Kentera oxybutynin transdermal patch

Kentera 3.9 mg / 24 hours transdermal patch

Oxybutynin

Read all of this leaflet carefully before you start using Kentera

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


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


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


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

In this leaflet:

1. What Kentera is and what it is used for

2. Before you use Kentera

3. How to use Kentera

4. Possible side effects

5. How to store Kentera

6. Further Information

What Kentera Is And What It Is Used For

Kentera is used in adults to control the symptoms of urge incontinence and/or increased urinary frequency and urgency.

Kentera works by allowing the bladder to expand and accommodate more urine.

Before You Use Kentera

Do not use Kentera:

• If you are hypersensitive (allergic) to oxybutynin or any of the ingredients of Kentera.


• If you have a rare condition called myasthenia gravis that makes the muscles in the body become weak and tire easily.


• If you experience incomplete bladder emptying during urination, the use of oxybutynin may increase this problem. You should discuss this problem with your doctor before using Kentera.


• If you have digestion problems caused by reduced emptying of the stomach after a meal you should consult your doctor before using Kentera.


• If you have glaucoma or a family history of glaucoma, tell your doctor.

Take special care with Kentera:

If you have any of the following:

• Liver problems


• Kidney problems


• Difficulty urinating


• Intestinal blockage


• Bloody stools


• Generalized muscle weakness


• Painful swallowing

Since treatment with oxybutynin may cause decreased perspiration, there is an increased risk of fever and heat stroke if you are exposed to high environmental temperatures.

Kentera is not recommended for use in children or adolescents.

Taking other medicines

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

Applying the Kentera patch at the same time as taking other medicines that have similar side effects such as dry mouth, constipation and drowsiness, may increase how often and how severe these side effects are experienced.

Oxybutynin may slow the digestive tract and thereby influence the adsorption of other oral medicines, or the use of this medicine together with other medicines may increase the effect of oxybutynin. Especially:-

• Ketoconasole, itraconazole or fluconazole (used for the treatment of fungal infections).


• Erythromycin a macrolide antibiotic (used to treat bacterial infections).


• Biperiden, levodopa, or amantadine (used to treat Parkinson’s disease).


• Antihistamines (used in the treatment of allergies such as hayfever).


• Phenothiazines or clozapine (used to treat mental illness).


• Tricyclic antidepressants (used to treat depression).


• Dipyridamole (used to treat blood clotting problems)


• Atropine and other anticholinergic medicines (used to treatment in stomach disorders such as irritable bowel syndrome).

Using Kentera with food and drink

Oxybutynin may cause drowsiness or blurred vision. Drowsiness may be increased by consumption of alcohol.

Pregnancy and breast-feeding

Ask your doctor for advice before taking any medicine.

Kentera should not to be used during pregnancy unless clearly necessary.

When oxybutynin is used during breast-feeding, a small amount is excreted in the mother’s milk. Use of oxybutynin while breast-feeding is therefore not recommended.

Driving and using machines:

Because Kentera may produce drowsiness, somnolence, or blurred vision, patients should be advised to exercise caution when driving or using machinery.

How To Use Kentera

Always use Kentera exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are not sure.

Apply a new Kentera patch twice weekly (every 3 to 4 days) according to the instructions for use. Change the patch on the same two days every week, for example, every Sunday and Wednesday or Monday and Thursday. Printed on the inside flap of your Kentera package, you will find a Kentera calendar checklist that will help you to remember your dosing schedule. Mark the schedule you plan to follow and remember always to change your patch on the same two days of the week you have chosen on your calendar. Make sure to wear only one patch at a time and wear your patch continuously, until it is time to apply a new one.

Where to apply

Apply the patch to a clean, dry, smooth area of skin on your abdomen, hips or buttocks. Avoid placing the patch in the waistline area to prevent tight clothing from rubbing against the patch. Do not expose the patch the sun. Place the patch underneath your clothing. Rotate application sites with each new application. Do not apply a patch to the same place on your body for at least 1 week.

How to apply

Each patch is individually sealed in a protective sachet. Please read all the information below before you begin to apply Kentera.

To apply Kentera:

Step 1: Choose a spot for the patch that is:

• Freshly washed, but dry and cool (wait a few minutes after taking a hot bath or shower).


• Free of body powder, lotion, and oil.


• Free of cuts, rashes or any other skin irritation.

Step 2: Open the sachet that contains the patch.

• Tear open along arrows marked on the right side of the sachet as shown in drawing below.


• Do not cut the sachet with scissors, which might damage the patch inside.


• Pull the patch out.


• Apply immediately to your skin; do not keep or store the patch outside the sealed sachet.

Step 3: Apply one half of the patch to your skin.

• Gently bend the patch and remove the first piece of protective liner, which covers the sticky surface of the patch.


• Without touching the sticky surface, firmly press the patch, adhesive face down, onto the part of the abdomen, hips or buttocks you have selected for application.

Step 4: Apply the second half of the patch to your skin.

• Bend the patch back over itself. Press down on the liner firmly.


• Push the liner forward a little to loosen the edge.


• Grab the loose edge at either corner and peel off the second piece of the liner. Try not to touch the sticky surface of the patch.


• Press the entire patch firmly onto the skin with your fingertips. Press for at least 10 seconds to make sure the patch will stay in place. Be sure all of it sticks to your skin, even around the edges.


• Discard the protective liners.

Bathing, showering, swimming and exercise:

You should wear each patch all the time until you apply a new one. Baths, showers, swimming and exercise should not affect the patch as long as you don’t rub the patch as you wash. Avoid soaking in a hot bath for a long period of time, which can make the patch come off.

If the patch comes off:

If the patch starts to lift off your skin, apply a little bit of pressure using your fingertips. The patch is designed to re-stick. Very rarely will the patch come off completely. If it does, try putting the same patch back on the same spot. If it sticks firmly all over, leave it on. If not, take it off and put a new patch on a new spot. No matter what day this happens, continue with the twice-a-week schedule that you have marked on your patch box.

If you forget to change the patch after 3-4 days:

As soon as you remember, remove the old patch and apply a new one to a new spot on your abdomen, hips or buttocks. No matter what day this happens, continue with the same twice-a-week schedule for your next patch, even if it means changing the new patch before 3 to 4 days have elapsed.

How to remove

When changing the patch, remove the old patch slowly. Fold it in half (sticky sides together) and throw it away to keep out of the reach of children and pets. Mild redness may be present at the application site. This redness should disappear within several hours after removal of the patch. If irritation persists, please contact your doctor.

Gently washing the application site with warm water and a mild soap should remove any adhesive that remains on your skin after removal of the patch. A small amount of baby oil may also be used to remove any excess residue. Rings of adhesive that become soiled may require a medical adhesive removal pad that should be available from your pharmacist. Alcohol or other strong solvents may cause skin irritation and should not be used.

After use the patch still contains substantial quantities of active ingredients. Remaining active ingredients of the patch may have harmful effects if reaching the aquatic environment. Hence, after removal, the used patch should be folded in half, adhesive side inwards so that the release membrane is not exposed, placed in the original sachet and then discarded safely out of reach of children. Any used or unused patches should be discarded according to local requirements or returned to the pharmacy. Used patches should not be flushed down the toilet nor placed in liquid waste disposal systems

If you use more Kentera than you should

The patient should not apply more than one patch at a time.

If you forget to use Kentera

Apply a Kentera patch as soon as you realise your patch is missing, or you have missed a scheduled day of application.

If you stop using Kentera

Your urge incontinence may return and you may have increased urinary frequency if you decide to stop using the patch. Continue to use Kentera as long as your doctor tells you to.

Talk to your doctor or pharmacist if you have any questions on the use of this medical product.

Possible Side Effects

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

The frequency of possible side effects listed below is defined using the following convention:

Very common (affects more than 1 user in 10)

Common (affects 1 to 10 users in 100)

Uncommon (affects 1 to 10 users in 1,000)

Rare (affects 1 to 10 users in 10,000)

Very rare (affects less than 1 user in 10,000)

Not known (frequency cannot be estimated from the available data).

Very common side effect: itching around the site of patch application.

Common side effects:

redness or rash at the site of patch application

dry mouth

constipation

diarrhoea

upset stomach

stomach pain

headache or sleepiness

urinary tract infections

blurred vision

dizziness

Uncommon side effects:

upper respiratory tract or fungal infections

palpitations

hot flushes

back pain

urinary retention

difficulty urinating

common cold

accidental injury

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

Storing Kentera

Keep out of the reach and sight of children.

Do not use Kentera after the date shown on the sachet and the carton

Do not refrigerate.

Do not freeze.

The used patches should be folded in half, adhesive side inwards so that the release membrane is not exposed, placed in the original sachet and then discarded safely out of the reach of children. Any used or unused patches should be discarded according to local requirements or returned to the pharmacy. Used patches should not be flushed down the toilet nor placed in liquid waste disposal systems.

Further Information

What Kentera contains

The active substance is oxybutynin. Each transdermal patch releases 3.9 mg of oxybutynin per 24 hours. Each patch of 39cm² contains 36mg of oxybutynin.

The other ingredients are: Each patch contains triacetin, and acrylic adhesive solution. The oxybutynin, triacetin and acrylic adhesive are coated on clear PET/EVA backing film and covered with a siliconised polyester release liner.

What Kentera looks like and contents of the pack

Kentera is a transdermal patch and it is packaged in cartons containing 2, 8, and 24 patches. Each patch consists of a clear backing film that has the pharmaceutical ingredients coated on the side containing the protective backing film. The backing film is to be removed prior to patch application.

Marketing Authorisation Holder and Manufacturer

Nicobrand Limited

189 Castleroe Road

Coleraine

BT51 3RP

Northern Ireland

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

United Kingdom

Recordati Pharmaceuticals

Isis House

43 Station Rd

Henley on Thames

OXON

RG9 1AT

Tel: 01491 576336

This leaflet was approved in 12/2009

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

Kefadim Vials

1. Name Of The Medicinal Product

'Kefadim'.

2. Qualitative And Quantitative Composition

			Vial Size
		500mg	1g	2g
Active constituent
	Ceftazidime pentahydrate	580mg	1.16g	2.33g
	equivalent to ceftazidime	500mg	1.0g	2.0g
Other constituents
	Sodium carbonate	59mg	118mg	236mg

3. Pharmaceutical Form

Powder for solution for injection

4. Clinical Particulars

4.1 Therapeutic Indications

Kefadim is indicated in the treatment of the following infections when due to susceptible micro- organisms:

Lower respiratory tract infections

Skin and soft tissue infections

Bone and joint infections

Urinary tract infections

Gynaecological infections

Intra-abdominal infections, including peritonitis

Septicaemia

Central nervous system infections, including meningitis. In meningitis, it is recommended that the results of a sensitivity test are known before treatment with ceftazidime as a single agent.

Kefadim may be used alone in cases of confirmed or suspected sepsis. It may also be used concomitantly with other antibiotics, such as aminoglycosides, in severe and life-threatening infections and in the immunocompromised patient.

4.2 Posology And Method Of Administration

Ceftazidime may be given intravenously or by deep intramuscular injection into a large muscle mass (such as the upper outer quadrant of the gluteus maximus, or lateral part of the thigh).

The guidelines for dosage of Kefadim are listed in Table 1.

Table 1: Recommended Dosage Schedule for Kefadim

	DOSE	FREQUENCY
Adults
Usual recommended dose	1g IV or im	q 8 or 12 h
Uncomplicated urinary tract infections	250mg IV or im	q 12 h
Bone and joint infections	2g IV	q 12 h
Complicated urinary tract infections	500mg IV or im	q 8 or 12 h
Uncomplicated pneumonia; mild skin and skin-structure infections	500mg-1g IV or im	q 8 h
Serious gynaecological and intra-abdominal infections	2g IV	q 8 h
Meningitis	2g IV	q 8 h
Very severe life-threatening infections, especially in immunocompromised patients	2g IV	q 8 h
Pseudomonal lung infections in patients with cystic fibrosis with normal renal function*	30-50mg/kg IV to a maximum of 6g/day	q 8 h
Neonates and children up to 2 months	12.5-30mg/kg IV	q 12 h
Infants and children (2 months to 12 years of age)	17-50mg/kg IV to a maximum of 6g/day**	q 8 h

*Although clinical improvement has been shown, complete eradication of infecting organisms cannot be expected in patients with chronic respiratory disease and cystic fibrosis.

**The higher dose should be reserved for immunocompromised children or children with cystic fibrosis or meningitis.

Adults and the elderly: The usual dosage range for ceftazidime is 500mg to 2g every eight to twelve hours. The dosage and route of administration should be determined by the susceptibility of the causative organisms, the severity of infection, and the condition and renal function of the patient.

In view of the reduced clearance of ceftazidime in acutely ill elderly patients, the daily dosage should not normally exceed 2g, especially in those over 80 years of age (Table 2).

Infants and children over 2 months of age: The dosage range is 50-150mg/kg/day IV, in three divided doses, with a maximum of 6g/day. The higher dose should be reserved for immunocompromised children, or children with cystic fibrosis or meningitis.

Neonates and children up to 2 months of age: The dosage range is 25 to 60mg/kg/day, given as two divided doses. In the neonate, the serum half-life of ceftazidime can be three to four times that in adults.

Dosage in impaired renal function: Ceftazidime is excreted by the kidneys, almost exclusively by glomerular filtration. Therefore, in patients with impaired renal function (GFR <50ml/min), it is recommended that the dose of ceftazidime should be reduced to compensate for its slower excretion. In patients with suspected renal insufficiency, an initial loading dose of 1g may be given. An estimate of GFR should be made to determine the appropriate maintenance dose. The recommended dosage is shown in Table 2.

Table 2: Recommended Maintenance Dosage of Kefadim in Patients with Renal Insufficiency

CREATININE CLEARANCE (ML/MIN)	RECOMMENDED DOSE OF KEFADIM	FREQUENCY
50-31	1g	q 12 h
30-16	1g	q 24 h
15-6	500mg	q 24 h
<5	500mg	q 48 h

When only serum creatinine is available, the following formula (Cockcroft's equation) may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function:

Males:

Females:

0.85 x above value

In patients with severe infections who would normally receive 6g of Kefadim daily, were it not for renal insufficiency, the dose in Table 2 may be increased by 50% or the dosing frequency increased appropriately. Continued dosage should be determined by further monitoring of creatinine clearance, severity of the infection, and susceptibility of the causative organism. In such patients, it is recommended that ceftazidime serum levels should be monitored and trough levels should not exceed 40mg/litre.

In children, as for adults, the creatinine clearance should be adjusted for body surface area or lean body mass and the dosing frequency reduced in cases of renal insufficiency.

The serum half-life of ceftazidime during haemodialysis ranges from 3 to 5 hours.

In patients undergoing haemodialysis, a loading dose of 1g of Kefadim is recommended, followed by 1g after each haemodialysis period. Kefadim can also be used in patients undergoing intraperitoneal and continuous ambulatory peritoneal dialysis (CAPD). In such patients, a loading dose of 1g of Kefadim may be given, followed by 500mg every 24 hours. In addition to intravenous use, Kefadim can be incorporated in the dialysis fluid at a concentration of 250mg for 2 litres of dialysis fluid.

NOTE: Kefadim should generally be continued for 2 days after the signs and symptoms of infection have disappeared, however, in complicated infections, longer therapy may be required.

Intramuscular administration: Kefadim should be reconstituted with Water for Injections PhEur or 0.5% or 1% Lignocaine Hydrochloride Injection BP. Refer to Table 3

Table 3:Preparation of Solutions of Kefadim

	AMOUNT OF DILUENT TO BE ADDED (ML)	APPROXIMATE AVAILABLE VOLUME (ML)	APPROXIMATE CEFTAZIDIME CONCENTRATION (MG/ML)
Intramuscular
500mg	1.5	1.925	260
1g	3.0	3.85	260
Intravenous
500mg	5	5.425	92
1g	10	10.85	92
2g	10	11.7	170
Infusion (100ml)
2g	100*	101.7	20

*Note: Addition should be in 2 stages (see 'Instructions for reconstitution' below).

Intravenous administration: For direct intermittent intravenous administration, reconstitute Kefadim with Water for Injections PhEur (see Table 3). Slowly inject the solution directly into the vein over a period of 3 to 5 minutes or give through the tubing of a giving set. Ceftazidime is compatible with the most commonly used intravenous fluids (see section 6.6).

For intravenous infusion, reconstitute the 2g infusion (100ml) vial with 100ml Water for Injections PhEur or one of the compatible intravenous fluids. Alternatively, reconstitute the 500mg, 1g or 2g vial and add an appropriate quantity of the resulting solution to an IV container with one of the compatible intravenous fluids.

Intermittent intravenous infusion with a Y-type giving set can be accomplished with compatible solutions. However, during infusion of a solution containing ceftazidime, it is desirable to discontinue the other solution.

When Kefadim is dissolved, carbon dioxide is released and a positive pressure develops. For ease of use, please follow the recommended techniques of reconstitution described below.

Instructions for reconstitution:

For 500mg im/IV, 1g im/IV and 2g IV vials

1. Inject the diluent and shake well to dissolve. The vials may contain a vacuum to assist injection of the diluent.

2. Carbon dioxide is released as the antibiotic dissolves, generating pressure within the vial. The solution will become clear within 1 to 2 minutes.

3. Invert the vial and completely depress the syringe plunger prior to insertion.

4. Insert the needle through the vial stopper. Be sure the needle remains within the solution and withdraw contents of the vial in the usual manner. Pressure in the vial may aid withdrawal.

5. The withdrawn solution may contain carbon dioxide bubbles, which should be expelled from the syringe before injection.

For 2g infusion vials

1. Inject 10ml of the diluent and shake to dissolve. The vials may contain a vacuum to assist injection of the diluent.

2. Carbon dioxide is released as the antibiotic dissolves, generating pressure within the vial. The solution will become clear within 1 to 2 minutes.

3. Insert a vent needle to release pressure before adding additional diluent to the vial. Add diluent and then remove the vent needle.

4. Additional pressure that may develop in the vial, especially after storage, should be relieved prior to administration to the patient.

NOTE: To preserve product sterility, it is important that a gas relief needle is not inserted through the vial closure before the product has dissolved.

4.3 Contraindications

Ceftazidime is contra-indicated in patients with known hypersensitivity to ceftazidime or cephalosporin antibiotics.

4.4 Special Warnings And Precautions For Use

Warnings

Before therapy with ceftazidime is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to ceftazidime, cephalosporins, penicillins, or other drugs. Ceftazidime should be given only with special caution to patients with type 1 or immediate hypersensitivity reactions to penicillin. If an allergic reaction to ceftazidime occurs, discontinue the drug. Serious acute hypersensitivity reactions may require epinephrine (adrenaline), hydrocortisone, antihistamine, or other emergency measures.

Pseudomembranous colitis has been reported with the use of ceftazidime, other cephalosporins and virtually all broad-spectrum antibiotics, therefore, it is important to consider its diagnosis in patients who develop diarrhoea in association with antibiotic use. Such colitis may range in severity from mild to life-threatening. Symptoms can appear during or after treatment.

Mild cases of pseudomembranous colitis usually respond to drug discontinuance alone. In moderate to severe cases, appropriate measures should be taken.

Precautions

Kefadim has not been shown to be nephrotoxic, however, because high and prolonged serum antibiotic concentrations can occur from usual doses in patients with transient or persistent reduction of urinary output because of renal insufficiency, the total daily dosage should be reduced when ceftazidime is administered to such patients to avoid the clinical consequences, eg, seizures due to elevated levels of antibiotics (see section 4.2). Continued dosage should be determined by degree of renal impairment, severity of infection and susceptibility of causative organisms.

As with other antibiotics, prolonged use of Kefadim may result in the overgrowth of non-susceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Kefadim should be used with caution in individuals with a history of gastro-intestinal disease, particularly colitis.

Ceftazidime does not interfere with enzyme-based tests for glycosuria. Slight interference with copper reduction methods (Benedict's, Fehling's, Clinitest) may be observed.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Nephrotoxicity has been reported following concomitant administration of cephalosporins and aminoglycoside antibiotics or potent diuretics, such as furosemide (frusemide). Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity and ototoxicity were not noted when Kefadim was given alone in clinical trials.

4.6 Pregnancy And Lactation

Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Kefadim. There are, however, no controlled studies in pregnant women. As animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Ceftazidime is excreted in human milk in low concentrations and consequently caution should be exercised when ceftazidime is administered to a nursing woman.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

The most common side-effects were local reactions following intravenous injection and allergic and gastro-intestinal reactions.

Local effects: Phlebitis or thrombophlebitis, and inflammation at the site of injection.

Hypersensitivity: Pruritus, urticarial rash, fever and very rarely angioedema and anaphylaxis (bronchospasm and/or hypotension).

Skin and subcutaneous tissue disorders: As with other cephalosporins, there have been rare reports of toxic epidermal necrolysis reported in association with ceftazidime.

Gastro-intestinal: Diarrhoea, nausea, vomiting and abdominal pain, pseudomembranous colitis (see section 4.4 - 'Warnings'). Very rarely, oral thrush.

Central nervous system: Headache, dizziness, paraesthesias and bad taste. There have been reports of neurological sequelae, including tremor, myoclonica, convulsions and encephalopathy, in patients with renal impairment in whom the dose of ceftazidime has not been appropriately reduced.

Reproductive system disorder: Candidiasis and vaginitis.

Laboratory test changes (usually transient): Eosinophilia, positive Coombs' test without haemolysis, thrombocytosis and slight elevations in one or more hepatic enzymes: AST (SGOT), ALT (SGPT), LDH, GGT and alkaline phosphatase. Transient elevations of blood urea, blood urea nitrogen and/or serum creatinine have been observed occasionally. Transient leucopenia, neutropenia, agranulocytosis, thrombocytopenia and lymphocytosis have been seen very rarely.

4.9 Overdose

Signs and symptoms: Toxic signs and symptoms following an overdose of ceftazidime may include pain, inflammation and phlebitis at the injection site. Overdosage can lead to neurological sequelae, including encephalopathy, convulsions and coma.

The administration of inappropriately large doses of parenteral cephalosporins may cause dizziness, paraesthesias and headaches. Seizures may occur following overdosage with some cephalosporins, particularly in patients with renal impairment in whom accumulation is likely to occur.

Laboratory abnormalities that may occur after an overdose include elevations in creatinine, BUN, liver enzymes and bilirubin, a positive Coombs' test, thrombocytosis, thrombocytopenia, eosinophilia, leucopenia and prolongation of the prothrombin time.

The subcutaneous median lethal dose in rats and mice ranged from 5.8 to 20g/kg and the intravenous median lethal dose in rabbits was >2g/kg.

Treatment: If seizures occur, the drug should be discontinued promptly; anti-convulsant therapy may be administered if clinically indicated. An airway should be established. Cardiac and vital signs monitoring is recommended, along with general symptomatic and supportive measures.

In cases of severe overdosage, especially in a patient with renal failure, combined haemodialysis and haemoperfusion may be considered if response to more conservative therapy fails.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ceftazidime is a semi-synthetic, beta-lactam antibiotic, for parenteral administration.

In vitro tests demonstrate that ceftazidime is bactericidal. It acts against a wide range of Gram-negative organisms, including strains resistant to gentamicin and other aminoglycosides. It is also active against Gram-positive organisms, and is highly stable to most clinically important beta-lactamases, whether plasmid or chromosomally mediated.

Ceftazidime has been shown to have in vitro activity against the following organisms:

Pseudomonas spp. (including Pseudomonas aeruginosa); Klebsiella spp. (including Klebsiella pneumoniae); Proteus mirabilis and Proteus vulgaris; Morganella morganii (formerly Proteus morganii); Providencia spp. (including Providencia rettgeri, formerly Proteus rettgeri); Escherichia coli; Enterobacter spp.; Citrobacter spp.; Serratia spp.; Salmonella spp.; Shigella spp.; Yersinia enterocolitica; Pasteurella multocida; Acinetobacter spp.; Neisseria gonorrhoeae; Neisseria meningitidis; Haemophilus influenzae (including ampicillin-resistant strains); Haemophilus parainfluenzae (including ampicillin-resistant strains); Staphylococcus aureus (methicillin-sensitive strains); Staphylococcus epidermidis (methicillin-sensitive strains); Streptococcus pyogenes; Streptococcus Group B; Streptococcus pneumoniae; Streptococcus spp.; Peptococcus spp.; Peptostreptococcus spp.; Clostridium spp.; (but not C. difficile); Bacteroides spp. (but most strains of B. fragilis are resistant).

Using the ICS agar dilution method (or its equivalent) for susceptibility testing, the criteria for dilution methods are:

MIC <16mg/litre:	Susceptible
MIC>16 but <64mg/litre:	Moderately susceptible (ie, susceptible to high dosage or if infection confined to tissues or fluids [eg, urine] in which high antibiotic levels are attained)
MIC	Resistant

and for the standard disc test using a 30 microgram ceftazidime disc, are (zone diameters):

Zone	Susceptible
Zone 15-17mm:	Moderately susceptible
Zone	Resistant

Ceftazidime is not active in vitro against methicillin-resistant staphylococci; Streptococcus faecalis and many other enterococci; Listeria monocytogenes; Campylobacter spp. or C. difficile.

Ceftazidime and the aminoglycosides have been shown to be synergistic in vitro against some strains of P. aeruginosa and the Enterobacteriaceae. Ceftazidime and carbenicillin have also been shown to be synergistic in vitro against P. aeruginosa

5.2 Pharmacokinetic Properties

After intravenous administration of 500mg or 1g of ceftazidime, over 5 minutes, to normal adults, mean peak serum concentrations were 45mg/litre and 90mg/litre, respectively. Following intravenous infusion of 500mg, 1g and 2g of ceftazidime, over 20 to 30 minutes, to normal adults, mean peak serum concentrations of 42, 69 and 170mg/litre, respectively, were achieved. The average serum concentrations in these adults, over an 8 hour period, are given in Table 4.

Table 4:Ceftazidime Concentrations in Serum

CEFTAZIDIME DOSAGE (IV)	SERUM CONCENTRATIONS (MG/LITRE)
	0.5h	1h	2h	4h	8h
500mg	42	25	12	6	2
1g	60	39	23	11	3
2g	129	75	42	13	5

Following intramuscular administration of 500mg and 1g ceftazidime to normal adults, mean peak serum concentrations at approximately 1 hour were 17mg/litre and 39mg/litre, respectively. Serum concentrations remained above 4mg/litre for 6 and 8 hours after the intramuscular administration of 500mg and 1g doses, respectively.

The half-life of ceftazidime was approximately 1.9 hours after intravenous administration and 2 hours after intramuscular administration.

Less than 10% of ceftazidime was protein bound and the degree of protein binding was independent of concentration.

Following multiple intravenous doses of 1g and 2g every 8 hours for 10 days, there was no evidence of accumulation of ceftazidime in the serum of individuals with normal renal function.

The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals who received 2g intravenously every 8 hours for 5 days. Therefore, dosage adjustment is not required for patients with hepatic dysfunction, unless renal function is also impaired.

Approximately 80% to 90% of a dose of ceftazidime is excreted unchanged by the kidneys over a 24 hour period. The elimination of ceftazidime by the kidneys resulted in high urinary concentrations.

Concentrations of ceftazidime in excess of the minimum inhibitory levels of common pathogens can be achieved in tissues such as bone, heart, bile, sputum, aqueous humour, synovial, pleural and peritoneal fluids.

Transplacental transfer of the antibiotic readily occurs.

Ceftazidime penetrates the intact blood-brain barrier poorly and low levels are achieved in the CSF in the absence of inflammation. Therapeutic levels of 4 to 20mg/litre or more are achieved in the CSF when the meninges are inflamed.

5.3 Preclinical Safety Data

Long-term studies in animals have not been performed to evaluate carcinogenic potential. However, a mouse micronucleus test and an Ames test were both negative for mutagenic effects.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium carbonate.

6.2 Incompatibilities

Solutions of Kefadim, like those of most beta-lactam antibiotics, should not be added to solutions of aminoglycoside antibiotics because of potential interaction. However, if concurrent therapy with Kefadim and an aminoglycoside is indicated, each of these antibiotics should be administered in different sites.

Precipitation has been reported when vancomycin has been added to ceftazidime in solution. Therefore, it would be prudent to flush giving sets and intravenous lines between administration of these two agents.

Kefadim is less stable in Sodium Bicarbonate Injection than in other intravenous fluids. Sodium Bicarbonate Injection is not recommended as a diluent. Solutions of Kefadim in 5% Dextrose or 0.9% Sodium Chloride Injection are stable for at least 6 hours at room temperature in plastic tubing, drip chambers and volume control devices of common intravenous infusion sets

6.3 Shelf Life

Unreconstituted vials: 2 years.

Reconstituted vials: It is good practice to reconstitute immediately prior to use. If this is not feasible, Kefadim should be stored in a refrigerator and used within 24 hours. After reconstitution, protection from light is not necessary. The pH of freshly reconstituted solutions ranges from 5.0 to 7.5.

6.4 Special Precautions For Storage

Unreconstituted vials: Protect from light. Do not store above 25°C.

6.5 Nature And Contents Of Container

Kefadim is supplied as a sterile dry powder in single-dose flint Type I or III glass vial with a rubber closure and aluminium seal containing 500mg, 1g and 2g ceftazidime (as pentahydrate) with sodium carbonate (118mg per gram of ceftazidime).

The total sodium content of the mixture is approximately 54mg (2.3mEq) per gram of ceftazidime

6.6 Special Precautions For Disposal And Other Handling

Solutions of Kefadim range from light yellow to amber, depending on the diluent and concentration.

Kefadim is compatible with the more commonly used intravenous infusion fluids. Solutions at concentrations between 1mg/ml and 40mg/ml in the following infusion fluids may be stored for up to 24 hours at room temperature: 0.9% Sodium Chloride Injection BP; M/6 Sodium Lactate Injection BP; Ringer's Injection USP; Lactated Ringer's Injection USP; 5% Dextrose Injection BP; 0.225% Sodium Chloride and 5% Dextrose Injection BP; 0.45% Sodium Chloride and 5% Dextrose Injection BP; 0.9% Sodium Chloride and 5% Dextrose Injection BP; 10% Dextrose Injection BP; and 10% Invert Sugar in Water for Injection.

At a concentration of 4mg/ml, Kefadim has been found compatible for 24 hours at room temperature in 0.9% Sodium Chloride Injection or 5% Dextrose Injection when admixed with cefuroxime sodium, 3mg/ml; heparin, 10u/ml or 50u/ml; or potassium chloride, 10mEq/l or 40mEq/l.

Parenteral drug products should be inspected visually and cloudy solutions should be discarded.

Kefadim powder and solutions will darken, depending on storage conditions. However, product potency is not adversely affected if storage conditions and storage periods are observed.

7. Marketing Authorisation Holder

Flynn Pharma Ltd

Alton House

4 Herbert Street

Dublin 2

Ireland

8. Marketing Authorisation Number(S)

Vials 500mg:	PL 13621/0014
Vials 1g:	PL 13621/0015
Vials 2g:	PL 13621/0016

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation:	1st June 2005

10. Date Of Revision Of The Text

1^st June 2005

Kwells 300 microgram tablets

1. Name Of The Medicinal Product

Kwells 300 microgram tablets

2. Qualitative And Quantitative Composition

Hyoscine Hydrobromide 300 microgram

For excipients, see section 6.1

3. Pharmaceutical Form

Tablet

Small pink circular, flat faced tablets with bevelled edges. One face is bisected by a score line and the other is plain.

4. Clinical Particulars

4.1 Therapeutic Indications

For the prevention of travel sickness.

4.2 Posology And Method Of Administration

Tablets to be sucked, chewed or swallowed

Adults:

1 tablet every 6 hours if required. Do not take more than 3 tablets in 24 hours.

Elderly

There is no special dosage regimen for the elderly and as such caution should be exercised

Children

Children over 10: ½-1 tablet every 6 hours if required. Do not take more than 1½-3 tablets in 24 hours.

Tablets to be taken up to 30 minutes before the start of the journey to prevent travel sickness, or at the onset of nausea.

4.3 Contraindications

Prostatic enlargement, paralytic ileus, pyloric stenosis, glaucoma and myasthenia gravis.

In addition, Kwells should not be given to patients with a known sensitivity to hyoscine hydrobromide or any other component of the product.

4.4 Special Warnings And Precautions For Use

The elderly and patients under medical care (in particular those at risk of acute urinary retention, or with cardiovascular, metabolic, gastrointestinal, liver or renal disease, or suffering from CNS disorders such as seizures) should consult a doctor before taking this product.

In patients with ulcerative colitis its use may lead to ileus or megacolon.

Antimuscarinics should be used with caution in persons with Down's Syndrome.

Caution is advisable in patients with diarrhoea.

Hyperthermia can occur at high ambient temperatures due to decreased sweating, therefore, Kwells should be used with caution in patients with fever.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The effects of hyoscine may be enhanced by other drugs with anticholinergic properties (including amantadine, some antihistamines, phenothiazine antipsychotics and tricyclic antidepressants), therefore, combining these drugs with hyoscine should be avoided.

There may be an increased risk of side effects when given with MAOIs due to inhibition of drug-metabolising enzymes.

The sedative effect of Kwells may be enhanced with alcohol or CNS depressants.

The reduction in gastric motility caused by Kwells may also affect the absorption of other drugs. There is an antagonism of effect of domperidone and metoclopramide on gastro-intestinal activity.

There could be a reduced effect of sublingual nitrate tablets due to the failure to dissolve properly under the tongue owing to dry mouth.

4.6 Pregnancy And Lactation

The safety of this medicine in pregnancy has not been established. It should only be used during pregnancy, particularly in the first trimester, if the expected benefit to the mother outweighs any potential risk to the developing foetus and on advice of a physician.

Caution is required during lactation as small amounts of this medicine may pass into breast milk.

4.7 Effects On Ability To Drive And Use Machines

May cause drowsiness. If affected do not drive or operate machinery.

4.8 Undesirable Effects

The listed adverse drug reactions are based on spontaneous reports, thus an organization according to CIOMS II categories of frequency is not pertinent.

General: hyperthermia at high temperatures due to decreased sweating.

Eye disorders: blurred vision, mydriasis.

Gastrointestinal disorders: dry mouth.

Immune system disorders: allergic reaction and anaphylactic reaction. Hypersensitivity reactions with respective laboratory and clinical manifestations, including asthma syndrome, mild to moderate reactions affecting skin, respiratory tract, gastrointestinal tract, and cardiovascular system, and symptoms such as rash, urticaria, oedema, pruritus, cardio-respiratory distress, have been reported.

Nervous system disorders: drowsiness, dizziness, sedation and somnolence are commonly reported. Central nervous system stimulation including restlessness, hallucinations and confusion, have been less frequently reported following the administration of hyoscine. There have been rare reports of an increase in seizure frequency in epileptic patients (the same caution for this patient population is included in Section 4.4).

4.9 Overdose

The symptoms of overdosage are tachycardia, arrhythmia, blurring of vision and photophobia, and urinary retention. Drowsiness is usual but paradoxical stimulation with hallucinations may occur.

Treatment: gastric lavage or induced emesis and symptomatic treatment.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Hyoscine hydrobromide is thought to act as an anticholinergic agent by both cutting off stimuli to the vestibular apparatus and also by acting directly on the vomiting centre.

5.2 Pharmacokinetic Properties

Hyoscine hydrobromide is readily absorbed from the gastro-intestinal tract, and in circulation is bound to plasma proteins. It is effective for about 4 hours and is almost entirely metabolised in the body.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol

Potato Starch

Gelatin Powder

Aluminium Stearate

Saccharin Sodium

Ferric Oxide

Purified Water (not detectable)

6.2 Incompatibilities

None known.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

Do not store above 25 °C.

6.5 Nature And Contents Of Container

1. Strip packs formed from 0.03mm soft-tempered aluminium coated with polyethylene.

a. Two strips of six tablets in cardboard carton.

b. One strip of twelve tablets in cardboard carton.

c. Strip of two tablets stapled into a cardboard cover.

2. Blister packs formed from 20um hard-tempered aluminium foil with either 250um opaque, white PVC or 250um opaque, white PVC coated with 40gsm PVDC

a. Two strips of six tablets in cardboard carton.

b. One strip of twelve tablets in cardboard carton

c. Strip of two tablets stapled into a cardboard cover.

Pack sizes: 2, 12

6.6 Special Precautions For Disposal And Other Handling

No special precautions necessary.

Administrative Data

7. Marketing Authorisation Holder

Bayer plc

Bayer House

Newbury

Berkshire

RG14 1JA

United Kingdom

8. Marketing Authorisation Number(S)

PL 0010/0329

9. Date Of First Authorisation/Renewal Of The Authorisation

12/10/2005

10. Date Of Revision Of The Text

19/11/2007

Kwells Kids

Kwells Kids

150 microgram tablets

Hyoscine Hydrobromide

Read all of this leaflet carefully because it contains important information for you and your child.

This medicine is available without prescription.

However, you still need to take Kwells Kids 150 microgram tablets carefully to get the best results from them.

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



• Ask your pharmacist if you need more information or advice.



• You must contact a doctor if your child’s symptoms worsen or do not improve.



• If your child has any unusual effects after taking this medicine, tell your doctor or pharmacist.

In This Leaflet:

• 1. What are Kwells Kids tablets and what are they used for?



• 2. Before you give Kwells Kids tablets to your child



• 3. How to take Kwells Kids tablets



• 4. Possible side effects



• 5. How to store Kwells Kids tablets



• 6. Further information

What Are Kwells Kids Tablets And What Are They Used For?

Kwells Kids 150 microgram tablets are used for the fast and effective prevention and control of travel sickness. Travel sickness happens when the brain receives mixed messages. Visual messages from the eyes inform the brain that the immediate surroundings are stationary, but a delicate balancing organ in the ear tells the brain that you are moving. This conflicting information triggers the nausea we associate with travel sickness.

The active substance in Kwells Kids tablets is hyoscine hydrobromide. Hyoscine hydrobromide temporarily reduces the effect of movement on the balance organs of the inner ear and the nerves responsible for nausea.

Because Kwells Kids tablets melt in the mouth, absorption into the bloodstream is very rapid and they can be taken up to 20–30 minutes before travelling or at the onset of sickness.

Before You Give Kwells Kids Tablets To Your Child

DO NOT give Kwells Kids tablets to your child if he or she:

• Is allergic (hypersensitive) to hyoscine hydrobromide or any of the other ingredients in the tablets (see Section 6. Further Information).



• Has any of the following conditions:
  
  • Glaucoma.
  
  
  • Blockage of intestines (Paralytic ileus).
  
  
  • Narrowing of stomach outlet (Pyloric stenosis).
  
  
  • Myasthenia gravis.
  
  
  • Enlarged prostate gland.
  
  

Before giving Kwells Kids tablets to your child, you should see your doctor if he or she:

• Is under medical care, especially for heart, metabolic, gastrointestinal, liver or kidney conditions.



• Has previously had a sudden painful inability to pass urine.



• Has ulcerative colitis.



• Has diarrhoea or fever.



• Has Down’s Syndrome.



• Suffers from seizures or fits.

Additional precautions:

This product should only be given to children over 4 years old.

Since it may cause drowsiness, children taking this medicine should not be left unattended.

Taking other medicines:

Tell your doctor or pharmacist if your child is taking or has recently taken any other medicines, including medicines obtained without a prescription.

Do not give Kwells Kids tablets to your child if he or she is taking any of the following medicines, unless advised by your doctor:

• Amantadine (an antiviral).



• Antihistamines.



• Antipsychotics.



• Antidepressants.



• Linezolid (an antibiotic).



• Domperidone and metoclopramide (for nausea and vomiting).



• Sublingual nitrates (for angina).

Taking Kwells Kids tablets with food and drink:

Do not drink alcohol while while taking Kwells Kids tablets as this may make you feel more drowsy.

Driving and using machines:

May cause drowsiness. If affected do not drive or operate machinery.

Pregnancy and breast-feeding:

Do not take Kwells Kids tablets if you are pregnant or breast-feeding unless recommended by your doctor or midwife.

How To Take Kwells Kids Tablets

If Kwells Kids tablets has been prescribed for your child by a doctor, follow any instructions he/she may have given you. If you purchased this product without a prescription, follow these directions closely:

The tablets can be sucked, chewed or swallowed. They have a scoreline so they can be halved if necessary. The tablets can be taken up to 30 minutes before travelling to prevent travel sickness, or even at the onset of nausea.

Children over 10 years: Give your child one or two tablets every 6 hours, as required. Do not give your child this medicine more than 3 times in 24 hours.

Children 4 to 10 years: Give your child half or one tablet every 6 hours, as required. Do not give your child this medicine more than 3 times in 24 hours.

Kwells Kids tablets should not be given to children under 4 years of age.

If your child takes more Kwells Kids tablets than recommended:

Symptoms of an overdose may include: fast or irregular heart-beat, difficulty passing water, blurred vision or dislike of bright light. Hallucinations may occur.

If your child has any of these symptoms or has taken more than the recommended dose, tell your doctor or contact your nearest Accident and Emergency Department immediately.

How to help avoid travel sickness:

• Sit with the head tilted back to stabilise the balancing mechanism in the ear.



• Ensure the vehicle you are in is well ventilated.



• Try to have a clear view of the window.



• Have a bite to eat before the journey to help keep the stomach settled, but avoid greasy food.



• If you travel by car take regular breaks for exercise, fresh air and refreshments.



• In an aeroplane you can ease the pressure on your ears by sucking a boiled sweet during take off and landing.



• NEVER read.



• Avoid strong smelling food, smoke, perfume, or petrol fumes.

Kwells Kids Side Effects

Like all medicines, Kwells Kids tablets can cause side effects, although not everybody gets them.

Some people have experienced blurred vision, dilated pupils, dry mouth, drowsiness and dizziness. Your child may also experience an increased body temperature due to decreased sweating.

Less frequently, there have been reports of restlessness, hallucinations and confusion.

If your child is epileptic, he or she might suffer from increased seizure frequency.

As with all medicines, some people may be allergic to the tablets. If your child is allergic, he or she may experience difficulty in breathing, coughing, wheezing or symptoms such as rash, itching and swelling.

If your child experiences any of these effects or reacts badly to the tablets in any other way, tell your doctor immediately.

How To Store Kwells Kids Tablets

Keep out of the reach and sight of children.

Do not store above 25ºC. This product should be stored in the original carton.

Do not use the tablets after the expiry date which is stated on the carton and blister pack. The expiry date refers to the last day of that month.

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

Further Information

What Kwells Kids tablets contain:

• The active substance is hyoscine hydrobromide at a strength of 150 micrograms.



• The other ingredients are mannitol (E421), potato starch, gelatine powder, aluminium stearate, and saccharin sodium (E954).

What Kwells Kids tablets look like and contents of the pack:

Kwells Kids tablets are small, circular, white and flat with a single scoreline on the surface. The carton contains 12 tablets packaged inside a blister pack.

Marketing Authorisation Holder:

Bayer plc

Consumer Care Division

Bayer House

Strawberry Hill

Newbury

Berkshire

RG14 1JA

United Kingdom

Manufacturer:

Pharmapac UK

Unit 20

Valley Road Business Park

Bidston

Wirral

CH41 7EL

United Kingdom

This leaflet was last approved in October 2007.

Remember: If you have any doubts about using Kwells Kids correctly, seek the advice of your doctor or pharmacist.

= Registered Trade Mark of Bayer AG, Germany

JANUVIA 100mg film-coated tablets

1. Name Of The Medicinal Product

JANUVIA®

2. Qualitative And Quantitative Composition

Each tablet contains sitagliptin phosphate monohydrate, equivalent to 100 mg sitagliptin.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet (tablet)

Round, beige film-coated tablet with “277” on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

For patients with type 2 diabetes mellitus, Januvia is indicated to improve glycaemic control :

as monotherapy

• in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.

as dual oral therapy in combination with

• metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control.

• a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance.

• a peroxisome proliferator-activated receptor gamma (PPARγ) agonist (i.e. a thiazolidinedione) when use of a PPARγ agonist is appropriate and when diet and exercise plus the PPARγ agonist alone do not provide adequate glycaemic control.

as triple oral therapy in combination with

• a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control.

• a PPARγ agonist and metformin when use of a PPARγ agonist is appropriate and when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control.

Januvia is also indicated as add

4.2 Posology And Method Of Administration

Posology

The dose of Januvia is 100 mg once daily. When Januvia is used in combination with metformin and/or a PPARγ agonist, the dose of metformin and/or PPARγ agonist should be maintained, and Januvia administered concomitantly.

When Januvia is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia. (See section 4.4.)

If a dose of Januvia is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

Special populations

Renal impairment

For patients with mild renal impairment (creatinine clearance [CrCl]

Clinical study experience with Januvia in patients with moderate or severe renal impairment is limited. Therefore, use of Januvia is not recommended in this patient population (see section 5.2).

Hepatic impairment

No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Januvia has not been studied in patients with severe hepatic impairment.

Elderly

No dose adjustment is necessary based on age. Limited safety data is available in patients

Paediatric population

Januvia is not recommended for use in children below 18 years of age due to a lack of data on its safety and efficacy.

Method of administration

Januvia can be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see section 4.4 and 4.8).

4.4 Special Warnings And Precautions For Use

General

Januvia should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Pancreatitis

In post-marketing experience there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotizing or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Januvia and other potentially suspect medicinal products should be discontinued.

Hypoglycaemia when used in combination with other anti-hyperglycaemic agents

In clinical trials of Januvia as monotherapy and as part of combination therapy with agents not known to cause hypoglycaemia (i.e. metformin and/or a PPARγ agonist), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo. When sitagliptin was added to a sulphonylurea, or to insulin, the incidence of hypoglycaemia was increased over that of placebo (see section 4.8). Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered (see section 4.2).

Renal impairment

As the experience is limited, patients with moderate to severe renal impairment should not be treated with Januvia (see section 5.2).

Hypersensitivity Reactions

Postmarketing reports of serious hypersensitivity reactions in patients treated with Januvia have been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with Januvia, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue Januvia, assess for other potential causes for the event, and institute alternative treatment for diabetes. (See section 4.8).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of other medicinal products on sitagliptin

Clinical data described below suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low.

Metformin: Co-administration of multiple twice-daily doses of 1000 mg metformin with 50 mg sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.

Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of p_max of sitagliptin by approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered. Therefore, meaningful interactions would not be expected with other p

In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e. ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the phamacokinetics of sitagliptin in patients with severe renal impairment or ESRD. The effects of potent CYP3A4 inhibitors in the setting of renal impairment has not been assessed in a clinical study.

In vitro transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.

Effects of sitagliptin on other medicinal products

In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT).

Sitagliptin had a small effect on plasma digoxin concentrations, and may be a mild inhibitor of p-glycoprotein in vivo.

Digoxin: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of Januvia daily for 10 days, the plasma AUC of digoxin was increased on average by 11 %, and the plasma C_max on average by 18 %. No dose adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of Januvia in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Due to lack of human data, Januvia should not be used during pregnancy.

Lactation

It is unknown whether sitagliptin is excreted in human breast milk. Animal studies have shown excretion of sitagliptin in breast milk. Januvia should not be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Januvia has no known influence on the ability to drive and use machines. However, when driving or operating machines, it should be taken into account that dizziness and somnolence have been reported.

In addition, patients should be alerted to the risk of hypoglycaemia when Januvia is used in combination with sulphonylurea agents or with insulin.

4.8 Undesirable Effects

In 11 large clinical trials of up to 2 years in duration, over 3,200 patients have received treatment with Januvia 100 mg per day alone or in combination with metformin, a sulphonylurea (with or without metformin), insulin (with or without metformin), or a PPARγ agent (with or without metformin). In a pooled analysis of 9 of these trials, the rate of discontinuation due to adverse experiences considered drug-related was 0.8 % with 100 mg per day and 1.5 % with other treatments. No adverse reactions considered as drug-related were reported in patients treated with sitagliptin occurring in excess (> 0.2 % and difference > 1 patient) of that in patients treated with control. In an additional combination study with a PPARγ agent (rosiglitazone) and metformin, no patients were discontinued due to adverse experiences considered as drug

Adverse reactions considered as drug-related reported in patients treated with sitagliptin occurring in excess (> 0.2 % and difference> 1 patient) of that in patients treated with placebo are listed below (Table 1) by system organ class and frequency. Frequencies are defined as: very common (

Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies

Adverse Reaction	Frequency of adverse reaction by treatment regimen
	Sitagliptin with Metformin1	Sitagliptin with a Sulphonylurea2	Sitagliptin with a Sulphonylurea and Metformin3	Sitagliptin with a PPARγ Agent (pioglitazone)4	Sitagliptin with a PPARγ Agent (rosiglitazone) and Metformin5	Sitagliptin with Insulin (+/6
Time-point	24	24	24	24	18	24-week
Infections and infestations
Influenza						Common
Metabolism and nutrition disorders
hypoglycaemia*		Common	Very common	Common	Common	Common
Nervous system disorders
Headache					Common	Common
Somnolence	Uncommon
Gastro-intestinal disorders
Diarrhoea	Uncommon				Common
dry mouth						Uncommon
nausea	Common
Flatulence				Common
constipation			Common			Uncommon
upper abdominal pain	Uncommon
vomiting					Common
General disorders and administration site conditions
Peripheral oedema				Common	Common
Investigations
blood glucose decreased	Uncommon

^*In clinical trials of Januvia as monotherapy and sitagliptin as part of combination therapy with metformin and/or a PPARγ agent, rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo.

¹ In this placebo-controlled 24-week study of sitagliptin 100 mg once daily in combination with metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/metformin compared to treatment with placebo/metformin was 9.3 % and 10.1 %, respectively.

In an additional 1-year study of sitagliptin 100 mg once daily in combination with metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/metformin compared to sulphonylurea/metformin was 14.5 % and 30.3 %, respectively.

In pooled studies of up to 1 year in duration comparing sitagliptin/metformin to a sulphonylurea agent/metformin, adverse reactions considered as drug-related reported in patients treated with sitagliptin 100 mg occurring in excess (> 0.2 % and difference> 1 patient) of that in patients receiving the sulphonylurea agent are as follows: anorexia (Metabolism and nutritional disorders; frequency uncommon) and weight decreased (Investigations; frequency uncommon).

² In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/glimepiride compared to treatment with placebo/glimepiride was 11.3 % and 6.6 %, respectively.

³ In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride and metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin in combination with glimepiride/metformin compared to treatment with placebo in combination with glimepiride/metformin was 18.1 % and 7.1 %, respectively.

⁴ In this 24-week study of the combination of sitagliptin 100 mg once daily and pioglitazone, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/pioglitazone compared to patients treated with placebo/pioglitazone was 9.1 % and 9.0 %, respectively.

⁵ In this study of sitagliptin 100 mg once daily in combination with rosiglitazone and metformin, which continued through 54 weeks, the incidence of adverse reactions considered as drug

⁶ In this 24

In addition, in monotherapy studies of up to 24 weeks in duration of sitagliptin 100 mg once daily alone compared to placebo, adverse reactions considered as drug-related reported in patients treated with sitagliptin in excess (> 0.2 % and difference> 1 patient) of that in patients receiving placebo are headache, hypoglycaemia, constipation, and dizziness.

In addition to the drug-related adverse experiences described above, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5 % and more commonly in patients treated with Januvia included upper respiratory tract infection and nasopharyngitis. Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with Januvia (not reaching the 5 % level, but occurring with an incidence of> 0.5 % higher with Januvia than that in the control group) included osteoarthritis and pain in extremity.

In an additional 24

In a 24-week study of initial combination therapy with sitagliptin and metformin administered twice daily (sitagliptin/metformin 50 mg/500 mg or 50 mg/1000 mg), the overall incidence of adverse reactions considered as drug-related in patients treated with the combination of sitagliptin and metformin compared to patients treated with placebo was 14.0 % and 9.7 %, respectively. The overall incidence of adverse reactions considered as drug-related in patients treated with the combination of sitagliptin and metformin was comparable to metformin alone (14.0 % each) and greater than sitagliptin alone (6.7 %), with the differences relative to sitagliptin alone primarily due to gastrointestinal adverse reactions.

Across clinical studies, a small increase in white blood cell count (approximately 200 cells/microl difference in WBC vs. placebo; mean baseline WBC approximately 6600 cells/microl) was observed due to an increase in neutrophils. This observation was seen in most but not all studies. This change in laboratory parameters is not considered to be clinically relevant.

No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed with Januvia treatment.

Post-marketing Experience:

During post-approval use of Januvia as monotherapy and/or in combination with other antihyperglycaemic agents, additional side effects have been reported (frequency not known): hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome (see section 4.4); acute pancreatitis, including fatal and non-fatal haemorrhagic and necrotizing pancreatitis (see section 4.4); impaired renal function, including acute renal failure (sometimes requiring dialysis); vomiting.

4.9 Overdose

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.

Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Medicines used in diabetes, Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH01.

Januvia is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP_1c (HbA_1c) and lower fasting and postprandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycaemia in patients with type 2 diabetes and in normal subjects. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP

In a two

Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination treatment (see Table 2).

Two studies were conducted to evaluate the efficacy and safety of Januvia monotherapy. Treatment with sitagliptin at 100 mg once daily as monotherapy provided significant improvements in HbA_1c, fasting plasma glucose (FPG), and 2

In a study in patients with type 2 diabetes and chronic renal impairment (creatinine clearance < 50 ml/min), the safety and tolerability of reduced doses of sitagliptin were investigated and generally similar to placebo. In addition, the reductions in HbA_1c and FPG with sitagliptin compared to placebo were generally similar to those observed in other monotherapy studies in patients with normal renal function (see section 5.2). The number of patients with moderate to severe renal impairment was too low to confirm safe use of sitagliptin in this type of patients.

Sitagliptin 100 mg once daily provided significant improvements in glycaemic parameters compared with placebo in two 24-week studies of sitagliptin as add-on therapy, one in combination with metformin and one in combination with pioglitazone. Change from baseline in body weight was similar for patients treated with sitagliptin relative to placebo. In these studies there was a similar incidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.

A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin (100 mg once daily) added to glimepiride alone or glimepiride in combination with metformin. The addition of sitagliptin to either glimepiride alone or to glimepiride and metformin provided significant improvements in glycaemic parameters. Patients treated with sitagliptin had a modest increase in body weight compared to those given placebo.

A 54

A 24

In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily in combination with metformin (500 mg or 1000 mg twice daily) provided significant improvements in glycaemic parameters compared with either monotherapy. The decrease in body weight with the combination of sitagliptin and metformin was similar to that observed with metformin alone or placebo; there was no change from baseline for patients on sitagliptin alone. The incidence of hypoglycaemia was similar across treatment groups.

Table 2. HbA_1c results in placebo-controlled monotherapy and combination therapy studies*

Study	Mean baseline HbA1c (%)	Mean change from baseline HbA1c (%)†	Placebo-corrected mean change in HbA1c (%)† (95 % CI)
Monotherapy Studies
Sitagliptin 100 mg once daily§ (N= 193)	8.0	-0.5	-0.6‡ (-0.8, -0.4)
Sitagliptin 100 mg once daily% (N= 229)	8.0	-0.6	-0.8‡ (-1.0, -0.6)
Combination Therapy Studies
Sitagliptin 100 mg once daily added to ongoing metformin therapy% (N=453)	8.0	-0.7	-0.7‡ (-0.8, -0.5)
Sitagliptin 100 mg once daily added to ongoing pioglitazone therapy% (N=163)	8.1	-0.9	-0.7‡ (-0.9, -0.5)
Sitagliptin 100 mg once daily added to ongoing glimepiride therapy% (N=102)	8.4	-0.3	-0.6‡ (-0.8, -0.3)
Sitagliptin 100 mg once daily added to ongoing glimepiride + metformin therapy% (N=115)	8.3	-0.6	-0.9‡ (-1.1, -0.7)
Sitagliptin 100 mg once daily added to ongoing rosiglitazone + metformin therapy (N=170) Week 18   Week 54	8.8   8.8	-1.0   -1.0	-0.7‡ (-0.9, -0.5) -0.8‡ (-1.0, -0.5)
Initial therapy (twice daily)%: Sitagliptin 50 mg + metformin 500 mg (N=183)	8.8	-1.4	-1.6‡ (-1.8, -1.3)
Initial therapy (twice daily)%: Sitagliptin 50 mg + metformin 1000 mg (N=178)	8.8	-1.9	-2.1‡ (-2.3, -1.8)
Sitagliptin 100 mg once daily added to ongoing insulin (+/% (N=305)	8.7	¶	‡,¶ (

* All Patients Treated Population (an intention-to-treat analysis).

^† Least squares means adjusted for prior antihyperglycaemic therapy status and baseline value.

^‡ p<0.001 compared to placebo or placebo + combination treatment.

^§ HbA_1c (%) at week 18.

^% HbA_1c (%) at week 24.

^¶ Least squares mean adjusted for metformin use at Visit 1 (yes/no), insulin use at Visit 1 (pre

A 24_1c from mean baseline values of 7.2 % was

In a study comparing the efficacy and safety of the addition of Januvia 100 mg once daily or glipizide (a sulphonylurea agent) in patients with inadequate glycaemic control on metformin monotherapy, sitagliptin was similar to glipizide in reducing HbA_1c . The mean glipizide dose used in the comparator group was 10 mg per day with approximately 40 % of patients requiring a glipizide dose of

The European Medicines Agency has deferred the obligation to submit the results of studies with Januvia in one or more subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic Properties

Absorption

Following oral administration of a 100_max) occurring 1 to 4 hours post-dose, mean plasma AUC of sitagliptin was 8.52 μM•hr, C_max was 950 nM. The absolute bioavailability of sitagliptin is approximately 87 %. Since coadministration of a high-fat meal with Januvia had no effect on the pharmacokinetics, Januvia may be administered with or without food.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for C_max and C_24hr (C_max increased in a greater than dose-proportional manner and C_24hr increased in a less than dose-proportional manner).

Distribution

The mean volume of distribution at steady state following a single 100

Biotransformation

Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79 % of sitagliptin is excreted unchanged in the urine.

Following a [¹⁴C]sitagliptin oral dose, approximately 16 % of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPPIn vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

In vitro data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.

Elimination

Following administration of an oral [¹⁴C]sitagliptin dose to healthy subjects, approximately 100 % of the administered radioactivity was eliminated in faeces (13 %) or urine (87 %) within one week of dosing. The apparent terminal t_1/2 following a 100

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporterIn vitro, sitagliptin did not inhibit OAT3 (IC50=160 μM) or p-glycoprotein (up to 250 μM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study sitagliptin had a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild inhibitor of p-glycoprotein.

Characteristics in patients

The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.

Renal impairment

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of sitagliptin (50

Patients with mild renal impairment did not have a clinically meaningful increase in the plasma concentration of sitagliptin as compared to normal healthy control subjects. An approximately 2

Hepatic impairment

No dose adjustment for Januvia is necessary for patients with mild or moderate hepatic impairment (Child-Pugh score

Elderly

No dose adjustment is required based on age. Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data. Elderly subjects (65 to 80 years) had approximately 19 % higher plasma concentrations of sitagliptin compared to younger subjects.

Paediatric

No studies with Januvia have been performed in paediatric patients.

Other patient characteristics

No dose adjustment is necessary based on gender, race, or body mass index (BMI). These characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.

5.3 Preclinical Safety Data

Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-effect level for this finding was 58

Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not carcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas at systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumours in rats was likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin (19

No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to and throughout mating.

In a pre-/postnatal development study performed in rats sitagliptin showed no adverse effects.

Reproductive toxicity studies showed a slight treatment-related increased incidence of fetal rib malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels more than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than 29 times the human exposure levels. Because of the high safety margins, these findings do not suggest a relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk of lactating rats (milk/plasma ratio: 4:1).

6. Pharmaceutical Particulars

6.1 List Of Excipients