Lorem ipsum dolor sit amet, consectetur adipiscing elit. Mauris eget ipsum non nulla elementum pretium vel in augue. Aenean efficitur fringilla erat. Quisque sed nisl urna. In eget faucibus arcu. Vestibulum nec nisl non lacus tempus pretium ac et mauris. Donec dictum cursus elit eget sagittis. Integer pretium vitae diam in varius. Cras vulputate pulvinar felis at molestie. Vestibulum neque purus, vehicula quis pretium eu, tristique a tortor. Aliquam a porttitor mi. Duis quis est egestas, tristique enim nec, pretium nibh. Mauris nisl nibh, vulputate mattis ligula sed, tempus dapibus ipsum. Etiam nec mauris felis. Morbi aliquam efficitur mauris, sit amet dictum justo commodo pharetra.

DETAIL INFORMATION

• In eget dictum arcu. Integer sed mattis enim.
• Proin rutrum non lectus a faucibus. Nullam a faucibus orci, et tincidunt massa.
• Praesent sed hendrerit quam, vitae bibendum odio.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus
• Duis ligula neque, ornare sit amet purus eu, lobortis commodo ligula.
• Ronec lobortis suscipit dui eu ullamcorper. Curabitur ultricies varius tortor nec elementum.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus, ante massa porta ante.
• Maximus leo nunc at nulla. Donec lobortis suscipit dui eu ullamcorper.
• Curabitur ultricies varius tortor nec elementum.

PRODUCT USER GUIDE

• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus
• Duis ligula neque, ornare sit amet purus eu, lobortis commodo ligula.
• Ronec lobortis suscipit dui eu ullamcorper. Curabitur ultricies varius tortor nec elementum.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus, ante massa porta ante.
• Maximus leo nunc at nulla. Donec lobortis suscipit dui eu ullamcorper.
• Curabitur ultricies varius tortor nec elementum.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Mauris eget ipsum non nulla elementum pretium vel in augue. Aenean efficitur fringilla erat. Quisque sed nisl urna. In eget faucibus arcu. Vestibulum nec nisl non lacus tempus pretium ac et mauris. Donec dictum cursus elit eget sagittis. Integer pretium vitae diam in varius. Cras vulputate pulvinar felis at molestie. Vestibulum neque purus, vehicula quis pretium eu, tristique a tortor. Aliquam a porttitor mi. Duis quis est egestas, tristique enim nec, pretium nibh. Mauris nisl nibh, vulputate mattis ligula sed, tempus dapibus ipsum. Etiam nec mauris felis. Morbi aliquam efficitur mauris, sit amet dictum justo commodo pharetra.

DETAIL INFORMATION

• In eget dictum arcu. Integer sed mattis enim.
• Proin rutrum non lectus a faucibus. Nullam a faucibus orci, et tincidunt massa.
• Praesent sed hendrerit quam, vitae bibendum odio.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus
• Duis ligula neque, ornare sit amet purus eu, lobortis commodo ligula.
• Ronec lobortis suscipit dui eu ullamcorper. Curabitur ultricies varius tortor nec elementum.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus, ante massa porta ante.
• Maximus leo nunc at nulla. Donec lobortis suscipit dui eu ullamcorper.
• Curabitur ultricies varius tortor nec elementum.

PRODUCT USER GUIDE

• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus
• Duis ligula neque, ornare sit amet purus eu, lobortis commodo ligula.
• Ronec lobortis suscipit dui eu ullamcorper. Curabitur ultricies varius tortor nec elementum.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus, ante massa porta ante.
• Maximus leo nunc at nulla. Donec lobortis suscipit dui eu ullamcorper.
• Curabitur ultricies varius tortor nec elementum.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Mauris eget ipsum non nulla elementum pretium vel in augue. Aenean efficitur fringilla erat. Quisque sed nisl urna. In eget faucibus arcu. Vestibulum nec nisl non lacus tempus pretium ac et mauris. Donec dictum cursus elit eget sagittis. Integer pretium vitae diam in varius. Cras vulputate pulvinar felis at molestie. Vestibulum neque purus, vehicula quis pretium eu, tristique a tortor. Aliquam a porttitor mi. Duis quis est egestas, tristique enim nec, pretium nibh. Mauris nisl nibh, vulputate mattis ligula sed, tempus dapibus ipsum. Etiam nec mauris felis. Morbi aliquam efficitur mauris, sit amet dictum justo commodo pharetra.

DETAIL INFORMATION

• In eget dictum arcu. Integer sed mattis enim.
• Proin rutrum non lectus a faucibus. Nullam a faucibus orci, et tincidunt massa.
• Praesent sed hendrerit quam, vitae bibendum odio.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus
• Duis ligula neque, ornare sit amet purus eu, lobortis commodo ligula.
• Ronec lobortis suscipit dui eu ullamcorper. Curabitur ultricies varius tortor nec elementum.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus, ante massa porta ante.
• Maximus leo nunc at nulla. Donec lobortis suscipit dui eu ullamcorper.
• Curabitur ultricies varius tortor nec elementum.

PRODUCT USER GUIDE

• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus
• Duis ligula neque, ornare sit amet purus eu, lobortis commodo ligula.
• Ronec lobortis suscipit dui eu ullamcorper. Curabitur ultricies varius tortor nec elementum.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus, ante massa porta ante.
• Maximus leo nunc at nulla. Donec lobortis suscipit dui eu ullamcorper.
• Curabitur ultricies varius tortor nec elementum.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Mauris eget ipsum non nulla elementum pretium vel in augue. Aenean efficitur fringilla erat. Quisque sed nisl urna. In eget faucibus arcu. Vestibulum nec nisl non lacus tempus pretium ac et mauris. Donec dictum cursus elit eget sagittis. Integer pretium vitae diam in varius. Cras vulputate pulvinar felis at molestie. Vestibulum neque purus, vehicula quis pretium eu, tristique a tortor. Aliquam a porttitor mi. Duis quis est egestas, tristique enim nec, pretium nibh. Mauris nisl nibh, vulputate mattis ligula sed, tempus dapibus ipsum. Etiam nec mauris felis. Morbi aliquam efficitur mauris, sit amet dictum justo commodo pharetra.

DETAIL INFORMATION

• In eget dictum arcu. Integer sed mattis enim.
• Proin rutrum non lectus a faucibus. Nullam a faucibus orci, et tincidunt massa.
• Praesent sed hendrerit quam, vitae bibendum odio.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus
• Duis ligula neque, ornare sit amet purus eu, lobortis commodo ligula.
• Ronec lobortis suscipit dui eu ullamcorper. Curabitur ultricies varius tortor nec elementum.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus, ante massa porta ante.
• Maximus leo nunc at nulla. Donec lobortis suscipit dui eu ullamcorper.
• Curabitur ultricies varius tortor nec elementum.

PRODUCT USER GUIDE

• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus
• Duis ligula neque, ornare sit amet purus eu, lobortis commodo ligula.
• Ronec lobortis suscipit dui eu ullamcorper. Curabitur ultricies varius tortor nec elementum.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus, ante massa porta ante.
• Maximus leo nunc at nulla. Donec lobortis suscipit dui eu ullamcorper.
• Curabitur ultricies varius tortor nec elementum.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Mauris eget ipsum non nulla elementum pretium vel in augue. Aenean efficitur fringilla erat. Quisque sed nisl urna. In eget faucibus arcu. Vestibulum nec nisl non lacus tempus pretium ac et mauris. Donec dictum cursus elit eget sagittis. Integer pretium vitae diam in varius. Cras vulputate pulvinar felis at molestie. Vestibulum neque purus, vehicula quis pretium eu, tristique a tortor. Aliquam a porttitor mi. Duis quis est egestas, tristique enim nec, pretium nibh. Mauris nisl nibh, vulputate mattis ligula sed, tempus dapibus ipsum. Etiam nec mauris felis. Morbi aliquam efficitur mauris, sit amet dictum justo commodo pharetra.

DETAIL INFORMATION

• In eget dictum arcu. Integer sed mattis enim.
• Proin rutrum non lectus a faucibus. Nullam a faucibus orci, et tincidunt massa.
• Praesent sed hendrerit quam, vitae bibendum odio.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus
• Duis ligula neque, ornare sit amet purus eu, lobortis commodo ligula.
• Ronec lobortis suscipit dui eu ullamcorper. Curabitur ultricies varius tortor nec elementum.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus, ante massa porta ante.
• Maximus leo nunc at nulla. Donec lobortis suscipit dui eu ullamcorper.
• Curabitur ultricies varius tortor nec elementum.

PRODUCT USER GUIDE

• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus
• Duis ligula neque, ornare sit amet purus eu, lobortis commodo ligula.
• Ronec lobortis suscipit dui eu ullamcorper. Curabitur ultricies varius tortor nec elementum.
• Sed bibendum pellentesque sapien. Maecenas luctus, ex rutrum feugiat rhoncus, ante massa porta ante.
• Maximus leo nunc at nulla. Donec lobortis suscipit dui eu ullamcorper.
• Curabitur ultricies varius tortor nec elementum.

Lodoz is indicated in patients with mild to moderate essential hypertension.

Bisoprolol fumerate and Hydrochlorothiazide (HCTZ) have been used individually and in combination for the treatment of hypertension. The combination provides an additive clinical response. The hypokalemic effects with HCTZ 6.25 mg combination are significantly lower than with HCTZ 25 mg. Bisoprolol fumerate is a highly selective β1 – adrenoceptor blocking agent, without significant membrane stabilizing or intrinsic sympathomimetic activities in its therapeutic dose range.

Hydrochlorothiazide is a thiazide diuretic with antihypertensive activity. Its diuretic effect is due to inhibition of active Na+ transport from the renal tubules to the blood, affecting Na+ reabsorption.

Composition:

Lodoz® 2.5: Each film-coated tablet contains bisoprolol fumarate 2.5 mg and hydrochlorothiazide 6.25 mg

Lodoz® 5: Each film- coated tablet contains bisoprolol fumarate 5 mg and hydrochlorothiazide 6.25 mg.

Indications: Lodoz is indicated in mild to moderate hypertension

Dosage and Administration:

Initial therapy: Antihypertensive therapy may be initiated with the lowest dose of Lodoz, on 2.5/ 6.25 mg tablet once daily. Subsequent titration (14 day intervals) may be carried out with Lodoz 5/ 6.25 mg tablets up to the maximum recommended dose 20/ 12.5 mg once daily, as appropriate.

Elderly Patients: Dosage adjustment on the basis of age is not usually necessary, unless there is also significant renal or hepatic dysfunction

Contraindications: Lodoz is contraindicated in patients in cardiogenic shock, overt cardiac failure (see WARNINGS), second or third degree AV block, marked sinus bradycardia, anuria, and hyprersensitivity to either component of this product or to other sulfonamide-derived drugs.

Warnings:

Cardiac failure: In general, beta-blocking agents should be avoided in patients with overt congestive failure.

Abrupt Cessation of therapy: Exacerbations of angina pectoris and, in some instances, myocardial infarction or ventricular arrhythmia, have been observed in patients with coronary artery disease, following abrupt cessation therapy with beta-blockers. Such patients should, therefore, be cautioned against interruption or discontinuation of therapy without the physician’s advice.

Peripheral Vascular Disease: Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

Bronchospastic Disease: Patients with bronchospastic pulmonary disease should, in general, not receive beta-blockers. Since, beta-selelctivity is not absolute, the lowest possible dose of lodoz should be used. Care should be taken to ensure that a beta2 agonist (bronchodilator) is easily available.

Diabetes and Hypoglycemia: Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.

Thyrotoxicosis: Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.

Hepatic Disease: Lodoz  should be used with caution in patients with impaired hepatic function or progressive liver disease.

Precautions:

General: Electrolyte and Fluid Balance Status: periodic determination of serum electrolytes should be performed, and patients should be observed for signs of fluid or electrolyte disturbances, i.e. hyponatremia, hypochloremic alkalosis, and hypokalemia and hypomagnesemia..

Parathyoid Disease: Calcium excretion is decreased by thiazides, and pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients or prolonged thiazide therapy.

Hyperuricemia: Hyperuricemia or acute gout may be precipitated in certain patietns receiving thiazide diuretics.

Adverse Reactions: Unsteadiness, vertigo, syncope, sleep and sensory disturbances, restlessness, cold extremitities, claudication, orthostatic hypotension, chest pain, abdominal pain, vomiting, constipation, dry mouth, musculoskeletal pains, rash, acne, ache, eczema, gout, dyspnea, malaise, edema, angioedema, transient blurred vision, etc.

Storage: Store at temperature not more than 25°C, protect from light.

Shelf-life: 36 months.

Presentation: Strip of 10 tablets.

For further details kindly refer the full prescribing information.

Sitagliptin

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

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

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

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

If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Januvia is and what it is used for

2. What you need to know before you take Januvia

3. How to take Januvia

4. Possible side effects

5. How to store Januvia

6. Contents of the pack and other information

1. What Januvia is and what it is used for

Januvia contains the active substance sitagliptin which is a member of a class of medicines called DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors) that lowers blood sugar levels in adult patients with type 2 diabetes mellitus.

This medicine helps to increase the levels of insulin produced after a meal and decreases the amount of sugar made by the body.

Your doctor has prescribed this medicine to help lower your blood sugar, which is too high because of your type 2 diabetes. This medicine can be used alone or in combination with certain other medicines (insulin, metformin, sulphonylureas, or glitazones) that lower blood sugar, which you may already be taking for your diabetes together with a food and exercise plan.

What is type 2 diabetes?

Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems like heart disease, kidney disease, blindness, and amputation.

2. What you need to know before you take Januvia

Do not take Januvia

if you are allergic to sitagliptin or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Cases of inflammation of the pancreas (pancreatitis) have been reported in patients receiving Januvia (see section 4).

Tell your doctor if you have or have had:

a disease of the pancreas (such as pancreatitis)

gallstones, alcohol dependence or very high levels of triglycerides (a form of fat) in your blood. These medical conditions can increase your chance of getting pancreatitis (see section 4).

type 1 diabetes

diabetic ketoacidosis (a complication of diabetes with high blood sugar, rapid weight loss, nausea or vomiting)

any past or present kidney problems.

an allergic reaction to Januvia (see section 4).

This medicine is unlikely to cause low blood sugar because it does not work when your blood sugar is low. However, when this medicine is used in combination with a sulphonylurea medicine or with insulin, low blood sugar (hypoglycaemia) can occur. Your doctor may reduce the dose of your sulphonylurea or insulin medicine.

Children and adolescents

Children and adolescents below 18 years should not use this medicine. It is not known if this medicine is safe and effective when used in children and adolescents under 18 years of age.

Other medicines and Januvia

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

In particular, tell your doctor if you are taking digoxin (a medicine used to treat irregular heart beat and other heart problems). The level of digoxin in your blood may need to be checked if taking with Januvia.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

You should not take this medicine during pregnancy.

It is not known if this medicine passes into breast milk. You should not take this medicine if you are breast-feeding or plan to breast-feed.

Driving and using machines

This medicine has no or negligible influence on the ability to drive and use machines. However, dizziness and drowsiness have been reported, which may affect your ability to drive or use machines.

Taking this medicine in combination with medicines called sulphonylureas or with insulin can cause hypoglycaemia, which may affect your ability to drive and use machines or work without safe foothold.

3. How to take Januvia

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

The usual recommended dose is:

one 100 mg film-coated tablet

once a day

by mouth

If you have kidney problems, your doctor may prescribe lower doses (such as 25 mg or 50 mg).

You can take this medicine with or without food and drink.

Your doctor may prescribe this medicine alone or with certain other medicines that lower blood sugar.

Diet and exercise can help your body use its blood sugar better. It is important to stay on the diet and exercise recommended by your doctor while taking Januvia.

If you take more Januvia than you should

If you take more than the prescribed dosage of this medicine, contact your doctor immediately.

If you forget to take Januvia

If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take a double dose of this medicine.

If you stop taking Januvia

Continue to take this medicine as long as your doctor prescribes it so you can continue to help control your blood sugar. You should not stop taking this medicine without talking to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

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

STOP taking Januvia and contact a doctor immediately if you notice any of the following serious side effects:

Severe and persistent pain in the abdomen (stomach area) which might reach through to your back with or without nausea and vomiting, as these could be signs of an inflamed pancreas (pancreatitis).

If you have a serious allergic reaction (frequency not known), including rash, hives, blisters on the skin/peeling skin and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing, stop taking this medicine and call your doctor right away. Your doctor may prescribe a medicine to treat your allergic reaction and a different medicine for your diabetes.

Some patients have experienced the following side effects after adding sitagliptin to metformin:

Common (may affect up to 1 in 10 people): low blood sugar, nausea, flatulence, vomiting

Uncommon (may affect up to 1 in 100 people): stomach ache, diarrhoea, constipation, drowsiness

Some patients have experienced different types of stomach discomfort when starting the combination of sitagliptin and metformin together (frequency is common).

Some patients have experienced the following side effects while taking sitagliptin in combination with a sulphonylurea and metformin:

Very common (may affect more than 1 in 10 people): low blood sugar

Common: constipation

Some patients have experienced the following side effects while taking sitagliptin and pioglitazone:

Common: flatulence, swelling of the hands or legs

Some patients have experienced the following side effects while taking sitagliptin in combination with pioglitazone and metformin:

Common: swelling of the hands or legs

Some patients have experienced the following side effects while taking sitagliptin in combination with insulin (with or without metformin):

Common: flu

Uncommon: dry mouth

Some patients have experienced the following side effects while taking sitagliptin alone in clinical studies, or during post-approval use alone and/or with other diabetes medicines:

Common: low blood sugar, headache, upper respiratory infection, stuffy or runny nose and sore throat, osteoarthritis, arm or leg pain

Uncommon: dizziness, constipation, itching

Frequency not known: kidney problems (sometimes requiring dialysis), vomiting, joint pain, muscle pain, back pain, interstitial lung disease

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine.

United Kingdom: Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Ireland:

HPRA Pharmacovigilance

Earlsfort Terrace

IRL Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website:www.hpra.ie

E-mail:medsafety@hpra.ie

5. How to store Januvia

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and the carton after ‘EXP’. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Januvia contains

The active substance is sitagliptin. Each film-coated tablet (tablet) contains sitagliptin phosphate monohydrate, equivalent to 25 mg sitagliptin.

The other ingredients are: In the tablet core: microcrystalline cellulose (E460), calcium hydrogen phosphate, anhydrous (E341), croscarmellose sodium (E468), magnesium stearate (E470b), and sodium stearyl fumarate. The tablet film coating contains: poly(vinyl alcohol), macrogol 3350, talc (E553b), titanium dioxide (E171), red iron oxide (E172), and yellow iron oxide (E172).

What Januvia looks like and contents of the pack

Round, pink film-coated tablet with “221” on one side.

Opaque blisters (PVC/PE/PVDC and aluminum). Packs of 14, 28, 30, 56, 84, 90 or 98 film-coated tablets and 50 x 1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Merck Sharp & Dohme Ltd.

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

United Kingdom

Manufacturer

Merck Sharp & Dohme Ltd.

Shotton Lane

Cramlington

Northumberland

NE23 3JU

United Kingdom

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

United Kingdom

Merck Sharp & Dohme Limited

Tel: +44 (0) 1992 467272

Email: medicalinformationuk@merck.com

This leaflet was last revised in June 2015.

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu.

© Merck Sharp & Dohme Limited 2015. All rights reserved.

PIL.JAN.25 mg.15.UK.4634.WS-0741 & PSUR 032

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

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

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

If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Januvia is and what it is used for

2. What you need to know before you take Januvia

3. How to take Januvia

4. Possible side effects

5. How to store Januvia

6. Contents of the pack and other information

1. What Januvia is and what it is used for

Januvia contains the active substance sitagliptin which is a member of a class of medicines called DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors) that lowers blood sugar levels in adult patients with type 2 diabetes mellitus.

This medicine helps to increase the levels of insulin produced after a meal and decreases the amount of sugar made by the body.

Your doctor has prescribed this medicine to help lower your blood sugar, which is too high because of your type 2 diabetes. This medicine can be used alone or in combination with certain other medicines (insulin, metformin, sulphonylureas, or glitazones) that lower blood sugar, which you may already be taking for your diabetes together with a food and exercise plan.

What is type 2 diabetes?

Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems like heart disease, kidney disease, blindness, and amputation.

2. What you need to know before you take Januvia

Do not take Januvia

if you are allergic to sitagliptin or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Cases of inflammation of the pancreas (pancreatitis) have been reported in patients receiving Januvia (see section 4).

Tell your doctor if you have or have had:

a disease of the pancreas (such as pancreatitis)

gallstones, alcohol dependence or very high levels of triglycerides (a form of fat) in your blood. These medical conditions can increase your chance of getting pancreatitis (see section 4).

type 1 diabetes

diabetic ketoacidosis (a complication of diabetes with high blood sugar, rapid weight loss, nausea or vomiting)

any past or present kidney problems.

an allergic reaction to Januvia (see section 4).

This medicine is unlikely to cause low blood sugar because it does not work when your blood sugar is low. However, when this medicine is used in combination with a sulphonylurea medicine or with insulin, low blood sugar (hypoglycaemia) can occur. Your doctor may reduce the dose of your sulphonylurea or insulin medicine.

Children and adolescents

Children and adolescents below 18 years should not use this medicine. It is not known if this medicine is safe and effective when used in children and adolescents under 18 years of age.

Other medicines and Januvia

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

In particular, tell your doctor if you are taking digoxin (a medicine used to treat irregular heart beat and other heart problems). The level of digoxin in your blood may need to be checked if taking with Januvia.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

You should not take this medicine during pregnancy.

It is not known if this medicine passes into breast milk. You should not take this medicine if you are breast-feeding or plan to breast-feed.

Driving and using machines

This medicine has no or negligible influence on the ability to drive and use machines. However, dizziness and drowsiness have been reported, which may affect your ability to drive or use machines.

Taking this medicine in combination with medicines called sulphonylureas or with insulin can cause hypoglycaemia, which may affect your ability to drive and use machines or work without safe foothold.

3. How to take Januvia

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

The usual recommended dose is:

one 100 mg film-coated tablet

once a day

by mouth

If you have kidney problems, your doctor may prescribe lower doses (such as 25 mg or 50 mg).

You can take this medicine with or without food and drink.

Your doctor may prescribe this medicine alone or with certain other medicines that lower blood sugar.

Diet and exercise can help your body use its blood sugar better. It is important to stay on the diet and exercise recommended by your doctor while taking Januvia.

If you take more Januvia than you should

If you take more than the prescribed dosage of this medicine, contact your doctor immediately.

If you forget to take Januvia

If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take a double dose of this medicine.

If you stop taking Januvia

Continue to take this medicine as long as your doctor prescribes it so you can continue to help control your blood sugar. You should not stop taking this medicine without talking to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

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

STOP taking Januvia and contact a doctor immediately if you notice any of the following serious side effects:

Severe and persistent pain in the abdomen (stomach area) which might reach through to your back with or without nausea and vomiting, as these could be signs of an inflamed pancreas (pancreatitis).

If you have a serious allergic reaction (frequency not known), including rash, hives, blisters on the skin/peeling skin and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing, stop taking this medicine and call your doctor right away. Your doctor may prescribe a medicine to treat your allergic reaction and a different medicine for your diabetes.

Some patients have experienced the following side effects after adding sitagliptin to metformin:

Common (may affect up to 1 in 10 people): low blood sugar, nausea, flatulence, vomiting

Uncommon (may affect up to 1 in 100 people): stomach ache, diarrhoea, constipation, drowsiness

Some patients have experienced different types of stomach discomfort when starting the combination of sitagliptin and metformin together (frequency is common).

Some patients have experienced the following side effects while taking sitagliptin in combination with a sulphonylurea and metformin:

Very common (may affect more than 1 in 10 people): low blood sugar

Common: constipation

Some patients have experienced the following side effects while taking sitagliptin and pioglitazone:

Common: flatulence, swelling of the hands or legs

Some patients have experienced the following side effects while taking sitagliptin in combination with pioglitazone and metformin:

Common: swelling of the hands or legs

Some patients have experienced the following side effects while taking sitagliptin in combination with insulin (with or without metformin):

Common: flu

Uncommon: dry mouth

Some patients have experienced the following side effects while taking sitagliptin alone in clinical studies, or during post-approval use alone and/or with other diabetes medicines:

Common: low blood sugar, headache, upper respiratory infection, stuffy or runny nose and sore throat, osteoarthritis, arm or leg pain

Uncommon: dizziness, constipation, itching

Frequency not known: kidney problems (sometimes requiring dialysis), vomiting, joint pain, muscle pain, back pain, interstitial lung disease

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine.

United Kingdom: Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Ireland:

HPRA Pharmacovigilance

Earlsfort Terrace

IRL Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website:www.hpra.ie

E-mail:medsafety@hpra.ie

5. How to store Januvia

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and the carton after ‘EXP’. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Januvia contains

The active substance is sitagliptin. Each film-coated tablet (tablet) contains sitagliptin phosphate monohydrate, equivalent to 25 mg sitagliptin.

The other ingredients are: In the tablet core: microcrystalline cellulose (E460), calcium hydrogen phosphate, anhydrous (E341), croscarmellose sodium (E468), magnesium stearate (E470b), and sodium stearyl fumarate. The tablet film coating contains: poly(vinyl alcohol), macrogol 3350, talc (E553b), titanium dioxide (E171), red iron oxide (E172), and yellow iron oxide (E172).

What Januvia looks like and contents of the pack

Round, pink film-coated tablet with “221” on one side.

Opaque blisters (PVC/PE/PVDC and aluminum). Packs of 14, 28, 30, 56, 84, 90 or 98 film-coated tablets and 50 x 1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Merck Sharp & Dohme Ltd.

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

United Kingdom

Manufacturer

Merck Sharp & Dohme Ltd.

Shotton Lane

Cramlington

Northumberland

NE23 3JU

United Kingdom

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

United Kingdom

Merck Sharp & Dohme Limited

Tel: +44 (0) 1992 467272

Email: medicalinformationuk@merck.com

This leaflet was last revised in June 2015.

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu.

© Merck Sharp & Dohme Limited 2015. All rights reserved.

PIL.JAN.25 mg.15.UK.4634.WS-0741 & PSUR 032

Bisoprolol 2.5 mg film coated tablet

Bisoprolol 5 mg film coated tablet

Bisoprolol 10 mg film coated tablet

2. Qualitative and quantitative composition

For 2.5mg:

Each film-coated tablet contains 2.5 mg Bisoprolol fumarate.

For 5mg:

Each film-coated tablet contains 5 mg Bisoprolol fumarate

For 10mg:

Each film-coated tablet contains 10 mg Bisoprolol fumarate

For a full list of excipients, see section 6.1

3. Pharmaceutical form

Film-coated tablet

For 2.5mg:

White to off white, round, biconvex, film coated tablets, debossed ‘b1′ on one side and break line on other side

For 5mg:

White to off white, round, biconvex, film coated tablets, debossed ‘b2′ on one side and break line on other side

For 10mg:

White to off white, round, biconvex, film coated tablets, debossed ‘b3′ on one side and break line on other side

The tablet can be divided into equal halves.

4. Clinical particulars

4.1 Therapeutic indications

Treatment of Hypertension

Treatment of stable chronic angina

Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides (for additional information see section 5.1)

4.2 Posology and method of administration

Administration:

For oral use.

Bisoprolol fumarate tablet should be taken in morning and can be taken with food in morning. They should be swallowed in liquid and should not be chewed.

Treatment of hypertension and chronic stable angina pectoris

Adults

The dosage should be individually adjusted. It is recommended to start with 5 mg per day. The usual dose is 10 mg once daily with a maximum recommended dose of 20 mg per day.

Patients with renal impairment

In patients with severe renal impairment (creatinine clearance < 20 ml/min) the dose should not exceed 10 mg once daily. This dosage may eventually be divided into halves.

Patients with severe liver impairment

No dosage adjustment is required, however careful monitoring is advised.

Elderly

No dosage adjustment is normally required. It is recommended to start with the lowest possible dose.

Children

There is no experience with bisoprolol in children, therefore its use cannot be recommended for children.

Discontinuation of treatment

Treatment should not be stopped abruptly (see section 4.4). The dosage should be diminished slowly by a weekly halving of the dose.

Treatment of stable chronic heart failure

Adults

Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker in case of intolerance to ACE inhibitors), a beta-blocker, diuretics, and when appropriate cardiac glycosides. Patients should be stable (without acute failure) when bisoprolol treatment is initiated.

It is recommended that the treating physician should be experienced in the management of chronic heart failure.

Transient worsening of heart failure, hypotension, or bradycardia may occur during the titration period and thereafter.

Titration phase

The treatment of stable chronic heart failure with bisoprolol requires a titration phase

The treatment with bisoprolol is to be started with a gradual uptitration according to the following steps:

– 1.25 mg once daily for 1 week, if well tolerated increase to

– 2.5 mg once daily for a further week, if well tolerated increase to

– 3.75 mg once daily for a further week, if well tolerated increase to

– 5 mg once daily for the 4 following weeks, if well tolerated increase to

– 7.5 mg once daily for the 4 following weeks, if well tolerated increase to

– 10 mg once daily for the maintenance therapy.

The maximum recommended dose is 10 mg once daily.

Close monitoring of vital signs (heart rate, blood pressure) and symptoms of worsening heart failure is recommended during the titration phase. Symptoms may already occur within the first day after initiating the therapy.

Treatment modification

If the maximum recommended dose is not well tolerated, gradual dose reduction may be considered.

In case of transient worsening of heart failure, hypotension, or bradycardia reconsideration of the dosage of the concomitant medication is recommended. It may also be necessary to temporarily lower the dose of bisoprolol or to consider discontinuation.

The reintroduction and/or uptitration of bisoprolol should always be considered when the patient becomes stable again.

If discontinuation is considered, gradual dose decrease is recommended, since abrupt withdrawal may lead to acute deterioration of the patient’s condition.

Treatment of stable chronic heart failure with bisoprolol is generally a long-term treatment.

Special population

Renal or hepatic impairment

There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired hepatic or renal function. Up titration of the dose in these populations should therefore be made with additional caution.

Elderly

No dosage adjustment is normally required.

Children`

There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for children.

4.3 Contraindications

Bisoprolol is contraindicated in chronic heart failure patients with:

– acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy

– cardiogenic shock

– second or third degree AV block (without a pacemaker)

– sick sinus syndrome

– sinoatrial block

– Symptomatic bradycardia

– Symptomatic hypotension

– severe bronchial asthma or severe chronic obstructive pulmonary disease

– late stages of peripheral arterial occlusive disease and Raynaud’s syndrome

– untreated phaeochromocytoma (see section 4.4)

– metabolic acidosis

– hypersensitivity to bisoprolol or to any of the excipients (See section 6.1)

4.4 Special warnings and precautions for use

Special warnings:

Applies only to chronic heart failure:

The treatment of stable chronic heart failure with bisoprolol has to be initiated with special titration phase (see section 4.2).

Applies to all indications:

Especially in patients with ischemic heart disease the cessation of therapy with bisoprolol must not be done abruptly unless clearly indicated, because this may lad to transition worsening of heart condition (See section 4.2).

Precautions:

Applies only to hypertension or angina pectoris:

Bisoprolol must be used with caution in patients with hypertension or angina pectoris and accompanying heart failure.

Applies only to chronic heart failure:

The initiation of treatment with bisoprolol necessitates regular monitoring. For posology and method of administration please (See section 4.2).

There is no therapeutic experience of bisoprolol treatment of heart failure in patients with the following diseases and conditions:

– insulin dependent diabetes mellitus (type I)

– severely impaired renal function

– severely impaired hepatic function

– restrictive cardiomyopathy

– congenital heart disease

– haemodynamically significant organic valvular disease

– myocardial infarction within 3 months

Applies to all indications:

Bisoprolol must be used with caution in:

– bronchospasm (bronchial asthma, obstructive airways diseases).

In bronchial asthma or other chronic obstructive lung diseases, which may cause symptoms, bronchodilating therapy is recommended to be given concomitantly. Occasionally an increase of the airway resistance may occur in patients with asthma, therefore the dose of beta2-stimulants may have to be increased.

– diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia (e.g. tachycardia, palpitations or sweating) can be masked.

– strict fasting

– ongoing desensitisation therapy

As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic effect.

– first degree AV block

– Prinzmetal’s angina

– peripheral arterial occlusive disease (intensification of complaints might happen especially during the start of therapy)

– general anaesthesia

In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction and intubation, and the post-operative period. It is currently recommended that maintenance beta-blockade be continued peri-operatively. The anaesthesist must be aware of beta-blockade because of the potential for interactions with other drugs, resulting in bradyarrhythmias, attenuation of the reflex tachycardia and the decreased reflex ability to compensate for blood loss. If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.

Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g. bisoprolol) after carefully balancing the benefits against the risks.

In patients with phaeochromocytoma bisoprolol must not be administered until after alpha-receptor blockade.

Under treatment with bisoprolol the symptoms of a thyrotoxicosis may be masked.

4.5 Interaction with other medicinal products and other forms of interaction

Combinations not recommended

Applies only to chronic heart failure:

• Class I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.

Applies to all indications:

• Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type: Negative influence on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients on β-blocker treatment may lead to profound hypotension and atrioventricular block.

• Centrally acting antihypertensive drugs such as clonidine and others (e.g. methyldopa, moxonodine, rilmenidine): Concomitant use of centrally acting antihypertensive drugs may worsen heart failure by a decrease in the central sympathetic tonus (reduction of heart rate and cardiac output, vasodilation). Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase risk of “rebound hypertension”.

Combinations to be used with caution

Applies only to hypertension or angina pectoris:

Class-I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.

Applies to all indications

• Calcium antagonists of the dihydropyridine type such as felodipine and amlodipine: Concomitant use may increase the risk of hypotension, and an increase in the risk of a further deterioration of the ventricular pump function in patients with heart failure cannot be excluded.

• Class-III antiarrhythmic drugs (e.g. amiodarone): Effect on atrio-ventricular conduction time may be potentiated.

• Topical beta-blockers (e.g. eye drops for glaucoma treatment) may add to the systemic effects of bisoprolol.

• Parasympathomimetic drugs: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia.

• Insulin and oral antidiabetic drugs: Increase of blood sugar lowering effect. Blockade of beta-adrenoreceptors may mask symptoms of hypoglycaemia.

• Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension (for further information on general anaesthesia see also section 4.4.).

• Digitalis glycosides: Reduction of heart rate, increase of atrio-ventricular conduction time.

• Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect of bisoprolol.

• β-Sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both agents.

• Sympathomimetics that activate both β- and α-adrenoceptors (e.g. noradrenaline, adrenaline): Combination with bisoprolol may unmask the α-adrenoceptor-mediated vasoconstrictor effects of these agents leading to blood pressure increase and exacerbated intermittent claudication. Such interactions are considered to be more likely with nonselective β-blockers.

• Concomitant use with antihypertensive agents as well as with other drugs with blood pressure lowering potential (e.g. tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of hypotension.

Combinations to be considered

• Mefloquine: increased risk of bradycardia

• Monoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the beta-blockers but also risk for hypertensive crisis.

• Rifampicin: Slight reduction of the half-life of bisoprolol due to the induction of hepatic drugmetabolising enzymes. Normally no dosage adjustment is necessary.

• Ergotamine derivatives: Exacerbation of peripheral circulatory disturbances.

4.6 Fertility, pregnancy and lactation

Pregnancy:

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn. In general, beta-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the fetus and newborn infant. If treatment with beta-adrenoceptor blockers is necessary, beta1-selective adrenoceptor blockers are preferable.

Bisoprolol is not recommended during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, the uteroplacental blood flow and the fetal growth should be monitored. In case of harmful effects on pregnancy or the fetus alternative treatment should be reccomended. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.

Lactation:

There are no data on the excretion of bisoprolol excreted in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol.

4.7 Effects on ability to drive and use machines

In a study with coronary heart disease patients bisoprolol did not impair driving performance. However, due to individual variations in reactions to the drug, the ability to drive a vehicle or to operate machinery may be impaired. This should be considered particularly at start of treatment and upon change of medication as well as in conjunction with alcohol.

4.8 Undesirable effects

The following definitions apply to the frequency terminology used hereafter:

Very common (≥ 1/10)

Common (≥ 1/100, < 1/10)

Uncommon (≥ 1/1,000, < 1/100)

Rare (≥ 1/10,000, < 1/1,000)

Very rare (< 1/10,000)

Psychiatric disorders:

Uncommon: sleep disorders, depression.

Rare: nightmares, hallucinations.

Nervous system disorders:

Common: dizziness*, headache*

Rare: syncope

Eye disorders:

Rare: reduced tear flow (to be considered if the patient uses lenses).

Very rare: conjunctivitis.

Ear and labyrinth disorders:

Rare: hearing disorders.

Cardiac disorders:

Very common: bradycardia (in patients with chronic heart failure).

Common: worsening of pre-existing heart failure (in patients with chronic heart failure).

Uncommon: AV-conduction disturbances, worsening of pre-existing heart failure (in patients with hypertension or angina pectoris); bradycardia (in patients with hypertension or angina pectoris).

Vascular disorders:

Common: feeling of coldness or numbness in the extremities, hypotension especially in patient with heart failure.

Respiratory, thoracic and mediastinal disorders:

Uncommon: bronchospasm in patients with bronchial asthma or a history of obstructive airways disease.

Rare: allergic rhinitis.

Gastrointestinal disorders:

Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.

Hepatobiliary disorders:

Rare: hepatitis.

Skin and subcutaneous tissue disorders:

Rare: hypersensitivity reactions (such as itching, flush, rash).

Very rare: beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.

Musculoskeletal and connective tissue disorders:

Uncommon: muscular weakness and cramps.

Reproductive system and breast disorders:

Rare: potency disorders

General disorders:

Common: asthenia (in patients with chronic heart failure), fatigue*.

Uncommon: asthenia (in patients with hypertension or angina pectoris)

Investigations:

Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT).

Applies only to hypertension or angina pectoris:

*These symptoms especially occur at the beginning of the therapy. They are generally mild and usually disappear within 1 – 2 weeks.

4.9 Overdose

The most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is limited experience with overdose of bisoprolol, only a few cases of overdose with bisoprolol have been reported. Bradycardia and/or hypotension were noted. All patients recovered. There is a wide inter-individual variation in sensitivity to one single high dose of bisoprolol and patients with heart failure are probably very sensitive.

In general, if overdose occurs, discontinuation of bisoprolol treatment and supportive and symptomatic treatment is recommended.

Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following general measures may be considered when clinically warranted.

Bradycardia: Administer intravenous atropine. If the response is inadequate, isoprenaline or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.

Hypotension: Intravenous fluids and vasopressors should be administered. Intravenous glucagon may be useful.

AV block (second or third degree): Patients should be carefully monitored and treated with isoprenaline infusion or temporary pacing.

Acute worsening of heart failure: Administer i.v. diuretics, inotropic agents, vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as isoprenaline, beta2-sympathomimetic drugs and/or aminophylline.

Hypoglycaemia: Administer i.v. glucose.

Limited data suggest that bisoprolol is hardly dialysable.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Beta blocking agents, selective

ATC Code: C07AB07

Bisoprolol is a potent highly beta1-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and without relevant membrane stabilising activity. It only shows low affinity to the beta2-receptor of the smooth muscles of bronchi and vessels as well as to the beta2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and beta2-mediated metabolic effects. Its beta1-selectivity extends beyond the therapeutic dose range.

Chronic heart failure:

In total 2647 patients were included in the CIBIS II trial. 83% (n = 2202) were in NYHA class III and 17% (n = 445) were in NYHA class IV. They had stable symptomatic systolic heart failure (ejection fraction ≤35%, based on echocardiography). Total mortality was reduced from 17.3% to 11.8% (relative reduction 34%). A decrease in sudden death (3.6% vs 6.3%, relative reduction 44%) and a reduced number of heart failure episodes requiring hospital admission (12% vs 17.6%, relative reduction 36%) was observed. Finally, a significant improvement of the functional status according to NYHA classification has been shown. During the initiation and titration of bisoprolol hospital admission due to bradycardia (0.53%), hypotension (0.23%), and acute decompensation (4.97%) were observed, but they were not more frequent than in the placebo-group (0%, 0.3% and 6.74%). The numbers of fatal and disabling strokes during the total study period were 20 in the bisoprolol group and 15 in the placebo group.

The CIBIS III trial investigated 1010 patients aged ≥65 years with mild to moderate chronic heart failure (CHF; NYHA class II or III) and left ventricular ejection fraction ≤35%, who had not been treated previously with ACE inhibitors, beta-blockers, or angiotensin receptor blockers. Patients were treated with a combination of bisoprolol and enalapril for 6 to 24 months after an initial 6 months treatment with either bisoprolol or enalapril.

There was a trend toward higher frequency of chronic heart failure worsening when bisoprolol was used as the initial 6 months treatment. Non inferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis, although the two strategies for initiation of CHF treatment showed a similar rate of the primary combined endpoint death and hospitalization at study end (32.4% in the bisoprolol-first group vs. 33.1 % in the enalapril-first group, per-protocol population). The study shows that bisoprolol can also be used in elderly chronic heart failure patients with mild to moderate disease.

Hypertension or angina pectoris:

Bisoprolol is used for the treatment of hypertension and angina pectoris. As with other Beta- 1-blocking agents, the method of acting in hypertension is unclear. However, it is known that Bisoprolol reduces plasma renin activity markedly.

Antianginal mechanism: Bisoprolol by inhibiting the cardiac beta receptors inhibits the response given to sympathetic activation. That results in the decrease of heart rate and contractility this way decreasing the oxygen demand of the cardiac muscle.

In acute administration in patients with coronary heart disease without chronic heart failure bisoprolol reduces the heart rate and stroke volume and thus the cardiac output and oxygen consumption. In chronic administration the initially elevated peripheral resistance decreases.

5.2 Pharmacokinetic properties

Bisoprolol is absorbed almost completely from the gastrointestinal tract. Together with the very small first pass effect in the liver, this results in a high bioavailability of approximately 90%. The plasma protein binding of bisoprolol is about 30 %. The distribution volume is 3.5 l/kg. The total clearance is approximately 15 l/h.

The plasma elimination half-life (10-12 hours) provides 24 hours efficacy following a once daily dosage.

Bisoprolol is excreted from the body by two routes, 50 % is metabolised by the liver to inactive metabolites which are then excreted by the kidneys. The remaining 50 % is excreted by the kidneys in an unmetabolised form. Since elimination takes place in the kidneys and the liver to the same extent a dosage adjustment is not required for patients with impaired liver function or renal insufficiency.

In patients with chronic heart failure (NYHA stage III) the plasma levels of bisoprolol are higher and the half life is prolonged compared to healthy volunteers. Maximum plasma concentration at steady state is 64±21 ng/ml at a daily dose of 10 mg and the half life is 17±5 hours.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity..

Like other beta-blockers, bisoprolol caused maternal (decreased food intake and decreased body weight) and embryo/fetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring, retarded physical development) at high doses but was not teratogenic.

6. Pharmaceutical particulars

6.1 List of excipients

Core Tablet:

Cellulose microcrystalline

Sodium starch glycolate(Type-A)

Povidone K-30

Silica colloidal anhydrous

Magnesium stearate (E572)

Coating:

Hypromellose E-15 (E464)

Macrogol 400 (E553)

Titanium dioxide (E171)

Talc

6.2 Incompatibilities

Not applicable

6.3 Shelf life

24 months

6.4 Special precautions for storage

Do not store above 30°C

6.5 Nature and contents of container

PVC/PVDC-Alu Blister or ALU-ALU Blister in Pack sizes of 20, 28, 30, 50, 56, 60, 90 and 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

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

7. Marketing authorisation holder

Accord Healthcare Ltd

Sage House 319, Pinner Road

North Harrow, Middlesex

HA1 4HF

United Kingdom

Glucophage SR prolonged release tablets contain the active ingredient metformin hydrochloride and belong to a group of medicines called biguanides, used in the treatment of diabetes.

Glucophage SR is used for the treatment of Type 2 (non- insulin dependent) diabetes mellitus when diet and exercise changes alone have not been enough to control blood glucose (sugar). Insulin is a hormone that enables body tissues to take glucose from the blood and to use it for energy or for storage for future use. People with Type 2 diabetes do not make enough insulin in their pancreas or their body does not respond properly to the insulin it does make. This causes a build-up of glucose in the blood which can cause a number of serious long-term problems so it is important that you continue to take your medicine, even though you may not have any obvious symptoms. Glucophage SR makes the body more sensitive to insulin and helps return to normal the way your body uses glucose.

Glucophage SR is associated with either a stable body weight or modest weight loss.
Glucophage SR Prolonged Release Tablets are specially made to release the drug slowly in your body and therefore are different to many other types of tablet containing metformin.

2. BEFORE YOU TAKE GLUCOPHAGE SR

Do not take Glucophage SR if:

• you are allergic to metformin or to any of the other ingredients which are listed later on in the leaflet (see under ‘6. Further information’). An allergic reaction may cause a rash, itching or shortness of breath.

• you have ketosis (this is a symptom of uncontrolled diabetes in which substances called ‘ketone bodies’ accumulate in the blood – you may notice that your breath has an unusual, fruity odour).

• you have long-term kidney or liver problems.

• you have had serious complications with your diabetes or other serious conditions which resulted in rapid
weight loss, nausea, vomiting or dehydration.

• you have a severe infection or have recently suffered a
severe injury.

• you have been treated for heart problems or have
recently had a heart attack or have severe circulatory
problems or breathing difficulties.

• you are a heavy drinker of alcohol.

• you are under 18 years of age.

Take special care with Glucophage SR.

After you have started taking your medicine:

If you have diabetes you should have your blood or urine tested for sugar regularly. You should return to your doctor at least once a year to check the function of your kidneys (more often if you are elderly or if you have kidney problems).

If you start to lose weight unexpectedly or suffer severe nausea or vomiting, uncontrolled rapid breathing or abdominal pains, stop taking the medicine and tell your doctor straight away. This can be a sign of a rare, but serious, complication with your diabetes called ‘lactic acidosis’ which means there is too much acid in the blood (see also under ‘4. Possible side effects’).

You may see some remains of the tablets in your stools. Do not worry- this is normal for this type of tablet.

If you need to have an X-ray examination involving the injection of a dye, tell the doctor that you take Glucophage SR as you may need to stop taking it for a few days afterwards.

Tell your doctor if you are going to have an operation under general anaesthetic, as you may need to stop taking Glucophage SR for a couple of days before and after the procedure.

You should continue to follow any dietary advice that your doctor has given you and you should make sure that you eat carbohydrates regularly throughout the day.

Do not stop taking this medicine without speaking to your doctor.

Taking Glucophage SR with other medicines:

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without prescription.

If you are taking any of the following medicines, your blood sugar levels may need to be checked more often and your dose adjusted:

• Steroids such as prednisolone, mometasone, beclometasone.

• Diuretics (water tablets) such as furosemide.

• Sympathomimetic medicines including epinephrine and dopamine used to treat heart attacks and low blood pressure. Epinephrine is also included in some dental anaesthetics.

You should avoid drinking alcohol and using alcohol- containing medicines as this will increase the risk of lactic acidosis (see under ‘4. Possible side effects’).

Taking Glucophage SR with food and drink:

You should take Glucophage SR with or immediately after food.

Pregnancy and breast-feeding

Do not take Glucophage SR if you are pregnant or breast feeding. Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Glucophage SR taken on its own does not cause ‘hypos’ (symptoms of low blood sugar or hypoglycaemia, such as faintness, confusion and increased sweating) and therefore should not affect your ability to drive or use machinery.

You should be aware, however, that Glucophage SR taken with other antidiabetic medicines can cause hypos, so in this case you should take extra care when driving or operating machinery.

3. HOW TO TAKE GLUCOPHAGE SR

Your doctor may prescribe Glucophage SR for you to take on its own, or in combination with other oral antidiabetic medicines or insulin.
Always take Glucophage SR exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Swallow the tablets whole with a glass of water, do not chew. Usually you will start treatment with 500 milligrams Glucophage SR daily. After you have been taking Glucophage SR for about 2 weeks, your doctor may measure your blood sugar and adjust the dose. The maximum daily dose is 2000 milligrams of Glucophage SR. Normally, you should take the tablets once a day, with your evening meal.

In some cases, your doctor may recommend that you take the tablets twice a day. Always take the tablets with food.

If you take more Glucophage SR than you should

If you take extra tablets by mistake you need not worry, but if you have unusual symptoms, contact your doctor. These symptoms may include weakness, confusion, fast breathing and new onset of nausea, vomiting or stomach pain. If the overdose is large, lactic acidosis is more likely and this is a medical emergency requiring treatment in hospital (see also under ‘4. Possible side effects’).

If you forget to take Glucophage SR

Take it as soon as you remember with some food. Do not take a double dose to make up for a forgotten dose.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Glucophage SR can cause side effects, although not everybody gets them. If you notice any of the following, stop taking Glucophage SR and see your doctor immediately:

• unexpected weight loss
• very severe nausea or vomiting
• very fast breathing which you cannot stop
• stomach pains or feeling cold
These can be signs of serious problems with your diabetes and may mean you have a very rare side effect called “lactic acidosis” (too much acid in the blood). If this happens, see a doctor as you will need treatment straight away.
• Abnormal liver function tests and hepatitis (inflammation

of the liver) which may result in jaundice. If you develop yellowing of the eyes and/or skin contact your doctor immediately.

Other possible side effects are listed by frequency as follows:
Very common (affects more than 1 person in 10):
• Diarrhoea, nausea, vomiting, stomach ache or loss of

appetite. If you get these, do not stop taking the tablets as these symptoms will normally go away in about 2 weeks. It helps if you take the tablets with or immediately after a meal.

Common (affects less than 1 person in 10, but more than 1 person in 100):
• Taste disturbance
Very rare (affects less than 1 person in 10,000):

• Decreased vitamin B12 levels
• Skin rashes including redness, itching and hives.
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.

5. HOW TO STORE GLUCOPHAGE SR

Keep Glucophage SR tablets out of the reach and sight of children.
Do not use them after the expiry date that is printed on the pack after “Use before:”. The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

What the tablets contain

Each prolonged release tablet contains 500, 750 or 1000 milligrams of the active ingredient metformin hydrochloride. The other ingredients are magnesium stearate, carmellose sodium and hypromellose. The 500 milligram tablet also contains microcrystalline cellulose.

What Glucophage SR looks like and contents of the pack

The 500 milligram tablets are white to off-white and capsule-shaped with ‘500’ on one side.
The 750 milligram tablets are white to off-white and capsule-shaped with ‘750’ on one side and ‘MERCK’ on the other side.

The 1000 milligrams tablets are white to off-white and capsule-shaped with ‘1000’ on one side and ‘MERCK’ on the other side.
Glucophage SR is supplied in packs of 28 and 56 prolonged release tablets.

Glucophage SR 500 mg, 750 mg and 1000 mg Prolonged Release Tablets are manufactured for Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX, UK by Famar Lyon, 29 avenue Charles de Gaulle, 69230 Saint-Genis Laval, France.

This leaflet was last revised in March 2015. Useful tips
• If you smoke, try to stop
• Take regular exercise

• Drink as little alcohol as possible
• Look after your feet. Ask about this at the surgery or

hospital
• Carry a card, bracelet or disk saying you are diabetic • Visit your diabetic clinic regularly

If you want more information about diabetes contact:

Diabetes UK Central Office Macleod House
10 Parkway
London NW1 7AA

Tel: 020 7424 1000

GLUCOPHAGE 850 mg Tablets

SCHEDULING STATUS: S3

PROPRIETARY NAME

(and dosage form):

GLUCOPHAGE 500 mg Tablets

GLUCOPHAGE 850 mg Tablets

COMPOSITION:

Each Glucophage 500 mg Tablet contains 500 mg Metformin Hydrochloride.

Each Glucophage 850 mg Tablet contains 850 mg Metformin Hydrochloride.

PHARMACOLOGICAL CLASSIFICATION:

A 21.2 – Oral Hypoglycaemic.

PHARMACOLOGICAL ACTION:

Glucophage is a biguanide oral anti-hyperglycaemic agent. Its mode of action is thought to be multifactorial and includes delayed uptake of glucose from the gastrointestinal tract, increased peripheral glucose utilisation mediated by increased insulin sensitivity, and inhibition of increased hepatic and renal gluconeogenesis. No hypoglycaemia occurs when Glucophage is used alone but can occur when given concomitantly with a sulphonylurea, insulin or alcohol.

INDICATIONS:

Non-insulin dependent diabetes when diet has failed and especially if the patient is overweight. Glucophage can be given alone as initial therapy, or can be administered in combination with a sulphonylurea. In insulin-dependent diabetes, Glucophage may be given as an adjuvant to patients whose symptoms are poorly controlled.

CONTRA-INDICATIONS:

Sensitivity to metformin hydrochloride. Diabetic coma and ketoacidosis, impairment of renal function, chronic liver disease, cardiac failure and recent myocardial infarction. History of, or states associated with, lactic acidosis such as shock or pulmonary insufficiency, alcoholism (acute or chronic), and conditions associated with hypoxemia. Pancreatitis. The use of Glucophage during pregnancy is not advised. There is no information available concerning the safety of Glucophage during lactation.

WARNINGS:

Sensitivity to metformin hydrochloride. Diabetic coma and ketoacidosis, impairment of renal function, chronic liver disease, cardiac failure and recent myocardial infarction. History of, or states associated with, lactic acidosis such as shock or pulmonary insufficiency, alcoholism (acute or chronic), and conditions associated with hypoxemia. Pancreatitis. The use of Glucophage during pregnancy is not advised. There is no information available concerning the safety of Glucophage during lactation.

DOSAGE AND DIRECTIONS FOR USE:

It is important that Glucophage tablets be taken in divided doses with meals.

Adults:

Initially, one 850 mg tablet twice a day or one 500 mg tablet three times a day, with or after food. Good diabetic control may be achieved within a few days, but it is not usual for the full effect to be delayed for up to two weeks. If control is incomplete a cautious increase in dosage to a maximum of 3 g daily is justified. Once control has been obtained it may be possible to reduce the dosage of Glucophage.

Children:

Glucophage is not recommended for use.

Elderly:

Glucophage is indicated in the elderly, but not when renal function is impaired.

Combination therapy – see “Special Precautions”

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:

Gastro-intestinal adverse effects with anorexia, nausea and vomiting. Metallic taste. Lactic acidosis has been associated with Glucophage but, has occurred to a greater extent in patients with contra-indications to therapy. In patients with a metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonaemia) lactic acidosis should be suspected and Glucophage therapy stopped. Lactic acidosis is a medical emergency which must be treated in hospital.

Glucophage is excreted by the kidney and regular monitoring of renal function is advised in all diabetics. Glucophage therapy should be stopped 2-3 days before surgery and clinical investigations such as intravenous urography and intravenous angiography and reinstated only after control of renal function has been regained. The use of Glucophage is not advised in conditions which may cause dehydration or in patients suffering from serious infections, trauma or on low calorie intake.

Patients receiving continuous Glucophage therapy should have an annual estimation of Vitamin B12 levels because of reports of decreased Vitamin B12 absorption.

During concomitant therapy with a sulphonylurea, blood glucose should be monitored because combined therapy may cause hypoglycaemia. Stabilisation of diabetic patients with Glucophage and insulin should be carried out in hospital because of the possibility of hypoglycaemia until the correct ratio of the two drugs has been obtained.

Reduced renal clearance of Glucophage has been reported during cimetidine therapy, so a dose reduction should be considered. An interaction between Glucophage and anticoagulants is a possibility and dosage of the latter may need adjustment.

Contra-indications should be carefully observed.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:

Hypoglycaemia can occur when Glucophage is given concomitantly with a sulphonylurea, insulin or alcohol. In excessive dosage, and particularly if there is a possibility of accumulation, lactic acidosis may develop. Intense symptomatic and supportive therapy is recommended which should be particularly directed at correcting fluid loss and metabolic disturbance.

IDENTIFICATION:

Glucophage 500 mg Tablets – White, round, biconvex, film-coated tablets.

Glucophage 850 mg Tablets – White, round shallow, biconvex film-coated tablets.

PRESENTATION:

Glucophage 500 mg Tablets 500 mg – 100’s and 500’s

Glucophage 850 mg Tablets 850 mg – 60’s and 300’s

STORAGE INSTRUCTIONS:

Store below 25°C. Protect from light and moisture.

Keep out of reach of children.

REGISTRATION NUMBER:

Glucophage 500 mg Tablets G3244 (Act 101/1965)

Glucophage 850 mg Tablets F/21.2/145

NAME AND BUSINESS ADDRESS OF THE APPLICANT:

Merck (Pty) Limited

1 Friesland Drive

Longmeadow Business Estate

Modderfontein, 1645

DATE OF PUBLICATION OF THIS PACKAGE INSERT:

26.08.1974

        Highland Print         F70616 P10/03

Updated on this site: January 2005

Source: Community Pharmacy