Sinthrome

Sinthrome Tablets 1mg

acenocoumarol

Read all of this leaflet carefully before you start taking this medicine

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


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


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


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

The information in this leaflet has been divided into the following sections:

• 1. What Sinthrome is and what it is taken for


• 2. Check before you take Sinthrome


• 3. How to take Sinthrome


• 4. Possible side effects


• 5. How to store Sinthrome


• 6. Further information

What Sinthrome is and what it is used for

Sinthrome belongs to a group of medicines called anticoagulants (blood thinning medicines).

Sinthrome is used to treat and prevent blood clots blocking the blood vessels e.g. deep vein thrombosis (DVT).

Sinthrome does not dissolve blood clots that have already formed but it may stop the clots from becoming larger and causing more serious problems.

Check before you take Sinthrome

Do not take Sinthrome:

• if you are allergic (hypersensitive) to acenocoumarol, any other medicines that you have taken to thin your blood or to any of the ingredients in Sinthrome (see Section 6 Further information)


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


• if you are an alcoholic


• if you have any mental illness for example, schizophrenia or dementia


• if you have recently had, or are about to have an operation on your spine, brain or eyes or any major surgery


• if you have had a stroke caused by bleeding into your brain


• if you suffer from very high blood pressure


• if you have a stomach ulcer or any intestinal bleeding


• if you pass blood in your water or cough up blood


• if you suffer from any bleeding disorders, bleeding problems or unexplained bruising


• if you have pericarditis or endocarditis – inflammation or infection around the heart which causes pain in the chest


• if you regularly drink cranberry juice or take cranberry extracts.

If any of the above applies to you, or if you are not sure, speak to your doctor or pharmacist before you take Sinthrome.

Take special care with Sinthrome

Before you take Sinthrome tell your doctor:

• if you have cancer


• if you have an infection or inflammation (swelling)


• if you have heart failure (which causes swelling and shortness of breath)


• if you have liver or kidney problems


• if you have an overactive thyroid


• if you are elderly


• if you suffer from a blood disorder such as protein C or protein S deficiency – this would cause you to bleed for longer than normal after a cut or injury.

You should not receive any injections into your muscles whilst you are taking Sinthrome.

If you need any injections into your spine or as part of a scan or X-ray test or if you need minor surgery, including dental surgery, make sure you discuss your treatment with your doctor first.

If you are involved in an accident while on Sinthrome you are likely to bleed more than normal. The doctor or hospital staff must be informed that you are taking Sinthrome immediately. Always carry your personal anticoagulation card (an identification card from your pharmacist stating that you are using this medicine).

If any of the above applies to you, or if you are not sure, speak to your doctor or pharmacist before you take Sinthrome.

Taking other medicines

Tell your doctor or pharmacist if you are taking or have taken any of the following medicines as they may interfere with Sinthrome:

• paracetamol and non-steroidal anti-inflammatories (NSAIDs) such as aspirin, ibuprofen and celecoxib - used for pain relief or to treat rheumatic diseases


• tramadol - a strong pain killer


• antibiotics such as rifampicin, amoxicillin and metronidazole- used to treat infections


• sulfonamides such as co-trimoxazole - used to treat infections


• sulphonylureas such as tolbutamide, chlorpropamide and glibenclamide - oral medicines for diabetes


• glucagon - used to treat low blood sugar levels


• thyroid hormones such as levothyroxine - used to treat an underactive thyroid


• allopurinol or sulfinpyrazone - for the treatment of gout and to lower uric acid levels


• anti-arrhythmic agents such as amiodarone and quinidine - medicines for an irregular heartbeat


• oral contraceptives such as Femodene, Logynon and Cilest - for birth control


• antiepileptics such as carbamazepine or phenytoin - used to treat epilepsy


• H₂-agonists such as cimetidine or ranitidine - used to treat stomach or intestinal ulcers


• Aminoglutethimide - used to treat cancer or Cushing’s syndrome


• barbiturates such as sodium amytal or Phenobarbital - for epilepsy or to help you sleep


• etacrynic acid or thiazide diuretics (“water tablets”) such as bendroflumethiazide or metolazone - for water retention or high blood pressure


• statins and other lipid lowering drugs such as fenofibrate, simvastatin or colestyramine - used to lower blood cholesterol levels


• imidazoles such as econazole and ketoconazole or griseofulvin - used to treat fungal infections


• antineoplastics such as mercaptopurine and 5-fluorouracil - for breast, gastrointestinal and skin cancer


• tamoxifen - for breast cancer and fertility


• anti-platelet medicines such as dipyridamole, clopidogrel - to prevent blood clots forming


• selective serotonin re-uptake inhibitors such as fluoxetine and paroxetine - used to treat anxiety and depression


• St John’s Wort - for depression


• protease inhibitors such as ritonavir or indinavir - used to treat HIV


• anabolic steroids - used as replacement therapy


• androgens such as testosterone and mesterolone - used as replacement therapy


• corticosteroids such as prednisolone and methylprednisolone - steroids used to treat inflammatory bowel disease, arthritis and certain skin conditions


• azathioprine - for organ transplantation, chronic inflammatory and autoimmune diseases


• disulfiram - for alcohol dependence


• heparin - to thin the blood in the treatment of deep vein thrombosis, blood clots or after surgery.

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

Taking with food and drink

Be careful when drinking alcohol as it may affect how Sinthrome thins your blood. Check with your doctor first.

You should avoid drinking cranberry juice or taking other cranberry products, such as capsules or concentrates as this could mean you do not receive the correct amount of acenocoumarol.

Pregnancy and breast-feeding

Do not take Sinthrome if you are pregnant. Sinthrome, like other anticoagulants can cause serious harm to your baby. Tell your doctor if you are pregnant or trying to become pregnant. Your doctor will discuss with you the potential risk of taking Sinthrome during pregnancy.

The decision to breast-feed while taking Sinthrome should be carefully considered with your doctor. You and your child may require blood tests if you are breast-feeding while you are taking Sinthrome. However, as a precaution, your doctor should prescribe vitamin K to your child to prevent their blood from being thinned.

If you are of child bearing age, a pregnancy test may be done by your doctor to rule out pregnancy before you are given Sinthrome. You may also be asked to use birth control while taking Sinthrome.

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

Driving and using machines

You can drive and use machines as normal while taking Sinthrome.

Important information about some of the ingredients of Sinthrome

Sinthrome tablets contain lactose, if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

How to take Sinthrome

Always take Sinthrome exactly as your doctor has told you to. You should check with your doctor or pharmacist if you are not sure.

Sinthrome should be taken as a single dose at the same time every day. Swallow your tablets whole with a drink of water.

Your doctor will arrange regular blood tests during treatment with Sinthrome to check on how fast your blood is clotting. This will help the doctor decide on your dose.

The dose of Sinthrome will vary from patient to patient and from day to day.

The following can be used as a guide:

Adults and elderly:

Most patients will receive doses of between 1 to 8 mg (milligrams) a day. A dose of 4 mg is usual on the first day of treatment.

Elderly patients, patients with liver disease or severe heart failure or malnourished patients may need lower doses.

Children:

Sinthrome is not recommended for children.

What to do if you take more Sinthrome than you should

If you accidentally take too many tablets, or someone else takes any of your medicine, you should tell your doctor immediately or contact the nearest accident and emergency department. You may require blood tests to monitor your condition and treatment may be required. Show any left-over medicines or the empty packet to the doctor.

If you forget to take Sinthrome

Do not worry. If you forget to take a dose, take it as soon as possible, unless it is almost time to take the next dose. Do not take a double dose. Then go on as before.

Sinthrome Side Effects

Like all medicines, Sinthrome can cause side effects, although not everyone gets them.

If you get any of the following, tell your doctor:

• unusual bleeding such as
  
  
  • bleeding from the gums
  
  
  • unexplained bruising or nosebleeds
  
  
  • heavy periods
  
  
  • heavy bleeding from cuts or wounds
  
  



• signs of bleeding inside the body such as
  
  • stomach or abdominal pain
  
  
  • backache
  
  
  • blood in the urine
  
  
  • bloody or black tarry stools
  
  
  • coughing up blood
  
  
  • dizziness
  
  
  • severe headache
  
  
  • joint pain or stiffness
  
  
  • blurred sight.
  
  

Tell your doctor or pharmacist if you think you have any of these or other problems with Sinthrome:

Other rare side effects (that affect less than 1 person in 1000):

• loss of appetite


• feeling or being sick


• skin rashes


• itching


• unexplained fever


• hair loss.

Very rare side effects (that affect less than 1 person in 10,000):

• red patches on the skin or bruising


• vasculitis (inflammation of the blood vessels)


• liver damage which can cause yellow eyes or skin.

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

How to store Sinthrome

Keep out of the reach and sight of children.

Do not take Sinthrome after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.

If your doctor decides to stop your treatment, return any unused medicine to the pharmacist. Only keep it if your doctor tells you to.

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

Further information

What Sinthrome contains

The active ingredient in this medicine is acenocoumarol. This is the new name for nicoumalone. The ingredient itself has not changed.

The other ingredients are lactose, hypromellose, magnesium stearate, maize starch, talc and silicon dioxide.

What Sinthrome looks like and contents of the pack

Sinthrome tablets are white, round, flat tablets, with “CG” imprinted on one side and “AA” on the other. They come in cartons of 100 tablets.

Marketing Authorisation Holder and Manufacturer

The product licence holder is:

Alliance Pharmaceuticals Ltd

Avonbridge House

Chippenham

Wiltshire

SN15 2BB

UK

Sinthrome is manufactured by:

Novartis Farmaceutica S.A.

Barberà del Vallés

Barcelona

Spain

The information in this leaflet applies only to Sinthrome. If you have any questions or you are not sure about anything, ask your doctor or a pharmacist.

This leaflet was last approved on 24^th April 2008.

Sinthrome is a registered trademark of Novartis Pharmaceuticals Limited and is used under licence by Alliance Pharmaceuticals Limited.

Alliance, Alliance Pharmaceuticals and associated devices are registered Trademarks

^© Alliance Pharmaceuticals Ltd 2008.

Metronidazole topical

Class: Antibacterials
VA Class: DE101
Chemical Name: 2-Methyl-5-nitro-1H-imidazole-1-ethanol
Molecular Formula: C₆H₉N₃O₃
CAS Number: 443-48-1
Brands: MetroCream, MetroGel, MetroGel-Vaginal, MetroLotion, Noritate, Vandazole

Introduction

Antibacterial and antiprotozoal;^{1 2 27 29 47 183} also has anti-inflammatory and immunosuppressive effects;^{1 2 14 17 21 28 180} nitroimidazole derivative.³

Uses for Metronidazole

Rosacea

Treatment of inflammatory lesions (papules and pustules) associated with rosacea (acne rosacea);^{1 2 8 9 10 16 17 18 19 20 21 47 180 184 207} topical gel designated an orphan drug by FDA for use in this condition.²³

Has no beneficial effects on telangiectasia,^{2 9 10 17 19 21 47} rhinophyma,⁴⁷ or ocular manifestations of rosacea.^{47 83}

Optimal treatment not determined; inflammatory lesions may respond to long-term treatment with topical anti-infectives (e.g., metronidazole) or oral anti-infectives (e.g., doxycycline, tetracycline, erythromycin, ampicillin, metronidazole).^{10 11 12 13 15 16 17 20 21 47 80 82 2 8 9 10 16 17 18 19 20 21 47 80 81 82} Topical metronidazole may be preferred to oral metronidazole;^{17 147} has been effective in patients with inadequate response or relapse with other therapies (e.g., oral tetracycline).^{2 10 17 21 62}

Effects appear palliative;^{17 18 19 47 81 61 99} manifestations recur commonly following discontinuance of therapy.^{17 18 19 47 61 99}

Adjunctive measures recommended to decrease exposure to factors that exacerbate rosacea (e.g., excessive sunlight, wind, hot liquids, spicy food, alcohol, extremes of heat and cold).^{2 12 80}

Bacterial Vaginosis

Treatment of bacterial vaginosis (formerly called Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, anaerobic vaginosis)^{109 111 112 114 115 119 120 122 123 139 153 183 214} in nonpregnant women.²¹⁴

CDC recommends treatment of bacterial vaginosis in all symptomatic women (including pregnant women).¹⁰⁹ In addition, asymptomatic pregnant women at high risk for complications of pregnancy should be screened (preferably at the first prenatal visit) and treatment initiated if needed.¹⁰⁹

Treatment recommendations for bacterial vaginosis in HIV-infected women are the same as those for women without HIV infection.¹⁰⁹

Regimens of choice in nonpregnant women are a 7-day regimen of oral metronidazole, a 5-day regimen of intravaginal metronidazole gel, or a 7-day regimen of intravaginal clindamycin cream;^{109 114} alternative regimens are a 7-day regimen of oral clindamycin or 3-day regimen of intravaginal clindamycin suppositories.^{109 114} The preferred regimens for pregnant women are a 7-day regimen of oral metronidazole or a 7-day regimen of oral clindamycin.¹⁰⁹

Regardless of regimen used, relapse or recurrence is common;^{109 110 120 122 138 153 162} an alternative regimen (e.g., oral therapy when topical was used initially) may be used in such situations.^{109 122}

Routine treatment of asymptomatic male sexual contacts of women who have relapsing or recurrent bacterial vaginosis not recommended.^{109 113 201 202 203}

Decubitus and Other Ulcers

Treatment of infected decubitus ulcers†;^{27 39 40 41 42 212} topical metronidazole designated an orphan drug by FDA for use in treatment of grade III or IV, anaerobically infected, decubitus ulcers.²³

Perioral Dermatitis

Treatment of perioral dermatitis†;^{210 211} topical gel designated an orphan drug by FDA for treatment of this condition.²³

Trichomoniasis

Has been used intravaginally as an adjunct to oral metronidazole for treatment of trichomoniasis caused by Trichomonas vaginalis† in selected cases (e.g., refractory infections),^{156 205} but not included in CDC recommendations for treatment of trichomoniasis.¹⁰⁹ Intravaginal metronidazole not effective used alone.¹¹⁴

Drug of choice for treatment of trichomoniasis is oral metronidazole or oral tinidazole.^{109 114 123 215 216}

Metronidazole Dosage and Administration

Administration

Administer topically to the skin^{2 180 184 207} or intravaginally^{183 214} in appropriate formulations.

Topical skin preparations (cream, gel, lotion) are for external use only and should not be used orally, intravaginally, or near or in eyes.^{1 177 180 184 207}

Intravaginal preparations are for intravaginal administration only and should not be used orally, topically on the skin, or near or in eyes.^{183 214}

Topical Administration

Apply topically to the skin as a 0.75 or 1% cream, 1% gel, or 0.75% lotion.^{1 19 180 184 207}

Prior to topical application, wash affected area with mild, nonirritating cleanser.^{1 2 180 184 207} To minimize risk of local irritation, some clinicians suggest application be delayed until about 15–20 minutes after skin cleansing.⁹⁹

Rub cream, gel, or lotion into affected area.^{1 19 180 184 207} Avoid contact with eyes.^{1 19 180 184 207}

If irritation occurs at application site, reduce application frequency or discontinue.^{1 19 180 184 207}

Cosmetics may be applied to skin after application of cream, gel, or lotion;^{1 47 180 184 207} allow lotion to dry ≥5 minutes before applying cosmetics.²⁰⁷

Intravaginal Topical Administration

Administer intravaginally as a 0.75% gel using vaginal applicators provided by the manufacturers.^{183 214}

If once-daily regimen used, administer dose at bedtime.^{183 214}

If once-daily regimen used, use new vaginal applicator for each dose.²¹⁴ If twice-daily regimen used, use new applicator each day; wash, rinse, and dry applicator after morning dose and discard after evening dose.²¹⁴

Dosage

Pediatric Patients

Bacterial Vaginosis

Treatment in Nonpregnant Postmenarchal Females

Intravaginal

0.75% gel: One applicatorful (approximately 37.5 g of metronidazole) once daily (at bedtime) or twice daily (in morning and evening) given for 5 consecutive days.²¹⁴

Adults

Rosacea

Topical

0.75% cream or lotion: Apply thin film to cleansed, affected area twice daily (morning and evening)^{180 207} or as directed by clinician.²⁰⁷

1% cream or gel: Apply thin film to cleansed, affected area once daily.^{1 184}

Optimum treatment duration not established;^{10 17 18 19 21 47 81} has been continued for ≥21 weeks in clinical studies.^{2 9 10 16 17 18 19 20 21 29}

Chronic therapy (usually intermittent) may be necessary, particularly for moderate to severe disease.^{61 99}

Clinical improvement usually occurs within 3 weeks.^{17 21} Once adequate response occurs, adjust frequency and duration of treatment according to disease course.⁴⁷

Although disease may remit during treatment,^{17 18 19} relapse occurs commonly following discontinuance.^{17 18 19 47 61 99}

Bacterial Vaginosis

Treatment in Nonpregnant Women

Intravaginal

0.75% gel: One applicatorful (approximately 37.5 g of metronidazole) once daily (at bedtime) or twice daily (in morning and evening) given for 5 consecutive days.^{109 111 112 114 115 183 214}

Cautions for Metronidazole

Contraindications

• 
  

  Known hypersensitivity to metronidazole, other nitroimidazole derivatives, or any ingredient in the formulation.^{1 180 183 184 207 214}

  
  

Warnings/Precautions

Warnings

Seizures and Peripheral Neuropathy

Convulsive seizures and peripheral neuropathy (characterized by numbness or paresthesia of an extremity) reported with oral or IV nitroimidazoles (e.g., metronidazole, tinidazole).^{183 217 214}

If abnormal neurologic signs develop with vaginal gel, promptly discontinue drug.^{183 214}

Use vaginal gel with caution in patients with history of CNS disease.^{183 214}

Interactions

Psychotic reactions reported in alcoholic patients receiving oral metronidazole and disulfiram concurrently;^{183 214} disulfiram-like reactions to alcohol reported in patients receiving oral metronidazole.^{106 183 214} Similar reactions could occur with intravaginal metronidazole.^{183 214}

Avoid intravaginal metronidazole in patients who have received disulfiram within the last 2 weeks.^{183 214} Caution patients to avoid drinking alcohol while being treated with intravaginal metronidazole.^{183 214} (See Specific Drugs under Interactions.)

General Precautions

Administration Precautions

Avoid contact with the eyes.^{1 180 183 184 207 214}

Topical cream, gel, or lotion may cause tearing.^{1 180 184 207}

Vaginal gel may cause ocular burning and irritation.^{183 214}

Iirrigate eyes with copious amounts of cool water if contact occurs.^{183 214}

Local Irritation

If reaction suggesting local irritation occurs, advise patient to use the topical preparation less frequently or discontinue use.^{1 180 184 207}

History of Blood Dyscrasia

Use with caution in patients with evidence or history of blood dyscrasia.^{1 180 184 207}

Transient leukopenia and neutropenia reported with systemic metronidazole;³⁰ adverse hematologic abnormalities not reported to date with topical metronidazole.^{2 21 47}

Vaginal Intercourse and Use of Vaginal Products

Patients treated with vaginal gel should not engage in vaginal intercourse^{111 112 113 183 214} and should not use other vaginal products (tampons, douches) during entire treatment course.^{111 112 113 214}

Vaginal intercourse or other vaginal products could reduce efficacy of intravaginal metronidazole (e.g., by dislodgment and/or dilution, by increased vaginal pH secondary to deposition of semen).^{111 112 113 214}

Superinfection

Symptoms of known or previously unrecognized vaginal candidiasis may become more prominent during intravaginal metronidazole therapy.^{183 214} Symptomatic Candida vaginitis reported during or immediately after therapy.^{183 214}

Systemic Adverse Effects

Although topical application to skin results in lower systemic absorption than oral or IV administration, adverse systemic effects (e.g., metallic taste,^{1 180 207} nausea,^{1 180 207} paresthesia,¹⁸⁴ tingling or numbness of extremities^{1 180 207} ) have been reported with topical metronidazole.^{1 180}

Although intravaginal administration results in lower systemic absorption than oral or IV administration, consider possibility that adverse effects reported with systemic metronidazole could occur when drug is given intravaginally.^{115 119 183 214}

Specific Populations

Pregnancy

Category B.^{1 180 183 184 207 214}

Safety and efficacy of intravaginal metronidazole for treatment of bacterial vaginosis in pregnant women not established.^{109 119 183 214} Existing data do not support use of intravaginal agents during pregnancy and intravaginal metronidazole not included in current CDC recommendations for treatment of bacterial vaginosis in pregnant women.¹⁰⁹

Lactation

Distributed into milk following oral or IV administration;^{1 30 45 131 180 183 184 207 214} not known whether distributed into milk following topical or intravaginal administration.^{183 f 214}

Discontinue nursing or the drug.^{1 180 183 184 207 214}

Pediatric Use

Safety and efficacy of topical^{1 180 184 207} or intravaginal¹⁸³ metronidazole not established in pediatric patients.

One manufacturer states safety and efficacy of vaginal gel established in postmenarchal females based on extrapolation of data from adult women; safety and efficacy of vaginal gel not established in premenarchal females.²¹⁴

Geriatric Use

Safety and efficacy of topical gel in geriatric patients ≥65 years of age appear similar to those in younger adults.¹

Insufficient experience with vaginal gel in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.²¹⁴

Hepatic Impairment

Use vaginal gel with caution in severe hepatic impairment.^{183 214}

Reduced elimination and increased plasma concentrations may occur in severe hepatic dysfunction.^{183 214}

Common Adverse Effects

Topical application to skin: Local effects such as erythema, irritation, stinging/burning, local allergic reactions, contact dermatitis, drying, pruritus, aggravated rosacea.^{1 47 180 184 207}

Intravaginal administration: Vaginal discharge,¹⁸³ symptomatic Candida cervicitis/vaginitis,¹⁸³ fungal infection,²¹⁴ vulvovaginal irritation,¹⁸³ dysmenorrhea,²¹⁴ GI effects (abdominal pain, GI discomfort, nausea, vomiting, diarrhea),^{183 214} headache,^{183 214} pruritus.²¹⁴

Interactions for Metronidazole

Because metronidazole can be absorbed systemically following topical application to skin^{1 2 9 10 21 47 207} or following intravaginal administration,^{119 131 132 183 214} the possibility that drug and laboratory test interactions could occur with these routes should be considered.^{106 183 f}

Specific Drugs and Laboratory Tests

Drug	Interaction	Comments
Alcohol	Disulfiram-like reactions reported rarely when alcohol ingested during intravaginal metronidazole treatment;106 183 214 such reactions not reported to date with topical application of metronidazole to skin21 47 61 99	Caution patients to avoid alcohol ingestion during intravaginal metronidazole treatment183 214
Anticoagulants, oral (warfarin)	Prolonged PT reported with systemic metronidazole 1 30 45 92 93 94 95 96 183 214	Consider possibility of potentiated anticoagulant effect if topical or intravaginal metronidazole used with oral anticoagulant therapy180 183 214
Cimetidine	Possible prolonged half-life and decreased clearance of metronidazole with concomitant cimetidine and oral or IV metronidazole182 183 214	Consider possibility of increased metronidazole adverse effects182
Disulfiram	Psychotic reactions reported in alcoholic patients receiving oral metronidazole and disulfiram concurrently92 97 168 169 183 214	Avoid concomitant use;92 97 214 do not initiate intravaginal metronidazole until 2 weeks after discontinuance of disulfiram183 214
Lithium	Increased lithium concentrations resulting in lithium toxicity reported after initiation of short-term oral metronidazole therapy in patients stabilized on relatively high lithium dosages181 183 214
Tests based on ultraviolet (UV) absorbance	Falsely decreased serum concentrations (including undetectable concentrations) of AST, ALT, LDH, triglycerides, or hexokinase glucose may be reported during metronidazole therapy if results are based on decreases in UV absorbance that occur during oxidation-reduction of NADH/NAD30 183 214 UV absorbance peaks of NADH and metronidazole are similar30 183 214	Use caution when interpreting test results based on UV absorbance during metronidazole therapy30 183 214

Metronidazole Pharmacokinetics

Absorption

Bioavailability

Absorbed systemically following topical application to skin; extent of absorption depends on formulation used (cream, gel, lotion).^{1 2 9 10 21 47 207}

Absorbed systemically following intravaginal administration;^{119 131 132 183 214} systemic bioavailability of vaginal gel averages 50–56%.^{119 131 132 183 186}

Following repeated topical application to the face of 1% cream (approximately 3.75 mg per dose) in adults with rosacea, serum concentrations were minimal or undetectable.⁹ Following topical application to the face of 1 g of 1% cream in healthy individuals, serum concentrations were minimal or undetectable and peak serum concentrations were attained within 8–12 hours after the dose.¹⁸⁴

Following topical application to the face of 1 g of 1% topical gel in adults with rosacea, peak serum concentrations of metronidazole were attained 6–10 hours after the dose and were <1% of concentrations reported with a single 250-mg oral dose.¹

Following topical application to the face of 1 g of 0.75% topical lotion (approximately 7.5 mg of metronidazole) twice daily for 4 days, drug was detectable in plasma of all patients and peak plasma concentrations were approximately 80 times lower than peak concentrations attained with a single 250-mg oral dose.²⁰⁷

Following intravaginal administration of 5 g of 0.75% vaginal gel (approximately 37.5 mg of metronidazole) in healthy women, peak serum concentrations were attained 4–17 hours after the dose and were approximately 2% of that attained after a single 500-mg oral dose.^{119 132 183 186 214}

Distribution

Extent

Not fully characterized following topical application to skin¹⁰ or intravaginal administration.^{176 177}

Crosses placenta following oral or IV administration;^{1 30 45 56 131 180 183 184 207} not known whether crosses placenta following topical application to skin¹ or intravaginal administration.¹⁸³

Distributed into milk following oral or IV administration;^{1 30 45 56 131 180 183 184 207 214} not known whether distributed into milk following topical application to skin¹ or intravaginal administration.¹⁸³

Elimination

Metabolism

Not fully characterized following topical application to skin¹⁰ or intravaginal administration.^{176 177}

Elimination Route

Any systemically absorbed drug probably metabolized in liver and excreted in urine.^{10 61}

Stability

Storage

Topical

Cream

20–25°C.^{180 184}

Gel

20–25°C (may be exposed to 15–30°C).¹

Lotion

20–25°C; do not freeze.²⁰⁷

Intravaginal

Gel

MetroGel-Vaginal: 15–30°C; do not freeze.¹⁸³

Vandazole: 20–25°C; do not freeze.²¹⁴

ActionsActions

• 
  

  Bactericidal, amebicidal, and trichomonacidal in action.^{2 30 48 52 56}

  
  


• 
  

  Un-ionized at physiologic pH⁴⁹ and readily taken up by anaerobic organisms or cells.^{48 49 50 56 72} In susceptible organisms or cells, metronidazole reduced by low-redox-potential electron transport proteins (e.g., nitroreductases such as ferredoxin);^{48 49 50 56 64 65 66 68 69 70 71 72} the reduction product(s) apparently are responsible for cytotoxic and antimicrobial effects of the drug (e.g., disruption of DNA, inhibition of nucleic acid synthesis).^{48 56 63 64 65 66 67 68 70 71 72}

  
  


• 
  

  Has direct anti-inflammatory effects^{2 14 17 21 28 180} and effects on neutrophil motility, lymphocyte transformation, and some aspects of cell-mediated immunity.^{2 10 32 33 34 35}

  
  


• 
  

  Mechanism of reducing inflammatory lesions (papules and pustules) and erythema in patients with rosacea not elucidated to date;^{1 2 6 10 11 17 19 21 28 29 184 207} these effects may result from anti-inflammatory or immunosuppressive actions of the drug.^{1 2 3 10 17 28 29 207}

  
  


• 
  

  Suppression of skin bacteria does not appear to play a major role in the mechanism of action of the drug in treatment of inflammatory lesions of rosacea;^{2 10 11 29} inactive in vitro against Propionibacterium acnes,^{2 4 5 48} staphylococci, and streptococci,^{2 48} and has no appreciable effects on the aerobic or anaerobic microflora of the skin of patients with rosacea.^{2 10 29}

  
  


• 
  

  Spectrum of activity includes most obligately anaerobic bacteria^{2 7 29 30 45 48 53 56 64} and many protozoa.^{2 29 30 48 52 64} Inactive against fungi^{2 3 48} and viruses⁴⁸ and most aerobic or facultatively anaerobic bacteria.^{2 7 30 45 48 73 74}

  
  


• 
  

  Gram-positive anaerobes: Active against Clostridium,^{2 30 45 48 53 55} C. difficile,^{54 55} C. perfringens,^{48 55} Eubacterium,^{2 30 45 48 53 54} Peptococcus,^{2 30 45 48 53 54 55} and Peptostreptococcus.^{2 7 30 45 48 53 55 124 128} Actinomyces, Lactobacillus,⁴⁸ Propionibacterium acnes,^{2 4 5 48} P. avidum,⁵ and P. granulosum⁵ generally are resistant.

  
  

  Gram-negative anaerobes: Active against Bacteroides fragilis,^{2 3 30 45 48 53 54 55 124 126 130} B. distasonis,^{30 45 54 55 124} B. ovatus,^{30 45 55 124} B. thetaiotaomicron,^{30 45 54 55 124} B. vulgatus,^{30 45 54 55 124} B. ureolyticus,^{124 126} Fusobacterium,^{2 7 30 45 48 53 55} Prevotella bivia,^{53 124 126 128 129} P. disiens,^{54 128} P. intermedia,^{7 124} P. melaninogenica,^{48 54 124 126 128 129} P. oralis,^{54 124 126 129} Porphyromonas,^{124 129} and Veillonella.^{7 54 55}

  
  


• 
  

  Other organisms: Active against Campylobacter fetus.⁴⁸ Most strains of Gardnerella vaginalis (formerly Haemophilus vaginalis) are susceptible only to relatively high concentrations in vitro.^{119 126 129 135 140 141 142} Concentrations readily achievable locally (750 mcg/mL) following intravaginal application of 0.75% vaginal gel have inhibited approximately 90% of strains tested in vitro.^{119 177}

  
  


• 
  

  Natural and acquired resistance has been reported in some T. vaginalis.^{48 52 75 76 77 78 79} Resistance also reported rarely in B. fragilis and other anaerobic bacteria following long-term therapy.^{44 48 215}

  
  

Advice to Patients

• 
  

  Importance of using topical or intravaginal metronidazole only as directed and only for the disorder for which drug was prescribed.^{1 180 183 184 207 f}

  
  


• 
  

  Advise patients that topical cream, gel, and lotion are for external use only and to avoid contact with eyes.^{1 180 184 207} (See Administration under Dosage and Administration.)

  
  


• 
  

  Advise patients that vaginal gel is for intravaginal administration only and to avoid contact with eyes.^{183 214} (See Administration under Dosage and Administration.) If such contact occurs, importance of irrigating eyes with copious amounts of cool water.^{177 183}

  
  


• 
  

  Instruct patients receiving vaginal gel regarding appropriate use of vaginal applicator.^f

  
  


• 
  

  Advise women using vaginal gel not to engage in vaginal intercourse¹¹¹

Topicort Gel

Pronunciation: dess-OX-ee-MET-ah-sone
Generic Name: Desoximetasone
Brand Name: Topicort

Topicort Gel is used for:

Relieving inflammation and itching of the skin.

Topicort Gel is a topical adrenocortical steroid. The precise way it works is unclear, but it is thought to reduce skin inflammation (redness, swelling, itching, and irritation) by stopping the production of certain chemicals in the body.

Do NOT use Topicort Gel if:

• you are allergic to any ingredient in Topicort Gel

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

Before using Topicort Gel:

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

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


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


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


• if you have a skin infection, measles, thinning of the skin, tuberculosis (TB), chicken pox, shingles, a positive TB skin test, or have recently had a vaccination

Some MEDICINES MAY INTERACT with Topicort Gel. Because little, if any, of Topicort Gel is absorbed into the blood, the risk of it interacting with another medicine is low.

Ask your health care provider if Topicort Gel may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Topicort Gel:

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

• Apply a small amount of medicine to the affected area(s). Gently rub the medicine in until it is evenly distributed. Wash your hands after applying the medicine, unless your hands are part of the treated area.


• Do not cover the treated area(s) with bandages or other dressings unless advised to do so by your health care provider.


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

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

Important safety information:

• Topicort Gel is for external use only. Avoid contact with eyes and other mucous membranes (nostrils, mouth). If Topicort Gel gets in your eyes, flush them with cool tap water immediately.


• Do NOT use more than the recommended dose or use for longer than prescribed without checking with your doctor.


• Do not use Topicort Gel for other skin conditions at a later time.


• If Topicort Gel was prescribed to treat the diaper area of a child, avoid using tight-fitting diapers or plastic pants.


• Corticosteroids may affect growth rate in CHILDREN and teenagers in some cases. They may need regular growth checks while they use Topicort Gel.


• Topicort Gel should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Topicort Gel while you are pregnant. It is not known if Topicort Gel is found in breast milk. If you are or will be breast-feeding while you use Topicort Gel, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Topicort Gel:

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

Mild, temporary stinging when first applied.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); itching, burning, redness, or swelling not present before using Topicort Gel.

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

See also: Topicort side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Topicort Gel may be harmful if swallowed.

Proper storage of Topicort Gel:

Store Topicort Gel at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Topicort Gel out of the reach of children and away from pets.

General information:

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


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


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Topicort resources

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

Compare Topicort with other medications

• Atopic Dermatitis
• Dermatitis
• Eczema
• Psoriasis

Cystitis Relief Tablets

1. Name Of The Medicinal Product

Cystitis Relief Tablets

2. Qualitative And Quantitative Composition

Active ingredient	mg/tablet
Citric Acid Ph Eur	1470.0
Sodium Bicarbonate Ph Eur	1735.0
Anhydrous Sodium Carbonate Ph Eur	137.5

3. Pharmaceutical Form

Effervescent tablet

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of the symptoms of cystitis in women only.

4.2 Posology And Method Of Administration

For oral administration.

Adult Women: Two tablets to be taken dissolved in water three times a day for 2 days.

Adult Men: Not recommended.

Children: Not recommended.

4.3 Contraindications

Hypertension, cardiovascular disease, renal disease, pregnancy, diabetes and patients on a low sodium diet.

4.4 Special Warnings And Precautions For Use

Medical advice should be sought if symptoms persist after the 2 day course of treatment.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically significant interactions known.

4.6 Pregnancy And Lactation

Cystitis tablets should not be taken during pregnancy.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

In view of the short duration of treatment, side effects are unlikely.

4.9 Overdose

In the event of overdosage, symptoms of fluid and electrolyte disturbance may occur. Treatment need only be symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Sodium citrate, produced from the reaction between citric acid and sodium bicarbonate, is an alkalinising agent which consequently renders the urine less acidic.

5.2 Pharmacokinetic Properties

Sodium citrate is readily absorbed from the gastrointestinal tract and metabolised in the liver to sodium bicarbonate. Less than 5% of the drug is excreted in the urine unchanged.

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars

6.1 List Of Excipients

Saccharin Sodium Ph Eur

Sorbitol Ph Eur

Flav F Pineapple 501085 Firme HSE

Purified Water Ph Eur

Total sodium per tablet is 535mg

6.2 Incompatibilities

None known

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Not applicable

6.5 Nature And Contents Of Container

Cold form strip pack containing a nylon/aluminium/polythene laminate and aluminium/polythene laminate.

Pack size: 12

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

The Boots Company PLC

1 Thane Road West

Nottingham NG2 3AA

8. Marketing Authorisation Number(S)

PL 0014/0559

9. Date Of First Authorisation/Renewal Of The Authorisation

17 December 1996

10. Date Of Revision Of The Text

November 1996

Cholestagel 625 mg film-coated tablets

1. Name Of The Medicinal Product

Cholestagel 625 mg film

2. Qualitative And Quantitative Composition

Each tablet contains 625 mg colesevelam (as hydrochloride).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film

Off

4. Clinical Particulars

4.1 Therapeutic Indications

Cholestagel co

Cholestagel as monotherapy is indicated as adjunctive therapy to diet for reduction of elevated total

Cholestagel can also be used in combination with ezetimibe, with or without a statin, in adult patients with primary hypercholesterolaemia, including patients with familial hypercholesterolaemia (see section 5.1).

4.2 Posology And Method Of Administration

Posology

Combination therapy

The recommended dose of Cholestagel for combination with a statin with or without ezetimibe is 4 to 6 tablets per day. The maximum recommended dose is 6 tablets per day taken as 3 tablets twice per day with meals or 6 tablets taken once per day with a meal. Clinical trials have shown that Cholestagel and statins can be co

Monotherapy

The recommended starting dose of Cholestagel is 6 tablets per day taken as 3 tablets twice per day with meals or 6 tablets once per day with a meal. The maximum recommended dose is 7 tablets per day.

During therapy, the cholesterol

When a drug interaction cannot be excluded with a concomitant medicinal product for which minor variations in the therapeutic level would be clinically important, or where no clinical data are available on co-administration, Cholestagel should be administered at least four hours before or at least four hours after the concomitant medication in order to minimize the risk of reduced absorption of the concomitant medication (see section 4.5).

Elderly population

There is no need for dose adjustment when Cholestagel is administered to elderly patients.

Paediatric population

Currently available data are described in section 5.1 but no recommendation on a posology can be made.

Method of administration

Cholestagel tablets should be taken orally with a meal and liquid.

4.3 Contraindications

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

• Bowel or biliary obstruction

4.4 Special Warnings And Precautions For Use

Prior to initiating therapy with Cholestagel, if secondary causes of hypercholesterolaemia (i.e., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease) are considered, these should be diagnosed and properly treated.

For patients on ciclosporin starting or stopping Cholestagel or patients on Cholestagel with a need to start ciclosporin: Cholestagel reduces the bioavailability of ciclosporin (see also section 4.5). Patients starting on ciclosporin already taking Cholestagel should have their ciclosporin blood concentrations monitored as normal and their dose adjusted as normal. Patients starting on Cholestagel already taking ciclosporin should have their blood concentrations monitored prior to combination therapy and frequently monitored immediately starting co

Caution should be exercised when treating patients with triglyceride levels greater than 3.4 mmol/L due to the triglyceride increasing effect with Cholestagel. Safety and efficacy are not established for patients with triglyceride levels greater than 3.4 mmol/L, since such patients were excluded from the clinical studies.

The safety and efficacy of Cholestagel in patients with dysphagia, swallowing disorders, severe gastrointestinal motility disorders, inflammatory bowel disease, liver failure or major gastrointestinal tract surgery have not been established. Consequently, caution should be exercised when Cholestagel is used in patients with these disorders.

Cholestagel can induce or worsen present constipation. The risk of constipation should especially be considered in patients with coronary heart disease and angina pectoris.

Anticoagulant therapy should be monitored closely in patients receiving warfarin or similar agents, since bile acid sequestrants, like Cholestagel, have been shown to reduce absorption of vitamin K and therefore interfere with warfarin's anticoagulant effect (see also section 4.5).

Cholestagel can affect the bioavailability of the oral contraceptive pill when administered simultaneously. It is important to ensure that Cholestagel is administered at least 4 hours after the oral contraceptive pill to minimise the risk of any interaction (see also section 4.5).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In general

Cholestagel may affect the bioavailability of other medicinal products. Therefore when a drug interaction cannot be excluded with a concomitant medicinal product for which minor variations in the therapeutic level would be clinically important, Cholestagel should be administered at least four hours before or at least four hours after the concomitant medication to minimize the risk of reduced absorption of the concomitant medication. For concomitant medications which require administration via divided doses, it should be noted that the required dose of Cholestagel can be taken once a day.

When administering medicinal products for which alterations in blood levels could have a clinically significant effect on safety or efficacy, physicians should consider monitoring serum levels or effects.

Interaction studies have only been performed in adults.

In interaction studies in healthy volunteers, Cholestagel had no effect on the bioavailability of digoxin, metoprolol, quinidine, valproic acid, and warfarin. Cholestagel decreased the C_max and AUC of sustained

There have been very rare reports of reduced phenytoin levels in patients who have received Cholestagel administered with phenytoin.

Anticoagulant therapy

Anticoagulant therapy should be monitored closely in patients receiving warfarin or similar agents, since bile acid sequestrants, like Cholestagel, have been shown to reduce absorption of vitamin K and therefore interfere with warfarin's anticoagulant effect. Specific clinical interaction studies with colesevelam and vitamin K have not been performed.

Levothyroxine

In an interaction study in healthy volunteers, Cholestagel reduced the AUC and C_max of levothyroxine when administered either concomitantly or after 1 hour. No interaction was observed when Cholestagel was administered at least four hours after levothyroxine.

Oral contraceptive pill

In an interaction study in healthy volunteers, Cholestagel reduced the C_max of norethindrone as well as the AUC and C_max of ethinylestradiol when administered simultaneously with the oral contraceptive pill. This interaction was also observed when Cholestagel was administered one hour after the oral contraceptive pill. However no interaction was observed when Cholestagel was administered four hours after the oral contraceptive pill.

Ciclosporin

In an interaction study in healthy volunteers, co₀ and C_max of ciclosporin by 34% by 44%, respectively. Therefore advice is given to closely monitor ciclosporin blood concentrations (see also section 4.4). In addition, based on theoretical grounds Cholestagel should be administered at least 4 hours after ciclosporin in order to further minimise the risks related to the concomitant administration of ciclosporin and Cholestagel. Furthermore, Cholestagel should always be administered at the same times consistently since the timing of intake of Cholestagel and ciclosporin could theoretically influence the degree of reduced bioavailability of ciclosporin.

Statins

When Cholestagel was co

Antidiabetic agents

Co₀ and C_max of glyburide by 32% and 47%, respectively. No interaction was observed when Cholestagel was administered four hours after glyburide.

Co_max of repaglinide, the clinical significance of which is unknown. No interaction was observed when Cholestagel was administered one hour after repaglinide.

No interaction was observed when Cholestagel and pioglitazone were administered simultaneously in healthy volunteers

Ursodeoxycholic acid

Cholestagel predominantly binds hydrophobic bile acids. In a clinical study Cholestagel did not affect the faecal excretion of endogenous (hydrophilic) ursodeoxycholic acid. However, formal interaction studies with ursodeoxycholic acid have not been performed. As noted in general, when a drug interaction cannot be excluded with a concomitant medicinal product, Cholestagel should be administered at least fours hour before or at least four hours after the concomitant medication to minimise the risk of reduced absorption of the concomitant medication. Monitoring of the clinical effects of treatment with ursodeoxycholic acid should be considered.

Other forms of interaction

Cholestagel did not induce any clinically significant reduction in the absorption of vitamins A, D, E or K during clinical studies of up to one year. However, caution should be exercised when treating patients with a susceptibility to vitamin K or fat-soluble vitamin deficiencies, such as patients with malabsorption. In these patients, monitoring vitamin A, D and E levels and assessing vitamin K status through the measurement of coagulation parameters is recommended and the vitamins should be supplemented if necessary.

4.6 Pregnancy And Lactation

Pregnancy

No clinical data are available on the use of Cholestagel in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.

Lactation

The safety of Cholestagel has not been established in breast-feeding women. Caution should be exercised when prescribing to breast-feeding women.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

In controlled clinical studies involving approximately 1400 patients, the following adverse reactions were reported in patients given Cholestagel. The reporting rate is classified as very common (

Investigations

Common: Serum triglycerides increased

Uncommon :Serum transaminase increased

Nervous system disorders

Common: Headache

Gastrointestinal disorders

Very common : Flatulence, constipation

Common : Vomiting, diarrhoea, dyspepsia, , abdominal pain, abnormal stools, nausea

Musculoskeletal and connective tissue disorders

Uncommon : Myalgia

The background incidence of flatulence and diarrhoea were higher in patients receiving placebo in the same controlled clinical studies. Only constipation and dyspepsia were reported by a higher percentage among those receiving Cholestagel, compared with placebo.

Adverse reactions were generally mild or moderate in intensity.

Cholestagel in combination with statins and in combination with ezetimibe was well tolerated and the adverse reactions observed were consistent with the known safety profile of statins or ezetimibe alone.

4.9 Overdose

Since Cholestagel is not absorbed, the risk of systemic toxicity is low. Gastrointestinal symptoms could occur. Doses in excess of the maximum recommended dose (4.5 g per day (7 tablets)) have not been tested.

Should overdosage occur, however, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction and the presence or absence of normal gut motility would determine treatment.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: bile acid sequestrants, ATC code: C10A C 04

The mechanism of action for the activity of colesevelam, the active substance in Cholestagel, has been evaluated in several in vitro and in vivo studies. These studies have demonstrated that colesevelam binds bile acids, including glycocholic acid, the major bile acid in humans. Cholesterol is the sole precursor of bile acids. During normal digestion, bile acids are secreted into the intestine. A major portion of bile acids is then absorbed from the intestinal tract and returned to the liver via the enterohepatic circulation.

Colesevelam is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. The LDL

In a 6-month dose-response study in patients with primary hypercholesterolaemia receiving 3.8 or 4.5 g Cholestagel daily, a 15 to 18% decrease in LDL

In a 6 week study 129 patients with mixed hyperlipidaemia were randomised to fenofibrate 160 mg plus 3.8 g Cholestagel or fenofibrate alone. The fenofibrate plus Cholestagel group (64 patients) demonstrated a 10% reduction on LDL

Multi

The effect of 3.8 g Cholestagel plus 10 mg ezetimibe versus 10 mg ezetimibe alone on LDL-C levels was assessed in a multicentre, randomised, double-blind, placebo-controlled, parallel-group study in 86 patients with primary hypercholesterolaemia over a 6-week treatment period. The combination of ezetimibe 10 mg and Cholestagel 3.8 g daily therapy in the absence of a statin resulted in a significant combined effect for LDL-C lowering by 32% demonstrating an additional effect of 11% LDL-C lowering with Cholestagel and ezetimibe compared to ezetimibe alone.

The addition of Cholestagel 3.8 g daily to maximally-tolerated statin and ezetimibe therapy was assessed in a multi-centre, randomised, double-blind, placebo-controlled study in 86 patients with familial hypercholesterolaemia. A total of 85% of the patients were on either atorvastatin (50% of whom received 80 mg dose) or rosuvastatin (72% of whom received 40 mg dose). Cholestagel resulted in a statistically significant LDL-C reduction of 11% and 11% at 6 and 12 weeks vs an increase of 7% and 1% in the placebo group; mean baseline levels were 3.75mmol/L and 3.86 mmol/L, respectively. Triglycerides in the Cholestagel group increased by 19% and 13% at 6 and 12 weeks vs an increase of 6% and 13% in the placebo group, but the increases were not significantly different. HDL-C and hsCRP levels were also not significantly different compared to placebo at 12 weeks.

In the paediatric population, the safety and efficacy of 1.9 or 3.8 g/day Cholestagel was assessed in an 8 week multi-centre, randomised, double-blind, placebo-controlled study in 194 boys and postmenarchal girls, aged 10-17 years, with heterozygous FH on a stable dose of statins (47 patients, 24%) or treatment-naïve to lipid-lowering therapy (147 patients, 76%). For all patients, Cholestagel resulted in a statistically significant LDL-C reduction of 11% at 3.8 g/day and 4% at 1.9 g/day, versus a 3% increase in the placebo group. For statin-naïve patients on monotherapy, Cholestagel resulted in a statistically significant LDL-C reduction of 12% at 3.8 g/day and 7% at 1.9 g/day, versus a 1% reduction in the placebo group (see section 4.2). There were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors, and the adverse reaction profile for Cholestagel was comparable to that seen with placebo.

Cholestagel has not been compared directly to other bile acid sequestrants in clinical trials.

So far, no studies have been conducted that directly demonstrate whether treatment with Cholestagel as monotherapy or combination therapy has any effect on cardiovascular morbidity or mortality.

5.2 Pharmacokinetic Properties

Cholestagel is not absorbed from the gastrointestinal tract.

5.3 Preclinical Safety Data

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Cellulose (E460), microcrystalline

Silica, colloidal anhydrous

Magnesium stearate

Water, purified

Film-coating:

Hypromellose (E464)

Diacetylated monoglycerides

Printing ink:

Iron oxide black (E172)

Hypromellose (E464)

Propylene glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Keep the bottle tightly closed in order to protect from moisture.

6.5 Nature And Contents Of Container

High density polyethylene bottles with a polypropylene cap.

Package sizes are:

24 tablets (1 X 24) 100 tablets (2 X 50) 180 tablets (1 X 180)

High density polyethylene bottles with a polypropylene cap without outer carton.

Package sizes are: 180 tablets (1 X 180)

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Genzyme Europe B.V., Gooimeer 10, NL-1411 DD Naarden, The Netherlands.

8. Marketing Authorisation Number(S)

EU/1/03/268/001-004

9. Date Of First Authorisation/Renewal Of The Authorisation

10 March 2004/12 March 2009

10. Date Of Revision Of The Text

03/2010

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/