4 328 350}

Use care when a face mask is used to avoid leakage since transient blurred vision and other adverse effects may result if the drug enters the eyes.^{2 225 250 275 328 350} (See Ocular Effects under Cautions.) Use of a mouthpiece may avoid inadvertent entry of drug into the eye.⁴

Place the mouthpiece of the nebulizer in the mouth or put on the nebulizer face mask.^{4 15 328} Breathe as calmly, deeply, and evenly as possible until the nebulizer stops producing mist.^{4 328}

Duration of treatment usually is about 5–15 minutes.^{4 328}

Ipratropium Bromide and Albuterol Sulfate

Empty entire contents of the single-use vial of solution into the nebulizer reservoir and attach reservoir to the mouthpiece or face mask and to the compressor according to the manufacturer’s instructions.³²⁸

Place the mouthpiece of the nebulizer in the mouth or put on the nebulizer face mask.³²⁸ Breathe as calmly, deeply, and evenly as possible until the nebulizer stops producing mist.³²⁸

Duration of treatment usually is about 5–15 minutes.³²⁸

Clean the nebulizer after use according to the manufacturer’s instructions.³²⁸

Dosage

Available as ipratropium bromide.

Dosage of oral inhalation aerosol expressed in terms of the monohydrate.^{1 320}

Dosage of inhalation solution for nebulization expressed in terms of anhydrous drug.^{4 329 330}

Using in vitro testing at an average flow rate of 3.6 L per minute for an average of ≤15 minutes, the Pari-LC Plus nebulizer delivered at the mouthpiece approximately 46 or 42% of the original dosage of albuterol or ipratropium bromide, respectively.³²⁷

Pediatric Patients

COPD

Inhalation

Patients ≥12 years of age: 36 mcg (2 inhalations) 4 times daily via a metered-dose aerosol, given alone or in fixed combination with albuterol (90 mcg via the mouthpiece).^{1 2 320} Additional inhalations should not exceed 216 mcg (12 inhalations) of ipratropium bromide in 24 hours.^{1 320}

Patients ≥12 years of age: 500 mcg (contents of 1 unit-dose vial) 3 or 4 times daily (i.e., every 6–8 hours) via a nebulizer.^{4 329}

Adults

COPD

Inhalation

Initially, 36 mcg (2 inhalations) 4 times daily via a metered-dose aerosol, given alone or in fixed combination with albuterol (90 mcg from the mouthpiece).^{1 2 320} Additional inhalations should not exceed 216 mcg (12 inhalations) in 24 hours.^{1 320}

Initially, 500 mcg 3 or 4 times daily (i.e., every 6–8 hours) via a nebulizer.^{4 329} With ipratropium bromide in fixed combination with albuterol sulfate (DuoNeb), 500 mcg 4 times daily.³²⁷ Additional inhalations should not exceed 6 inhalations daily.³²⁷

Prescribing Limits

Pediatric Patients

COPD

Inhalation

Maximum 216 mcg (12 inhalations via a metered-dose inhaler) in 24 hours.^{1 320}

Maximum 12 inhalations via metered-dose inhaler in 24 hours with the fixed combination of ipratropium bromide and albuterol sulfate.³²⁰

500 mcg 3–4 times daily via a nebulizer in patients ≥12 years of age.^{4 329}

Adults

COPD

Inhalation

Maximum 216 mcg (12 inhalations via a metered-dose inhaler) in 24 hours;^{1 320} frequency of administration should not exceed 4 times daily.^{1 267 323}

Maximum 12 inhalations via metered-dose inhaler in 24 hours with the fixed combination of ipratropium bromide and albuterol sulfate.³²⁰

500 mcg 3–4 times daily via a nebulizer.^{4 329}

Special Populations

Geriatric Patients

Dosage adjustments based solely on age are not necessary.^{1 4}

Cautions for Ipratropium Bromide

Contraindications

• 
  

  Known hypersensitivity to the drug or any other component of the formulation, or to atropine or its derivatives.^{1 4 329}

  
  


• 
  

  Known hypersensitivity to soya lecithin or related food products, including soybeans and peanuts.^{1 277 320}

  
  

Warnings/Precautions

Warnings

Acute Bronchospasm

Delayed onset of action; not indicated for initial treatment.^{1 4} Generally should not be used alone for the management of acute bronchospasm, when a rapid response is required.^{1 4 164 225}

Sensitivity Reactions

Immediate hypersensitivity reactions, including rash, angioedema of the tongue, lips, and face, urticaria, bronchospasm, oropharyngeal edema, and anaphylactic reaction.^{1 4 196 213 277 285 320 329}

Possible paradoxical bronchospasm.^{1 4 190 191 196 270 271 272 273 320}

General Precautions

Worsening COPD

Contact a clinician immediately if a previously effective dosage regimen fails to provide the usual relief (e.g., need to increase the dose or frequency of administration of the drug).¹ Do not increase the dose or frequency of inhalation without consultation with a clinician.¹

Ocular Effects

Possible temporary blurred vision,^{1 2 4 10 328 349} mydriasis,^{1 225 250 275} ocular pain,^{4 328 329 349} conjunctival or corneal congestion associated with visual halos or colored images,¹ or precipitation or worsening of angle-closure glaucoma^{4 173 329 337 349} following inadvertent contact of ipratropium with the eyes.^{4 190 191 328 349}

Minimize ocular exposure by using a mouthpiece rather than a face mask during administration via a nebulizer.^{4 190 191 329} During oral inhalation of aerosol, close eyes.^{1 2} Inhalation aerosol should not be administered using the open-mouth technique in these patients with angle-closure glaucoma.^{173 190 191} Use with caution in patients with angle-closure glaucoma.^{1 4}

Genitourinary Effects

Possible urinary retention/difficulty,^{1 4 251 252 320 329} urinary tract infection,^{4 320 329} or dysuria.^{4 320}

Use with caution in patients with bladder neck obstruction or prostatic hypertrophy.^{1 4 190 191 225 329}

Cardiovascular Effects

Possible adverse cardiovascular effects (e.g., tachycardia, palpitations, aggravated hypotension or hypertension).^{1 4 329}

Use of Fixed Combination

When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.

Specific Populations

Pregnancy

Category B.¹

Lactation

Use with caution.^{1 2 4 329}

Pediatric Use

Safety and efficacy of oral inhalation not established in children <12 years of age.^{1 4 320 329}

Hepatic Impairment

Use with caution.^{4 329}

Renal Impairment

Use with caution.^{4 329}

Common Adverse Effects

Bronchitis, upper respiratory tract infection,³²⁰ cough,^{1 2 4 87 120 285} and dryness of the mouth,^{1 2 14 16 60 90 120 127} throat,^{1 75 90} or tongue⁸⁷ with ipratropium aerosol. Adverse effects resulting in discontinuance of nebulized ipratropium most frequently include bronchitis, dyspnea, and bronchospasm.^{4 329}

Interactions for Ipratropium Bromide

Limited systemic absorption following oral inhalation; interactions with systemically administered drugs unlikely.^{2 190 191}

Specific Drugs

Drug	Interaction	Comments
Antimuscarinic agents	Potential pharmacodynamic interaction (additive effects)1 320	Caution advised with concomitant administration1
Methylxanthine derivatives	No adverse drug interactions reported115 120 121 132 157 158 149 187 220 261 305 329
β-Adrenergic agonists	Potential pharmacodynamic interaction (additive effects)4 6 133 147 152 155 225 228 246 248 260 262 278 279 285 287 288 289	If concomitant therapy is required, consider cautious use of cardioselective β-adrenergic blocking agents115 132 139 146 153 154 181 216
Corticosteroids	No adverse drug interactions reported91 115 119 120 121 124 132 153 154 160 329
Cromolyn sodium	No adverse drug interactions reported132 159

Ipratropium Bromide Pharmacokinetics

Absorption

Bioavailability

Only minimally absorbed into systemic circulation following oral inhalation.^{1 2 4 6 14 106 228 229 230}

Onset

Bronchodilation evident within 15 minutes following oral aerosol inhalation^{1 2 111 120 230} and within 15–30 minutes following oral inhalation via nebulization.^{4 86 281}

Duration

Bronchodilation generally persists for 3–4 hours following oral aerosol inhalation^{1 2 111 120 230} and for 4–5 hours following nebulization.^{4 86 281}

Distribution

Extent

Does not readily penetrate the CNS.^{2 4 12} It is not known whether the drug crosses the placenta or is distributed into milk.^{1 4 6}

Plasma Protein Binding

0–9%.^{1 4}

Elimination

Metabolism

Metabolized partially to at least 8 metabolites.^{4 8 106}

Elimination Route

Excreted principally in feces as unchanged drug.^{2 3 6 7 107 109} Following oral inhalation of radiolabeled ipratropium bromide, about 69 and 3.2% of the dose was excreted in feces and urine, respectively, within 6–7 days.^{6 106 109} Undergoes some biliary elimination.^{6 7}

Half-life

1.6 hours (t_½β with IV administration).^{4 190 229}

Stability

Storage

Oral Inhalation

15–30 °C (metered-dose inhalers or inhalation solution of ipratropium bromide).^{1 3 4 281 320}

2–25°C (oral inhalation solution of ipratropium bromide in fixed combination with albuterol sulfate); protect from light.^{327 328}

ActionsActions

• 
  

  A nonselective competitive antagonist at muscarinic receptors present in airways and other organs.^{2 224 225 232}

  
  


• 
  

  Relaxes smooth muscles of bronchi and bronchioles.^{1 2 4 6}

  
  


• 
  

  Blocks acetylcholine-induced stimulation of guanyl cyclase and reduces formation of cyclic guanosine monophosphate (cGMP), a mediator of bronchoconstriction.^{1 2 4 6}

  
  


• 
  

  Exhibits greater antimuscarinic activity on bronchial smooth muscle than on secretory (e.g., salivary, gastric) glands.^{6 7 12 16 18 34 225}

  
  


• 
  

  Tolerance to bronchodilating effect does not develop with prolonged use.^{4 14 90 91 92 115 116 117 118 119 120 121 168 225 278}

  
  

Advice to Patients

• 
  

  Importance of providing patients with a copy of the manufacturer’s patient information.^{1 4}

  
  


• 
  

  Importance of using proper administration technique.^{1 4}

  
  


• 
  

  Importance of advising patients that oral inhalation is not intended for occasional use.^{1 4} Use consistently throughout the course of therapy for maximum effectiveness.^{1 4}

  
  


• 
  

  Importance of contacting a clinician if symptoms of COPD are not relieved by usually effective doses or if they worsen.¹ Do not increase the dosage or frequency of administration without consultation with a clinician.¹

  
  


• 
  

  Importance of advising patients to close their eyes during oral inhalation of aerosol^{1 2} to avoid inadvertent contact of the drug with the eyes and subsequent adverse effects.^{1 10}

  
  


• 
  

  Importance of contacting a clinician immediately if ocular symptoms develop.¹

  
  


• 
  

  Importance of advising patients that blurring of vision, precipitation or aggravation of narrow angle glaucoma, mydriasis, visual halos, colored images in association with conjunctival or corneal congestion, or eye pain or discomfort may result from contact of the inhalation solution with the eyes.¹

  
  


• 
  

  Importance of informing clinicians if ocular adverse effects develop.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.³²⁰

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ipratropium Bromide

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral Inhalation	Aerosol	18 mcg/metered spray	Atrovent (with chlorofluorohydrocarbon propellants and soya lecithin)	Boehringer Ingelheim
	Solution, for nebulization	0.02%*	Atrovent (preservative-free)	Boehringer Ingelheim
			Ipratropium Bromide Inhalation Solution (preservative-free)	Alpharma, Dey, Holopack, Nephron, Novex, Roxane, RxElite, Teva, Warrick

Ipratropium Bromide Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral Inhalation Only	Aerosol	18 mcg with Albuterol Sulfate 90 mcg (of albuterol) per metered spray	Combivent (with chlorofluorohydrocarbon propellants and soya lecithin)	Boehringer Ingelheim
	Solution, for nebulization	0.5 mg with Albuterol Sulfate 2.5 mg (of albuterol) per 3 mL	DuoNeb	Dey

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Combivent 103-18MCG/ACT Aerosol (BOEHRINGER INGELHEIM): 14/$189.99 or 44/$535.94

DuoNeb 0.5-2.5 (3)MG/3ML Solution (DEY LABS): 180/$134.89 or 540/$386.3

DuoNeb 0.5-2.5 (3)MG/3ML Solution (DEY LABS): 90/$73.58 or 270/$207.64

Ipratropium Bromide 0.02% Solution (WATSON LABS): 62/$13.99 or 125/$18.98

Ipratropium-Albuterol 0.5-2.5 (3)MG/3ML Solution (MYLAN): 90/$39.99 or 270/$99.96

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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3. Boehringer Ingelheim. Atrovent product information form for American Hospital Formulary Service. Ridgefield, CT; 1987 Feb.

4. Boehringer Ingelheim. Atrovent (ipratropium bromide) 0.02% inhalation solution prescribing information. Ridgefield, CT; 1998 Oct.

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26. Nolte D. The action of Sch 1000 MDI on experimental bronchoconstriction induced by various types of nonspecific and pharmacodynamic irritants in young asthmatics. Postgrad Med J. 1975; 51(Suppl 7):103.

27. Beumer HM. The antagonistic effect of several doses of inhaled Sch 1000 administered by metered dose inhaler (MDI) on a Bird respirator on acetylcholine-induced bronchospasm. Postgrad Med J. 1975; 51(Suppl 7):101-2.

28. Harnett J, Spector SL. Blocking effect of SCH 1000, isoproterenol, and the combination on methacholine and histamine inhalations. J Allergy Clin Immunol. 1976; 57:261.

29. Kersten W. The role of Sch 1000 MDI in preventing a rise in total airways resistance (R_t) induced by inhaled allergen in patients with atopic asthma. Postgrad Med J. 1975; 51(Suppl 7):103.

30. Killian D, Mellon A, Hargreave FE. Protective effect of drugs on histamine-induced asthma. J Allergy Clin Immunol. 1976; 57:263.

31. Germouty J. The possible antagonism between Sch 1000 MDI and beta-blocking agents. Postgrad Med. 1975; 51(Suppl 7):103.

32. Chan-Yeung M. The effect of Sch 1000 and disodium cromoglycate on exercise-induced asthma. Chest. 1977; 71:320-3. [PubMed 138577]

33. Tullett WM, Patel KR, Berkin KE et al. Effect of lignocaine, sodium cromoglycate, and ipratropium bromide in exercise-induced asthma. Thorax. 1982; 37:737-40. [PubMed 6218645]

34. Hartley JPR, Davies BH. Cholinergic blockade in the prevention of exercise-induced asthma. Thorax. 1980; 35:680-5. [PubMed 6449753]

35. Borut TC, Tashkin DP, Fischer TJ et al. Comparison of aerosolized atropine sulfate and Sch 1000 on exercise-induced bronchospasm in children. J Allergy Clin Immunol. 1977; 60:127-33. [IDIS 92840] [PubMed 141471]

36. Poppius H, Salorinne Y, Viljanen AA. Inhalation of a new anticholinergic drug, Sch 1000, in asthma and chronic bronchitis: effect on airway resistance, thoracic gas volume, blood gases and exercise-induced asthma. Bull Physiopathol Resp. 1972; 8:643-52.

37. Poppius H, Salorinne Y, Viljanen AA. The role of Sch 1000 MDI in preventing exercise-induced asthma. Postgrad Med J. 1975; 51(Suppl 7):105.

38. Weinberg EG. Experience with Sch 1000 MDI in the treatment of exercise-induced asthma in children. Postgrad Med J. 1975; 51(Suppl 7):128.

39. Thomson NC, Patel KR, Kerr JW. Sodium cromoglycate and ipratropium bromide in exercise-induced asthma. Thorax. 1978; 33:694-9. [PubMed 154747]

40. Sanguinetti CM, De Luca S, Gasparini S et al. Evaluation of Duovent in the prevention of exercise-induced asthma. Respiration. 1986; 50(Suppl 2):181-5. [PubMed 2951802]

41. Dry J, Pradalier A, Leynadier F et al. Recherche d’une prévention de la bronchoconstriction induite par une épreuve d’efforts chez l’asthmatique par un atropinique de synthèse: le Sch 1000. (French; with English abstract.) Thérapie. 1977; 32:181-8.

42. Anderson S, Seale JP, Ferris L et al. An evaluation of pharmacotherapy for exercise-induced asthma. J Allergy Immunol. 1979; 64:612-24.

43. Poppius H, Sovijärvi ARA, Tammilehto L. Controlled study on the preventing effect of inhaled ipratropium powder on asthma induced by breathing cold air during exercise. Respiration. 1984; 46(Suppl):45-6. [PubMed 6436932]

44. Wolkove N, Kreisman H, Frank H et al. The effect of ipratropium on exercise-induced bronchoconstriction. Ann Allergy. 1981; 47:311-5. [IDIS 164243] [PubMed 6459045]

45. Scano G, Stendardi L, Gigliotti G et al. Comparative effects of SCH 1000 and fenoterol after histamine-induced bronchoconstricition in asymptomatic asthmatics. Intl J Clin Pharmacol Ther Toxicol. 1984; 22:81-5.

46. Dorward AJ, Patel KR. A comparison of ketotifen with clemastine, ipratropium bromide and sodium cromoglycate in exercise-induced asthma. Clin Allergy. 1982; 12:355-61. [PubMed 6214337]