ANATERA 100mg / ml solution for injection

1. Name Of The Medicinal Product

Anatera 100 mg/ml solution for injection

2. Qualitative And Quantitative Composition

1 ml solution contains 100 mg fluorescein (as 113.2 mg fluorescein sodium)

One 5 ml vial contains 500 mg fluorescein (as 566 mg fluorescein sodium)

Contains sodium (from fluorescein sodium and sodium hydroxide) at amounts up to 1.45% (approximately 3.15 mmol), per dose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection

Clear, red-orange solution

4. Clinical Particulars

4.1 Therapeutic Indications

This medicinal product is for diagnostic use only.

For fluorescein angiography of the ocular fundus.

4.2 Posology And Method Of Administration

Posology

Use in adults, including the elderly:

5 ml of Anatera 100 mg/ml solution for injection rapidly into the antecubital vein after taking precautions to avoid extravasation. In cases when highly sensitive imaging systems e.g., scanning laser ophthalmoscope are used, the dose of this product should be reduced to 2 ml of Anatera 100 mg/ml solution for injection.

Use in pediatric patients:

Anatera 100 mg/ml solution for injection has not been studied in children and dose-adaptation data are not available. Therefore, Anatera 100 mg/ml solution for injection should not be used in patients below 18 years as efficacy and safety in this group have not been established.

Use in patients with renal insufficiency (glomerular filtration rate below 20 ml/min):

Limited experience in renally impaired subjects (glomerular filtration rate below 20 ml/min) suggests that, in general, no dose adjustment is required although a longer excretion rate in patients with renal impairment is possible (see section 5.2).

Dialysed patients: Reduce dose to 2.5 ml (half a vial)

Method of administration and fluorescence angiography

Anatera 100 mg/ml solution for injection should be used exclusively by qualified physicians with technical expertise in performing and interpreting fluorescence angiography.

This product should only be administered intravenously.

Flush intravenous cannulas with sterile sodium chloride solution (0.9%) before and after medicinal products are injected to avoid physical incompatibility reactions. The injection should be administered rapidly (1 ml per second is normally recommended) into the antecubital vein, after taking precautions to avoid extravasation using a 23 gauge butterfly needle for injection. Luminescence usually appears in the retina and choroidal vessels in 7 to 14 seconds.

For further instructions on the correct administration/use of this product, see sections 6.2 and 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Anatera 100 mg/ml solution for injection should not be injected intrathecally or intra-arterial.

4.4 Special Warnings And Precautions For Use

Fluorescein sodium can induce serious intolerance reactions.

Detailed questioning of each patient must be carried out before the angiography to search for any history of cardiopulmonary disease or allergy or concomitant medications (such as beta-blocking agents, including eye-drops solutions). If the examination appears to be really necessary for a patient treated with beta-blocking agents (including eye-drops solutions), this examination should be performed under the supervision of a physician experienced in intensive care (resuscitation). Beta-blocking agents could reduce the vascular compensation reactions to anaphylactic shock and reduce the effectiveness of adrenaline in the case of cardiovascular collapse. Before any fluorescein sodium injection, the physician should seek information about concomitant treatment with a beta-blocking agent.

In the event of serious intolerance reactions during a first angiography, the benefit of an additional fluorescein angiography should be balanced with the risk of severe hypersensitivity reactions (with fatal outcome in some cases).

These reactions of intolerance are always unpredictable but they are more frequent in patients who have previously experienced an adverse reaction after fluorescein injection (symptoms other than nausea and vomiting) or in patients with history of allergy such as food or drug induced urticaria, asthma, eczema, allergic rhinitis. Intradermal skin tests are not reliable in predicting these intolerance reactions and so their use can be dangerous. A specialized allergy consultation should be undertaken to make this diagnosis.

Premedication can be undertaken. However, the risk of occurrence of severe adverse drug reactions still remains. Premedication includes mainly oral antihistaminic H1 drugs, followed by corticosteroids, before injection of fluorescein. Given the low incidence of these adverse reactions, such pre-medication is not recommended for all patients.

The risk of hypersensitivity reactions with fluorescein sodium requires:

− Close monitoring of the patient by the ophthalmologist performing the examination, throughout the examination and for at least 30 minutes after;

− Maintaining the infusion line for at least 5 minutes, to treat a possible severe adverse reaction without delay;

−To have at one's disposal appropriate material for emergency resuscitation which is based at first on the installation of a 2nd intravenous line, allowing the restoration of the plasma volume (aqueous solution polyionic or colloidal substitute of plasma) and the intravenous injection of adrenaline at the recommended dosage (see section 4.5).

Note:

Extravasation should be avoided due to the high pH of fluorescein solution which can result in severe local tissue damage (severe pain in the arm for several hours, sloughing of the skin; superficial phlebitis). When extravasation occurs, the injection should be immediately discontinued.

If an X-ray procedure is conducted within 36 hours of injection (maximum duration of fluorescein elimination from the body), the resultant high visibility of the excretory organs in the X-ray image may lead to misinterpretation.

This medicinal product contains up to 3.15 mmol (72.45 mg) sodium per dose. This should be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Fluorescein is a relatively inert dye and specific drug interaction studies have not been reported. There are few case reports on potential interactions with organic anion transporters and interference with certain laboratory tests. Compounds that inhibit or compete with the active transport of organic anions (e.g., probenicid) may affect the systemic profile of fluorescein.

The concomitant use of Anatera 100 mg/ml solution for injection with beta-blocking agents (including eye-drops solutions) may rarely provoke severe anaphylactic reactions (see section 4.4).

Concomitant intravenous injection of other solutions or the mixing of Anatera 100 mg/ml solution for injection with other solutions should be avoided as the possibility of interactions cannot be excluded.

It is possible that fluorescein may influence certain blood and urine values for 3 to 4 days after application.

4.6 Pregnancy And Lactation

Pregnancy

There are insufficient data available concerning the use of Anatera 100 mg/ml solution for injection in pregnancy. Animal studies do not indicate teratogenic effects (see section 5.3). However, due to limited experience, caution should be exercised when considering the use of Anatera 100 mg/ml solution for injection during pregnancy.

Lactation

Fluorescein sodium is excreted in human milk for up to 4 days. Following fluorescein angiography, breast-feeding should therefore be discontinued for 4 days and the milk should be pumped off and discarded during this period.

4.7 Effects On Ability To Drive And Use Machines

If mydriasis is necessary for the examination with fluorescence angiography visual acuity is influenced and thus affects the ability to react in traffic or use machinery. The patient must be made aware that after application and until visual acuity returns to normal, driving a vehicle or operating dangerous machinery is prohibited.

4.8 Undesirable Effects

The most frequently reported treatment related undesirable effects were nausea, vomiting, syncope and pruritis. More severe adverse reactions have been reported shortly after fluorescein injection such as angioedema, respiratory disorders (bronchospasm, laryngeal oedema, respiratory failure), anaphylactic shock, hypotension, respiratory arrest and cardiac arrest.

Additionally, a yellowish discoloration of the skin could appear but usually disappears within 6 to 12 hours. Urine, which may also exhibit a bright yellow colouration, returns to its normal colour after 24 to 36 hours.

The following undesirable effects were assessed to be treatment-related and are classified according to the following convention: very common (

Immune system disorders:

Uncommon: hypersensitivity

Rare: anaphylactic reaction

Very Rare: anaphylactic shock

Nervous system disorders:

Common: syncope

Uncommon: paresthesia, dizziness, headache

Very Rare: convulsion

Not Known: vertebrobasilar insufficiency

Cardiac disorders:

Rare: cardiac arrest

Very Rare: angina pectoris, bradycardia, tachycardia

Vascular disorders:

Uncommon: thrombophlebitis

Rare: hypotension, shock

Very Rare: hypertension, vasospasm, vasodilation, pallor, hot flush

Respiratory, thoracic and mediastinal disorders:

Uncommon: cough, throat tightness

Rare: bronchospasm

Very Rare: respiratory arrest, pulmonary oedema, asthma, laryngeal oedema, dyspnoea, nasal oedema, sneezing

Gastrointestinal disorders:

Very Common: nausea

Common: abdominal discomfort, vomiting

Uncommon: abdominal pain

Skin and subcutaneous tissue disorders:

Common: pruritus

Uncommon: urticaria

General disorders and administration site conditions:

Common: extravasation

Uncommon: dysphasia, pain, feeling hot

4.9 Overdose

No case of overdose has been reported.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: DIAGNOSTIC AGENTS, Colouring agents

ATC code: S01JA01

Fluorescein sodium is a fluorochrome used in medicine as a diagnostic stain. Fluorescein is used to make the blood vessels of the ocular fundus visible (angiography of the retina and choroid).

5.2 Pharmacokinetic Properties

Distribution:

Within 7 to 14 seconds after intravenous administration into antecubital vein, fluorescein usually appears in the central artery of the eye. Within a few minutes of intravenous administration of fluorescein, a yellowish discoloration of the skin occurs, which begins to fade 6 to 12 hours after dosing. Various estimates of volume of distribution indicate that fluorescein distributes well into interstitial space (0.5 L/kg).

Metabolism:

Fluorescein undergoes rapid metabolism to fluorescein monoglucuronide. After intravenous administration of fluorescein sodium (14 mg/kg) to 7 healthy subjects, approximately 80% of fluorescein in plasma was converted to glucuronide conjugate after a period of 1 hour post dose, indicating relatively rapid conjugation.

Excretion:

Fluorescein and its metabolites are mainly eliminated via renal excretion. After intravenous administration, the urine remains slightly fluorescent for 24 to 36 hours. A renal clearance of 1.75 ml/min/kg and a hepatic clearance (due to conjugation) of 1.50 ml/min/kg have been estimated. The systemic clearance of fluorescein is essentially complete by 48 to 72 hours after administration of 500 mg fluorescein. Although a longer excretion rate in patients with renal impairment is possible, limited experience in renally impaired subjects (glomerular filtration rate below 20 ml/min) suggests that, in general, no dose adjustment is required.

5.3 Preclinical Safety Data

Non-clinical data for sodium fluorescein reveal no special hazard for humans based on studies of single dose toxicity.

Fluorescein did not show teratogenic effects in rats and rabbits. Fluorescein crosses the placental barrier. After the intravenous application of 500 mg/kg intense fluorescence was detectable both in the fetus and the amniotic fluid.

Studies on mutagenicity did not show any mutagenic effects of fluorescein sodium

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium hydroxide (for pH-adjustment)

Hydrochloric acid (for pH-adjustment)

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

To avoid physical incompatibilities, this product must not be administered simultaneously with other solutions for injection with acid pH (especially antihistamines) by the same intravenous route (see section 4.2 for information about cannulas).

Once opened the vial must be immediately used.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 25°C.

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

Glass (type I) vial with grey chlorobutyl coated rubber stopper and aluminum seal with polypropylene flip-off cap.

Pack containing 12 vials of 5 ml injection solution

6.6 Special Precautions For Disposal And Other Handling

The solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles. For single use only. Any unused product or waste material should be disposed of in accordance with local requirements. Do not use Anatera 100 mg/ml solution for injection if the vial is cracked or damaged in any way.

7. Marketing Authorisation Holder

Alcon Laboratories (UK) ltd

Pentagon Park

Boundary Way

Hemel Hempstead

Herts HP2 7UD

8. Marketing Authorisation Number(S)

PL 00649/0377

9. Date Of First Authorisation/Renewal Of The Authorisation

24/04/2008

10. Date Of Revision Of The Text

11/02/2009

Zosyn

Pronunciation: PI-per-a-SIL-in/TAZ-oh-BAK-tam
Generic Name: Piperacillin/Tazobactam
Brand Name: Zosyn

Zosyn is used for:

Treating moderate to severe infections caused by certain bacteria.

Zosyn is an antibacterial agent. It works by blocking the bacteria's cell wall growth, which kills the bacteria.

Do NOT use Zosyn if:

• you are allergic to any ingredient in Zosyn


• you have a history of allergic reaction to any penicillin (eg, amoxicillin), cephalosporin (eg, cephalexin), beta-lactam antibiotic (eg, imipenem), or beta-lactamase inhibitor (eg, clavulanic acid)


• you are taking a tetracycline antibiotic (eg, doxycycline)

Contact your doctor or health care provider right away if any of these apply to you.

Before using Zosyn:

Some medical conditions may interact with Zosyn. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have cystic fibrosis, bowel inflammation, bleeding problems, congestive heart failure, or kidney problems


• if you are on dialysis, or if you have a history of severe diarrhea or bowel problems due to an antibiotic


• if you are on a salt-restricted diet or have low blood potassium levels

Some MEDICINES MAY INTERACT with Zosyn. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Aminoglycosides (eg, tobramycin) or oral contraceptives (birth control pills) because their effectiveness may be decreased by Zosyn


• Anticoagulants (eg, warfarin) because their effectiveness may be decreased or the risk of their side effects may be increased by Zosyn


• Chemotherapy or diuretics (eg, furosemide, hydrochlorothiazide) because the risk of side effects, such as low blood potassium levels, may be increased


• Heparin, methotrexate, or nondepolarizing muscle relaxants (eg, vecuronium) because the risk of their side effects may be increased by Zosyn


• Probenecid because it may increase the risk of Zosyn's side effects


• Tetracyclines (eg, doxycycline) because they may decrease Zosyn's effectiveness

This may not be a complete list of all interactions that may occur. Ask your health care provider if Zosyn may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Zosyn:

Use Zosyn as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Zosyn is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Zosyn at home, a health care provider will teach you how to use it. Be sure you understand how to use Zosyn. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.


• Do not use Zosyn if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.


• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


• If you miss a dose of Zosyn, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Zosyn.

Important safety information:

• Zosyn may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use Zosyn with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Zosyn may reduce the number of clot-forming cells (platelets) in your blood. Avoid activities that may cause bruising or injury. Tell your doctor if you have unusual bruising or bleeding. Tell your doctor if you have dark, tarry, or bloody stools.


• Hormonal birth control (eg, birth control pills) may not work as well while you are using Zosyn. To prevent pregnancy, use an extra form of birth control (eg, condoms).


• Zosyn only works against bacteria; it does not treat viral infections (eg, the common cold).


• Be sure to use Zosyn for the full course of treatment. If you do not, the medicine may not clear up your infection completely. The bacteria could also become less sensitive to this or other medicines. This could make the infection harder to treat in the future.


• Long-term or repeated use of Zosyn may cause a second infection. Tell your doctor if signs of a second infection occur. Your medicine may need to be changed to treat this.


• Mild diarrhea is common with antibiotic use. However, a more serious form of diarrhea, (pseudomembranous colitis) may rarely occur. This may develop while you use the antibiotic or within several months after you stop using it. Contact your doctor right away if stomach pain or cramps, severe diarrhea, or bloody stools occur. Do not treat diarrhea without first checking with your doctor.


• Tell your doctor or dentist that you take Zosyn before you receive any medical or dental care, emergency care, or surgery.


• Diabetes patients - Zosyn may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Diabetes patients - Zosyn may cause the results of some tests for urine glucose to be wrong. Ask your doctor before you change your diet or the dose of your diabetes medicine.


• Zosyn may interfere with certain lab tests. Be sure your doctor and lab personnel know you are using Zosyn.


• Lab tests, including complete blood cell counts and blood electrolyte levels, may be performed while you use Zosyn. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Zosyn with caution in the ELDERLY; they may be more sensitive to its effects.


• Zosyn should be used with extreme caution in CHILDREN younger than 2 months old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Zosyn while you are pregnant. Zosyn is found in breast milk. If you are or will be breast-feeding while you use Zosyn, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Zosyn:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Agitation; constipation; diarrhea; dizziness; headache; indigestion; nausea; pain, swelling, or redness at the injection site; sleeplessness; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody stools; chest pain; decreased urination; depression; fainting; fast, slow, or irregular heartbeat; fever, chills, or sore throat; hallucination; inflammation at the injection site; prolonged muscle relaxation; red, swollen, or blistered skin; seizures; severe diarrhea, vomiting, or stomach pain; shortness of breath; swelling of the hands, ankles, or feet; tremor; unusual bleeding or bruising; unusual tiredness or weakness; vaginal irritation or discharge; vein inflammation or tenderness; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Zosyn side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include confusion; convulsions; excitability; loss of consciousness; severe nausea, vomiting, or diarrhea.

Proper storage of Zosyn:

Zosyn is usually handled and stored by a health care provider. If you are using Zosyn at home, store Zosyn as directed by your pharmacist or health care provider. Keep Zosyn out of the reach of children and away from pets.

General information:

• If you have any questions about Zosyn, please talk with your doctor, pharmacist, or other health care provider.


• Zosyn is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Zosyn. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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• Zosyn Drug Interactions
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• Zosyn Prescribing Information (FDA)


• Zosyn Monograph (AHFS DI)


• Zosyn Advanced Consumer (Micromedex) - Includes Dosage Information


• Zosyn Consumer Overview

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Ibuprofen Chewable Tablets

Pronunciation: EYE-bue-PROE-fen
Generic Name: Ibuprofen
Brand Name: Examples include Children's Motrin and Motrin Junior Strength

Ibuprofen Chewable Tablets are a nonsteroidal anti-inflammatory drug (NSAID). It may cause an increased risk of serious and sometimes fatal heart and blood vessel problems (eg, heart attack, stroke). The risk may be greater if you already have heart problems or if you take Ibuprofen Chewable Tablets for a long time. Do not use Ibuprofen Chewable Tablets right before or after bypass heart surgery.

Ibuprofen Chewable Tablets may cause an increased risk of serious and sometimes fatal stomach ulcers and bleeding. Elderly patients may be at greater risk. This may occur without warning signs.

Ibuprofen Chewable Tablets are used for:

Treating minor aches and pains caused by the common cold, flu, sore throat, headaches, or toothaches. It may be used to reduce fever. It may also be used for other conditions as determined by your doctor.

Ibuprofen Chewable Tablets are an NSAID. Exactly how it works is not known. It may block certain substances in the body that are linked to inflammation. NSAIDs treat the symptoms of pain and inflammation. They do not treat the disease that causes those symptoms.

Do NOT use Ibuprofen Chewable Tablets if:

• you are allergic to any ingredient in Ibuprofen Chewable Tablets


• you have had a severe allergic reaction (eg, severe rash, hives, trouble breathing, growths in the nose, dizziness) to aspirin or an NSAID (eg, ibuprofen, celecoxib)


• you have recently had or will be having bypass heart surgery


• you are in the last 3 months of pregnancy

Contact your doctor or health care provider right away if any of these apply to you.

Before using Ibuprofen Chewable Tablets:

Some medical conditions may interact with Ibuprofen Chewable Tablets. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal product, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a history of kidney or liver disease, diabetes, or stomach or bowel problems (eg, bleeding, perforation, ulcers, persistent or returning stomach pain or heartburn)


• if you have a history of swelling or fluid buildup, lupus, phenylketonuria, asthma, growths in the nose (nasal polyps), or mouth inflammation


• if you have high blood pressure, blood disorders, bleeding or clotting problems, heart problems (eg, heart failure), or blood vessel disease, or if you are at risk for any of these diseases


• if you are dehydrated or have low fluid volume (eg, caused by diarrhea, vomiting, not drinking fluids)


• if you have poor health or low blood sodium levels, you drink alcohol, or you have a history of alcohol abuse

Some MEDICINES MAY INTERACT with Ibuprofen Chewable Tablets. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Anticoagulants (eg, warfarin), aspirin, corticosteroids (eg, prednisone), heparin, or selective serotonin reuptake inhibitors (SSRIs) (eg, fluoxetine) because the risk of stomach bleeding may be increased


• Probenecid because it may increase the risk of Ibuprofen Chewable Tablets's side effects


• Cyclosporine, lithium, methotrexate, or quinolones (eg, ciprofloxacin) because the risk of their side effects may be increased by Ibuprofen Chewable Tablets


• Angiotensin-converting enzyme (ACE) inhibitors (eg, enalapril) or diuretics (eg, furosemide, hydrochlorothiazide) because their effectiveness may be decreased by Ibuprofen Chewable Tablets

This may not be a complete list of all interactions that may occur. Ask your health care provider if Ibuprofen Chewable Tablets may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Ibuprofen Chewable Tablets:

Use Ibuprofen Chewable Tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Ibuprofen Chewable Tablets comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Ibuprofen Chewable Tablets refilled.


• Take Ibuprofen Chewable Tablets by mouth with or without food. It may be taken with food if it upsets your stomach. Taking it with food may not lower the risk of stomach or bowel problems (eg, bleeding, ulcers). Talk with your doctor or pharmacist if you have persistent stomach upset.


• Chew well before swallowing.


• If you miss a dose of Ibuprofen Chewable Tablets and you are taking it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose. Go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about the proper use of Ibuprofen Chewable Tablets.

Important safety information:

• Ibuprofen Chewable Tablets may cause dizziness or drowsiness. These effects may be worse if you take it with alcohol or certain medicines. Use Ibuprofen Chewable Tablets with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Serious stomach ulcers or bleeding can occur with the use of Ibuprofen Chewable Tablets. Taking it in high doses or for a long time, smoking, or drinking alcohol increases the risk of these side effects. Taking Ibuprofen Chewable Tablets with food will NOT reduce the risk of these effects. Contact your doctor or emergency room at once if you develop severe stomach or back pain; black, tarry stools; vomit that looks like blood or coffee grounds; or unusual weight gain or swelling.


• Do NOT take more than the recommended dose or use for longer than 10 days for pain or 2 days for sore throat without checking with your doctor.


• If stomach pain or upset gets worse or does not get better, check with your doctor. If pain or fever gets worse or lasts for more than 3 days, check with your doctor.


• If a child using Ibuprofen Chewable Tablets does not get any relief within 24 hours, contact the child's doctor.


• Check with your doctor if you have a severe or persistent sore throat. Check with your doctor if you have a sore throat with fever, headache, nausea, and vomiting.


• Ibuprofen Chewable Tablets has ibuprofen in it. Before you start any new medicine, check the label to see if it has ibuprofen in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• Some of these products contain phenylalanine. If you must have a diet that is low in phenylalanine, ask your pharmacist if it is in your product.


• Do not take aspirin while you are using Ibuprofen Chewable Tablets unless your doctor tells you to.


• Use Ibuprofen Chewable Tablets with caution in the ELDERLY; they may be more sensitive to its effects, including stomach bleeding and kidney problems.


• Different brands of Ibuprofen Chewable Tablets may have different dosing instructions for CHILDREN. Follow the dosing instructions on the package labeling. If your doctor has given you instructions, follow those. If you are unsure of the dose to give a child, check with your doctor or pharmacist.


• PREGNANCY and BREAST-FEEDING: Ibuprofen Chewable Tablets may cause harm to the fetus. Do not take it during the last 3 months of pregnancy. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of taking Ibuprofen Chewable Tablets while you are pregnant. It is not known if Ibuprofen Chewable Tablets are found in breast milk. Do not breast-feed while taking Ibuprofen Chewable Tablets.

Possible side effects of Ibuprofen Chewable Tablets:

All medicines can cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; diarrhea; dizziness; gas; headache; heartburn; nausea; stomach pain or upset.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; trouble breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody or black, tarry stools; change in the amount of urine produced; chest pain; confusion; dark urine; depression; fainting; fast or irregular heartbeat; fever, chills, or persistent sore throat; mental or mood changes; numbness of an arm or leg; one-sided weakness; red, swollen, blistered, or peeling skin; ringing in the ears; seizures; severe headache or dizziness; severe or persistent stomach pain or nausea; severe vomiting; shortness of breath; stiff neck; sudden or unexplained weight gain; swelling of hands, legs, or feet; unusual bruising or bleeding; unusual joint or muscle pain; unusual tiredness or weakness; vision or speech changes; vomit that looks like coffee grounds; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Ibuprofen side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include decreased urination; loss of consciousness; seizures; severe dizziness or drowsiness; severe nausea or stomach pain; slow or troubled breathing; unusual bleeding or bruising; vomit that looks like coffee grounds.

Proper storage of Ibuprofen Chewable Tablets:

Store Ibuprofen Chewable Tablets at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Ibuprofen Chewable Tablets out of the reach of children and away from pets.

General information:

• If you have any questions about Ibuprofen Chewable Tablets, please talk with your doctor, pharmacist, or other health care provider.


• Ibuprofen Chewable Tablets are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Ibuprofen Chewable Tablets. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Ibuprofen resources

• Ibuprofen Side Effects (in more detail)
• Ibuprofen Dosage
• Ibuprofen Use in Pregnancy & Breastfeeding
• Drug Images
• Ibuprofen Drug Interactions
• Ibuprofen Support Group
• 51 Reviews for Ibuprofen - Add your own review/rating

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Eucalyptus Oil BP

1. Name Of The Medicinal Product

Eucalyptus Oil BP

2. Qualitative And Quantitative Composition

Eucalyptus Oil BP 100.0% v/v.

3. Pharmaceutical Form

Essential Oil.

4. Clinical Particulars

4.1 Therapeutic Indications

1. For relief of the symptoms of catarrhal colds.

2. For relief of the symptoms of minor muscular sprains and cramps

4.2 Posology And Method Of Administration

1. a) By inhalation from drops of oil spilled onto a handkerchief which is then sniffed.

b) By inhalation of vapour from drops of oil spilled into a bowl of hot water (50°C) 'steam inhalation' and the humid vapour inhaled.

2. As a rubefacient during massage of sprains and cramps where massage is an appropriate treatment.

Recommended Dose and Dosage Schedule

Adults, the elderly and children over 1 year:

1 a) Sprinkle a few drops on to a handkerchief and inhale as required.

b) A few drops into warm/hot water (50°C) and inhale the humid vapour, as required.

2. A few drops on the hand to lubricate the massage of appropriate areas as required.

4.3 Contraindications

Sensitivity to Eucalyptus Oil.

Not recommended for infants under 1 year.

4.4 Special Warnings And Precautions For Use

Keep all medicines out of the reach and sight of children.

Not to be take orally.

If symptoms persist consult your doctor

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known

4.6 Pregnancy And Lactation

No evidence can be found as to the safety of the product in pregnancy or lactation. The use of all drugs should be avoided during the first trimester.

4.7 Effects On Ability To Drive And Use Machines

At the dosage indicated, no evidence can be found that the product affects the ability to drive or to use machinery

4.8 Undesirable Effects

When used as a rubefacient it may induce skin sensitisation and eczema.

No adverse effects of inhalation are reported but in sensitised individuals the precipitation of hay fever or asthma are potential unwanted effects

4.9 Overdose

Symptoms: poisoning with eucalyptus oil may cause epigastric burning, nausea and vomiting, dizziness, muscular weakness, miosis, tachycardia, a feeling of suffocation, cyanosis, ataxia, pulmonary damage, delirium, convulsions and CNS depression, including coma. Deaths have been recorded from doses as low as 3.5ml.

Emergency procedures: after ingestion the stomach should be emptied by aspiration and lavage. Demulcent drinks may be given. Large volumes of fluid should be given provided renal function is adequate. Effects of excessive inhalation should be treated by removal to fresh air.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

When the vapour is inhaled eucalyptus oil acts to ventilate the bronchial passages and relieve bronchitis and associated conditions. It is also a rubefacient.

5.2 Pharmacokinetic Properties

After ingestion excretion takes place via the lungs, skin and kidneys.

5.3 Preclinical Safety Data

None

6. Pharmaceutical Particulars

6.1 List Of Excipients

None

6.2 Incompatibilities

None known

6.3 Shelf Life

14ml:	36 months unopened.
25ml:	36 months unopened.
50ml:	36 months unopened.
500ml:	36 months unopened.
2000ml:	36 months unopened

6.4 Special Precautions For Storage

Store below 25°C.

Keep container tightly closed

6.5 Nature And Contents Of Container

14ml: Oval, ribbed, white glass bottle with plastic cap.

25ml, 50ml, 500ml, and 2000ml: Amber glass bottle with plastic cap, or white plastic child resistant cap with EPE/Saranex liner.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

L. C. M. Ltd.

Linthwaite Laboratories

Huddersfield

HD7 5QH

8. Marketing Authorisation Number(S)

PL 12965/0011

9. Date Of First Authorisation/Renewal Of The Authorisation

13.04.94/21.05.99

10. Date Of Revision Of The Text

20.12.03

11 DOSIMETRY (IF APPLICABLE)

Not Applicable

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

Not Applicable

Zerlor

Generic Name: acetaminophen, caffeine, and dihydrocodeine (a SEET a MIN oh fen, KAF een, dye HYE droe KOE deen)

Brand Names: Panlor SS, Trezix, Zerlor

What is Zerlor (acetaminophen, caffeine, and dihydrocodeine)?

Dihydrocodeine a narcotic pain reliever.

Acetaminophen is a less potent pain reliever that increases the effects of dihydrocodeine.

Caffeine is a central nervous system stimulant. It relaxes muscle contractions in blood vessels to improve blood flow.

The combination of acetaminophen, caffeine, and dihydrocodeine is used to relieve moderate to severe pain.

Acetaminophen, caffeine, and dihydrocodeine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Zerlor (acetaminophen, caffeine, and dihydrocodeine)?

Tell your doctor if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You may not be able to take medicine that contains acetaminophen. Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death. Avoid drinking alcohol. It may increase your risk of liver damage while taking acetaminophen. Dihydrocodeine may be habit-forming and should be used only by the person it was prescribed for. Keep the medication in a secure place where others cannot get to it. This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Tell your doctor if the medicine seems to stop working as well in relieving your pain.

What should I discuss with my healthcare provider before taking Zerlor (acetaminophen, caffeine, and dihydrocodeine)?

Do not use this medication if you are allergic to acetaminophen (Tylenol) or dihydrocodeine, or if you have a stomach condition called paralytic ileus, or severe or uncontrolled asthma. Tell your doctor if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You may not be able to take medicine that contains acetaminophen. Dihydrocodeine may be habit forming and should be used only by the person it was prescribed for. Never share acetaminophen, caffeine, and dihydrocodeine with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it.

To make sure you can safely take this medicine, tell your doctor if you have any of these other conditions:

• 
  

  sleep apnea or other breathing disorders;

  
  


• 
  

  liver or kidney disease;

  
  


• 
  

  a history of head injury or brain tumor;

  
  


• 
  

  epilepsy or other seizure disorder;

  
  


• 
  

  low blood pressure;

  
  


• 
  

  a stomach or intestinal disorder;

  
  


• 
  

  underactive thyroid;

  
  


• 
  

  a pancreas disorder;

  
  


• 
  

  Addison's disease or other adrenal gland disorder;

  
  


• 
  

  enlarged prostate, urination problems;

  
  


• 
  

  curvature of the spine;

  
  


• 
  

  mental illness; or

  
  


• 
  

  a history of drug or alcohol addiction.

  
  

FDA pregnancy category C. It is not known whether this medication is harmful to an unborn baby, but it could cause breathing problems or addiction/withdrawal symptoms in a newborn. Tell your doctor if you are pregnant or plan to become pregnant while using acetaminophen, caffeine, and dihydrocodeine. Dihydrocodeine can pass into breast milk and may harm a nursing baby. The use of this medication by some nursing mothers may lead to life-threatening side effects in the baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Zerlor (acetaminophen, caffeine, and dihydrocodeine)?

Take exactly as prescribed. Never take acetaminophen, caffeine, and dihydrocodeine in larger amounts, or for longer than recommended by your doctor. Follow the directions on your prescription label. Tell your doctor if the medicine seems to stop working as well in relieving your pain.

Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death. Do not stop using acetaminophen, caffeine, and dihydrocodeine suddenly after long-term use, or you could have unpleasant withdrawal symptoms. Ask your doctor how to avoid withdrawal symptoms when you stop using acetaminophen, caffeine, and dihydrocodeine. This medication can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using acetaminophen, caffeine, and dihydrocodeine. If you need surgery, tell the surgeon ahead of time that you are using acetaminophen, caffeine, and dihydrocodeine. You may need to stop using the medicine for a short time. Store at room temperature away from moisture and heat.

Keep track of the amount of medicine used from each new bottle. Acetaminophen, caffeine, and dihydrocodeine is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.

What happens if I miss a dose?

Since acetaminophen, caffeine, and dihydrocodeine is taken as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of acetaminophen, caffeine, and dihydrocodeine can be fatal.

The first signs of an acetaminophen overdose include loss of appetite, nausea, vomiting, stomach pain, sweating, and confusion or weakness. Later symptoms may include pain in your upper stomach, dark urine, and yellowing of your skin or the whites of your eyes.

Overdose symptoms may also include extreme drowsiness or insomnia, restless feeling, tremors, fast heart rate, pinpoint pupils, fainting, weak pulse, seizure (convulsions), coma, blue lips, shallow breathing, or no breathing.

What should I avoid while taking Zerlor (acetaminophen, caffeine, and dihydrocodeine)?

Avoid drinking alcohol. It may increase your risk of liver damage while taking acetaminophen. This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Ask a doctor or pharmacist before using any other cold, allergy, pain, or sleep medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose. Check the label to see if a medicine contains acetaminophen or APAP.

While you are taking this medication, avoid taking diet pills, caffeine pills, or other stimulants (such as ADHD medications) without your doctor's advice.

Zerlor (acetaminophen, caffeine, and dihydrocodeine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Stop using acetaminophen, caffeine, and dihydrocodeine and call your doctor at once if you have a serious side effect such as:

• 
  

  shallow breathing, slow heartbeat;

  
  


• 
  

  fast or pounding heart rate, feeling light-headed, fainting;

  
  


• 
  

  confusion, hallucinations, unusual thoughts or behavior;

  
  


• 
  

  muscle twitching;

  
  


• 
  

  problems with urination;

  
  


• 
  

  easy bruising or bleeding; or

  
  


• 
  

  nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

  
  

Less serious side effects include:

• 
  

  feeling dizzy or drowsy, shaky or agitated;

  
  


• 
  

  mild nausea, vomiting, upset stomach; constipation, diarrhea;

  
  


• 
  

  mood changes, sleep problems (insomnia);

  
  


• 
  

  sweating, urinating more than usual;

  
  


• 
  

  ringing in your ears, blurred vision; or

  
  


• 
  

  dry mouth.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Zerlor (acetaminophen, caffeine, and dihydrocodeine)?

Before using this medication, tell your doctor if you regularly use other medicines that make you sleepy (such as cold or allergy medicine, sedatives, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by dihydrocodeine.

Tell your doctor about all other medicines you use, especially:

• 
  

  ciprofloxacin (Cipro);

  
  


• 
  

  atropine (Donnatal, and others), benztropine (Cogentin), dimenhydrinate (Dramamine), glycopyrrolate (Robinul), isoniazid, mepenzolate (Cantil), methscopolamine (Pamine), or scopolamine (Transderm-Scop);

  
  


• 
  

  bladder or urinary medications such as oxybutynin (Ditropan, Oxytrol), tolterodine (Detrol), or solifenacin (Vesicare);

  
  


• 
  

  a blood thinner such as warfarin (Coumadin, Jantoven);

  
  


• 
  

  a bronchodilator such as ipratropium (Atrovent) or tiotropium (Spiriva);

  
  


• 
  

  irritable bowel medications such as dicyclomine (Bentyl), hyoscyamine (Anaspaz, Levsin, and others), or propantheline (Pro-Banthine);

  
  


• 
  

  seizure medicine such as carbamazepine (Carbatrol, Equetro, Tegretol) or phenytoin (Dilantin); or

  
  


• 
  

  an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate).

  
  

This list is not complete and other drugs may interact with acetaminophen, caffeine, and dihydrocodeine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Zerlor resources

• Zerlor Side Effects (in more detail)
• Zerlor Use in Pregnancy & Breastfeeding
• Zerlor Drug Interactions
• Zerlor Support Group
• 0 Reviews for Zerlor - Add your own review/rating

• Panlor DC MedFacts Consumer Leaflet (Wolters Kluwer)


• Trezix Prescribing Information (FDA)

Compare Zerlor with other medications

• Pain

Where can I get more information?

• Your pharmacist can provide more information about acetaminophen, caffeine, and dihydrocodeine.

See also: Zerlor side effects (in more detail)

Pioglitazone 30mg Tablets

1. Name Of The Medicinal Product

Pioglitazone Sandoz 30 mg, Tablets

2. Qualitative And Quantitative Composition

Pioglitazone 30 mg

Each tablet contains 30 mg pioglitazone (as pioglitazone hydrochloride).

Excipient(s): Lactose monohydrate 154 mg

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet

Pioglitazone 30 mg

white, round tablet, with imprint “PGT 30” on one side and with score line on both sides

The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

Pioglitazone is indicated in the treatment of type 2 diabetes mellitus:

as monotherapy

- in adult patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance

Pioglitazone is also indicated for combination with insulin in type 2 diabetes mellitus adult patients with insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance (see section 4.4).

After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6 months to assess adequacy of response to treatment (e.g. reduction in HbA1c). In patients who fail to show an adequate response, pioglitazone should be discontinued. In light of potential risks with prolonged therapy, prescribers should confirm at subsequent routine reviews that the benefit of pioglitazone is maintained (see section 4.4).

4.2 Posology And Method Of Administration

Posology

Pioglitazone treatment may be initiated at 15 mg or 30 mg once daily. The dose may be increased in increments up to 45 mg once daily.

In combination with insulin, the current insulin dose can be continued upon initiation of pioglitazone therapy. If patients report hypoglycaemia, the dose of insulin should be decreased.

Special population

Elderly

No dosage adjustment is necessary for elderly patients (see section 5.2). Physicians should start treatment with the lowest available dose and increase the dose gradually, particularly when pioglitazone is used in combination with insulin (see section 4.4 Fluid retention and cardiac failure).

Renal impairment

No dosage adjustment is necessary in patients with impaired renal function (creatinine clearance> 4 ml/min) (see section 5.2). No information is available from dialysed patients therefore pioglitazone should not be used in such patients.

Hepatic impairment

Pioglitazone should not be used in patients with hepatic impairment (see section 4.3 and 4.4).

Paediatric population

The safety and efficacy of Pioglitazone in children and adolescents under 18 years of age have not been established. No data are available.

Method of administration

Pioglitazone tablets are taken orally once daily with or without food. Tablets should be swallowed with a glass of water.

4.3 Contraindications

Pioglitazone is contraindicated in patients with:

- hypersensitivity to the active substance or to any of the excipients

- cardiac failure or history of cardiac failure (NYHA stages I to IV)

- hepatic impairment

- diabetic ketoacidosis

- current bladder cancer or a history of bladder cancer

- uninvestigated macroscopic haematuria

4.4 Special Warnings And Precautions For Use

Fluid retention and cardiac failure:

Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure. When treating patients who have at least one risk factor for development of congestive heart failure (e.g. prior myocardial infarction or symptomatic coronary artery disease or the elderly), physicians should start with the lowest available dose and increase the dose gradually. Patients should be observed for signs and symptoms of heart failure, weight gain or oedema; particularly those with reduced cardiac reserve. There have been post-marketing cases of cardiac failure reported when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure. Patients should be observed for signs and symptoms of heart failure, weight gain and oedema when pioglitazone is used in combination with insulin. Since insulin and pioglitazone are both associated with fluid retention, concomitant administration may increase the risk of oedema. Pioglitazone should be discontinued if any deterioration in cardiac status occurs.

A cardiovascular outcome study of pioglitazone has been performed in patients under 75 years with type 2 diabetes mellitus and pre-existing major macrovascular disease. Pioglitazone or placebo was added to existing antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed an increase in reports of heart failure, however this did not lead to an increase in mortality in this study.

Elderly

Combination use with insulin should be considered with caution in the elderly because of increased risk of serious heart failure.

In light of age- related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully both before and during treatment in the elderly.

Bladder Cancer

Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with pioglitazone (19 cases from 12506 patients, 0.15%) than in control groups (7 cases from 10212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, P=0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups. Available epidemiological data also suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone in particular in patients treated for the longest durations and with the highest cumulative doses. A possible risk after short term treatment cannot be excluded.

Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks include age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigated before starting pioglitazone therapy.

Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment.

Monitoring of liver function:

There have been rare reports of hepatocellular dysfunction during post-marketing experience (see section 4.8). It is recommended, therefore, that patients treated with pioglitazone undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with pioglitazone in all patients. Therapy with pioglitazone should not be initiated in patients with increased baseline liver enzyme levels (ALT> 2.5 X upper limit of normal) or with any other evidence of liver disease.

Following initiation of therapy with pioglitazone, it is recommended that liver enzymes be monitored periodically based on clinical judgement. If ALT levels are increased to 3 X upper limit of normal during pioglitazone therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain> 3 X the upper limit of normal, therapy should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with pioglitazone should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, the medicinal product should be discontinued.

Weight gain:

In clinical trials with pioglitazone there was evidence of dose related weight gain, which may be due to fat accumulation and in some cases associated with fluid retention. In some cases weight increase may be a symptom of cardiac failure, therefore weight should be closely monitored. Part of the treatment of diabetes is dietary control. Patients should be advised to adhere strictly to a calorie-controlled diet.

Haematology:

There was a small reduction in mean haemoglobin (4 % relative reduction) and haematocrit (4.1 % relative reduction) during therapy with pioglitazone, consistent with haemodilution. Similar changes were seen in metformin (haemoglobin 3 - 4 % and haematocrit 3.6 – 4.1 % relative reductions) and to a lesser extent sulphonylurea and insulin (haemoglobin 1 – 2 % and haematocrit 1 – 3.2 % relative reductions) treated patients in comparative controlled trials with pioglitazone.

Hypoglycaemia:

As a consequence of increased insulin sensitivity, patients receiving pioglitazone in dual or triple oral therapy with a sulphonylurea or in dual therapy with insulin may be at risk for dose-related hypoglycaemia, and a reduction in the dose of the sulphonylurea or insulin may be necessary.

Eye disorders:

Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone. Many of these patients reported concurrent peripheral oedema. It is unclear whether or not there is a direct association between pioglitazone and macular oedema but prescribers should be alert to the possibility of macular oedema if patients report disturbances in visual acuity; an appropriate ophthalmological referral should be considered.

Others:

An increased incidence in bone fractures in women was seen in a pooled analysis of adverse reactions of bone fracture from randomised, controlled, double blind clinical trials in over 8100 pioglitazone and 7400 comparator treated patients, on treatment for up to 3.5 years.

Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).

The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with pioglitazone and 1.1 fractures per 100 patient years in women treated with a comparator. The observed excess risk of fractures for women in this dataset on pioglitazone is therefore 0.8 fractures per 100 patient years of use.

In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100 patient years) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).

The risk of fractures should be considered in the long term care of women treated with pioglitazone.

As a consequence of enhancing insulin action, pioglitazone treatment in patients with polycystic ovarian syndrome may result in resumption of ovulation. These patients may be at risk of pregnancy. Patients should be aware of the risk of pregnancy and if a patient wishes to become pregnant or if pregnancy occurs, the treatment should be discontinued (see section 4.6).

Pioglitazone should be used with caution during concomitant administration of cytochrome P450 2C8 inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely. Pioglitazone dose adjustment within the recommended posology or changes in diabetic treatment should be considered (see section 4.5).

Pioglitazone tablets contain lactose monohydrate and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Co-administration of pioglitazone with sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea. Studies in man suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 and 3A4. In vitro studies have shown no inhibition of any subtype of cytochrome P450. Interactions with substances metabolised by these enzymes, e.g. oral contraceptives, cyclosporin, calcium channel blockers, and HMGCoA reductase inhibitors are not to be expected.

Co-administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported to result in a 3-fold increase in AUC of pioglitazone. Since there is a potential for an increase in dose-related adverse events, a decrease in the dose of pioglitazone may be needed when gemfibrozil is concomitantly administered. Close monitoring of glycaemic control should be considered (see section 4.4). Co-administration of pioglitazone with rifampicin (an inducer of cytochrome P450 2C8) is reported to result in a 54% decrease in AUC of pioglitazone. The pioglitazone dose may need to be increased when rifampicin is concomitantly administered. Close monitoring of glycaemic control should be considered (see section 4.4).

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate human data to determine the safety of pioglitazone during pregnancy. Foetal growth restriction was apparent in animal studies with pioglitazone. This was attributable to the action of pioglitazone in diminishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during pregnancy thereby reducing the availability of metabolic substrates for foetal growth. The relevance of such a mechanism in humans is unclear and pioglitazone should not be used in pregnancy.

Breastfeeding

Pioglitazone has been shown to be present in the milk of lactating rats. It is not known whether pioglitazone is secreted in human milk. Therefore, pioglitazone should not be administered to breast-feeding women.

Fertility

In animal fertility studies there was no effect on copulation, impregnation or fertility index.

4.7 Effects On Ability To Drive And Use Machines

Pioglitazone has no or negligible effect on the ability to drive and use machines. However patients who experience visual disturbance should be cautious when driving or using machines.

4.8 Undesirable Effects

Adverse reactions reported in excess (> 0.5 %) of placebo and as more than an isolated case in patients receiving pioglitazone in double-blind studies are listed below as MedDRA preferred term by system organ class and absolute frequency. Frequencies are defined as: very common (

Adverse reaction	Frequency of adverse reactions of pioglitazone by treatment regimen
Monotherapy	Combination
with metformin	with sulphonylurea	with metformin and sulphonylurea	with insulin
Infections and infestations
upper respiratory tract infection	common	common	common	common	common
bronchitis					common
sinusitis	uncommon	uncommon	uncommon	uncommon	uncommon
Blood and lymphatic system disorders
anaemia		common
Metabolism and nutrition disorders
hypo-glycaemia			uncommon	very common	common
appetite increased			uncommon
Nervous system disorders
hypo-aesthesia	common	common	common	common	common
headache		common	uncommon
dizziness			common
insomnia	uncommon	uncommon	uncommon	uncommon	uncommon
Eye disorders
visual disturbance1	common	common	uncommon
macular oedema2	not known	not known	not known	not known	not known
Ear and labyrinth disorders
vertigo			uncommon
Cardiac disorders
heart failure3					common
Neoplasms benign, malignant and unspecified (including cysts and polyps)
bladder cancer	uncommon	uncommon	uncommon	uncommon	uncommon
Respiratory, thoracic and mediastinal disorders
dyspnoea					common
Gastrointestinal disorders
flatulence		uncommon	common
Skin and subcutaneous tissue disorders
sweating			uncommon
Musculoskeletal and connective tissue disorders
fracture bone4	common	common	common	common	common
arthralgia		common		common	common
back pain					common
Renal and urinary disorders
haematuria		common
glycosuria			uncommon
proteinuria			uncommon
Reproductive system and breast disorders
erectile dysfunction		common
General disorders and administration site conditions
oedema					very common
fatigue			uncommon
Investigations
weight increased5	common	common	common	common	common
blood creatine phospho-kinase increased				common
increased lactic dehydro-genase			uncommon
alanine aminotransferase increased6	not known	not known	not known	not known	not known

¹ Visual disturbance has been reported mainly early in treatment and is related to changes in blood glucose due to temporary alteration in the turgidity and refractive index of the lens as seen with other hypoglycaemic treatments.

²Oedema was reported in 6 – 9 % of patients treated with pioglitazone over one year in controlled clinical trials. The oedema rates for comparator groups (sulphonylurea, metformin) were 2 – 5 %. The reports of oedema were generally mild to moderate and usually did not require discontinuation of treatment.

³ In controlled clinical trials the incidence of reports of heart failure with pioglitazone treatment was the same as in placebo, metformin and sulphonylurea treatment groups, but was increased when used in combination therapy with insulin. In an outcome study of patients with pre-existing major macrovascular disease, the incidence of serious heart failure was 1.6 % higher with pioglitazone than with placebo, when added to therapy that included insulin. However, this did not lead to an increase in mortality in this study. Heart failure has been reported rarely with marketing use of pioglitazone, but more frequently when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure.

⁴ A pooled analysis was conducted of adverse reactions of bone fractures from randomised, comparator controlled, double blind clinical trials in over 8100 patients in the pioglitazone-treated groups and 7400 in the comparator-treated groups of up to 3.5 years duration. A higher rate of fractures was observed in women taking pioglitazone (2.6%) versus comparator (1.7%). No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).

In the 3.5 year PROactive study, 44/870 (5.1%) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).

⁵In active comparator controlled trials mean weight increase with pioglitazone given as monotherapy was 2 – 3 kg over one year. This is similar to that seen in a sulphonylurea active comparator group. In combination trials pioglitazone added to metformin resulted in mean weight increase over one year of 1.5 kg and added to a sulphonylurea of 2.8 kg. In comparator groups addition of sulphonylurea to metformin resulted in a mean weight gain of 1.3 kg and addition of metformin to a sulphonylurea a mean weight loss of 1.0 kg.

⁶ In clinical trials with pioglitazone the incidence of elevations of ALT greater than three times the upper limit of normal was equal to placebo but less than that seen in metformin or sulphonylurea comparator groups. Mean levels of liver enzymes decreased with treatment with pioglitazone. Rare cases of elevated liver enzymes and hepatocellular dysfunction have occurred in post-marketing experience. Although in very rare cases fatal outcome has been reported, causal relationship has not been established.

4.9 Overdose

In clinical studies, patients have taken pioglitazone at higher than the recommended highest dose of 45 mg daily. The maximum reported dose of 120 mg/day for four days, then 180 mg/day for seven days was not associated with any symptoms.

Hypoglycaemia may occur in combination with sulphonylureas or insulin. Symptomatic and general supportive measures should be taken in case of overdose.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins; ATC code: A10 BG 03.

Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to act via activation of specific nuclear receptors (peroxisome proliferator activated receptor gamma) leading to increased insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment with pioglitazone has been shown to reduce hepatic glucose output and to increase peripheral glucose disposal in the case of insulin resistance.

Fasting and postprandial glycaemic control is improved in patients with type 2 diabetes mellitus. The improved glycaemic control is associated with a reduction in both fasting and postprandial plasma insulin concentrations. A clinical trial of pioglitazone vs. gliclazide as monotherapy was extended to two years in order to assess time to treatment failure (defined as appearance of HbA_1c1c < 8.0 %) was sustained in 69 % of patients treated with pioglitazone, compared with 50 % of patients on gliclazide. In a two-year study of combination therapy comparing pioglitazone with gliclazide when added to metformin, glycaemic control measured as mean change from baseline in HbA_1c was similar between treatment groups after one year. The rate of deterioration of HbA_1c during the second year was less with pioglitazone than with gliclazide.

In a placebo controlled trial, patients with inadequate glycaemic control despite a three month insulin optimisation period were randomised to pioglitazone or placebo for 12 months. Patients receiving pioglitazone had a mean reduction in HbA_1c of 0.45 % compared with those continuing on insulin alone, and a reduction of insulin dose in the pioglitazone treated group.

HOMA analysis shows that pioglitazone improves beta cell function as well as increasing insulin sensitivity. Two-year clinical studies have shown maintenance of this effect.

In one year clinical trials, pioglitazone consistently gave a statistically significant reduction in the albumin/creatinine ratio compared to baseline.

The effect of pioglitazone (45 mg monotherapy vs. placebo) was studied in a small 18-week trial in type 2 diabetics. Pioglitazone was associated with significant weight gain. Visceral fat was significantly decreased, while there was an increase in extra-abdominal fat mass. Similar changes in body fat distribution on pioglitazone have been accompanied by an improvement in insulin sensitivity. In most clinical trials, reduced total plasma triglycerides and free fatty acids, and increased HDL-cholesterol levels were observed as compared to placebo, with small, but not clinically significant increases in LDL-cholesterol levels.

In clinical trials of up to two years duration, pioglitazone reduced total plasma triglycerides and free fatty acids, and increased HDL cholesterol levels, compared with placebo, metformin or gliclazide. Pioglitazone did not cause statistically significant increases in LDL cholesterol levels compared with placebo, whilst reductions were observed with metformin and gliclazide. In a 20-week study, as well as reducing fasting triglycerides, pioglitazone reduced post prandial hypertriglyceridaemia through an effect on both absorbed and hepatically synthesised triglycerides. These effects were independent of pioglitazone's effects on glycaemia and were statistically significant different to glibenclamide.

In PROactive, a cardiovascular outcome study, 5238 patients with type 2 diabetes mellitus and pre-existing major macrovascular disease were randomised to pioglitazone or placebo in addition to existing antidiabetic and cardiovascular therapy, for up to 3.5 years. The study population had an average age of 62 years; the average duration of diabetes was 9.5 years. Approximately one third of patients were receiving insulin in combination with metformin and/or a sulphonylurea. To be eligible patients had to have had one or more of the following: myocardial infarction, stroke, percutaneous cardiac intervention or coronary artery bypass graft, acute coronary syndrome, coronary artery disease, or peripheral arterial obstructive disease. Almost half of the patients had a previous myocardial infarction and approximately 20% had had a stroke. Approximately half of the study population had at least two of the cardiovascular history entry criteria. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II antagonists, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates).

Although the study failed regarding its primary endpoint, which was a composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation, coronary revascularisation and leg revascularisation, the results suggest that there are no long-term cardiovascular concerns regarding use of pioglitazone. However, the incidences of oedema, weight gain and heart failure were increased. No increase in mortality from heart failure was observed.

5.2 Pharmacokinetic Properties

Absorption:

Following oral administration, pioglitazone is rapidly absorbed, and peak plasma concentrations of unchanged pioglitazone are usually achieved 2 hours after administration. Proportional increases of the plasma concentration were observed for doses from 2 – 60 mg. Steady state is achieved after 4–7 days of dosing. Repeated dosing does not result in accumulation of the compound or metabolites. Absorption is not influenced by food intake. Absolute bioavailability is greater than 80 %.

Distribution:

The estimated volume of distribution in humans is 0.25 l/kg.

Pioglitazone and all active metabolites are extensively bound to plasma protein (> 99 %).

Biotransformation:

Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. This is predominantly via cytochrome P450 2C8 although other isoforms may be involved to a lesser degree. Three of the six identified metabolites are active (M-II, M-III, and M-IV). When activity, concentrations and protein binding are taken into account, pioglitazone and metabolite M-III contribute equally to efficacy. On this basis M-IV contribution to efficacy is approximately three-fold that of pioglitazone, whilst the relative efficacy of M-II is minimal.

In vitro studies have shown no evidence that pioglitazone inhibits any subtype of cytochrome P450. There is no induction of the main inducible P450 isoenzymes 1A, 2C8/9, and 3A4 in man.

Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Concomitant administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) or with rifampicin (an inducer of cytochrome P450 2C8) is reported to increase or decrease, respectively, the plasma concentration of pioglitazone (see section 4.5).

Elimination:

Following oral administration of radiolabelled pioglitazone to man, recovered label was mainly in faeces (55%) and a lesser amount in urine (45 %). In animals, only a small amount of unchanged pioglitazone can be detected in either urine or faeces. The mean plasma elimination half-life of unchanged pioglitazone in man is 5 to 6 hours and for its total active metabolites 16 to 23 hours.

Elderly:

Steady state pharmacokinetics are similar in patients age 65 and over and young subjects.

Patients with renal impairment:

In patients with renal impairment, plasma concentrations of pioglitazone and its metabolites are lower than those seen in subjects