Cortifoam

Generic Name: hydrocortisone acetate

Dosage Form: rectal aerosol, foam
Cortifoam®

(hydrocortisone acetate rectal aerosol)

10% Rectal Foam

Cortifoam Description

Cortifoam® (hydrocortisone acetate rectal aerosol) 10% Rectal Foam contains hydrocortisone acetate 10% in a base containing propylene glycol, emulsifying wax, polyoxyethylene-10-stearyl ether, cetyl alcohol, methylparaben, propylparaben, trolamine, purified water and inert propellants: isobutane and propane.

Each application delivers approximately 900 mg of foam containing 80 mg of hydrocortisone (90 mg of hydrocortisone acetate).

The molecular weight of hydrocortisone acetate is 404.50. It is designated chemically as pregn-4-ene-3,20-dione,21-(acetyloxy)-11,17-dihydroxy-,(11β)-. The empirical formula is C23H32O6 and the structural formula is:

Hydrocortisone acetate, a synthetic adrenocortical steroid, is a white to practically white, odorless, crystalline powder. It is insoluble in water (1 mg/100 mL) and slightly soluble in alcohol and chloroform.

Cortifoam - Clinical Pharmacology

Cortifoam® provides effective topical administration of an anti-inflammatory corticosteroid as adjunctive therapy of ulcerative proctitis. Direct observations of methylene blue-containing foam have shown staining about 10 centimeters into the rectum.

Indications and Usage for Cortifoam

Cortifoam® is indicated as adjunctive therapy in the topical treatment of ulcerative proctitis of the distal portion of the rectum in patients who cannot retain hydrocortisone or other corticosteroid enemas.

Contraindications

Cortifoam® is contraindicated in patients who are hypersensitive to any components of this product.

Local contraindications to the use of intrarectal steroids include obstruction, abscess, perforation, peritonitis, fresh intestinal anastomoses, extensive fistulas and sinus tracts.

Warnings

General

Do not insert any part of the aerosol container directly into the anus. Contents of the container are under pressure. Do not burn or puncture the aerosol container. Do not store at temperatures above 120°F. Because Cortifoam® is not expelled, systemic hydrocortisone absorption may be greater from Cortifoam® than from corticosteroid enema formulations. If there is not evidence of clinical or proctologic improvement within two or three weeks after starting Cortifoam® therapy, or if the patient's condition worsens, discontinue the drug.

Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS).

Cardio-renal

Corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Endocrine

Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.

Infections

General Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Fungal infections

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS, Drug Interactions, Amphotericin B injection and potassium-depleting agents).

Special pathogens

Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, and Toxoplasma.

It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea.

Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids should not be used in cerebral malaria.

Tuberculosis

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Vaccination

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison's disease.

Viral infections

Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents should be considered.

Ophthalmic

Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex.

Precautions

General

The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual.

Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.

Cardio-renal

As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.

Endocrine

Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.

Gastrointestinal

Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Where surgery is imminent, it is hazardous to wait more than a few days for a satisfactory response to medical treatment.

Do not employ in immediate or early postoperative period following ileorectostomy.

Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent.

There is an enhanced effect of corticosteroids in patients with cirrhosis.

Musculoskeletal

Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy.

Neuro-psychiatric

An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

Ophthalmic

Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored.

Information for Patients

Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection.

Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

Drug Interactions

Aminoglutethimide

Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression.

Amphotericin B injection and potassium-depleting agents

When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.

Antibiotics

Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance.

Anticholinesterases

Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.

Anticoagulants, oral

Coadministration of corticosteroids and warfarin result in inhibition of response to warfarin. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect.

Antidiabetics

Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.

Antitubercular drugs

Serum concentrations of isoniazid may be decreased.

Cholestyramine

Cholestyramine may increase the clearance of corticosteroids.

Cyclosporine

Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use.

Digitalis glycosides

Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia.

Estrogens, including oral contraceptives

Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect.

Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin)

Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased.

Ketoconazole

Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects.

Nonsteroidal anti-inflammatory agents (NSAIDS)

Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids.

Skin tests

Corticosteroids may suppress reactions to skin tests.

Vaccines

Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccination).

Carcinogenesis, Mutagenesis, Impairment of Fertility

No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis.

Steroids may increase or decrease motility and number of spermatozoa in some patients.

Pregnancy

Teratogenic effects

Pregnancy Category C

Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Nursing Mothers

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when corticosteroids are administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS

(listed alphabetically, under each subsection)

Allergic reactions: Anaphylactoid reaction, anaphylaxis, angioedema.

Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.

Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.

Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients.

Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention.

Where hypokalemia and other symptoms associated with fluid and electrolyte imbalance call for potassium supplementation and salt poor or salt-free diets, these may be instituted and are compatible with diet requirements for ulcerative proctitis.

Gastrointestinal: Abdominal distention, elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis.

Metabolic: Negative nitrogen balance due to protein catabolism.

Musculoskeletal: Aseptic necrosis of femoral and humeral heads, Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, steroid myopathy, tendon rupture, vertebral compression fractures.

Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo.

Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections.

Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain.

Overdosage

Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced.

Cortifoam Dosage and Administration

The usual dose is one applicatorful once or twice daily for two or three weeks, and every second day thereafter, administered rectally. Directions for use, below and on the carton, describe how to use the aerosol container and applicator. Satisfactory response usually occurs within five to seven days marked by a decrease in symptoms. Symptomatic improvement in ulcerative proctitis should not be used as the sole criterion for evaluating efficacy. Sigmoidoscopy is also recommended to judge dosage adjustment, duration of therapy, and rate of improvement.

It Should Be Emphasized that Dosage Requirements are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient's individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient's condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

Directions For Use

(1)

Shake foam container vigorously for 5-10 seconds before each use. Do not remove container cap during use of the product.

(2)

Hold container upright on a level surface and gently place the tip of the applicator onto the nose of the container cap. CONTAINER MUST BE HELD UPRIGHT TO OBTAIN PROPER FLOW OF MEDICATION.

(3)

Pull plunger past the fill line on the applicator barrel.

(4)

To fill applicator barrel, press down firmly on cap flanges, hold for 1 – 2 seconds and release. Pause 5 – 10 seconds to allow foam to expand in applicator barrel. Repeat until foam reaches fill line. Remove applicator from container cap. Allow some foam to remain on the applicator tip. A burst of air may come out of container with first pump.

(5)

Hold applicator firmly by barrel, making sure thumb and middle finger are positioned securely underneath and resting against barrel wings. Place index finger over the plunger. Gently insert tip into anus. Once in place, push plunger to expel foam, then withdraw applicator.

CAUTION: Do not insert any part of the aerosol container directly into the anus. Apply to anus only with enclosed applicator.

(6)

After each use, applicator parts should be pulled apart for thorough cleaning with warm water. The container cap and underlying tip should also be pulled apart and rinsed to help prevent build-up of foam and possible blockage.

How is Cortifoam Supplied

Cortifoam® is supplied in an aerosol container with a special rectal applicator. Each applicator delivers approximately 900 mg of foam containing approximately 80 mg of hydrocortisone as 90 mg of hydrocortisone acetate. When used correctly, the aerosol container will deliver a minimum of 14 applications.

NDC 68220-140-15           15 g

Store at controlled room temperature, 20°-25°C (68°-77°F).

DO NOT REFRIGERATE.

Rx only

Marketed and Distributed by:

ALAVEN®

PHARMACEUTICAL LLC

Marietta, GA 30067

For Medical Inquiries, call toll-free 1-888-317-0001

www.alavenpharm.com

4009471

Rev. 08/08

PRINCIPAL DISPLAY PANEL - 15 g Carton

NDC 68220-140-15

Cortifoam®

(hydrocortisone acetate 10%)

rectal foam

Rx Only

ALAVEN®

PHARMACEUTICAL LLC

15 g net wt

PRINCIPAL DISPLAY PANEL - 15 g Label

NDC 68220-140-15

Cortifoam®

(hydrocortisone acetate 10%)

rectal foam

Rx Only

15 g net wt

HOLD UPRIGHT TO

DISPENSE

SHAKE WELL BEFORE USE

ALAVEN®

PHARMACEUTICAL LLC

Cortifoam   hydrocortisone acetate  aerosol, foam

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 68220-140 Route of Administration RECTAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength hydrocortisone acetate (hydrocortisone) hydrocortisone acetate 1500 mg  in 15 g

Inactive Ingredients Ingredient Name Strength propylene glycol   cetyl alcohol   methylparaben   propylparaben   trolamine   water   isobutane   propane

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 68220-140-15 1 CONTAINER In 1 CARTON contains a CONTAINER 1 15 g In 1 CONTAINER This package is contained within the CARTON (68220-140-15)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA017351	02/12/1982

Labeler - Alaven Pharmaceutical LLC (140210829)

Revised: 11/2009Alaven Pharmaceutical LLC

More Cortifoam resources

• Cortifoam Use in Pregnancy & Breastfeeding
• Cortifoam Drug Interactions
• Cortifoam Support Group
• 15 Reviews for Cortifoam - Add your own review/rating

• Cortifoam foam, enema Concise Consumer Information (Cerner Multum)


• Cortifoam Foam MedFacts Consumer Leaflet (Wolters Kluwer)


• Hydrocortisone Monograph (AHFS DI)


• Hydrocortisone Professional Patient Advice (Wolters Kluwer)


• Colocort Enema MedFacts Consumer Leaflet (Wolters Kluwer)


• Cortef Concise Consumer Information (Cerner Multum)


• Cortef Advanced Consumer (Micromedex) - Includes Dosage Information


• Cortef MedFacts Consumer Leaflet (Wolters Kluwer)


• Hydrocortisone Buteprate topical Monograph (AHFS DI)


• Solu-Cortef Solution MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Cortifoam with other medications

• Anal Itching
• Aphthous Stomatitis, Recurrent
• Atopic Dermatitis
• Dermatitis
• Eczema
• Gingivitis
• Hemorrhoids
• Proctitis
• Pruritus
• Psoriasis
• Seborrheic Dermatitis
• Skin Rash
• Ulcerative Colitis, Active

Hydromol HC Intensive

1. Name Of The Medicinal Product

Hydromol HC Intensive

2. Qualitative And Quantitative Composition

Hydromol HC Intensive contains the active ingredients Hydrocortisone, PhEur 1% w/w and Urea, BP 10% w/w.

3. Pharmaceutical Form

Translucent white cream.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of all dry ichthyotic, eczematous conditions of the skin, including atopic, infantile, chronic allergic and irritant eczema, asteatotic, hyperkeratotic and lichenified eczema, neurodermatitis and prurigo.

4.2 Posology And Method Of Administration

Adults, children and the elderly. A small amount should be applied topically to the preferably dry affected areas twice daily. In resistant lesions occlusive dressings may be used but this is usually unnecessary because of the self occlusive nature of the special base.

4.3 Contraindications

Primary bacterial, viral and fungal diseases of the skin and secondarily infected eczemas or intertrigo acne, perioral dermatitis, rosacea and, in general, should not be used on weeping surfaces.

Known hypersensitivity to the active ingredients or any of its excipients.

4.4 Special Warnings And Precautions For Use

Caution should be exercised when using in children. In infants and children, long term continuous therapy should be avoided, as adrenal suppression can occur even without occlusion. Excessive absorption may occur when applied under napkins. Where possible treatment in infants should be limited to 5-7 days.

Application to moist or fissured skin may cause temporary irritation.

As with corticosteroids in general, prolonged application to the face and eyelids is undesirable and the cream should be kept away from the eyes.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

There is inadequate evidence for safety in human pregnancy. Topical administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate and intra-uterine growth retardation. There may, therefore, be a very small risk of such effects in the human foetus.

4.7 Effects On Ability To Drive And Use Machines

Hydromol HC Intensive does not interfere with the ability to drive or use machines.

4.8 Undesirable Effects

If used correctly Hydromol HC Intensive is unlikely to cause side effects. However, the following events have been observed with topical steroids, and although are rare with hydrocortisone, may occur, especially with long-term use; spread and worsening of untreated infection; thinning of the skin; irreversible striae atrophicae and telangiectasia; contact dermatitis, perioral dermatitis; acne; mild depigmentation which may be reversible. Atrophic changes may occur in intertriginous areas or nappy areas in young children.

4.9 Overdose

Chronically, grossly excessive over-use on large areas of skin in, for example, children could result in adrenal suppression of the hypothalamic-pituitary axis (HPA) as well as topical and systemic signs and symptoms of high corticosteroid dosage. In such cases, treatment should not stop abruptly. Adrenal insufficiency may require treatment with systemic hydrocortisone. Ingestion of a large amount of Hydromol HC Intensive would be expected to result in gastrointestinal irritation, nausea, and possibly vomiting. Symptomatic and supportive care should be given. Liberal oral administration of milk or water may be helpful.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Hydrocortisone is a naturally occurring glucocorticoid with proven anti-inflammatory and vasoconstrictive properties. Urea has been demonstrated to have hydrating, keratolytic and anti-pruritic properties. As such, urea has additional therapeutic effect in dry hyperkeratotic skin conditions. Hydromol HC Intensive contains hydrocortisone and urea in a specially formulated base which assists the percutaneous transportation of the active ingredients to the site of action. Due to this formulation, Hydromol HC Intensive acts as a moderately potent topical corticosteroid. The base is self-occlusive and fulfils the functions of both an ointment and a cream.

5.2 Pharmacokinetic Properties

Therapeutic activity of hydrocortisone depends upon the adequate penetration through the horny layer of the skin. The urea in the formulation solubilises part of the hydrocortisone and has a keratolytic effect. Both these factors increase penetration of the hydrocortisone

5.3 Preclinical Safety Data

None stated

6. Pharmaceutical Particulars

6.1 List Of Excipients

White soft paraffin, maize starch, isopropyl myristate, sycrowax HR-C, palmitic acid, sorbitan laurate and Arlatone G.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Two years

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Supplied in tubes of 30g and 100g.

6.6 Special Precautions For Disposal And Other Handling

A patient leaflet is provided with details of use and handling of the product.

7. Marketing Authorisation Holder

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

8. Marketing Authorisation Number(S)

PL 16853/0060.

9. Date Of First Authorisation/Renewal Of The Authorisation

13 February 1990

10. Date Of Revision Of The Text

1^st February 2010

11. LEGAL STATUS

POM

Advagraf 0.5mg, 1mg, 3mg & 5mg Prolonged-release hard capsules

Advagraf 0.5 mg prolonged-release hard capsules

Advagraf 1 mg prolonged-release hard capsules

Advagraf 3 mg prolonged-release hard capsules

Advagraf 5 mg prolonged-release hard capsules

Tacrolimus

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 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 Advagraf is and what it is used for


• 2. Before you take Advagraf


• 3. How to take Advagraf


• 4. Possible side effects


• 5. How to store Advagraf


• 6. Further information

What Advagraf Is And What It Is Used For

Advagraf is an immunosuppressant. Following your organ transplant (liver, kidney), your body’s immune system will try to reject the new organ. Advagraf is used to control your body’s immune response, enabling your body to accept the transplanted organ.

You may also be given Advagraf for an ongoing rejection of your transplanted liver, kidney, heart or other organ when any previous treatment you were taking was unable to control this immune response after your transplantation.

Prograf and Advagraf contain both the active substance, tacrolimus. However, Advagraf is taken once daily, whereas Prograf is taken twice daily. This is because Advagraf capsules allow for a prolonged release of tacrolimus.

Before You Take Advagraf

Do not take Advagraf

• if you are allergic (hypersensitive) to tacrolimus or any of the other ingredients of Advagraf (see section 6).


• if you are allergic to sirolimus or to any macrolide-antibiotic (e.g. erythromycin, clarithromycin, josamycin).

Take special care with Advagraf

Tell your doctor if any of the following apply to you:

• if you are taking any medicines mentioned below under ‘Using other medicines’.


• if you have or have had liver problems


• if you have diarrhoea for more than one day


• if you need to receive any vaccinations

Your doctor may need to adjust your dose of Advagraf.

You should keep in regular contact with your doctor. From time to time, your doctor may need to do blood, urine, heart, eye tests, to set the right dose of Advagraf.

The use of Advagraf is not recommended in children and adolescents under 18 years.

You should limit your exposure to the sun and UV (ultraviolet) light whilst taking Advagraf. This is because immunosuppressants could increase the risk of skin cancer. Wear appropriate protective clothing and use a sunscreen with a high sun protection factor.

Using 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 and herbal preparations.

It is not recommended that Advagraf is taken with ciclosporin.

Advagraf blood levels can be affected by other medicines you take, and blood levels of other medicines can be affected by taking Advagraf, which may require an increase or decrease in Advagraf dose. In particular, you should tell your doctor if you are taking or have recently taken medicines like:

• antifungal medicines and antibiotics, particularly so-called macrolide antibiotics, used to treat infections e.g. ketoconazole, fluconazole, itraconazole, voriconazole, clotrimazole, erythromycin, clarithromycin, josamycin, and rifampicin


• HIV protease inhibitors (e.g ritonavir), used to treat HIV infection


• medicines for stomach ulcer and acid reflux (e.g. omeprazol, lansoprazol or cimetidine)


• antiemetics, used to treat nausea and vomiting (e.g. metoclopramide)


• cisapride or the antacid magnesium-aluminium-hydroxide, used to treat heartburn


• the contraceptive pill or other hormone treatments with ethinylestradiol, hormone treatments with danazol


• medicines used to treat high blood pressure or heart problems (e.g. nifedipine, nicardipine, diltiazem and verapamil)


• medicines known as “statins” used to treat elevated cholesterol and triglycerides


• phenytoin or phenobarbital, used to treat epilepsy


• the corticosteroids prednisolone and methylprednisolone, belonging to the class of corticosteroids used to treat inflammations or suppress the immune system (e.g. in transplant rejection)


• nefazodone, used to treat depression


• Herbal preparations containing St. John’s Wort (Hypericum perforatum)

Tell your doctor if you are taking or need to take ibuprofen, amphotericin B or antivirals (e.g. aciclovir). These may worsen kidney or nervous system problems when taken together with Advagraf.

Your doctor also needs to know if you are taking potassium supplements or certain diuretics used for heart failure, hypertension and kidney disease, (e.g. amiloride, triamterene, or spironolactone), non-steroidal anti-inflammatory drugs (NSAIDs, e.g. ibuprofen) used for fever, inflammation and pain, anticoagulants (blood thinners), or oral medicines for diabetes, while you take Advagraf.

If you need to have any vaccinations, please tell your doctor before.

Taking Advagraf with food and drink

Take Advagraf on an empty stomach or 2 to 3 hours after a meal. Wait at least 1 hour until the next meal.

Avoid grapefruit (also as juice) while on treatment with Advagraf, since it can affect its levels

Pregnancy and breast-feeding

If you are, think you might be or are planning to become pregnant, ask your doctor for advice before using Advagraf.

Advagraf passes into breast milk. Therefore, you should not breast-feed whilst using Advagraf.

Driving and using machines

Do not drive or use any tools or machines if you feel dizzy or sleepy, or have problems seeing clearly after taking Advagraf. These effects are more frequent if you also drink alcohol.

Important information about some of the ingredients of Advagraf

Advagraf contains lactose (milk sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

The printing ink used on Advagraf capsules contains soya lecithin. If you are allergic to peanut or soya, talk to your doctor to determine whether you should use this medicine.

How To Take Advagraf

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

Make sure that you receive the same tacrolimus medicine every time you collect your prescription, unless your transplant specialist has agreed to change to a different tacrolimus medicine. This medicine should be taken once a day. If the appearance of this medicine is not the same as usual, or if dosage instructions have changed, speak to your doctor or pharmacist as soon as possible to make sure that you have the right medicine.

The starting dose to prevent the rejection of your transplanted organ will be determined by your doctor calculated according to your body weight. Initial daily doses just after transplantation will generally be in the range of

0.10 – 0.30 mg per kg body weight per day

depending on the transplanted organ.

Your dose depends on your general condition and on which other immunosuppressive medication you are taking.

Following the initiation of your treatment with Advagraf, frequent blood tests will be taken by your doctor to define the correct dose. Afterwards regular blood tests by your doctor will be required to define the correct dose and to adjust the dose from time to time. Your doctor will usually reduce your Advagraf dose once your condition has stabilised. Your doctor will tell you exactly how many capsules to take.

You will need to take Advagraf every day as long as you need immunosuppression to prevent rejection of your transplanted organ. You should keep in regular contact with your doctor.

Advagraf is taken orally once daily in the morning. Take the capsules immediately following removal from the blister. The capsules should be swallowed whole with a glass of water. Do not swallow the desiccant contained in the foil wrapper.

If you take more Advagraf than you should

If you have accidentally taken too much Advagraf, contact your doctor or nearest hospital emergency department immediately.

If you forget to take Advagraf

If you have forgotten to take your Advagraf capsules in the morning, take them as soon as possible on the same day. Do not take a double dose the next morning.

If you stop taking Advagraf

Stopping your treatment with Advagraf may increase the risk of rejection of your transplanted organ. Do not stop your treatment unless your doctor tells you to do so.

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

Possible Side Effects

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

Advagraf reduces your body’s defence mechanism (immune system), which will not be as good at fighting infections. Therefore, you may be more prone to infections while you are taking Advagraf.

Severe effects may occur, including allergic and anaphylactic reactions. Benign and malignant tumours have been reported following Advagraf treatment.

Possible side effects are listed according to the following categories:

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 effects:

• Increased blood sugar, diabetes mellitus, increased potassium in the blood


• Difficulty in sleeping


• Trembling, headache


• Increased blood pressure


• Liver function tests abnormal


• Diarrhoea, nausea


• Kidney problems

Common side effects:

• Reduction in blood cell counts (platelets, red or white blood cells), increase in white blood cell counts, changes in red blood cell counts (seen in blood tests)


• Reduced magnesium, phosphate, potassium, calcium or sodium in the blood, fluid overload, increased uric acid or lipids in the blood, decreased appetite, increased acidity of the blood, other changes in the blood salts (seen in blood tests)


• Anxiety symptoms, confusion and disorientation, depression, mood changes, nightmare, hallucination, mental disorders


• Fits, disturbances in consciousness, tingling and numbness (sometimes painful) in the hands and feet, dizziness, impaired writing ability, nervous system disorders


• Blurred vision, increased sensitivity to light, eye disorders


• Ringing sound in your ears


• Reduced blood flow in the heart vessels, faster heartbeat


• Bleeding, partial or complete blocking of blood vessels, reduced blood pressure


• Shortness in breath, changes in the lung tissue, collection of liquid around the lung, inflammation of the pharynx, cough, flu-like symptoms


• Stomach problems such as inflammation or ulcer causing abdominal pain or diarrhoea, bleeding in the stomach, inflammation or ulcer in the mouth, collection of fluid in the belly, vomiting, abdominal pain, indigestion, constipation, passing wind, bloating, loose stools


• Bile duct disorders, yellowing of the skin due to liver problems, liver tissue damage and inflammation of the liver


• Itching, rash, hair loss, acne, increased sweating


• Pain in joints, limbs or back, muscle cramps


• Insufficient function of the kidneys, reduced production of urine, impaired or painful urination


• General weakness, fever, collection of fluid in your body, pain and discomfort, increase of the enzyme alkaline phosphatase in your blood, weight gain, feeling of temperature disturbed


• Insufficient function of your transplanted organ

Uncommon side effects:

• Changes in blood clotting, reduction in the number of all types of blood cells (seen in blood tests)


• Dehydration, inability to urinate


• Abnormal blood test results: reduced protein or sugar, increased phosphate, increase of the enzyme lactate dehydrogenase


• Coma, bleeding in the brain, stroke, paralysis, brain disorder, speech and language abnormalities, memory problems


• Clouding of the eye lens, impaired hearing


• Irregular heartbeat, stop of heartbeat, reduced performance of your heart, disorder of the heart muscle, enlargement of the heart muscle, stronger heartbeat, abnormal ECG, heart rate and pulse abnormal


• Blood clot in a vein of a limb, shock


• Difficulties in breathing, respiratory tract disorders, asthma


• Obstruction of the gut, increased blood level of the enzyme amylase, reflux of stomach content in your throat, delayed emptying of the stomach


• Inflammation of the skin, burning sensation in the sunlight


• Joint disorders


• Painful menstruation and abnormal menstrual bleeding


• Failure of some organs, flu-like illness, increased sensitivity to heat and cold, feeling of pressure on your chest, jittery or abnormal feeling, weight loss

Rare side effects:

• Small bleedings in your skin due to blood clots


• Increased muscle stiffness


• Blindness, deafness


• Collection of fluid around the heart


• Acute breathlessness


• Cyst formation in your pancreas


• Problems with blood flow in the liver


• Serious illness with blistering of skin, mouth, eyes and genitals; increased hairiness


• Thirst, fall, feeling of tightness in your chest, decreased mobility, ulcer

Very rare side effects:

• Muscular weakness


• Abnormal heart scan


• Liver failure


• Painful urination with blood in the urine


• Increase of fat tissue

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

How To Store Advagraf

Keep out of the reach and sight of children.

Do not use Advagraf after the expiry date which is stated on the carton after “Exp”. The expiry date refers to the last day of that month. Use all the prolonged-release hard capsules within 1 year of opening the aluminium wrapping.

Store in the original package in order to protect from moisture.

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 Advagraf contains

• The active substance is tacrolimus.
  
  
  Each capsule of Advagraf 0.5 mg contains 0.5 mg of tacrolimus.
  
  Each capsule of Advagraf 1 mg contains 1 mg of tacrolimus.
  
  Each capsule of Advagraf 3 mg contains 3 mg of tacrolimus.
  
  Each capsule of Advagraf 5 mg contains 5 mg of tacrolimus.


• The other ingredients are:
  Capsule content: Hypromellose, ethylcellulose, lactose, magnesium stearate.
  Capsule shell: Titanium dioxide (E171), yellow iron oxide (E 172), red iron oxide (E 172), sodium laurilsulfate, gelatin.
  Printing ink: Shellac, lecithin (soya), simeticone, red iron oxide (E 172), hydroxypropylcellulose.

What Advagraf looks like and contents of the pack

Advagraf 0.5 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with “0.5 mg” on the light yellow capsule cap and “647” on the orange capsule body, containing white powder.

Advagraf 0.5 mg is supplied in blisters containing 10 capsules within a protective foil wrapper, including a desiccant. Packs of 30, 50 and 100 prolonged-release capsules are available.

Advagraf 1 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with “1 mg” on the white capsule cap and “677” on the orange capsule body, containing white powder.

Advagraf 1 mg is supplied in blisters containing 10 capsules within a protective foil wrapper, including a desiccant. Packs of 30, 50, 60 and 100 prolonged-release capsules are available.

Advagraf 3 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with “3 mg” on the orange capsule cap and “637” on the orange capsule body, containing white powder.

Advagraf 3 mg is supplied in blisters containing 10 capsules within a protective foil wrapper, including a desiccant. Packs of 30, 50 and 100 prolonged-release capsules are available.

Advagraf 5 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with “5 mg” on the greyish red capsule cap and “687” on the orange capsule body, containing white powder.

Advagraf 5 mg is supplied in blisters containing 10 capsules within a protective foil wrapper, including a desiccant. Packs of 30, 50 and 100 prolonged-release hard capsules are available.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Astellas Pharma Europe B.V.

Elisabethhof 19

2353 EW Leiderdorp

Netherlands

Manufacturer:

Astellas Ireland Co., Ltd.

Killorglin

County Kerry

Ireland

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

United Kingdom

Astellas Pharma Ltd.

Lovett House

Lovett Road

Staines

Middlesex

TW18 3AZ

UK

Tel:+ 44 (0) 1784 419615

This leaflet was last approved in 01/2010

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

130710

Clear Up Prep

Dosage Form: gel
Drug Facts

ACTIVE INGREDIENT

Salicylic Acid 2% w/w.

INACTIVE INGREDIENTS

WATER • SORBITOL • ETHOXYDIGLYCOL • GLYCOLIC ACID • METHYL GLUCETH-20 • SODIUM CITRATE • GLYCERIN • LACTIC ACID • SODIUM HYDROXIDE • CELLULOSE GUM • XANTHAN GUM • ETHYLHEXYLGLYCERIN • PROPYLENE GLYCOL • PHENOXYETHANOL • CITRUS MEDICA LIMONUM (LEMON) FRUIT EXTRACT • HEDERA HELIX (IVY) EXTRACT • SAPONARIA OFFICINALIS EXTRACT •

ARCTIUM LAPPA ROOT EXTRACT • SALVIA OFFICINALIS (SAGE) LEAF EXTRACT •

DIRCETIONS

Cover the eyes with cotton pads soaked in Blue Water. With the fingertips, apply evenly to the face and neck Clear Up Prep Lotion, making sure to avoid the lips.

Application: 2-3 minutes | Pause: 7-8 minutes

WARNINGS

Enter section text here

image of carton label

image of tube 5ml label

Enter section text here

Keep out of reach of children.

Enter section text here

Clear Up Prep  salicylic acid  gel

Product Information Product Type HUMAN OTC DRUG NDC Product Code (Source) 62499-395 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SALICYLIC ACID (SALICYLIC ACID) SALICYLIC ACID 2 g  in 100 g

Inactive Ingredients Ingredient Name Strength WATER   SORBITOL   DIETHYLENE GLYCOL MONOETHYL ETHER   GLYCOLIC ACID   METHYL GLUCETH-20   SODIUM CITRATE   GLYCERIN   LACTIC ACID   SODIUM HYDROXIDE   PROPYLENE GLYCOL   PHENOXYETHANOL   CARBOXYMETHYLCELLULOSE SODIUM   XANTHAN GUM   ETHYLHEXYLGLYCERIN   LEMON OIL   SAPONARIA OFFICINALIS ROOT   ARCTIUM LAPPA ROOT   SAGE OIL

Product Characteristics Color blue (dark bleu) Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 62499-395-11 1 TUBE In 1 CARTON contains a TUBE (62499-395-10) 1 62499-395-10 5 g In 1 TUBE This package is contained within the CARTON (62499-395-11)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
OTC monograph final	part358H	07/01/2010

Labeler - Laboratoire Dr. Renaud (202501565)

Revised: 07/2010Laboratoire Dr. Renaud

More Clear Up Prep resources

• Clear Up Prep Side Effects (in more detail)
• Clear Up Prep Use in Pregnancy & Breastfeeding
• Clear Up Prep Drug Interactions
• Clear Up Prep Support Group
• 1 Review for Clear Up Prep - Add your own review/rating

Compare Clear Up Prep with other medications

• Acne
• Dermatological Disorders
• Warts

Boots Cough and Decongestant Syrup 6 Years Plus

1. Name Of The Medicinal Product

Boots Cough and Decongestant Syrup 6 Years +

2. Qualitative And Quantitative Composition

Active ingredient	% w/v
Guaifenesin Ph Eur Pseudoephedrine hydrochloride	1.0 0.2

3. Pharmaceutical Form

Syrup

4. Clinical Particulars

4.1 Therapeutic Indications

A combination expectorant and decongestant for the relief of acute productive (chesty) cough, nasal congestion and congestion of the mucous membranes of the upper respiratory tract associated with the common cold.

4.2 Posology And Method Of Administration

For oral administration.

Children 6 to 12 years: Two 5ml spoonfuls three or four times a day.

Not more than 4 doses should be given in any 24 hours.

This medicine is contraindicated in children under 6 years of age (see section 4.3).

Children of 6-12 years of age: not to be used for more than 5 days without the advice of a doctor. Parents and carers should seek medical attention if the child's condition deteriorates during treatment.

Warning: Do not exceed the stated dose.

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

4.3 Contraindications

Hypersensitivity to the active substances or any of the excipients or intolerance to other sympathomimetics.

Severe renal impairment

Cardiovascular disease including hypertension and peripheral vascular disease.

Diabetes mellitus

Phaeochromocytoma

Hyperthyroidism

Closed angle glaucoma

Concomitant use of other sympathomimetic decongestants

Monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping treatment (see section 4.5).

Beta-blockers – (see section 4.5).

Not to be used in children under the age of 6 years.

4.4 Special Warnings And Precautions For Use

Guaifenesin

Ask a doctor before use if you suffer from a chronic cough, if you have asthma or are suffering from an acute asthma attack.

Stop use and ask a healthcare professional if your cough lasts for more than 5 days, comes back, or is accompanied by a fever, rash, or persistent headache.

Do not take with a cough suppressant.

Pseudoephedrine

If any of the following occur, this medicine should be stopped

Hallucinations

Restlessness

Sleep disturbances

Caution in moderate to severe renal impairment.

Pseudoephedrine should be used with caution when administered to patients taking antihypertensive agents, tricyclic antidepressants, other sympathomimetic agents such as decongestants, appetite suppressants and amphetamine-like psycho-stimulants. The effects of a single dose on the blood pressure of these patients should be observed before recommending repeated or unsupervised treatment.

Do not give with any other cough and cold medicine.

If symptoms do not go away, talk to your pharmacist or doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Pseudoephedrine

MAOIs and/or RIMAs: should not be given to patients treated with MAOIs or within 14 days of stopping treatment: increased risk of hypertensive crisis.

Moclobemide: risk of hypertensive crisis.

Antihypertensives: (including adrenergic neurone blockers, diuretics & beta-blockers): pseudoephedrine may block the hypotensive effects.

Cardiac glycosides: increased risk of dysrhythmias.

Ergot alkaloids (ergotamine & methysergide): increased risk of ergotism.

Appetite suppressants and amphetamine-like psycho-stimulants: risk of hypertension.

Oxytocin: risk of hypertension.

Enhances effects of anticholinergic drugs (such as TCAs).

Should not be given with other sympathomimetics such as decongestants, and thyroid hormones. Should not be given to patients undergoing general anaesthesia as them may induce ventricular arrhythmias.

Guaifenesin

If urine is collected within 24 hours of a dose of guaifenesin a metabolite of guaifenesin may cause a colour interference with laboratory determinations of urinary 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmandelic acid (VMA).

4.6 Pregnancy And Lactation

Since the product is intended only for use in children, information on its use in pregnancy and lactation is not relevant.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

Guaifenesin

The following side effects may be associated with the use of guaifenesin:

Gastrointestinal disorders: nausea, vomiting, gastrointestinal discomfort.

Immune system disorders: hypersensitivity reactions.

Pseudoephedrine

Cardiovascular disorders: tachycardia, palpitations, other cardiac dysrythmias.

Gastrointestinal disorders: nausea and/or vomiting, dry mouth.

General disorders and administration site conditions: irritability, thirst, tolerance with dependence has been reported with prolonged administration of pseudoephedrine-containing preparations.

Immune system disorders: hypersensitivity reactions, including cross-sensitivity that may occur with other sympathomimetics.

Musculoskeletal and connective tissue disorders: muscular weakness.

Nervous system disorders: headache, giddiness, tremor, anxiety, restlessness, excitability, insomnia, hallucinations (particularly in children) and paranoid delusions.

Psychiatric disorders: sleep disturbance.

Renal and urinary disorders: difficulty in micturition including urinary retention.

Skin and subcutaneous tissue disorders: skin reactions including rash, sweating.

Vascular disorders: hypertension.

4.9 Overdose

Symptoms of overdosage include headache, nausea, vomiting, tachycardia, urinary retention, hallucinations, coma, tremor, excitement, convulsions, respiratory depression, hypertension and arrhythmias.

Initial treatment consists of either emesis or gastric lavage, if appropriate. Otherwise treatment should be symptomatic and supportive, including the administration of a beta blocker if supraventricular tachycardia supervenes.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pseudoephedrine acts directly on both alpha and to a lesser extent beta adrenergic receptors. It is believed that the alpha adrenergic effects result from inhibition of the production of cyclic AMP by inhibition of the enzyme adenyl cyclase, whereas beta adrenergic effects result from stimulation of adenyl cyclase activity. Pseudoephedrine also has an indirect effect by releasing noradrenaline from its storage sites.

Guaifenesin reduces the viscosity of tenacious sputum and is used as an expectorant.

5.2 Pharmacokinetic Properties

Pseudoephedrine is absorbed from the gastrointestinal tract. It is resistant to metabolism by monoamine oxidase and is largely excreted unchanged in the urine together with small amounts of its hepatic metabolite. It has an elimination half-life of several hours.

Guaifenesin is readily absorbed from the gastrointestinal tract. It is metabolised and excreted in the urine.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maltitol solution

Hydroxyethyl cellulose

Glycerin

Purified water

Potassium sorbate

Acesulfame K

Sodium citrate

Citric acid monohydrate

Levomenthol

Alcohol 96%

Blackcurrant flavour

Vanilla bean extract

6.2 Incompatibilities

None stated

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Do not store above 30°C.

6.5 Nature And Contents Of Container

Amber PET bottle with polypropylene child resistant closure fitted with an expanded polyethylene liner.

Pack sizes: 100ml, 125ml, 150ml, 200ml

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

England

ML 00014/01

8. Marketing Authorisation Number(S)

PL 00014/0545

9. Date Of First Authorisation/Renewal Of The Authorisation

31 January 1997 / 30 January 2002

10. Date Of Revision Of The Text

May 2009

Ropinirole 0.5 mg Film-Coated Tablets (Actavis UK Ltd)

1. Name Of The Medicinal Product

Ropinirole 0.5 mg Film-Coated Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains ropinirole hydrochloride equivalent to 0.5 mg ropinirole base.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Ropinirole 0.5 mg Film-Coated Tablets are yellow, round (7mm in diameter), biconvex, and embossed with R0.5 on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Ropinirole is indicated for the symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome (see Section 5.1).

4.2 Posology And Method Of Administration

Oral use.

Adults

Individual dose titration against efficacy and tolerability is recommended.

Ropinirole should be taken just before bedtime, however the dose can be taken up to 3 hours before retiring. Ropinirole may be taken with food, to improve gastrointestinal tolerance.

Treatment initiation (week 1)

The recommended initial dose is 0.25 mg once daily (administered as above) for 2 days. If this dose is well tolerated the dose should be increased to 0.5 mg once daily for the remainder of week 1.

Therapeutic regimen (week 2 onwards)

Following treatment initiation, the daily dose should be increased until optimal therapeutic response is achieved. The average dose in clinical trials, in patients with moderate to severe Restless Legs Syndrome, was 2.0 mg once a day.

The dose may be increased to 1.0 mg once a day at week 2. The dose may then be increased by 0.5 mg per week over the next two weeks to a dose of 2.0 mg once a day. In some patients, to achieve optimal improvement, the dose may be increased gradually up to a maximum of 4.0 mg once a day. In clinical trials the dose was increased by 0.5 mg each week to 3.0 mg once a day and then by 1.0 mg up to the maximum recommended dose of 4.0 mg once a day as shown in Table 1.

Doses above 4.0 mg once daily have not been investigated in Restless Legs Syndrome patients.

Table 1 - Dose titration

Week	2	3	4	5*	6*	7*
Dose (mg) / once daily	1.0	1.5	2.0	2.5	3.0	4.0

* To achieve optimal improvement in some patients.

The patient's response to ropinirole should be evaluated after 3 months treatment (see Section 5.1). At this time the dose prescribed and the need for continued treatment should be considered. If treatment is interrupted for more than a few days it should be re-initiated by dose titration carried out as above.

Children and Adolescents

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

Elderly

The clearance of ropinirole is decreased in patients over 65 years of age. Any increase in dosage should be gradual and titrated against the symptomatic response.

Renal impairment

No dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance between 30 and 50 ml/min).

4.3 Contraindications

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

Severe renal impairment (creatinine clearance < 30ml/min).

Severe hepatic impairment.

4.4 Special Warnings And Precautions For Use

Ropinirole should not be used to treat neuroleptic akathisia, tasikinesia (neuroleptic-induced compulsive tendency to walk), or secondary Restless Legs Syndrome (e.g. caused by renal failure, iron deficiency anaemia or pregnancy).

During treatment with ropinirole, paradoxical worsening of Restless Legs Syndrome symptoms occurring with earlier onset (augmentation), and reoccurrence of symptoms in the early morning hours (early morning rebound), may be observed. If this occurs, treatment should be reviewed and dosage adjustment or discontinuation of treatment may be considered.

In Parkinson's disease, ropinirole has been associated uncommonly with somnolence and episodes of sudden sleep onset (see Section 4.8) however in Restless Legs Syndrome, this phenomenon is very rare. Nevertheless, patients must be informed of this phenomenon and advised to exercise caution while driving or operating machines during treatment with ropinirole. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of dosage or termination of therapy may be considered.

Patients with major psychotic disorders should not be treated with dopamine agonists unless the potential benefits outweigh the risks.

Impulse control disorders including pathological gambling and hypersexuality, and increased libido, have been reported in patients treated with dopamine agonists, including ropinirole, principally for Parkinson's disease. Those disorders were reported especially at high doses and were generally reversible upon reduction of the dose or treatment discontinuation. Risk factors such as a history of compulsive behaviours were present in some cases (see section 4.8).

Ropinirole should be administered with caution to patients with moderate hepatic impairment. Undesirable effects should be closely monitored.

Due to the risk of hypotension, patients with severe cardiovascular disease (in particular coronary insufficiency) should be treated with caution.

Ropinirole Film-Coated Tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ropinirole is principally metabolised by the cytochrome P450 isoenzyme CYP1A2. A pharmacokinetic study (with a ropinirole dose of 2 mg, three times a day) revealed that ciprofloxacin increased the C_max and AUC of ropinirole by 60% and 84% respectively, with a potential risk of adverse events. Hence, in patients already receiving ropinirole, the dose of ropinirole may need to be adjusted when medicinal products known to inhibit CYP1A2, e.g. ciprofloxacin, enoxacin or fluvoxamine, are introduced or withdrawn.

A pharmacokinetic interaction study between ropinirole (at a dose of 2 mg, three times a day) and theophylline, a substrate of CYP1A2, revealed no change in the pharmacokinetics of either ropinirole or theophylline. Therefore, it is not expected that ropinirole will compete with the metabolism of other medicinal products which are metabolised by CYP1A2.

Based on in-vitro data, ropinirole has little potential to inhibit cytochrome P450 at therapeutic doses. Hence, ropinirole is unlikely to affect the pharmacokinetics of other medicinal products, via a cytochrome P450 mechanism.

Smoking is known to induce CYP1A2 metabolism. Therefore, if patients stop or start smoking during treatment with ropinirole, dose adjustment may be required.

Increased plasma concentrations of ropinirole have been observed in patients treated with hormone replacement therapy. In patients already receiving hormone replacement therapy, ropinirole treatment may be initiated in the usual manner. However, it may be necessary to adjust the ropinirole dose, in accordance with clinical response, if hormone replacement therapy is stopped or introduced during treatment with ropinirole.

No pharmacokinetic interaction has been seen between ropinirole and domperidone (a medicinal product used to treat nausea and vomiting) that would necessitate dosage adjustment of either medicinal product. Domperidone antagonises the dopaminergic actions of ropinirole peripherally and does not cross the blood-brain barrier. Hence its value as an anti-emetic in patients treated with centrally acting dopamine agonists

Neuroleptics and other centrally active dopamine antagonists, such as sulpiride or metoclopramide, may diminish the effectiveness of ropinirole and, therefore, concomitant use of these medicinal products with ropinirole should be avoided.

4.6 Pregnancy And Lactation

There are no adequate data from the use of ropinirole in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). As the potential risk for humans is unknown, it is recommended that ropinirole is not used during pregnancy unless the potential benefit to the patient outweighs the potential risk to the foetus.

Ropinirole should not be used in nursing mothers as it may inhibit lactation.

4.7 Effects On Ability To Drive And Use Machines

Patients being treated with ropinirole and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such effects have resolved (see also Section 4.4).

4.8 Undesirable Effects

Adverse drug reactions are listed below by system organ class and frequency. Frequencies from clinical trials are determined as excess incidence over placebo and are classed as Very Common (> 1/10) or Common (> 1/100 to < 1/10) or uncommon (> 1/1000 to < 1/100).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Use of ropinirole in Restless Legs Syndrome

In Restless Legs Syndrome clinical trials the most common adverse drug reaction was nausea (approximately 30% of patients). Undesirable effects were normally mild to moderate and experienced at the start of therapy or on increase of dose and few patients withdrew from the clinical studies due to undesirable effects.

Table 2 lists the adverse drug reactions reported for ropinirole in the 12-week clinical trials at

Table 2 - Adverse drug reactions reported in 12-week Restless Legs Syndrome clinical trials (ropinirole n=309, placebo n=307)

Psychiatric Disorders
Common:	Nervousness
Uncommon:	Confusion
Nervous System Disorders
Common:	Syncope, Somnolence, Dizziness (including vertigo)
Vascular Disorders
Uncommon:	Postural hypotension, hypotension
Gastrointestinal Disorders
Very Common:	Vomiting, Nausea
Common:	Abdominal pain
General Disorders and Administration Site Conditions
Common:	Fatigue

Hallucinations were reported uncommonly in the open label long-term studies.

Paradoxical worsening of Restless Legs Syndrome symptoms occurring with earlier onset (augmentation), and reoccurrence of symptoms in the early morning hours (early morning rebound), may be observed during treatment with ropinirole.

Management of undesirable effects

Dose reduction should be considered if patients experience significant undesirable effects. If the undesirable effect abates, gradual up-titration can be re-instituted. Anti-nausea medicinal products that are not centrally active dopamine antagonists, such as domperidone, may be used if required.

Other experience with Ropinirole

Ropinirole is also indicated for the treatment of Parkinson's disease. The adverse drug reactions reported in patients with Parkinson's disease on ropinirole monotherapy and adjunct therapy at doses up to 24 mg/day at excess incidence over placebo are described below.

Table 3 - Adverse drug reactions reported in Parkinson's disease clinical trials at doses up to 24 mg/day

Psychiatric Disorders
Common:	Hallucinations, Confusion
Uncommon:	Increased libido
Nervous System Disorders
Very Common:	Syncope, Dyskinesia, Somnolence
Gastrointestinal Disorders
Very Common:	Nausea
Common:	Vomiting, Abdominal pain, Heartburn
General Disorders and Administration Site Conditions
Common:	Leg oedema

Post marketing reports

Hypersensitivity reactions (including urticaria, angioedema, rash, pruritus)

Psychotic reactions (other than hallucinations) including delirium, delusion, paranoia have been reported.

Impulse control disorders including pathological gambling and hypersexuality, and increased libido, have been reported (see section 4.4).

In Parkinson's disease, ropinirole is associated with somnolence and has been associated uncommonly (>1/1,000, <1/100) with excessive daytime somnolence and sudden sleep onset episodes, however, in Restless Legs Syndrome, this phenomenon is very rare (<1/10,000).

Following ropinirole therapy, postural hypotension or hypotension has been reported uncommonly (>1/1,000, <1/100), rarely severe.

Very rare cases of hepatic reactions (<1/10,000), mainly increase of liver enzymes, have been reported.

4.9 Overdose

It is anticipated that the symptoms of ropinirole overdose will be related to its dopaminergic activity. These symptoms may be alleviated by appropriate treatment with dopamine antagonists such as neuroleptics or metoclopramide.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Dopamine agonist ATC code: N04BC04

Mechanism of action

Ropinirole is a non-ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors.

Clinical efficacy

Ropinirole Film-coated Tablets should only be prescribed to patients with moderate to severe idiopathic Restless Legs Syndrome. Moderate to severe idiopathic Restless Legs Syndrome is typically represented by patients who suffer with insomnia or severe discomfort in the limbs.

In the four 12-week efficacy studies, patients with Restless Legs Syndrome were randomised to ropinirole or placebo, and the effects on the IRLS scale scores at week 12 were compared to baseline. The mean dose of ropinirole for the moderate to severe patients was 2.0 mg/day. In a combined analysis of moderate to severe Restless Legs Syndrome patients from the four 12-week studies, the adjusted treatment difference for the change from baseline in IRLS scale total score at week 12 Last Observation Carried Forward (LOCF) Intention To Treat population was -4.0 points (95% CI -5.6, -2.4, p<0.0001; baseline and week 12 LOCF mean IRLS points: ropinirole 28.4 and 13.5; placebo 28.2 and 17.4).

A 12-week placebo-controlled polysomnography study in Restless Legs Syndrome patients examined the effect of treatment with ropinirole on periodic leg movements of sleep. A statistically significant difference in the periodic leg movements of sleep was seen between ropinirole and placebo from baseline to week 12.

Although sufficient data is not available to adequately demonstrate the long term efficacy of ropinirole in Restless Legs Syndrome (see Section 4.2), in a 36-week study, patients who continued on ropinirole demonstrated a significantly lower relapse rate compared with patients randomised to placebo (33% versus 58%, p=0.0156).

A combined analysis of data from moderate to severe Restless Legs Syndrome patients, in the four 12-week placebo-controlled studies, indicated that ropinirole-treated patients reported significant improvements over placebo on the parameters of the Medical Outcome Study Sleep Scale (scores on 0-100 range except sleep quantity). The adjusted treatment differences between ropinirole and placebo were: sleep disturbance (-15.2, 95% CI -19.37, -10.94; p<0.0001), sleep quantity (0.7 hours, 95% CI 0.49, 0.94; p<0.0001), sleep adequacy (18.6, 95% CI 13.77, 23.45; p<0.0001) and daytime somnolence (-7.5, 95% CI -10.86, -4.23; p<0.0001).

A rebound phenomenon following discontinuation of ropinirole treatment (end of treatment rebound) cannot be excluded. In clinical trials, although the average IRLS total scores 7-10 days after withdrawal of therapy were higher in ropinirole-treated patients than in placebo-treated patients, the severity of symptoms following withdrawal of therapy generally did not exceed the baseline assessment in ropinirole-treated patients.

In clinical studies most patients were of Caucasian origin.

Study of the effect of ropinirole on cardiac repolarisation

A thorough QT study conducted in male and female healthy volunteers who received doses of 0.5, 1, 2 and 4 mg of ropinirole film-coated (immediate release) tablets once daily showed a maximum increase of the QT interval duration at the 1mg dose of 3.46 milliseconds (point estimate) as compared to placebo. The upper bound of the one sided 95% confidence interval for the largest mean effect was less than 7.5 milliseconds. The effect of ropinirole at higher doses has not been systematically evaluated.

The available clinical data from a thorough QT study do not indicate a risk of QT prolongation at doses of ropinirole up to 4 mg/day.

5.2 Pharmacokinetic Properties

Absorption

The bioavailability of ropinirole is about 50% (36% to 57%), with C_max reached on average 1.5 hours after the dose. A high fat meal decreases the rate of absorption of Ropinirole, as shown by a delay in median T_max by 2.6 hours and an average 25% decrease in C_max.

Distribution

Plasma protein binding of ropinirole is low (10 - 40%). Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approx. 7 l/kg).

Metabolism

Ropinirole is primarily cleared by the cytochrome P450 enzyme, CYP1A2, and its metabolites are mainly excreted in the urine. The major metabolite is at least 100 times less potent than ropinirole in animal models of dopaminergic function.

Elimination

Ropinirole is cleared from the systemic circulation with an average elimination half-life of approximately 6 hours. No change in the oral clearance of ropinirole is observed following single and repeated oral administration. Wide inter-individual variability in the pharmacokinetic parameters has been observed.

Linearity

The pharmacokinetics of ropinirole are linear overall (C_max and AUC) in the therapeutic range between 0.25 mg and 4 mg, after a single dose and after repeated dosing.

Population-related characteristics

In patients over 65 years of age, a reduction in the systemic clearance of ropinirole by about 30% is possible.

In patients with mild to moderate renal impairment (creatinine clearance between 30 and 50 ml/min), no change in the pharmacokinetics of ropinirole is observed. No data is available in patients with severe renal impairment.

Paediatric population

Limited pharmacokinetic data obtained in adolescents (12-17 years, n=9) showed that the systemic exposure following single doses of 0.125 mg and 0.25 mg was similar to that observed in adults (see also section 4.2; subparagraph “Children and adolescents).

5.3 Preclinical Safety Data

Toxicology: The toxicology profile is principally determined by the pharmacological activity of the drug: behavioural changes, hypoprolactinaemia, decrease in blood pressure and heart rate, ptosis and salivation. In the albino rat only, retinal degeneration was observed in a long term study at a high dose (50 mg/kg), probably associated with an increased exposure to light.

Genotoxicity: Genotoxicity was not observed in the usual battery of in vitro and in vivo tests.

Carcinogenicity: From two-year studies conducted in the mouse and rat at dosages up to 50 mg/kg/day there was no evidence of any carcinogenic effect in the mouse. In the rat, the only drug-related lesions were Leydig cell hyperplasia and testicular adenoma resulting from the hypoprolactinaemic effect of ropinirole. These lesions are considered to be a species specific phenomenon and do not constitute a hazard with regard to the clinical use of ropinirole.

Reproductive Toxicity: Administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg/day (approximately 15 times the AUC at the maximum dose in humans), increased foetal death at 90 mg/kg/day (approximately 25 times the AUC at the maximum dose in humans) and digit malformations at 150 mg/kg/day (approximately 40 times the AUC at the maximum dose in humans). There were no teratogenic effects in the rat at 120 mg/kg/day (approximately 30 times the AUC at the maximum dose in humans) and no indication of an effect on development in the rabbit.

Safety Pharmacology: In vitro studies have shown that ropinirole inhibits hERG-mediated currents. The IC₅₀ is 5-fold higher than the expected maximum plasma concentration in patients treated at the highest recommended dose (4 mg/day), see section 5.1.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Lactose monohydrate

Microcrystalline cellulose

Pregelatinised starch

Magnesium stearate

Film coating:

Opadry II 85F32111 (Polyvinyl alcohol, Titanium dioxide, Macrogol 3350, Talc, Iron oxide yellow)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Do not store above 25°C

Store in the original package in order to protect from light

HDPE tablet containers only:

Keep the container tightly closed in order to protect from moisture

6.5 Nature And Contents Of Container

Aluminium/Aluminium blister or induction sealed HDPE tablet containers of 2, 5, 7, 10, 12, 14, 20, 21, 28, 30, 50, 56, 60, 84, 100, 126 and 210 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Caduceus Pharma Limited

6^th Floor, 94 Wigmore Street,

London W1U 3RF

UK

8. Marketing Authorisation Number(S)

PL 24668/0079

9. Date Of First Authorisation/Renewal Of The Authorisation

21/01/2011

10. Date Of Revision Of The Text

25/03/2011