Clasteon 400mg Capsules

1. Name Of The Medicinal Product

CLASTEON^® 400mg capsules

Sodium Clodronate 400mg capsules

2. Qualitative And Quantitative Composition

Each capsule contains 400mg sodium clodronate (as the tetrahydrate). For excipients, see 6.1.

3. Pharmaceutical Form

Hard capsules for oral administration.

The capsules are oblong, white and blue, marked “CLASTEON^®”.

4. Clinical Particulars

4.1 Therapeutic Indications

Sodium clodronate is indicated for the management of osteolytic lesions, hypercalcaemia and bone pain associated with skeletal metastases in patients with carcinoma of the breast or multiple myeloma. Sodium clodronate capsules are also indicated for the maintenance of clinically acceptable serum calcium levels in patients with hypercalcaemia of malignancy initially treated with an intravenous infusion of sodium clodronate

4.2 Posology And Method Of Administration

Adequate fluid intake should be maintained during treatment.

Adults; The recommended dose is 4 capsules (1600mg sodium clodronate) daily. If necessary, the dosage may be increased but should not exceed a maximum of 8 capsules (3200mg sodium clodronate) daily.

The capsules may be taken as a single dose or in two equally divided doses if necessary to improve gastrointestinal tolerance. Sodium clodronate capsules should be swallowed with a little fluid, but not milk, at least one hour before or one hour after food.

Elderly; No special dosage recommendations.

Children; Safety and efficacy in children has not been established.

Use in renal impairment; In patients with renal insufficiency with creatinine clearance between 10 and 30ml/min, the daily dose should be reduced to one half the recommended adult dose. Serum creatinine should be monitored during therapy. Sodium clodronate is contra-indicated in patients with creatinine clearance below 10ml/min.

The oral bioavailability of bisphosphonates is poor. Bioequivalence studies have shown appreciable differences in bioavailability between different oral formulations of sodium clodronate, as well as marked inter and intra patient variability. Dose adjustment may be required if the formulation is changed.

4.3 Contraindications

Hypersensitivity to sodium clodronate or to any of the excipients. Acute, severe inflammatory conditions of the gastrointestinal tract. Pregnancy and lactation. Renal failure with creatinine clearance below 10ml/min, except for short term use in the presence of purely functional renal insufficiency caused by elevated serum calcium levels. Concomitant use of other bisphosphonates.

4.4 Special Warnings And Precautions For Use

Sodium clodronate should be administered with care to patients with renal insufficiency. It is recommended that appropriate monitoring of hydration status and renal function with serum creatinine measurement be carried out during treatment. Serum calcium should be monitored periodically.

No information is available on the potential carcinogenicity of sodium clodronate, but patients have been treated in clinical trials for up to 2 years. The duration of the treatment is therefore at the discretion of the physician, according to the status of the underlying malignancy.

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.

Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique, fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of other bisphosphonates is contraindicated.

As aminoglycosides can cause hypocalcaemia concomitant clodronate should be administered with caution.

Patients receiving NSAID's in addition to sodium clodronate have developed renal dysfunction. However, a synergistic action has not been established.

Concomitant use of estramustine phosphate with clodronate has been reported to increase the serum concentration of estramustine phosphate by 80% at the maximum.

Calcium rich foods, mineral supplements and antacids may impair absorption as sodium clodronate forms complexes with divalent ions.

4.6 Pregnancy And Lactation

There are limited amount of data from the use of clodronate in pregnant women. Sodium clodronate is not recommended during pregnancy and in women of childbearing potential not using effective contraception. Although in animals clodronate passes through the placental barrier, it is not known if it passes into the foetus in humans. Furthermore, it is not known if clodronate can cause foetal damage or affect reproduction in humans.

It is unknown whether clodronate is excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with sodium clodronate.

4.7 Effects On Ability To Drive And Use Machines

No effects.

4.8 Undesirable Effects

The most common reported drug reaction is diarrhoea which is usually mild and occurs more commonly with higher doses.

These adverse reactions may occur when using sodium clodronate:

System Organ Class	Common	Rare	Frequency unknown
Metabolism and nutrition disorders	Asymptomatic hypocalcaemia	Symptomatic hypocalcaemia Increased levels of serum parathyroid hormone associated with decreased serum calcium levels Increased levels of serum alkaline phosphatase*
Gastrointestinal disorders	Diarrhoea** Nausea** Vomiting**
Hepatobiliary disorders	Levels of transaminases increased – usually within normal range	Levels of transaminases increased to more than twice the normal range without associated abnormal hepatic function.
Skin and subcutaneous tissue disorders		Hypersensitivity reaction manifesting as skin reaction e.g. pruritus, urticaria, exfoliative dermatitis
Respiratory, thoracic and mediastinal disorders		Bronchospasm in patients with and without a previous history of asthma	Impairment pf respiratory function in patients with aspirin-sensitive asthma Hypersensitivity reactions manifesting as respiratory disorder
Renal and urinary disorders			Impairment of renal function (elevation of serum creatinine and proteinuria), severe renal damage Single cases of renal failure, in rare cases with fatal outcome, especially with concomitant use of NSAIDs, most often diclofenac.
Musculoskeletal and connective tissue disorders			Isolated cases of osteonecrosis of the jaw, primarily in patients previously treated with amino-bisphosphonates such as zoledronate and pamidronate (see section 4.4) Severe bone, joint and/or muscle pain has been reported in patients taking sodium clodronate. However, such reports have been infrequent and in randomised placebo controlled studies no differences are apparent between placebo and sodium clodronate treated patients. The onset of symptoms varied from days to several months after starting sodium clodronate.

* in patients with metastatic disease, may also be due to hepatic and bone disease.

** usually mild – use of the divided dose regimen rather than a single daily dose may improve gastro-intestinal tolerance.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

During post-marketing experience the following reactions have been reported (frequency rare):

Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)

4.9 Overdose

Symptoms:

Increases in serum creatinine and renal dysfunction have been reported with high intravenous doses of clodronate. It is theoretically possible that hypocalcaemia may develop up to 2 or 3 days following the overdose.

Treatment:

Treatment of overdose should be symptomatic. Adequate hydration should be ensured, and renal function and serum calcium should be monitored. Serum calcium should be monitored and oral or parenteral calcium supplementation may be needed.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Sodium clodronate is a bisphosphonate which has a high affinity to bone. It is mainly the portion of the dose adsorbed to bone which is pharmacologically active. The pharmacological effect of sodium clodronate is to suppress osteoclast mediated bone resorption as judged by bone histology and decreases in serum calcium, urine calcium and urinary excretion of hydroxyproline, without adversely affecting mineralisation.

5.2 Pharmacokinetic Properties

Oral bioavailability is in the order of 2%.

Sodium clodronate is not metabolised. The volume of distribution is approximately 0.3L/kg. Elimination from serum is rapid, 75% of the dose is recovered unchanged in urine within 24 hours.

The elimination kinetics best fit a 3 compartment model. The first two compartments have relatively short half-lives. The third compartment is probably the skeleton. Elimination half life is approximately 12 - 13 hours.

5.3 Preclinical Safety Data

Sodium clodronate shows relatively little toxicity either on single oral administration or after daily oral administration for a period of up to 6 months. In rats, a dose of 200mg/kg/day in the chronic toxicity test is at the limit of tolerability. In dogs, 40mg/kg/day chronically is within the tolerated range.

On daily administration of 500mg/kg for 6 weeks to rats, signs of renal failure with a clear rise in BUN, and initial liver parenchymal reaction with rises of SGOT, SGPT and AP occurred. No significant haematological changes were found in the toxicological investigations.

Investigations for mutagenic properties did not show any indication of mutagenic potency.

Reproduction toxicology investigations did not provide any indication of peri and post natal disorders, teratogenic damage or disorders of fertility.

It is not known if sodium clodronate passes into the mother's milk or through the placenta.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule content: Maize starch, Talc, Magnesium stearate, Sodium starch glycolate.

Capsule shell: Titanium dioxide (E171), Indigotin (E132), Gelatin.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

PVC/PVDC/aluminium blister packs:3 years.

6.4 Special Precautions For Storage

No special precautions for storage.

6.5 Nature And Contents Of Container

PVC/PVDC/aluminium Blister Packs containing 30, 60 or 120 capsules.

6.6 Special Precautions For Disposal And Other Handling

No special instructions.

7. Marketing Authorisation Holder

Beacon Pharmaceuticals Limited

85 High Street, Tunbridge Wells, Kent TN1 1YG

8. Marketing Authorisation Number(S)

PL 18157/0028

9. Date Of First Authorisation/Renewal Of The Authorisation

15 May 2007 / 13/09/2011

10. Date Of Revision Of The Text

04/11/2011

Clove Oil BP

1. Name Of The Medicinal Product

Clove Oil BP.

2. Qualitative And Quantitative Composition

Clove Oil BP 100% v/v.

3. Pharmaceutical Form

Dental Solution

4. Clinical Particulars

4.1 Therapeutic Indications

For the temporary relief of toothache.

4.2 Posology And Method Of Administration

Local.

Adults, the elderly and children:

Apply on cotton wool to the tooth cavity as required.

4.3 Contraindications

Contra-indicated in patients hypersensitive to clove oil or eugenol.

4.4 Special Warnings And Precautions For Use

Use with caution in the mouth or if sensitive to clove oil.

Avoid contact with the skin.

Repeated use may cause gum damage.

Seek dental attention as soon as possible.

Use with caution in children under 2 years.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

May enhance inhibition of platelet activity in patients receiving anti-coagulant therapy.

4.6 Pregnancy And Lactation

As for all medicines, use only with caution during pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Contact with skin or soft tissue may cause transient irritation, contact dermatitis, inflammation of the lips, and inflammation or ulceration of the mouth.

Patients may become sensitive to clove oil.

4.9 Overdose

Accidental oral ingestion of clove oil may lead to CNS depression, urinary abnormalities, anion-gap acidosis, deterioration of liver function, coma, seizure and low blood glucose levels.

Treatment should be supportive and symptomatic; there have been reports in the literature that N-acetylcysteine has been successfully used as an antidote.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Clove Oil has local anaesthetic, antiseptic and antihistaminic properties, and is used as an anodyne in toothache.

5.2 Pharmacokinetic Properties

Clove Oil acts at the site of application.

No data exists on the human pharmacokinetics of Eugenol the principle ingredient of Clove Oil.

In the rat 20-30% of Eugenol is metabolised to homovanillic acid and 4-hydroxy-3-methoxymandelic acid.

5.3 Preclinical Safety Data

None.

6. Pharmaceutical Particulars

6.1 List Of Excipients

None.

6.2 Incompatibilities

None known.

6.3 Shelf Life

10ml:	36 months unopened.
50ml:	36 months unopened.

6.4 Special Precautions For Storage

Store below 25°C.

Keep container tightly closed and protect from light.

6.5 Nature And Contents Of Container

10ml & 50ml: amber glass bottle with plastic cap or white plastic child resistant cap with EPE/Saranex liner or white 28mm polypropylene cap with Tamper Evident band and EPE/ Saranex liner.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

L.C.M. Ltd.

Linthwaite Laboratories

Huddersfield

HD7 5QH

England.

8. Marketing Authorisation Number(S)

PL: 12965/0006

9. Date Of First Authorisation/Renewal Of The Authorisation

25.08.93 / 11.11.98/

10. Date Of Revision Of The Text

10.11.2008

11 DOSIMETRY (IF APPLICABLE)

Not Applicable

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

Not Applicable

Clinorette Tablet

1. Name Of The Medicinal Product

Clinorette

2. Qualitative And Quantitative Composition

17-β estradiol 2 mg (white tablets)

17-β estradiol 2 mg and norethisterone 1 mg (pink tablets)

3. Pharmaceutical Form

Calendar pack consisting of 16, round, white biconvex, film coated tablets and 12 round, pink biconvex film coated tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in peri- and post-menopausal women with an intact uterus. Second line therapy for prevention of postmenopausal osteoporosis in women at high risk of future fractures where other therapies are ineffective or inappropriate.

4.2 Posology And Method Of Administration

Administration: Oral

Clinorette is continuous sequential HRT product. The calendar pack consists of 28 tablets. The 16 white tablets contain 2 mg of 17-β estradiol and the 12 pink tablets contain 2 mg of 17-β estradiol and 1 mg of norethisterone. One tablet is taken each day; a treatment cycle consists of 28 days. A menstrual type vaginal bleed usually occurs at the end of the treatment cycle or after administration of the last pink, norethisterone containing, tablet.

Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.

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.

Starting Clinorette

Menstruating women take the first tablet on the fifth day of menstrual bleeding. If menstruation has stopped, or is infrequent or sporadic, the first tablet can be taken at any time. Patients changing from a cyclic or continuous sequential preparation should complete the cycle and then start Clinorette without a break in therapy. Patients changing from a continuous combined preparation may start therapy at any time if amenorrhoea is established, or otherwise start on the first day of bleeding.

Missed doses

If a dose is forgotten the patient should be advised to take it as soon as they remember. However, if a whole day has passed, patients should be advised not to take the missed tablet but to continue to take one tablet daily. A missed dose may increase the likelihood of break-through bleeding and spotting.

Children or males: Clinorette is not intended for children or males.

Use in the elderly: There are no special dosage requirements.

4.3 Contraindications

Known, past or suspected breast cancer;

Known or suspected oestrogen 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 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 (section 4.3) and warnings (section 4.4) 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 currently accepted screening practices, modified 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 Clinorette, in particular:

- Leiomyoma (uterine fibroids) or endometriosis;

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

- Risk factors for oestrogen dependent tumours, e.g. 1^st 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 when 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 progestogen 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.

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-progestogen 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 progestogen was added, either sequentially or continuously, and regardless of type of progestogen. 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-progestogen 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 (Body Mass Index> 30 kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the 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 post-operative 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 four to six weeks earlier, if possible. Treatment should not be re-started 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, dyspnoea).

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 Estrogen/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 or 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 (medroxyprogesterone acetate). 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 ingredients in Clinorette is increased.

Women with pre-existing hypertriglyceridemia should be followed closely during oestrogen replacement or hormone replacement therapy since rare cases of large increases in 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 radio-immunoassay) or T3 levels (by radioimmunoassay). 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, ie corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically 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.

Clinorette is not an oral contraceptive neither will it restore fertility. Women of child bearing potential should be advised to adhere to non-hormonal contraceptive methods.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The metabolism of oestrogens and progestogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (eg phenobarbital, phenytoin, carbamazepine) and anti-infectives (eg 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 progestogens.

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

4.6 Pregnancy And Lactation

Clinorette is not indicated during pregnancy. If pregnancy occurs during medication with Clinorette, treatment should be withdrawn immediately. Data on a limited number of exposed pregnancies indicate adverse effects of norethisterone on the foetus. At doses higher than normally used in OC and HRT formulations, masculinisation of female foetuses has been observed.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of oestrogens with progestogens, indicate no teratogenic or foetotoxic effects.

Clinorette is not indicated during lactation.

.

4.7 Effects On Ability To Drive And Use Machines

No effects on the ability to drive and use machines are reported.

4.8 Undesirable Effects

Genito-urinary system– breakthrough bleeding, spotting, change in menstrual flow, dysmenorrhoea, premenstrual like syndrome, increase in size of uterine fibroids, vaginal candidiasis, change in cervical erosion and in degree of cervical secretion, cystitis like syndrome.

Breasts– tenderness, enlargement, secretion, breast cancer (see below)

Gastrointestinal– nausea, vomiting, abdominal cramps, bloating, cholestatic jaundice.

Skin– chloasma or melasma which may persist when drug is discontinued, erythema multiforme, erythema nodosum, haemorrhagic eruption, loss of scalp hair, hirsutism.

Eyes– steepening of corneal curvature, intolerance to contact lenses.

CNS– headaches, migraine, dizziness, mental depression, chorea.

Miscellaneous– increase or decrease in weight, reduced carbohydrate tolerance, aggravation of porphyria, oedema, change in libido, leg cramps.

Other adverse reactions have been reported in association with oestrogen 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 Warnings and precautions for use”.

– Myocardial infarction and stroke

– Gall bladder disease

– Probable dementia (see section 4.4)

– Vascular purpura

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 progestogen 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-progestogen 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-progestogen 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 progestogen 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-progestogen 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 + progestogen 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 progestogen to oestrogen-only therapy greatly reduces this increased risk.

4.9 Overdose

Nausea and vomiting may occur after overdosage. Treatment should be symptomatic; there is no specific antidote.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

The active ingredient, synthetic 17- β 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.

Norethisterone: As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestagen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

5.2 Pharmacokinetic Properties

17- β estradiol is absorbed rapidly after oral administration. The rate and completeness of absorption of 17- β estradiol from the white oestrogen only tablets contained in Clinorette were found to be bioequivalent to a standard 17- β estradiol 2mg preparation as assessed by the maximum concentrations achieved (Clinorette Oestrogen only tablets C_max = 187 pmol/L), time to maximum concentration (T_max) and area under the concentration time curve (AUC).

The oestrogens and their esters are handled in the body in much the same way as are the endogenous hormones. Inactivation of oestrogen is carried out mainly in the liver. A certain proportion of the oestrogen is excreted into the bile and then reabsorbed from the intestine.

After oral administration, norethisterone is absorbed from the GI tract with peak plasma concentrations occurring at 1 to 2 hours. It undergoes first-pass metabolism by the liver. Norethisterone is highly protein bound (about 60% to albumin and 35% to sex hormone binding globulin (SHBG)). Administration with an oestrogen (as in Clinorette) increases the proportion bound to SHBG.

5.3 Preclinical Safety Data

Studies in animals have indicated that administration of very high doses of oestrogens will induce neoplastic tumours in some animal species.

The results of preclinical studies of 17- β estradiol have not suggested any unwanted effects at therapeutic doses used in humans.

Norethisterone, like other progestagens has been shown to cause virilisation of female foetuses in rats and monkeys and embryolethal effects at high doses.

6. Pharmaceutical Particulars

6.1 List Of Excipients

17 beta estradiol tablets

Lactose EP

Crospovidone USNF

Povidone EP

Talc EP

Magnesium stearate EP

Opadry white Y-I-7000 HSE (methocel E5, titanium dioxide, propylene glycol)

Combination tablet

Lactose EP

Crospovidone USNF

Povidone EP

Talc EP

Magnesium stearate EP

Opadry white Y-I-7000 HSE (methocel E5, titanium dioxide, propylene glycol)

Erythrosine lake HSE

6.2 Incompatibilities

None known

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Store below 25°C in a dry dark place.

6.5 Nature And Contents Of Container

PVC and aluminium foil calendar blister pack enclosed in a cardboard carton. Each pack contains 28 tablets.

6.6 Special Precautions For Disposal And Other Handling

None stated.

Administrative Data

7. Marketing Authorisation Holder

ReSource Medical UK Limited

2 Carlton Avenue, Staincliff, Batley, WF17 7AQ, UK

8. Marketing Authorisation Number(S)

PL 21812/0002

9. Date Of First Authorisation/Renewal Of The Authorisation

23 August 1996

10. Date Of Revision Of The Text

October 2005

Co-danthramer capsules and Strong Co-danthramer capsules

Co-danthramer capsules and Strong Co-danthramer capsules

Poloxamer 188 and Dantron

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

In this leaflet:

1. What Co-danthramer capsules and Strong Co-danthramer capsules are and what they are used for

2. Before you take Co-danthramer capsules or Strong Co-danthramer capsules

3. How to take Co-danthramer capsules and Strong Co-danthramer capsules

4. Possible side effects

5. How to store Co-danthramer capsules and Strong Co-danthramer capsules

6. Further information

What Co-danthramer capsules and Strong Co-danthramer capsules are and what they are used for

These capsules have been prescribed for you to prevent or treat constipation.

Constipation may cause pain, tenderness, bloating (around the stomach), wind and vomiting. Increasing the amount of fibre (fruit, vegetables, wholemeal bread, pasta, brown rice) and fluids you eat and drink may help reduce the problem.

These capsules are only suitable for certain patients and should only be taken by the person for whom they have been prescribed.

Co-danthramer and Strong Co-danthramer capsules contain the active ingredients poloxamer 188 and dantron. Poloxamer 188 belongs to a group of medicines called faecal softeners and dantron to a group called laxatives. The other ingredients are listed in section 6 of this leaflet.

Before you take Co-danthramer capsules or Strong Co-danthramer capsules

Do not take Co-danthramer capsules or Strong Co-danthramer capsules if:

• you are allergic (hypersensitive) to poloxamer 188 or dantron;


• you are allergic to any of the other ingredients of the capsules (see section 6 ‘Further Information’);


• your constipation is caused by a blockage of the bowel (intestine).

Constipation may cause stomach ache, however if you have a severe pain in your stomach please talk to your doctor before taking this medicine.

Strong Co-danthramer capsules should not be given to children under 12 years of age.

Take special care with Co-danthramer capsules and Strong Co-danthramer capsules

Talk to your doctor before taking this medicine if you suffer from loss of bladder or bowel control (incontinence).

Children who still wear nappies should not be given Co-danthramer capsules.

Taking other medicines

Your doctor may have prescribed your capsules at the same time as some other medicines. This may be to prevent you from getting constipation.

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

Pregnancy and breastfeeding

Do not take these capsules if you are pregnant, likely to become pregnant or are breastfeeding.

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

Important information about some of the ingredients of Co-danthramer capsules and Strong Co-danthramer capsules

These capsules contain soya oil. If you are allergic to peanuts or soya do not take these capsules.

How to take Co-danthramer capsules and Strong Co-danthramer capsules

Two different strengths of capsule are available. Your doctor will decide whether Co-danthramer or Strong Co-danthramer capsules suit you best.

Always take these capsules exactly as your doctor has told you. The label on your medicine will tell you how many capsules to take and how often. You should check with your doctor or pharmacist if you are not sure.

Take your capsules just before you go to bed and always swallow them with a glass of water.

Adults

The usual dose is one or two Co-danthramer or Strong Co-danthramer capsules.

Children

Children may take the Co-danthramer capsules only. The usual dose for children is one capsule.

Children under 12 years of age should not be given Strong Co-danthramer capsules.

If you take more capsules than you should

Drink plenty of water and call your doctor or hospital straight away. When seeking medical attention make sure that you take this leaflet and any remaining capsules with you to show to the doctor.

If you forget to take your capsules

If you miss a dose you should take it as soon as you remember and then carry on as before. Do not take a double dose to make up for a forgotten capsule.

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

Possible side effects

Like all medicines, Co-danthramer and Strong Co-danthramer capsules can cause side effects, although not everybody gets them.

All medicines can cause allergic reactions, although serious allergic reactions are rare. Tell your doctor immediately if you get any sudden wheeziness, difficulties in breathing, swelling of the eyelids, face or lips, rash or itching especially those covering your whole body.

You may find the skin around your bottom turns pink or red when you take these capsules. Your urine may also turn pink or red. Don’t worry, this is quite normal and is harmless.

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

How to store Co-danthramer capsules and Strong Co-danthramer capsules

Keep out of the reach and sight of children.

Do not use any capsules after the expiry date which is stated on the carton. EXP 08 2010 means that you should not take the capsules after the last day of that month i.e. August 2010.

Do not store your capsules above 30°C.

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 Co-danthramer capsules and Strong Co-danthramer capsules contain

The active ingredients are poloxamer 188 and dantron. Each Co-danthramer capsule contains 200 mg of poloxamer 188 and 25 mg of dantron. Each Strong Co-danthramer capsule contains 500 mg of poloxamer 188 and 37.5 mg of dantron.

The other ingredients are:

• Butylhydroxytoluene (E321)


• Gelatin


• Iron oxide (E172)


• Sodium dodecyl sulphate


• Indigo carmine (E132)


• Erythrosine (E127)


• Titanium dioxide (E171)


• Soya lecithin


• Shellac


• 2-Ethoxyethanol


• Dimeticone

What Co-danthramer capsules and Strong Co-danthramer capsules look like and the contents of the pack

Co-danthramer capsules are light brown and orange in colour and are marked CX and NAPP.

Strong Co-danthramer capsules are light brown and green in colour and are marked CXF and NAPP.

In each box there are 10 or 60 capsules.

Marketing Authorisation Holder and Manufacturer

The capsules are made by

Bard Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

UK

for the marketing authorisation holder

Napp Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

UK

This leaflet is also available in large print, Braille or as an audio CD. To request a copy, please call the RNIB Medicine Information line (free of charge) on:

0800 198 5000

You will need to give details of the product name and reference number.

These are as follows:

Product name: Co-danthramer capsules

Reference number: 16950/0017

This leaflet was last approved in January 2010

Co-danthramer capsules and Strong Co-danthramer capsules are protected by European Patent
(UK) No. 0642786.

The NAPP device (logo) is a Registered Trade Mark.

© 2008 Napp Pharmaceuticals Limited

P0088-A R1V6 UK AW 14-10-08

Clarityn Allergy 1mg / ml Syrup

1. Name Of The Medicinal Product

Clarityn Allergy 1mg/ml Syrup

2. Qualitative And Quantitative Composition

Each ml of syrup contains 1mg loratadine.

The quantity of sucrose in the loratadine syrup composition is 600 mg/ml. The amount of sucrose per 5 ml (5 mg) dose is 3 grams.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Syrup

Clear, colourless to light yellow syrup.

4. Clinical Particulars

4.1 Therapeutic Indications

Clarityn/Clarityn Allergy/Boots Hayfever Relief All Day Syrup is indicated for the symptomatic treatment of allergic rhinitis and chronic idiopathic urticaria.

4.2 Posology And Method Of Administration

Adults and children over 12 years of age :

10mg once daily (10ml (10mg) of the syrup once daily).

The syrup may be taken without regard to mealtime.

Children 2 to 12 years of age are dosed by weight:

Body weight more than 30kg : 10mg once daily (10ml (10mg) of the syrup once daily).

Body weight 30kg or less : 5ml (5mg) of the syrup once daily.

Efficacy and safety of Clarityn/Clarityn Allergy/Boots Hayfever Relief All Day Syrup in children under 2 years of age has not been established.

Patients with severe liver impairment should be administered a lower initial dose because they may have reduced clearance of loratadine. An initial dose of 10mg every other day is recommended for adults and children weighing more than 30kg and for children weighing 30kg or less, 5ml (5mg) every other day is recommended.

No dosage adjustments are required in the elderly or in patients with renal insufficiency.

4.3 Contraindications

Clarityn/Clarityn Allergy/Boots Hayfever Relief All Day Syrup is contraindicated in patients who are hypersensitive to the active substance or to any of the excipients in these formulations.

4.4 Special Warnings And Precautions For Use

Clarityn/Clarityn Allergy/Boots Hayfever Relief All Day Syrup should be administered with caution in patients with severe liver impairment (see section 4.2).

This medicinal product contains sucrose; thus patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose isomaltase insufficiency should not take this medicine.

The administration of Clarityn/Clarityn Allergy/Boots Hayfever Relief All Day Syrup should be discontinued at least 48 hours before skin tests since antihistamines may prevent or reduce otherwise positive reactions to dermal reactivity index.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

When administered concomitantly with alcohol, Clarityn/Clarityn Allergy/Boots Hayfever Relief All Day Syrup has no potentiating effects as measured by psychomotor performance studies.

Potential interaction may occur with all known inhibitors of CYP3A4 or CYP2D6 resulting in elevated levels of loratadine (see Section 5.2), which may cause an increase in adverse events.

4.6 Pregnancy And Lactation

Loratadine was not teratogenic in animal studies. The safe use of loratadine during pregnancy has not been established. The use of Clarityn/Clarityn Allergy/Boots Hayfever Relief All Day Syrup during pregnancy is therefore not recommended.

Loratadine is excreted in breast milk, therefore the use of loratadine is not recommended in breast-feeding women.

4.7 Effects On Ability To Drive And Use Machines

In clinical trials that assessed driving ability, no impairment occurred in patients receiving loratadine. However, patients should be informed that very rarely some people experience drowsiness, which may affect their ability to drive or use machines.

4.8 Undesirable Effects

In clinical trials in a paediatric population children aged 2 through 12 years, common adverse reactions reported in excess of placebo were headache (2.7%), nervousness (2.3%), and fatigue (1%).

In clinical trials involving adults and adolescents in a range of indications including AR and CIU, at the recommended dose of 10mg daily, adverse reactions with loratadine were reported in 2% of patients in excess of those treated with placebo. The most frequent adverse reactions reported in excess of placebo were somnolence (1.2%), headache (0.6%), increased appetite (0.5%) and insomnia (0.1%). Other adverse reactions reported very rarely during the post-marketing period are listed in the following table.

Immune System disorders	Anaphylaxis
Nervous system disorders	Dizziness
Cardiac disorders	Tachycardia, palpitation
Gastrointestinal disorders	Nausea, dry mouth, gastritis
Hepatobiliary disorders	Abnormal hepatic function
Skin and subcutaneous tissue disorders	Rash, alopecia
General disorders and administration site conditions	Fatigue

4.9 Overdose

Overdosage with loratadine increased the occurrence of anticholinergic symptoms. Somnolence, tachycardia and headache have been reported with overdoses.

In the event of overdose, general symptomatic and supportive measures are to be instituted and maintained for as long as necessary. Administration of activated charcoal as a slurry with water may be attempted. Gastric lavage may be considered. Loratadine is not removed by haemodialysis and it is not known if loratadine is removed by peritoneal dialysis. Medical monitoring of the patient is to be continued after emergency treatment.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group : antihistamines – H₁ antagonist, ATC code : R06A X13.

Loratadine, the active ingredient in Clarityn/Clarityn Allergy/Boots Hayfever Relief All Day Syrup, is a tricyclic antihistamine with selective, peripheral H₁-receptor activity.

Loratadine has no clinically significant sedative or anticholinergic properties in the majority of the population and when used at the recommended dosage.

During long-term treatment there were no clinically significant changes in vital signs, laboratory test values, physical examinations or electrocardiograms.

Loratadine has no significant H₂-receptor activity. It does not inhibit norepinephrine uptake and has practically no influence on cardiovascular function or on intrinsic cardiac pacemaker activity.

5.2 Pharmacokinetic Properties

After oral administration, loratadine is rapidly and well absorbed and undergoes an extensive first pass metabolism, mainly by CYP3A4 and CYP2D6. The major metabolite-desloratadine (DL)- is pharmacologically active and responsible for a large part of the clinical effect. Loratadine and DL achieve maximum plasma concentrations (T_max) between 1-1.5 hours and 1.5-3.7 hours after administration, respectively.

Increase in plasma concentrations of loratadine has been reported after concomitant use with ketoconazole, erythromycin and cimetidine in controlled trials, but without clinically significant changes (including electrocardiographic).

Loratadine is highly bound (97% to 99%) and its active metabolite moderately bound (73% to 76%) to plasma proteins.

In healthy subjects, plasma distribution half-lives of loratadine and its active metabolite are approximately 1 and 2 hours, respectively. The mean elimination half-lives in healthy adult subjects were 8.4 hours (range = 3 to 20 hours) for loratadine and 28 hours (range = 8.8 to 92 hours) for the major active metabolite.

Approximately 40% of the dose is excreted in the urine and 42% in the faeces over a 10 day period and mainly in the form of conjugated metabolites. Approximately 27% of the dose is eliminated in the urine during the first 24 hours. Less than 1% of the active substance is excreted unchanged in active form, as loratadine or DL.

The bioavailability parameters of loratadine and of the active metabolite are dose proportional.

The pharmacokinetic profile of loratadine and its metabolites is comparable in healthy volunteers and in healthy geriatric volunteers.

Concomitant ingestion of food can delay slightly the absorption of loratadine but without influencing the clinical effect.

In patients with chronic renal impairment, both the AUC and peak plasma levels (C_max) increased for loratadine and its metabolite as compared to the AUCs and peak plasma levels (C_max) of patients with normal renal function. The mean elimination half-lives of loratadine and its metabolite were not significantly different from that observed in normal subjects. Haemodialysis does not have an effect on the pharmacokinetics of loratadine or its active metabolite in subjects with chronic renal impairment.

In patients with chronic alcoholic liver disease, the AUC and peak plasma levels (C_max) of loratadine were double while the pharmacokinetic profile of the active metabolite was not significantly changed from that in patients with normal liver function. The elimination half-lives for loratadine and its metabolite were 24 hours and 37 hours, respectively, and increased with increasing severity of liver disease.

Loratadine and its active metabolite are excreted in the breast milk of lactating women.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

In reproductive toxicity studies, no teratogenic effects were observed. However, prolonged parturition and reduced viability of offspring were observed in rats at plasma levels (AUC) 10 times higher than those achieved with clinical doses.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene glycol (E1520);

Glycerin (E422);

Citric Acid Monohydrate;

Sodium Benzoate (E211);

Sucrose;

Artificial Peach Flavour;

Purified Water

6.2 Incompatibilities

None known

6.3 Shelf Life

24 months; after first opening, the syrup is stable for 1 month.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

Do not freeze.Keep the bottle in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

Amber glass bottle of 60, 70, 100 or 120ml with a tamper-evident, child-proof, polypropylene cap. A 5ml plastic spoon is included.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

UK

8. Marketing Authorisation Number(S)

PL 00025/0583

9. Date Of First Authorisation/Renewal Of The Authorisation

16^th March 1992/8^th November 2007

10. Date Of Revision Of The Text

11 January 2011

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

CLARITYN SYRUP/UK/02-11/01

Ciproxin Tablets 750mg (Bayer plc)

1. Name Of The Medicinal Product

Ciproxin 750 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 750 mg ciprofloxacin (as hydrochloride).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Oblong, nearly white to slightly yellowish tablets marked with “CIP 750” on one side and “BAYER” on the reverse side.

4. Clinical Particulars

4.1 Therapeutic Indications

Ciproxin 750 mg film-coated tablets are indicated for the treatment of the following infections (see sections 4.4 and 5.1). Special attention should be paid to available information on resistance to ciprofloxacin before commencing therapy.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Adults

• Lower respiratory tract infections due to Gram-negative bacteria

- exacerbations of chronic obstructive pulmonary disease

- broncho-pulmonary infections in cystic fibrosis or in bronchiectasis

- pneumonia

• Chronic suppurative otitis media

• Acute exacerbation of chronic sinusitis especially if these are caused by Gram-negative bacteria

• Urinary tract infections

• Gonococcal uretritis and cervicitis

• Epididymo-orchitis including cases due to Neisseria gonorrhoeae

• Pelvic inflammatory disease including cases due to Neisseria gonorrhoeae

In the above genital tract infections when thought or known to be due to Neisseria gonorrhoeae it is particularly important to obtain local information on the prevalence of resistance to ciprofloxacin and to confirm susceptibility based on laboratory testing.

• Infections of the gastro-intestinal tract (e.g. travellers' diarrhoea)

• Intra-abdominal infections

• Infections of the skin and soft tissue caused by Gram-negative bacteria

• Malignant external otitis

• Infections of the bones and joints

• Treatment of infections in neutropenic patients

• Prophylaxis of infections in neutropenic patients

• Prophylaxis of invasive infections due to Neisseria meningitidis

• Inhalation anthrax (post-exposure prophylaxis and curative treatment)

Children and adolescents

• Broncho-pulmonary infections in cystic fibrosis caused by Pseudomonas aeruginosa

• Complicated urinary tract infections and pyelonephritis

• Inhalation anthrax (post-exposure prophylaxis and curative treatment)

Ciprofloxacin may also be used to treat severe infections in children and adolescents when this is considered to be necessary.

Treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents (see sections 4.4 and 5.1).

4.2 Posology And Method Of Administration

The dosage is determined by the indication, the severity and the site of the infection, the susceptibility to ciprofloxacin of the causative organism(s), the renal function of the patient and, in children and adolescents the body weight.

The duration of treatment depends on the severity of the illness and on the clinical and bacteriological course.

Treatment of infections due to certain bacteria (e.g. Pseudomonas aeruginosa, Acinetobacter or Staphylococci) may require higher ciprofloxacin doses and co-administration with other appropriate antibacterial agents.

Treatment of some infections (e.g. pelvic inflammatory disease, intra-abdominal infections, infections in neutropenic patients and infections of bones and joints) may require co-administration with other appropriate antibacterial agents depending on the pathogens involved.

Adults

Indications	Daily dose in mg	Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin)
Infections of the lower respiratory tract	500 mg twice daily to 750 mg twice daily	7 to 14 days
Infections of the upper respiratory tract	Acute exacerbation of chronic sinusitis	500 mg twice daily to 750 mg twice daily	7 to 14 days
Chronic suppurative otitis media	500 mg twice daily to 750 mg twice daily	7 to 14 days
Malignant external otitis	750 mg twice daily	28 days up to 3 months
Urinary tract infections	Uncomplicated cystitis	250 mg twice daily to 500 mg twice daily	3 days
In pre-menopausal women, 500 mg single dose may be used
Complicated cystitis, Uncomplicated pyelonephritis	500 mg twice daily	7 days
Complicated pyelonephritis	500 mg twice daily to 750 mg twice daily	at least 10 days, it can be continued for longer than 21 days in some specific circumstances (such as abscesses)
Prostatitis	500 mg twice daily to 750 mg twice daily	2 to 4 weeks (acute) to 4 to 6 weeks (chronic)
Genital tract infections	Gonococcal uretritis and cervicitis	500 mg as a single dose	1 day (single dose)
Epididymo-orchitis and pelvic inflammatory diseases	500 mg twice daily to 750 mg twice daily	at least 14 days
Infections of the gastro-intestinal tract and intra-abdominal infections	Diarrhoea caused by bacterial pathogens including Shigella spp. other than Shigella dysenteriae type 1 and empirical treatment of severe travellers' diarrhoea	500 mg twice daily	1 day
Diarrhoea caused by Shigella dysenteriae type 1	500 mg twice daily	5 days
Diarrhoea caused by Vibrio cholerae	500 mg twice daily	3 days
Typhoid fever	500 mg twice daily	7 days
Intra-abdominal infections due to Gram-negative bacteria	500 mg twice daily to 750 mg twice daily	5 to 14 days
Infections of the skin and soft tissue	500 mg twice daily to 750 mg twice daily	7 to 14 days
Bone and joint infections	500 mg twice daily to 750 mg twice daily	max. of 3 months
Treatment of infections or prophylaxis of infections in neutropenic patients Ciprofloxacin should be co-administered with appropriate antibacterial agent(s) in accordance to official guidance.	500 mg twice daily to 750 mg twice daily	Therapy should be continued over the entire period of neutropenia
Prophylaxis of invasive infections due to Neisseria meningitidis	500 mg as a single dose	1 day (single dose)
Inhalation anthrax post-exposure prophylaxis and curative treatment for persons able to receive treatment by oral route when clinically appropriate. Drug administration should begin as soon as possible after suspected or confirmed exposure.	500 mg twice daily	60 days from the confirmation of Bacillus anthracis exposure

Children and adolescents

Indications	Daily dose in mg	Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin)
Cystic fibrosis	20 mg/kg body weight twice daily with a maximum of 750 mg per dose.	10 to 14 days
Complicated urinary tract infections and pyelonephritis	10 mg/kg body weight twice daily to 20 mg/kg body weight twice daily with a maximum of 750 mg per dose.	10 to 21 days
Inhalation anthrax post-exposure prophylaxis and curative treatment for persons able to receive treatment by oral route when clinically appropriate. Drug administration should begin as soon as possible after suspected or confirmed exposure.	10 mg/kg body weight twice daily to 15 mg/kg body weight twice daily with a maximum of 500 mg per dose.	60 days from the confirmation of Bacillus anthracis exposure
Other severe infections	20 mg/kg body weight twice daily with a maximum of 750 mg per dose.	According to the type of infections

Geriatric patients

Geriatric patients should receive a dose selected according to the severity of the infection and the patient's creatinine clearance.

Renal and hepatic impairment

Recommended starting and maintenance doses for patients with impaired renal function:

Creatinine Clearance [mL/min/1.73 m²]	Serum Creatinine [µmol/L]	Oral Dose [mg]
> 60	< 124	See Usual Dosage.
30	124 to 168	250
< 30	> 169	250
Patients on haemodialysis	> 169	250
Patients on peritoneal dialysis	> 169	250

In patients with impaired liver function no dose adjustment is required.

Dosing in children with impaired renal and/or hepatic function has not been studied.

Method of administration

Tablets are to be swallowed unchewed with fluid. They can be taken independent of mealtimes. If taken on an empty stomach, the active substance is absorbed more rapidly. Ciprofloxacin tablets should not be taken with dairy products (e.g. milk, yoghurt) or mineral-fortified fruit-juice (e.g. calcium-fortified orange juice) (see section 4.5).

In severe cases or if the patient is unable to take tablets (e.g. patients on enteral nutrition), it is recommended to commence therapy with intravenous ciprofloxacin until a switch to oral administration is possible.

4.3 Contraindications

• Hypersensitivity to the active substance, to other quinolones or to any of the excipients (see section 6.1).

• Concomitant administration of ciprofloxacin and tizanidine (see section 4.5).

4.4 Special Warnings And Precautions For Use

Severe infections and mixed infections with Gram-positive and anaerobic pathogens

Ciprofloxacin monotherapy is not suited for treatment of severe infections and infections that might be due to Gram-positive or anaerobic pathogens. In such infections ciprofloxacin must be co-administered with other appropriate antibacterial agents.

Streptococcal Infections (including Streptococcus pneumoniae)

Ciprofloxacin is not recommended for the treatment of streptococcal infections due to inadequate efficacy.

Genital tract infections

Epididymo-orchitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae. Ciprofloxacin should be co-administered with another appropriate antibacterial agent unless ciprofloxacin-resistant Neisseria gonorrhoeae can be excluded. If clinical improvement is not achieved after 3 days of treatment, the therapy should be reconsidered.

Intra-abdominal infections

There are limited data on the efficacy of ciprofloxacin in the treatment of post-surgical intra-abdominal infections.

Travellers' diarrhoea

The choice of ciprofloxacin should take into account information on resistance to ciprofloxacin in relevant pathogens in the countries visited.

Infections of the bones and joints

Ciprofloxacin should be used in combination with other antimicrobial agents depending on the results of the microbiological documentation.

Inhalational anthrax

Use in humans is based on in-vitro susceptibility data and on animal experimental data together with limited human data. Treating physicians should refer to national and/or international consensus documents regarding the treatment of anthrax.

Children and adolescents

The use of ciprofloxacin in children and adolescents should follow available official guidance. Ciprofloxacin treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents.

Ciprofloxacin has been shown to cause arthropathy in weight-bearing joints of immature animals. Safety data from a randomised double-blind study on ciprofloxacin use in children (ciprofloxacin: n=335, mean age = 6.3 years; comparators: n=349, mean age = 6.2 years; age range = 1 to 17 years) revealed an incidence of suspected drug-related arthropathy (discerned from joint-related clinical signs and symptoms) by Day +42 of 7.2% and 4.6%. Respectively, an incidence of drug-related arthropathy by 1-year follow-up was 9.0% and 5.7%. The increase of suspected drug-related arthropathy cases over time was not statistically significant between groups. Treatment should be initiated only after a careful benefit/risk evaluation, due to possible adverse events related to joints and/or surrounding tissue.

Broncho-pulmonary infections in cystic fibrosis

Clinical trials have included children and adolescents aged 5

Complicated urinary tract infections and pyelonephritis

Ciprofloxacin treatment of urinary tract infections should be considered when other treatments cannot be used, and should be based on the results of the microbiological documentation.

Clinical trials have included children and adolescents aged 1

Other specific severe infections

Other severe infections in accordance with official guidance, or after careful benefit-risk evaluation when other treatments cannot be used, or after failure to conventional therapy and when the microbiological documentation can justify a ciprofloxacin use.

The use of ciprofloxacin for specific severe infections other than those mentioned above has not been evaluated in clinical trials and the clinical experience is limited. Consequently, caution is advised when treating patients with these infections.

Hypersensitivity

Hypersensitivity and allergic reactions, including anaphylaxis and anaphylactoid reactions, may occur following a single dose (see section 4.8) and may be life-threatening. If such reaction occurs, ciprofloxacin should be discontinued and an adequate medical treatment is required.

Musculoskeletal System

Ciprofloxacin should generally not be used in patients with a history of tendon disease/disorder related to quinolone treatment. Nevertheless, in very rare instances, after microbiological documentation of the causative organism and evaluation of the risk/benefit balance, ciprofloxacin may be prescribed to these patients for the treatment of certain severe infections, particularly in the event of failure of the standard therapy or bacterial resistance, where the microbiological data may justify the use of ciprofloxacin.

Tendinitis and tendon rupture (especially Achilles tendon), sometimes bilateral, may occur with ciprofloxacin, as soon as the first 48 hours of treatment. The risk of tendinopathy may be increased in elderly patients or in patients concomitantly treated with corticosteroids (see section 4.8).

At any sign of tendinitis (e.g. painful swelling, inflammation), ciprofloxacin treatment should be discontinued. Care should be taken to keep the affected limb at rest.

Ciprofloxacin should be used with caution in patients with myasthenia gravis (see section 4.8).

Photosensitivity

Ciprofloxacin has been shown to cause photosensitivity reactions. Patients taking ciprofloxacin should be advised to avoid direct exposure to either extensive sunlight or UV irradiation during treatment (see section 4.8).

Central Nervous System

Quinolones are known to trigger seizures or lower the seizure threshold. Ciprofloxacin should be used with caution in patients with CNS disorders which may be predisposed to seizure. If seizures occur ciprofloxacin should be discontinued (see section 4.8). Psychiatric reactions may occur even after the first administration of ciprofloxacin. In rare cases, depression or psychosis can progress to self-endangering behaviour. In these cases, ciprofloxacin should be discontinued.

Cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances or muscle weakness, alone or in combination) have been reported in patients receiving ciprofloxacin. Ciprofloxacin should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition (see section 4.8).

Cardiac disorders

Since ciprofloxacin is associated with cases of QT prolongation (see section 4.8), caution should be exercised when treating patients at risk for torsades de pointes arrhythmia.

Gastrointestinal System

The occurrence of severe and persistent diarrhoea during or after treatment (including several weeks after treatment) may indicate an antibiotic-associated colitis (life-threatening with possible fatal outcome), requiring immediate treatment (see section 4.8). In such cases, ciprofloxacin should immediately be discontinued, and an appropriate therapy initiated. Anti-peristaltic drugs are contraindicated in this situation.

Renal and urinary system

Crystalluria related to the use of ciprofloxacin has been reported (see section 4.8). Patients receiving ciprofloxacin should be well hydrated and excessive alkalinity of the urine should be avoided.

Hepatobiliary system

Cases of hepatic necrosis and life-threatening hepatic failure have been reported with ciprofloxacin (see section 4.8). In the event of any signs and symptoms of hepatic disease (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), treatment should be discontinued.

Glucose-6-phosphate dehydrogenase deficiency

Haemolytic reactions have been reported with ciprofloxacin in patients with glucose-6-phosphate dehydrogenase deficiency. Ciprofloxacin should be avoided in these patients unless the potential benefit is considered to outweigh the possible risk. In this case,potential occurrence of haemolysis should be monitored.

Resistance

During or following a course of treatment with ciprofloxacin bacteria that demonstrate resistance to ciprofloxacin may be isolated, with or without a clinically apparent superinfection. There may be a particular risk of selecting for ciprofloxacin-resistant bacteria during extended durations of treatment and when treating nosocomial infections and/or infections caused by Staphylococcus and Pseudomonas species.

Cytochrome P450

Ciprofloxacin inhibits CYP1A2 and thus may cause increased serum concentration of concomitantly administered substances metabolised by this enzyme (e.g. theophylline, clozapine, ropinirole, tizanidine). Co-administration of ciprofloxacin and tizanidine is contra-indicated. Therefore, patients taking these substances concomitantly with ciprofloxacin should be monitored closely for clinical signs of overdose, and determination of serum concentrations (e.g. of theophylline) may be necessary (see section 4.5).

Methotrexate

The concomitant use of ciprofloxacin with methotrexate is not recommended (see section 4.5).

Interaction with tests

The in-vitro activity of ciprofloxacin against Mycobacterium tuberculosis might give false negative bacteriological test results in specimens from patients currently taking ciprofloxacin.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of other products on ciprofloxacin:

Chelation Complex Formation

The simultaneous administration of ciprofloxacin (oral) and multivalent cation-containing drugs and mineral supplements (e.g. calcium, magnesium, aluminium, iron), polymeric phosphate binders (e.g. sevelamer), sucralfate or antacids, and highly buffered drugs (e.g. didanosine tablets) containing magnesium, aluminium, or calcium reduces the absorption of ciprofloxacin. Consequently, ciprofloxacin should be administered either 1

Food and Dairy Products

Dietary calcium as part of a meal does not significantly affect absorption. However, the concurrent administration of dairy products or mineral-fortified drinks alone (e.g. milk, yoghurt, calcium-fortified orange juice) with ciprofloxacin should be avoided because absorption of ciprofloxacin may be reduced.

Probenecid

Probenecid interferes with renal secretion of ciprofloxacin. Co-administration of probenecid and ciprofloxacin increases ciprofloxacin serum concentrations.

Effects of ciprofloxacin on other medicinal products:

Tizanidine

Tizanidine must not be administered together with ciprofloxacin (see section 4.3). In a clinical study with healthy subjects, there was an increase in serum tizanidine concentration (C_max increase: 7-fold, range: 4 to 21-fold; AUC increase: 10-fold, range: 6 to 24-fold) when given concomitantly with ciprofloxacin. Increased serum tizanidine concentration is associated with a potentiated hypotensive and sedative effect.

Methotrexate

Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate and increased risk of methotrexate-associated toxic reactions. The concomitant use is not recommended (see section 4.4).

Theophylline

Concurrent administration of ciprofloxacin and theophylline can cause an undesirable increase in serum theophylline concentration. This can lead to theophylline-induced side effects that may rarely be life threatening or fatal. During the combination, serum theophylline concentrations should be checked and the theophylline dose reduced as necessary (see section 4.4).

Other xanthine derivatives

On concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline), raised serum concentrations of these xanthine derivatives were reported.

Phenytoin

Simultaneous administration of ciprofloxacin and phenytoin may result in increased or reduced serum levels of phenytoin such that monitoring of drug levels is recommended.

Oral anticoagulants

.Simultaneous administration of ciprofloxacin with warfarin may augment its anti-coagulant effects. There have been many reports of increases in oral anticoagulant activity in patients receiving antibacterial agents, including fluoroquinolones. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the fluoroquinolone to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant agent.

Ropinirole

It was shown in a clinical study that concomitant use of ropinirole with ciprofloxacin, a moderate inhibitor of the CYP450 1A2 isozyme, results in an increase of C_max and AUC of ropinirole by 60% and 84%, respectively. Monitoring of ropinirole-related side effects and dose adjustment as appropriate is recommended during and shortly after co-administration with ciprofloxacin (see section 4.4).

Clozapine

Following concomitant administration of 250 mg ciprofloxacin with clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Clinical surveillance and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised (see section 4.4).

4.6 Pregnancy And Lactation

Pregnancy

The data that are available on administration of ciprofloxacin to pregnant women indicates no malformative or feto/neonatal toxicity of ciprofloxacin. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. In juvenile and prenatal animals exposed to quinolones, effects on immature cartilage have been observed, thus, it cannot be excluded that the drug could cause damage to articular cartilage in the human immature organism / foetus (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of ciprofloxacin during pregnancy.

Lactation

Ciprofloxacin is excreted in breast milk. Due to the potential risk of articular damage, ciprofloxacin should not be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Due to its neurological effects, ciprofloxacin may affect reaction time. Thus, the ability to drive or to operate machinery may be impaired.

4.8 Undesirable Effects

The most commonly reported adverse drug reactions (ADRs) are nausea and diarrhoea.

ADRs derived from clinical studies and post-marketing surveillance with Ciproxin (oral, intravenous, and sequential therapy) sorted by categories of frequency are listed below. The frequency analysis takes into account data from both oral and intravenous administration of ciprofloxacin.

System Organ Class	Common	Uncommon	Rare	Very Rare < 1/10 000	Frequency not known (cannot be estimated from available data)
Infections and Infestations		Mycotic superinfections	Antibiotic associated colitis (very rarely with possible fatal outcome) (see section 4.4)
Blood and Lymphatic System Disorders		Eosinophilia	Leukopenia Anaemia Neutropenia Leukocytosis Thrombocytopenia Thrombocytaemia	Haemolytic anaemia Agranulocytosis Pancytopenia (life-threatening) Bone marrow depression (life-threatening)
Immune System Disorders			Allergic reaction Allergic oedema / angiooedema	Anaphylactic reaction Anaphylactic shock (life-threatening) (see section 4.4) Serum sickness-like reaction
Metabolism and Nutrition Disorders		Anorexia	Hyperglycaemia
Psychiatric Disorders		Psychomotor hyperactivity / agitation	Confusion and disorientation Anxiety reaction Abnormal dreams Depression Hallucinations	Psychotic reactions (see section 4.4)
Nervous System Disorders		Headache Dizziness Sleep disorders Taste disorders	Par- and Dysaesthesia Hypoaesthesia Tremor Seizures (see section 4.4) Vertigo	Migraine Disturbed coordination Gait disturbance Olfactory nerve disorders Intracranial hypertension	Peripheral neuropathy (see section 4.4)
Eye Disorders			Visual disturbances	Visual colour distortions
Ear and Labyrinth Disorders			Tinnitus Hearing loss / Hearing impaired
Cardiac Disorders			Tachycardia		Ventricular arrhythmia, QT prolongation, torsades de pointes *
Vascular Disorders			Vasodilatation Hypotension Syncope	Vasculitis
Respiratory, Thoracic and Mediastinal Disorders			Dyspnoea (including asthmatic condition)
Gastrointestinal Disorders	Nausea Diarrhoea	Vomiting Gastrointestinal and abdominal pains Dyspepsia Flatulence		Pancreatitis
Hepatobiliary Disorders