Scheriproct Suppositories

1. Name Of The Medicinal Product

Scheriproct® Suppositories

2. Qualitative And Quantitative Composition

Each yellowish-white suppository contains:

Prednisolone hexanoate 1.3 mg

Cinchocaine hydrochloride 1.0 mg

3. Pharmaceutical Form

Suppository

4. Clinical Particulars

4.1 Therapeutic Indications

For the symptomatic relief of haemorrhoids and pruritus ani in the short term (5-7 days).

4.2 Posology And Method Of Administration

One Scheriproct suppository to be inserted daily. In severe cases one suppository two to three times daily at the beginning of treatment. The suppositories should be inserted after defaecation.

4.3 Contraindications

Viral infections. Primary bacterial or fungal infections. Secondary infections of the skin in the absence of appropriate anti-infective therapy. Known sensitivity to local anaesthetics.

4.4 Special Warnings And Precautions For Use

Warnings: In infants, long-term continuous therapy with topical corticosteroids should be avoided. Occlusion is not appropriate on the perineum. Adrenal suppression can occur, even without occlusion. As with all topical steroids, there is a risk of developing skin atrophy following extensive therapy. The application of unusually large quantities of topical corticoids may result in the absorption of systemically active amounts of corticoid. Secondarily infected dermatoses definitely require additional therapy with antibiotics or chemotherapeutic agents. This treatment can often be topical, but for heavy infections systemic antibacterial therapy may be necessary. If fungal infections are present, a topically active antimycotic should be applied.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

There is inadequate evidence of 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 on the human foetus.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

As with all topical steroids, there is a risk of developing skin atrophy following extensive therapy. Allergic skin reactions may occur.

4.9 Overdose

None stated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Prednisolone hexanoate - On local application, exerts a powerful anti-inflammatory action which is superior to that of both cortisone and hydrocortisone. Its effects include a reduction of capillary dilatation, intercellular oedema and inflammatory infiltration within tissues, and the inhibition of vascularisation.

Cinchocaine hydrochloride - Has a local anaesthetic effect on mucous membranes and, in combination with prednisolone hexanoate, provides a quick relief of painful and pruritic symptoms.

5.2 Pharmacokinetic Properties

No data are available on the rectal absorption of prednisolone hexanoate in humans. However, the extent of the rectal absorption from a similar lipophilic corticosteroid ester, fluocortolone pivalate, amounted to only about 15% of the dose with the cream and only 5% of the dose from the suppository.

No data are available on the elimination of prednisolone hexanoate in humans. It is known that corticosteroids are excreted in the urine.

In-vitro and in-vivo investigations with corticosteroid esters (halogenated and nonhalogenated corticoids) have shown that these compounds are split extremely rapidly into the corticoid and fatty acid by the esterases which are ubiquitously present in the body. For this reason, after topical application and percutaneous absorption of prednisolone hexanoate, the steroid alcohol, prednisolone, becomes systemically available.

Inactivation of free prednisolone is carried out by the liver and to a small extent by the kidneys.

5.3 Preclinical Safety Data

There are no preclinical safety data which could be of relevance to the prescriber and which are not already included in other relevant sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Hard fat

6.2 Incompatibilities

None known.

6.3 Shelf Life

Two years

6.4 Special Precautions For Storage

Do not store above 25^oC

6.5 Nature And Contents Of Container

Laminated aluminium foil strip packs. Packs of 12 suppositories.

6.6 Special Precautions For Disposal And Other Handling

In order to restore the consistency of suppositories which have become soft owing to warm temperature, they should be put into cold water before the covering is removed.

Keep out of reach of children.

7. Marketing Authorisation Holder

Intendis GmbH

Max-Dohrn-Strasse 10

D-10589

Berlin

Germany

8. Marketing Authorisation Number(S)

PL 28428/0004

9. Date Of First Authorisation/Renewal Of The Authorisation

9 September 1999

10. Date Of Revision Of The Text

29 September 2006

Senokot 7.5 mg / 5 ml Syrup

1. Name Of The Medicinal Product

Senokot 7.5 mg/5 ml Syrup.

2. Qualitative And Quantitative Composition

Each 5 ml of Senokot Syrup contains calcium sennosides equivalent to 7.5 mg per 5 ml total sennosides (calculated as sennoside B).

3. Pharmaceutical Form

Syrup.

Amber, slightly viscous liquid.

4. Clinical Particulars

4.1 Therapeutic Indications

As a laxative for the relief of occasional or non-persistent constipation.

4.2 Posology And Method Of Administration

Senokot 7.5 mg/5 ml Syrup is for oral administration.

Adults, including the elderly and children over 12: Two 5 ml spoonfuls.

Not to be given to children under 12 years except on medical advice. Where administration to children is necessary, the recommended dose is as follows.

Children over 6 years: One 5 ml spoonful.

Children aged 2 to 6 years: Half to one 5 ml spoonful in 24 hours.

Senokot should be taken as a single dose at bedtime by adults and in the morning by children.

New users should start with the lowest dose and increase it, if necessary, by one half of the initial dose each day. Once regularity has been regained the dosage should be gradually reduced and stopped.

4.3 Contraindications

Senokot 7.5 mg/5 ml Syrup should not be given when any undiagnosed acute or persistent abdominal symptoms are present.

4.4 Special Warnings And Precautions For Use

Not to be given to children except on medical advice.

If there is no bowel movement after three days consult a doctor.

If laxatives are needed every day or abdominal pain persists consult a doctor.

Each 5 ml of syrup can provide up to 3.2 kcal and this should be taken into account when treating diabetics.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

The Physician should be satisfied that there is no underlying gastro intestinal pathology masking as constipation before recommending this product. Enquiry should be made about bowel habit, (particularly recent changes in bowel habit such as persistent diarrhoea or constipation), evacuation and bleeding per rectum.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

There is some evidence for the safety of senna derived products in human pregnancy which have been in use for many years without apparent illconsequence. If laxative treatment is required during pregnancy Senokot 7.5 mg/5 ml Syrup may be used.

Anthraquinones are excreted into breast milk, but clinical studies have shown that breast-fed infants of mothers taking senna derived products did not show any significant side-effects.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Temporary mild griping may occur during adjustment of the dosage. Hypersensitivity reactions associated with the esters of hydroxybenzoates (parabens) may occur.

4.9 Overdose

Where diarrhoea is severe conservative measures are usually sufficient; generous amounts of fluid, especially fruit drinks, should be given.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

The sugar moiety of the sennosides is removed by bacteria in the large intestine releasing the active anthrone fraction. This stimulates peristalsis via the submucosal and myenteric nerve plexuses. Sennosides act in 8 – 12 hours.

5.2 Pharmacokinetic Properties

The action of the sennosides is colon specific and does not depend upon systemic absorption.

5.3 Preclinical Safety Data

No preclinical findings of relevance to the prescriber have been reported.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Potassium sorbate E202

Methyl parahydroxybenzoate E218

Propyl parahydroxybenzoate E216

Maltitol liquid E965

Xanthan gum

Anti-foam (Medical C) emulsion

Prune flavour

Citric acid anhydrous

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

Eighteen months.

6.4 Special Precautions For Storage

Do not store above 25°C. Do not freeze.

6.5 Nature And Contents Of Container

Glass bottle with a polypropylene cap with a polyethylene tamper-evident band with an expanded polyethylene wad containing 100, 150 or 200 ml syrup.

6.6 Special Precautions For Disposal And Other Handling

No special instructions

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Limited,

Dansom Lane,

Hull,

HU8 7DS.

United Kingdom

8. Marketing Authorisation Number(S)

PL 00063/0123.

9. Date Of First Authorisation/Renewal Of The Authorisation

8^th April 2005

10. Date Of Revision Of The Text

11/04/2007

Sandrena 1.0 mg gel

1. Name Of The Medicinal Product

Sandrena 1 mg gel

2. Qualitative And Quantitative Composition

Estradiol hemihydrate corresponding to 1.0 mg estradiol per single-dose container.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Gel, single-dose container. Smooth, opalescent gel.

4. Clinical Particulars

4.1 Therapeutic Indications

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women.

Experience of treating women more than 65 years old is limited.

4.2 Posology And Method Of Administration

Sandrena is a gel for transdermal use. Sandrena can be used for continuous or cyclical treatment.

The usual starting dose is 1.0 mg estradiol (1.0 g gel) daily but the selection of the initial dose can be based on the severity of the patient's symptoms. Depending on the clinical response, the dosage can be readjusted after 2-3 cycles individually from 0.5 g to 1.5 g per day, corresponding to 0.5 to 1.5 mg estradiol per day. For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used.

In patients with an intact uterus, it is recommended to combine Sandrena with an adequate dose of progestagen, for adequate duration for at least 12-14 consecutive days per month or to oppose oestrogen-stimulated hyperplasia of the endometrium. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.

In women who are not using hormone replacement therapy (HRT), or women transferring from continuous combined HRT-product, treatment with Sandrena may be started on any convenient day. In women transferring from a sequential HRT regimen, treatment should begin the day following completion of the prior regimen.

If the patient has forgotten to apply one dose, the forgotten dose is to be applied as soon as possible if the dose is not more than 12 hours late. If the dose is more than 12 hours late, the dose should be forgotten and continue as normal. Forgetting a dose may increase the likelihood of break-through bleeding and spotting.

There is no relevant indication for use of Sandrena in children.

Method of administration

The Sandrena dose is applied once daily on the skin of the lower trunk of the right or left thigh, on alternate days. The application surface should be 1-2 times the size of a hand. Sandrena should not be applied on the breasts, on the face or irritated skin. After application the gel should be allowed to dry for a few minutes and the application site should not be washed within 1 hour. Contact of the gel with eyes should be avoided. Hands should be washed after application.

4.3 Contraindications

- Known, past or suspected breast cancer

- Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer)

- Undiagnosed genital bleeding

- Untreated endometrial hyperplasia

- Previous idiopathic or current venous thromboembolism [deep venous thrombosis, pulmonary embolism]

- Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction)

- Acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal

- Known hypersensitivity to the active substances or to any of the excipients

- Porphyria

4.4 Special Warnings And Precautions For Use

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

Medical examination/follow-up

Before initiating or reinstituting hormone replacement therapy (HRT), a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' below). Investigations including mammography should be carried out in accordance with current accepted screening practices, modified according to the clinical needs of the individual.

Conditions which need supervision

If any of the following conditions are present, have occurred previously and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be-aggravated during treatment with Sandrena, in particular:

- Leiomyoma (uterine fibroids) or endometriosis

- A history of, or risk factors for thromboembolic disorders (see below)

- Risk factors for estrogen-dependent tumours e.g. 1st degree heredity for breast cancer

- Hypertension

- Liver disorders (e.g. liver adenoma)

- Diabetes mellitus with or without vascular involvement

- Cholelithiasis

- Migraine or (severe) headache

- Systemic lupus erythematosus

- A history of endometrial hyperplasia (see below)

- Epilepsy

- Asthma

- Otosclerosis

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in case a contra-indication is discovered and in the following situations:

- Jaundice or deterioration in liver function

- Significant increase in blood pressure

- New onset of migraine-type headache

- Pregnancy

Endometrial hyperplasia

- The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestagen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk.

- Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

- Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestagens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.

Breast cancer

A randomised placebo-controlled trial, the Women's Health Initiative study (WHI) and epidemiological studies, including the Million Women Study (MWS) have reported an increased risk of breast cancer in women taking oestrogens, oestrogen-progestagen combinations or tibolone for HRT for several years (see Section 4.8).

For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake, but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine oestrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine oestrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Venous thromboembolism

- HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two to threefold higher risk for users compared with non-users. For non-users it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.

- Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI > 30 kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

- Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

- The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.

- If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnea).

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated oestrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Oestrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity and mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated oestrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated oestrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian cancer

Long-term (at least 5-10 years) use of oestrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than oestrogen-only products.

Other conditions

- Oestrogens may cause fluid retention and, therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredient in Sandrena is increased.

- Women with pre-existing hypertriglyceridemia should be followed closely during HRT, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.

- Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin.

- There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

This medicinal product contains propylene glycol and therefore may cause skin irritation.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The metabolism of oestrogens (and progestagens) may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamezapine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of oestrogens and progestagens.

With transdermal administration, the first-pass effect in the liver is avoided and, thus, transdermally applied oestrogens (and progestagens) might be less affected than oral hormones by enzyme inducers.

Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.

4.6 Pregnancy And Lactation

Pregnancy

Sandrena is not indicated during pregnancy. If pregnancy occurs during medication with Sandrena, treatment should be withdrawn immediately.

The results of most epidemiological studies to date relevant to inadvertent fetal exposure to oestrogens indicate no teratogenic or fetotoxic effect.

Lactation

Sandrena is not indicated during lactation

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

The most common adverse drug reactions such as headache and breast tenderness occur during the first months of treatment, however they usually subside with continued treatment.

The most frequent adverse reaction of Sandrena is breast pain/tenderness, which occurs in 4.7 % of users.

Undesirable effects according to organ system class associated with Sandrena treatment are presented in the table below.

Organ system class	Common ADRs, (	Uncommon ADRs, (	Rare ADRs, (
Metabolism and nutrition disorders	Oedema, weight increase
Psychiatric disorders		Changes in libido and mood
Nervous system disorders	Headache	Migraine
Vasculardisorders			Hypertension, venous thromboembolism
Gastrointestinal disorders	Nausea, vomiting, stomach cramps
Hepatobiliary disorders			Alterations in liver function and biliary flow
Skin and subcutaneous tissue disorders			Rash
Reproductive system and breast disorders	Unscheduled vaginal bleeding or spotting Breast pain/tension
General disorders and administration site conditions	Skin irritation

Breast cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For oestrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80 % of HRT use was oestrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

For oestrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone.

The MWS reported that, compared to never users, the use of various types of oestrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of oestrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68). The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of oestrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below.

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

- For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

- For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be:

- For users of oestrogen-only replacement therapy:

	- between 0 and 3 (best estimate = 1.5) for 5 years' use
	- between 3 and 7 (best estimate = 5) for 10 years' use.

- For users of oestrogen plus progestagen combined HRT:

	- between 5 and 7 (best estimate = 6) for 5 years' use
	- between 18 and 20 (best estimate = 19) for 10 years' use.

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to oestrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years. According to calculations from the trial data, it is estimated that:

- For 1000 women in the placebo group,

- about 16 cases of invasive breast cancer would be diagnosed in 5 years.

- For 1000 women who used oestrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be

- between 0 and 9 (best estimate = 4) for 5 years' use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).

Endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed oestrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and oestrogen dose, the reported increase in endometrial cancer risk among unopposed oestrogen users varies from 2-to 12-fold greater compared with non-users. Adding a progestagen to oestrogen-only therapy greatly reduces this increased risk.

Other adverse reactions have been reported in association with oestrogen/progestagen treatment:

- Oestrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer.

- Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among HRT users than among non-users. For further information see sections 4.3 Contraindications and 4.4 Special warnings and special precautions for use.

- Myocardial infarction and stroke.

- Gall bladder disease.

- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.

- Probable dementia (see section 4.4)

4.9 Overdose

Generally, oestrogens are well tolerated even in massive doses. Overdose effects generally lead to breast tenderness, abdominal or pelvis swelling, anxiety, irritability. These symptoms disappear when the treatment is stopped or when the dose is reduced.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Natural and semisynthetic oestrogens, plain, ATC code G03CA03.

The active ingredient in Sandrena, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms.

Clinical trial information

The pharmacodynamics of Sandrena are similar to those of oral oestrogens, but the major difference to oral administration lies in the pharmacokinetic profile. The clinical efficacy of Sandrena in the treatment of menopausal symptoms is comparable to that of peroral oestrogen.

Relief of oestrogen-deficiency symptoms and bleeding patterns

Relief of menopausal symptoms was achieved during the first few weeks of treatment.

5.2 Pharmacokinetic Properties

Sandrena is an alcohol-based estradiol gel. When applied to the skin the alcohol evaporates rapidly and estradiol is absorbed through the skin into the circulation. Application of Sandrena on area of 200-400 cm² (size of one to two hands) does not affect the amount of estradiol absorbed. However, if Sandrena is applied to larger area absorption decreases significantly. To some extent, however, the estradiol is stored in the subcutaneous tissue from where it is released gradually into circulation. Percutaneous administration circumvents the hepatic first-pass metabolism. For these reasons, the fluctuations in the plasma oestrogen concentrations with Sandrena are less pronounced than peroral oestrogen.

Percutaneous doses of 0.5, 1.0 and 1.5 mg of estradiol (0.5, 1.0 and 1.5 g Sandrena) result in mean C_max concentrations in plasma of 143, 247 and 582 pmol/l, respectively. The corresponding mean C_average concentrations over the dosing interval are 75, 124 and 210 pmol/l. The corresponding mean C_min concentrations were 92, 101 and 152 pmol/l, respectively. During Sandrena treatment the estradiol/oestrone ratio remains between 0.4 and 0.7, while for oral oestrogen treatment it usually drops to less than 0.2.

The mean estradiol exposure at steady state of Sandrena is 82 per cent compared with an equivalent oral dose of estradiol valerate. Otherwise the metabolism and excretion of transdermal estradiol follow the fate of natural oestrogens.

5.3 Preclinical Safety Data

Estradiol is a natural female hormone with an established clinical use, therefore no toxicological studies have been performed with Sandrena. The necessary studies on the irritant effects of the gel were studied in rabbits and skin sensitisation in guinea pig. Based on the results from these studies it can be concluded that Sandrena very infrequently could cause mild skin irritation. Skin irritation can be reduced by daily change of the application site.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Carbomer 974P

Trolamine

Propylene glycol

Ethanol 96 %

Water, purified

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 25 °C.

6.5 Nature And Contents Of Container

Single dose aluminium foil container (PET/Aluminium/PE) supplied in packages containing 28 or 91 single-dose containers. Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Orion Corporation, Orionintie 1, P.O. Box 65, FIN-02101, Espoo, Finland

8. Marketing Authorisation Number(S)

PL 27925/0016

9. Date Of First Authorisation/Renewal Of The Authorisation

19/11/1996 / 31/03/2010

10. Date Of Revision Of The Text

31/03/2010

Singulair Paediatric 5 mg Chewable Tablets

1. Name Of The Medicinal Product

SINGULAIR® Paediatric 5 mg Chewable Tablets

2. Qualitative And Quantitative Composition

One chewable tablet contains montelukast sodium, which is equivalent to 5 mg montelukast.

Excipient: Aspartame (E 951) 1.5 mg per tablet.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Chewable tablet.

Pink, round, biconvex, diameter 9.5 mm, with 'SINGULAIR' engraved on one side and 'MSD 275' on the other.

4. Clinical Particulars

4.1 Therapeutic Indications

SINGULAIR is indicated in the treatment of asthma as add-on therapy in those patients with mild to moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom “as-needed” short-acting β-agonists provide inadequate clinical control of asthma.

SINGULAIR may also be an alternative treatment option to low-dose inhaled corticosteroids for patients with mild persistent asthma who do not have a recent history of serious asthma attacks that required oral corticosteroid use, and who have demonstrated that they are not capable of using inhaled corticosteroids (see section 4.2).

SINGULAIR is also indicated in the prophylaxis of asthma in which the predominant component is exercise-induced bronchoconstriction.

4.2 Posology And Method Of Administration

The dosage for paediatric patients 6-14 years of age is one 5 mg chewable tablet daily to be taken in the evening. If taken in connection with food, SINGULAIR should be taken 1 hour before or 2 hours after food. No dosage adjustment within this age group is necessary.

General recommendations:

The therapeutic effect of SINGULAIR on parameters of asthma control occurs within one day. Patients should be advised to continue taking SINGULAIR even if their asthma is under control, as well as during periods of worsening asthma.

No dosage adjustment is necessary for patients with renal insufficiency, or mild to moderate hepatic impairment. There are no data on patients with severe hepatic impairment. The dosage is the same for both male and female patients.

SINGULAIR as an alternative treatment option to low-dose inhaled corticosteroids for mild persistent asthma:

Montelukast is not recommended as monotherapy in patients with moderate persistent asthma. The use of montelukast as an alternative treatment option to low-dose inhaled corticosteroids for children with mild persistent asthma should only be considered for patients who do not have a recent history of serious asthma attacks that required oral corticosteroid use and who have demonstrated that they are not capable of using inhaled corticosteroids (see section 4.1). Mild persistent asthma is defined as asthma symptoms more than once a week but less than once a day, nocturnal symptoms more than twice a month but less than once a week, normal lung function between episodes. If satisfactory control of asthma is not achieved at follow-up (usually within one month), the need for an additional or different anti-inflammatory therapy based on the step system for asthma therapy should be evaluated. Patients should be periodically evaluated for their asthma control.

Therapy with SINGULAIR in relation to other treatments for asthma.

When treatment with SINGULAIR is used as add-on therapy to inhaled corticosteroids, SINGULAIR should not be abruptly substituted for inhaled corticosteroids (see section 4.4).

10 mg tablets are available for adults 15 years of age and older.

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

Patients should be advised never to use oral montelukast to treat acute asthma attacks and to keep their usual appropriate rescue medication for this purpose readily available. If an acute attack occurs, a short-acting inhaled β-agonist should be used. Patients should seek their doctor's advice as soon as possible if they need more inhalations of short-acting β-agonists than usual.

Montelukast should not be abruptly substituted for inhaled or oral corticosteroids.

There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given concomitantly.

In rare cases, patients on therapy with anti-asthma agents including montelukast may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These cases usually, but not always, have been associated with the reduction or withdrawal of oral corticosteroid therapy. The possibility that leukotriene receptor antagonists may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. Patients who develop these symptoms should be reassessed and their treatment regimens evaluated.

SINGULAIR contains aspartame, a source of phenylalanine. Patients with phenylketonuria should take into account that each 5 mg chewable tablet contains phenylalanine in an amount equivalent to 0.842 mg phenylalanine per dose.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma. In drug-interactions studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following medicinal products: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl oestradiol/norethindrone 35/1), terfenadine, digoxin and warfarin.

The area under the plasma concentration curve (AUC) for montelukast was decreased approximately 40% in subjects with co-administration of phenobarbital. Since montelukast is metabolised by CYP 3A4, caution should be exercised, particularly in children, when montelukast is co-administered with inducers of CYP 3A4, such as phenytoin, phenobarbital and rifampicin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of medicinal products primarily metabolised by CYP 2C8) demonstrated that montelukast does not inhibit CYP 2C8 in vivo. Therefore, montelukast is not anticipated to markedly alter the metabolism of medicinal products metabolised by this enzyme (eg., paclitaxel, rosiglitazone, and repaglinide).

4.6 Pregnancy And Lactation

Use during pregnancy

Animal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/foetal development.

Limited data from available pregnancy databases do not suggest a causal relationship between SINGULAIR and malformations (i.e. limb defects) that have been rarely reported in worldwide post marketing experience.

SINGULAIR may be used during pregnancy only if it is considered to be clearly essential.

Use during lactation

Studies in rats have shown that montelukast is excreted in milk (see section 5.3). It is not known if montelukast is excreted in human milk.

SINGULAIR may be used in breast-feeding mothers only if it is considered to be clearly essential.

4.7 Effects On Ability To Drive And Use Machines

Montelukast is not expected to affect a patient's ability to drive a car or operate machinery. However, in very rare cases, individuals have reported drowsiness or dizziness.

4.8 Undesirable Effects

Montelukast has been evaluated in clinical studies as follows:

• 10 mg film-coated tablets in approximately 4,000 adult patients 15 years of age and older, and

• 5 mg chewable tablets in approximately 1,750 paediatric patients 6 to 14 years of age.

The following drug-related adverse reactions in clinical studies were reported commonly (

Body System Class	Adult Patients 15 years and older (two 12-week studies; n=795)	Paediatric Patients 6 to 14 years old (one 8-week study; n=201) (two 56-week studies; n=615)
Nervous system disorders	headache	headache
Gastro-intestinal disorders	abdominal pain

With prolonged treatment in clinical trials with a limited number of patients for up to 2 years for adults, and up to 12 months for paediatric patients 6 to 14 years of age, the safety profile did not change.

Post-marketing Experience

Adverse reactions reported in post-marketing use are listed, by System Organ Class and specific Adverse Experience Term, in the table below. Frequency Categories were estimated based on relevant clinical trials.

System Organ Class	Adverse Experience Term	Frequency Category*
Infections and infestations	upper respiratory infection†	Very Common
Blood and lymphatic system disorders	increased bleeding tendency	Rare
Immune system disorder	hypersensitivity reactions including anaphylaxis	Uncommon
hepatic eosinophilic infiltration	Very Rare
Psychiatric disorders	dream abnormalities including nightmares, insomnia, somnambulism, irritability, anxiety, restlessness, agitation including aggressive behaviour or hostility, depression	Uncommon
tremor	Rare
hallucinations, suicidal thinking and behaviour (suicidality)	Very Rare
Nervous system disorder	dizziness, drowsiness paraesthesia/hypoesthesia, seizure	Uncommon
Cardiac disorders	palpitations	Rare
Respiratory, thoracic and mediastinal disorders	epistaxis	Uncommon
Churg-Strauss Syndrome (CSS) (see section 4.4)	Very Rare
Gastrointestinal disorders	diarrhoea‡, nausea‡, vomiting‡	Common
dry mouth, dyspepsia	Uncommon
Hepatobiliary disorders	elevated levels of serum transaminases (ALT, AST)	Common
hepatitis (including cholestatic, hepatocellular, and mixed-pattern liver injury).	Very Rare
Skin and subcutaneous tissue disorders	rash‡	Common
bruising, urticaria, pruritus	Uncommon
angiooedema	Rare
erythema nodosum	Very Rare
Musculoskeletal, connective tissue and bone disorders	arthralgia, myalgia including muscle cramps	Uncommon
General disorders and administration site conditions	pyrexia‡	Common
asthenia/fatigue, malaise, oedema,	Uncommon
*Frequency Category: Defined for each Adverse Experience Term by the incidence reported in the clinical trials data base: Very Common ( † This adverse experience, reported as Very Common in the patients who received montelukast, was also reported as Very Common in the patients who received placebo in clinical trials. ‡ This adverse experience, reported as Common in the patients who received montelukast, was also reported as Common in the patients who received placebo in clinical trials.

4.9 Overdose

No specific information is available on the treatment of overdose with montelukast. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to patients for 22 weeks and in short-term studies, up to 900 mg/day to patients for approximately one week without clinically important adverse experiences.

There have been reports of acute overdose in post-marketing experience and clinical studies with montelukast. These include reports in adults and children with a dose as high as 1000 mg (approximately 61 mg/kg in a 42 month old child). The clinical and laboratory findings observed were consistent with the safety profile in adults and paediatric patients. There were no adverse experiences in the majority of overdose reports. The most frequently occurring adverse experiences were consistent with the safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

It is not known whether montelukast is dialysable by peritoneal- or haemo-dialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Leukotriene receptor antagonist

ATC Code: RO3D CO3

The cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT) found in the human airway and cause airway actions, including bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment.

Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT₁ receptor. In clinical studies, montelukast inhibits bronchoconstriction due to inhaled LTD₄ at doses as low as 5 mg. Bronchodilation was observed within two hours of oral administration. The bronchodilation effect caused by a β-agonist was additive to that caused by montelukast. Treatment with montelukast inhibited both early- and late-phase bronchoconstriction due to antigen challenge. Montelukast, compared with placebo, decreased peripheral blood eosinophils in adult and paediatric patients. In a separate study, treatment with montelukast significantly decreased eosinophils in the airways (as measured in sputum) and in peripheral blood while improving clinical asthma control.

In studies in adults, montelukast 10 mg once daily, compared with placebo, demonstrated significant improvements in morning FEV₁ (10.4% vs 2.7% change from baseline), AM peak expiratory flow rate (PEFR) (24.5 L/min vs 3.3 L/min change from baseline), and significant decrease in total β-agonist use (-26.1% vs -4.6% change from baseline). Improvement in patient-reported daytime and night-time asthma symptoms scores was significantly better than placebo.

Studies in adults demonstrated the ability of montelukast to add to the clinical effect of inhaled corticosteroid (% change from baseline for inhaled beclometasone plus montelukast vs beclometasone, respectively for FEV₁ : 5.43% vs 1.04%; β-agonist use: -8.70% vs 2.64%). Compared with inhaled beclometasone (200 μg twice daily with a spacer device), montelukast demonstrated a more rapid initial response, although over the 12-week study, beclometasone provided a greater average treatment effect (% change from baseline for montelukast vs beclometasone, respectively for FEV₁ : 7.49% vs 13.3%; β-agonist use: -28.28% vs -43.89%). However, compared with beclometasone, a high percentage of patients treated with montelukast achieved similar clinical responses (e.g. 50% of patients treated with beclometasone achieved an improvement in FEV₁ of approximately 11% or more over baseline while approximately 42% of patients treated with montelukast achieved the same response).

In an 8-week study in paediatric patients 6 to 14 years of age, montelukast 5 mg once daily, compared with placebo, significantly improved respiratory function (FEV₁ 8.71% vs 4.16% change from baseline; AM PEFR 27.9 L/min vs 17.8 L/min change from baseline) and decreased 'as-needed' β-agonist use (-11.7% vs +8.2% change from baseline).

In a 12-month study comparing the efficacy of montelukast to inhaled fluticasone on asthma control in paediatric patients 6 to 14 years of age with mild persistent asthma, montelukast was non-inferior to fluticasone in increasing the percentage of asthma rescue-free days (RFDs), the primary endpoint. Averaged over the 12-month treatment period, the percentage of asthma RFDs increased from 61.6 to 84.0 in the montelukast group and from 60.9 to 86.7 in the fluticasone group. The between group difference in LS mean increase in the percentage of asthma RFDs was statistically significant (-2.8 with a 95% CI of -4.7, -0.9), but within the limit pre-defined to be clinically not inferior. Both montelukast and fluticasone also improved asthma control on secondary variables assessed over the 12 month treatment period:

• FEV₁ increased from 1.83 L to 2.09 L in the montelukast group and from 1.85 L to 2.14 L in the fluticasone group. The between-group difference in LS mean increase in FEV₁ was -0.02 L with a 95% CI of -0.06, 0.02. The mean increase from baseline in % predicted FEV₁ was 0.6% in the montelukast treatment group, and 2.7% in the fluticasone treatment group. The difference in LS means for the change from baseline in the % predicted FEV₁ was -2.2% with a 95% CI of -3.6, -0.7.

• The percentage of days with β-agonist use decreased from 38.0 to 15.4 in the montelukast group, and from 38.5 to 12.8 in the fluticasone group. The between group difference in LS means for the percentage of days with β-agonist use was 2.7 with a 95% CI of 0.9, 4.5.

• The percentage of patients with an asthma attack (an asthma attack being defined as a period of worsening asthma that required treatment with oral steroids, an unscheduled visit to the doctor's office, an emergency room visit, or hospitalisation) was 32.2 in the montelukast group and 25.6 in the fluticasone group; the odds ratio (95% CI) being significant: equal to 1.38 (1.04, 1.84).

• The percentage of patients with systemic (mainly oral) corticosteroid use during the study period was 17.8% in the montelukast group and 10.5% in the fluticasone group. The between group difference in LS means was significant: 7.3% with a 95% CI of 2.9; 11.7.

Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximal fall in FEV₁ 22.33% for montelukast vs 32.40% for placebo; time to recovery to within 5% of baseline FEV₁ 44.22 min vs 60.64 min). This effect was consistent throughout the 12-week study period. Reduction in EIB was also demonstrated in a short term study in paediatric patients (maximal fall in FEV₁ 18.27% vs 26.11%; time to recovery to within 5% of baseline FEV₁ 17.76 min vs 27.98 min). The effect in both studies was demonstrated at the end of the once-daily dosing interval.

In aspirin-sensitive asthmatic patients receiving concomitant inhaled and/or oral corticosteroids, treatment with montelukast, compared with placebo, resulted in significant improvement in asthma control (FEV₁ 8.55% vs -1.74% change from baseline and decrease in total β-agonist use -27.78% vs 2.09% change from baseline).

5.2 Pharmacokinetic Properties

Absorption: Montelukast is rapidly absorbed following oral administration. For the 10 mg film-coated tablet, the mean peak plasma concentration (C_max) is achieved three hours (T_max) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and C_max are not influenced by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10 mg film-coated tablet was administered without regard to the timing of food ingestion.

For the 5 mg chewable tablet, the C_max is achieved in two hours after administration in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.

Distribution: Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8-11 litres. Studies in rats with radiolabelled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabelled material at 24 hours post-dose were minimal in all other tissues.

Biotransformation: Montelukast is extensively metabolised. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and children.

In vitro studies using human liver microsomes indicate that cytochromes P450 3A4, 2A6 and 2C9 are involved in the metabolism of montelukast. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Elimination: The plasma clearance of montelukast averages 45 ml/min in healthy adults. Following an oral dose of radiolabelled montelukast, 86% of the radioactivity was recovered in 5-day faecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile.

Characteristics in patients: No dosage adjustment is necessary for the elderly or mild to moderate hepatic insufficiency. Studies in patients with renal impairment have not been undertaken. Because montelukast and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in patients with renal impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic insufficiency (Child-Pugh score >9).

With high doses of montelukast (20- and 60-fold the recommended adult dose), a decrease in plasma theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg once daily.

5.3 Preclinical Safety Data

In animal toxicity studies, minor serum biochemical alterations in ALT, glucose, phosphorus and triglycerides were observed which were transient in nature. The signs of toxicity in animals were increased excretion of saliva, gastro-intestinal symptoms, loose stools and ion imbalance. These occurred at dosages which provided >17-fold the systemic exposure seen at the clinical dosage. In monkeys, the adverse effects appeared at doses from 150 mg/kg/day (>232-fold the systemic exposure seen at the clinical dose). In animal studies, montelukast did not affect fertility or reproductive performance at systemic exposure exceeding the clinical systemic exposure by greater than 24-fold. A slight decrease in pup body weight was noted in the female fertility study in rats at 200 mg/kg/day (>69-fold the clinical systemic exposure). In studies in rabbits, a higher incidence of incomplete ossification, compared with concurrent control animals, was seen at systemic exposure >24-fold the clinical systemic exposure seen at the clinical dose. No abnormalities were seen in rats. Montelukast has been shown to cross the placental barrier and is excreted in breast milk of animals.

No deaths occurred following a single oral administration of montelukast sodium at doses up to 5000 mg/kg in mice and rats (15,000 mg/m² and 30,000 mg/m² in mice and rats, respectively) the maximum dose tested. This dose is equivalent to 25,000 times the recommended daily adult human dose (based on an adult patient weight of 50 kg).

Montelukast was determined not to be phototoxic in mice for UVA, UVB or visible light spectra at doses up to 500 mg/kg/day (approximately >200-fold based on systemic exposure).

Montelukast was neither mutagenic in in vitro and in vivo tests nor tumorigenic in rodent species.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol

Microcrystalline cellulose

Hyprolose (E463)

Red ferric oxide (E172)

Croscarmellose sodium

Cherry flavour

Aspartame (E951)

Magnesium stearate.

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

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

6.5 Nature And Contents Of Container

Packaged in polyamide/PVC/aluminium blister package in:

Blisters in packages of: 7, 10, 14, 20, 28, 30, 50, 56, 84, 90, 98, 100, 140 and 200 tablets.

Blisters (unit doses), in packages of: 49, 50 and 56 tablets.

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

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

7. Marketing Authorisation Holder

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK

8. Marketing Authorisation Number(S)

PL 00025/0357

9. Date Of First Authorisation/Renewal Of The Authorisation

15 January 1998/25 August 2007

10. Date Of Revision Of The Text

August 2011

LEGAL CATEGORY

POM

© Merck Sharp & Dohme Limited 2011. All rights reserved.

SPC.SGA-5mg.10.UK.3362.II-060-WS-003

Scholl Verruca Removal System

1. Name Of The Medicinal Product

Scholl Verruca Removal System.

2. Qualitative And Quantitative Composition

Salicylic Acid Ph Eur 40% w/w.

3. Pharmaceutical Form

Plaster.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of common warts on the feet and hands.

4.2 Posology And Method Of Administration

Adults and children: Select a medicated disc from those supplied which best fits the size of the wart. Leave medicated disc in place on wart for 48 hours and repeat treatment. Continue treatment for up to twelve weeks if necessary. No distinction is made between age groups. Neonates: neonates should not be treated.

4.3 Contraindications

Not to be used by diabetics or those with severe circulatory disorders, except following a doctor's permission and recommendation. Not to be used if the skin around the wart is inflamed or broken. Not to be used on moles, birthmarks, warts with hair growing from them, genital warts or warts on the face or mucous membranes.

4.4 Special Warnings And Precautions For Use

Discontinue use and remove dressing if excessive discomfort or irritation is experienced. Do not apply to normal skin. For external use only.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not relevant to cutaneous use.

4.6 Pregnancy And Lactation

Safety during pregnancy and lactation has not been established.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Local irritation may occur.

4.9 Overdose

None stated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: keratolytics. Mechanism of action: the mechanism of action of salicylic acid has not been established. Pharmacodynamic effects: Salicylates have analgesic, anti-inflammatory and antipyretic properties, much of which is ascribed to an inhibition of prostaglandin synthesis. However, the relevant pharmacodynamic effect of salicylic acid for this product is its 'keratolytic' action. The mechanism of this effect has been investigated in animals and in man, and appears to be due to a reduction of intercellular cohesion and/or increasing endogenous hydration. The exact mechanism of action however has not yet been elucidated.

5.2 Pharmacokinetic Properties

Salicylic acid can be absorbed following topical application. Plasma salicylate is largely protein-bound and is metabolised by oxidation and conjugation with some excreted unchanged. The elimination of salicylate follows first-order kinetics with a half-life of about four hours except with high systemic doses which result in saturation of the elimination mechanism.

5.3 Preclinical Safety Data

Salicylic acid has a low acute toxicity with oral LD₅₀ values of 480mg/kg in the mouse and 891mg/kg in the rat. It is a dermal irritant but systemic toxicity from application of Scholl Verruca Removal System is extremely unlikely because of the small quantities applied.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Polyvinyl Alkyl Ether (Low Molecular Weight); Polyvinyl Alkyl Ether (High Molecular Weight); Titanium Dioxide; Liquid Paraffin; 4,4-thio-bis-2-tert-butyl-5-methylphenol; Red Iron Oxide; Black Iron Oxide; Backing material; Twill Cloth; Polyethylene foam-coated plaster (closed cell).

6.2 Incompatibilities

Not relevant.

6.3 Shelf Life

Shelf life of the product as packed for sale: 3 years. Shelf life after first opening the container: 6 weeks.

6.4 Special Precautions For Storage

Store below 25^oC.

6.5 Nature And Contents Of Container

Sachet. Three separate sachets each containing fifteen medicated adhesive discs. Each set of fifteen discs comprised of three sizes of disc (3x5). Each pack contains fifteen cover plasters. These may be composed of an ecru coloured twill cloth for the standard product or tan coloured closed cell polyethylene foam coated plasters for the washproof variant. Both types of plaster are coated with a pressure sensitive adhesive.

6.6 Special Precautions For Disposal And Other Handling

Select a medicated disc from those supplied that best fits the size of the wart. Apply medicated disc to the wart with the fabric side uppermost. Cover medicated disc with one of the adhesive covering plasters supplied.

7. Marketing Authorisation Holder

Scholl Consumer Products Limited, Tubiton House, Oldham, OL1 3HS.

8. Marketing Authorisation Number(S)

PL 0587/0038.

9. Date Of First Authorisation/Renewal Of The Authorisation

27^th June 1994 / 29^th June 1999.

10. Date Of Revision Of The Text

August 2001.

Sea-Legs Tablets

1. Name Of The Medicinal Product

Sea-Legs Tablets

2. Qualitative And Quantitative Composition

Meclozine Hydrochloride BP 12.5mg

3. Pharmaceutical Form

Tablets for oral administration

4. Clinical Particulars

4.1 Therapeutic Indications

For the prevention and treatment of motion sickness. Sea-Legs are for oral administration.

4.2 Posology And Method Of Administration

Adults and Children over 12 years:

Two tablets (25mg) per 24 hours. The tablets may be taken one hour prior to commencement of journey or, as Sea-Legs can remain active for 24 hours one dose can be taken the previous night.

Children 6-12 years:

One tablet (12.5mg) per 24 hours.

Children 2-6 years:

Half a tablet (6.25mg) per 24 hours.

4.3 Contraindications

Pregnancy.

4.4 Special Warnings And Precautions For Use

Avoid alcoholic drink.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Contraindicated in pregnancy.

4.7 Effects On Ability To Drive And Use Machines

May cause drowsiness. If affected, do not drive or operate machinery. Avoid alcoholic drink.

4.8 Undesirable Effects

None known.

4.9 Overdose

No specific statement.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Meclozine hydrochloride is a piperazine derivative with the properties of antihistamines. It is used for its anti-emetic action which may last for up to 24 hours. Sedative effects are not marked. It is used for the prevention and treatment of motion sickness.

5.2 Pharmacokinetic Properties

In general, antihistamines are readily absorbed from the gastrointestinal tract, metabolised in the liver and excreted usually mainly as metabolites in the urine.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Maize starch

Sodium starch glycolate

Magnesium stearate

Povidone powder

Industrial methylated spirits

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C

6.5 Nature And Contents Of Container

A cellulose/aluminium foil/polythene laminate carrying 12 or 28 tablets overwrapped with a cardboard envelope; or (a) purelay-pharm 100E white opaque (polypropylene) and (b) purelay-lid (polypropylene).

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Seton Products Limited, Tubiton House, Oldham, OL1 3HS.

8. Marketing Authorisation Number(S)

PL 11314/0011.

9. Date Of First Authorisation/Renewal Of The Authorisation

16/02/94 / 26/03/99

10. Date Of Revision Of The Text

December 2003

Salofalk Rectal Foam 1g

Salofalk 1g Rectal Foam

Mesalazine

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 Salofalk rectal foam is and what it is used for


• 2. Before you use Salofalk rectal foam


• 3. How to use Salofalk rectal foam


• 4. Possible side effects


• 5. How to store Salofalk rectal foam


• 6. Further information

What Salofalk Rectal Foam Is And What It Is Used For

Salofalk rectal foam contains the active substance mesalazine, an anti-inflammatory agent used to treat inflammatory bowel disease.

Salofalk rectal foam is used for the treatment of:

• Inflammation of the large intestine (colon) and rectum (back passage) known by doctors as ulcerative colitis.

Before You Use Salofalk Rectal Foam

Do not use Salofalk rectal foam:

• If you are or have been told you are allergic (hypersensitive) to salicylic acid, to salicylates such as Aspirin or to any of the other ingredients of Salofalk rectal foam (these are listed in section 6, Further information).


• If you have a serious liver and/or kidney disease.


• If you have a stomach or duodenal ulcer.


• If you have a tendency to bleed easily or you have ever been told that there is a problem with the clotting of your blood.

Take special care with Salofalk rectal foam.

Before you start using this medicine you should tell your doctor:

• If you have a history of problems with your lungs, particularly if you suffer from bronchial asthma.


• If you have a history of allergy to sulphasalazine, a substance related to mesalazine.


• If you suffer with problems of your liver.


• If you suffer with problems of your kidney.

Further precautions:

During treatment your doctor may want to keep you under close medical supervision, where you will have regular blood and urine tests.

Using other medicines

Please tell your doctor if you take or use any of the medicines mentioned below as the effects of these medicines may change (interactions):

• 
  Certain agents that inhibit blood clotting (medicines for thrombosis or to thin your blood)


• 
  Glucocorticoids (certain steroid-like anti-inflammatory agents, such as prednisolone)


• 
  Sulphonyl ureas (substances used to control your blood sugar, such as glibenclamide)


• 
  Methotrexate (an agent used to treat leukaemia or immune disorders)


• 
  Probenecid/sulphinpyrazone (agents used to treat gout)


• 
  Spironolactone/frusemide (agents used to treat heart problems)


• 
  Rifampicin (substance used against tuberculosis)


• 
  Medicines containing azathioprine or 6-mercaptopurine (used to treat immune disorders.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. It may still be all right for you to use Salofalk rectal foam and your doctor will be able to decide what is suitable for you.

Pregnancy and breast-feeding

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

You should only use Salofalk rectal foam during pregnancy if your doctor tells you to.

Salofalk rectal foam should not be used during breast-feeding as the drug and its metabolite may pass into breast milk.

Driving and using machines

There are no effects on the ability to drive and use machines.

Important information about some of the ingredients of Salofalk rectal foam

This medicine contains sulphite which may very rarely cause allergic reactions, which may be experienced in the form of breathing problems.

This medicine contains propylene glycol, which can cause certain blood changes, and may cause slight to mild skin irritation.

This medicine contains cetostearyl alcohol which may cause local skin reactions (e.g. contact dermatitis).

How To Use Salofalk Rectal Foam

Always use Salofalk rectal foam exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Method of administration:

This medicine may only be used rectally, so it has to be inserted through the anus. It is not intended to be taken by mouth. Do not swallow.

Dosage:

Dose for adults:

The usual dose is 2 spray actuations once a day at bedtime. If you have difficulty retaining this amount of foam, it may also be administered in two separate doses: one at bedtime and the other during the night or early in the morning (after excreting the first dose).

Emptying your bowels before using Salofalk rectal foam produces the best results.

Children:

Salofalk rectal foam should not be used in children because there is little experience and only limited documentation for an effect in children.

Preparing to use the foam:

Push the applicator firmly onto the spout of the spray can.

Shake the spray can for about 20 seconds to mix the contents.

Before first use, remove the safety lock (plastic flap) from under the pump dome.

Twist the dome on the top of the spray can until the semi-circular gap underneath is in line with the nozzle. The spray can is now ready for use.

Using the foam:

Place your index finger on the top of pump dome and turn the can upside down. Please note that the spray can will only work properly when held with the pump dome pointing down.

Insert the applicator into your rectum as far as possible. The best way to do this is to place one foot on a chair or stool. To administer a dose of Salofalk rectal foam, push down fully the pump dome once and slowly release it. For the second spray, push the dome again and release slowly. Wait 10-15 seconds before withdrawing the applicator as the foam still expands a little and would otherwise drop out of the applicator.

After administering the foam, remove the applicator and dispose of it as household waste in the plastic bag provided. Use a new applicator for another administration.

• Please wash your hands and try not to empty your bowels until the next morning.


• If you go to hospital or see another doctor, tell them you are using this medicine.

You should use Salofalk rectal foam regularly and consistently to achieve the desired effect.

Duration of treatment:

How long you will use the medicine depends upon your condition. Your doctor will decide how long you are to continue the medication.

Mild acute episodes of inflammatory bowel disease (ulcerative colitis) generally subside after 4-6 weeks. If long-term treatment is required, your doctor will prescribe you an oral form of mesalazine, e.g. Salofalk granules.

If you think that the effect of Salofalk rectal foam is too strong or too weak, talk to your doctor.

If you use more Salofalk rectal foam than you should

Contact a doctor if you are in doubt, so he or she can decide what to do.

If you use too much Salofalk rectal foam on one occasion, just take your next dose as prescribed. Do not use a smaller amount.

If you forget to use Salofalk rectal foam

Do not take a larger than normal dose of Salofalk rectal foam next time, but continue treatment at the prescribed dosage.

If you stop using Salofalk rectal foam

Do not stop taking this product until you have talked to your doctor.

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

Possible Side Effects

Like all medicines, Salofalk rectal foam can cause side effects, although not everybody gets them.

All medicines can cause allergic reactions although serious allergic reactions are very rare. If you get any of the following symptoms after taking this medicine, you should contact your doctor immediately:

• 
  Allergic skin rash
  


• 
  Fever
  


• 
  Breathing difficulties.
  

If you experience the following serious side effects, stop taking the medicine and contact your doctor immediately:

If you experience a serious reduction of your general health condition with fever, and/or sore throat and mouth, please report to your doctor immediately. The symptoms might derive from a reduction in the number of white blood cells in your blood (agranulocytosis). This may increase your chances of suffering from a serious infection.

A blood test will be taken to check possible reduction of white blood cells. It is important to inform your doctor about your medicine.

The following side effects have also been reported:

Common side effects (that affect less than 1 in 10 patients):

• Abdominal discomfort.

Uncommon side effects (that affect less than 1 in 100 patients):

• Anal discomfort, anal irritation and painful urgent need to empty the bowels.

Rare side effects (that affect less than 1 in 1,000 patients):

• Abdominal pain, diarrhoea, wind, nausea and vomiting


• Headache, dizziness.

Very Rare side effects (that affect less than 1 in 10,000 patients):

• Changes in kidney function, sometimes with swollen limbs or flank pain because of renal disorders


• Chest pain, breathlessness or swollen limbs because of heart disorders


• Severe abdominal pain because of acute inflammation of the pancreas


• Severe breathlessness because of allergic inflammation of the lung


• Severe diarrhoea and abdominal pain because of allergic inflammation of the intestine


• Skin rash or inflammation


• Muscle and joint pain


• Fever, sore throat, or malaise because of blood count changes


• Jaundice or abdominal pain because of liver and bile flow disorders


• Hair loss and the development of baldness.


• Numbness and tingling in the hands and feet (peripheral neuropathy)


• Reversible decrease in semen production

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 Salofalk Rectal Foam

Keep out of the reach and sight of children.

Do not use Salofalk rectal foam after the expiry date which is stated on the carton and the spray can. The expiry date refers to the last day of that month.

The contents of the container must be used within 12 weeks after first opening.

Do not store above 25°C.

Do not refrigerate or freeze.

The container is pressurised and contains 3.75% by weight of flammable propellant. Protect from sunlight and temperatures over 50°C. Do not force open, pierce or burn empty containers, even after use. Do not spray near a flame or incandescent material.

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 Salofalk rectal foam contains

The active substance of Salofalk rectal foam is mesalazine and each spray actuation contains 1 g of mesalazine.

The other ingredients are sodium metabisulphite (E223), disodium edetate, cetostearyl alcohol, polysorbate 60, propylene glycol and propane, n-butane, isobutane as propellants.

What Salofalk rectal foam looks like and contents of the pack

Salofalk rectal foam is a white-greyish to slightly reddish-violet and creamy firm foam.

Salofalk rectal foam is available in packs containing 1 spray can and 14 applicators and as a bundle pack. A bundle pack consists of 4 packs containing 1 spray can and 14 applicators each.

Each spray can of Salofalk rectal foam contains 80 grams of foam, which is sufficient for 14 spray actuations (equivalent to 7 doses).

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Dr. Falk Pharma GmbH

Leinenweberstr. 5

D-79108 Freiburg

Germany

Tel +49 (0) 761 / 1514-0

Fax+49(0) 761 / 1514-321

E-mail:
zentrale@drfalkpharma.de

Salofalk rectal foam is approved in the following EU countries under the trademark Salofalk: Austria, Denmark, Finland, Germany, Great Britain, Greece, Ireland, Luxembourg, The Netherlands, Norway, Portugal, Spain and Sweden.

This leaflet was last approved in MM/YYYY

May 2010

Marketing authorisation number:

PL 08637/003