1. Name Of The Medicinal Product

Diazepam Forte Syrup 5mg/5ml

2. Qualitative And Quantitative Composition

Each 5ml contains 5mg of Diazepam B.P.

3. Pharmaceutical Form

Oral Solution

4. Clinical Particulars 4.1 Therapeutic Indications

Diazepam has anticonvulsant, anxiolytic, sedative, muscle relaxant and amnesic properties.

Diazepam Forte Syrup 5mg/5ml is indicated for

Adults

i) For the short-term relief (2-4 weeks only) of anxiety that is severe, disabling or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness;

ii) As a sedative and premedicant;

iii) As an anticonvulsant in the management of status epilepticus, febrile convulsions and poisoning;

iv) In the control of muscle spasms as in tetanus;

v) In the management of alcohol withdrawal symptoms;

vi) In selected cases it may be useful in the management of cerebral spasticity;

Children

i) Night terrors and somnambulism;

ii) Premedication;

iii) In the control of muscle spasms as in tetanus;

iv) In selected cases, it may be useful in controlling tension and irritability in cerebral spasticity;

The use of diazepam to treat short term anxiety is inappropriate and unsuitable. Diazepam should be used to treat insomnia only when it is severe, disabling or subjecting the individual to extreme stress.

4.2 Posology And Method Of Administration

Adults:

Anxiety States: 2mg three times daily up to 30mg daily in divided doses.

Insomnia associated with Anxiety: 5mg to 15mg before retiring.

Muscle Spasms: 2mg to 15mg daily in divided doses up to 60mg in severe spastic disorders such as cerebral spasticity, epilepsy and muscle spasms associated with upper-motor neurone disease.

In the control of muscle spasms as in tetanus: 3mg to 10mg/kg bodyweight daily.

Alcohol Withdrawal Symptoms: 5mg to 20mg repeated within 2 to 4 hours if necessary.

Premedication in Dental Patients: 5mg the night before, 5mg on waking and another 5mg 2 hours before the appointment.

Elderly or Debilitated patients: The dosage should be half that recommended in adults.

Children:

Night Terrors and Somnambulism: 1mg to 5mg daily before retiring.

Premedication: 2mg to 10mg.

Management of Cerebral Spasticity: 2mg to 40mg daily in divided doses.

In the control of Muscle spasms as in Tetanus: 3mg to 10mg/kg bodyweight daily.

Doses should be repeated only on medical advice. Long-term chronic use is not recommended and treatment should always be tapered off gradually. When a benzodiazepine is used as a hypnotic, treatment should, if possible, be intermittent.

Route of administration

Oral.

4.3 Contraindications

Patients with a known sensitivity to benzodiazepines, acute pulmonary insufficiency; respiratory depression.

4.4 Special Warnings And Precautions For Use

The lowest dose that can control the symptoms should be used and treatment should not be continued beyond 4 weeks. The risk of dependence increases when high dosages are attained, especially when given over long periods. This is particularly so in patients with a history of alcoholism, drug abuse or in patients with marked personality disorders.

Treatment should always be tapered off gradually. Sudden cessation of treatment can result in symptoms such as depression, nervousness, rebound insomnia, irritability, sweating and diarrhoea even in patients receiving normal therapeutic doses for short periods of time. Abrupt withdrawal following high dosage may produce confusion, toxic psychosis, convulsions or a condition resembling delirium tremens.

Diazepam should not be used to treat chronic psychoses or phobic or obsessional states. Because diazepam-induced disinhibition may precipitate suicidal or aggressive behaviour, it should not be used alone to treat depression or anxiety related depression. Caution must be exercised when treating patients with personality disorders.

Elderly or debilitated patients may be more prone to adverse effects and care must be taken in patients with impaired liver or kidney function. Care is also required in patients with organic brain disease (particularly arteriosclerosis).

Diazepam should be avoided in cases of loss or bereavement as psychological adjustment may be inhibited by benzodiazepines.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Sedation, or respiratory or cardiovascular depression may be enhanced if diazepam is combined with centrally acting drugs such as alcohol, anaesthetics, analgesics, antidepressants, hypnotics, neuroleptics and tranquillisers. Concomitant intake with alcohol is not recommended since the sedative effect is increased. Diazepam is primarily metabolised by hepatic microsomal oxidation and drugs which affect liver enzymes, such as cimetidine and phenobarbitone, may alter its pharmacokinetics. Diazepam has been reported to be displaced from protein-binding sites by sodium valproate.

4.6 Pregnancy And Lactation

If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects that she is pregnant.

If, for compelling medical reasons, the product is administered during the late phase of pregnancy or during labour at high doses, effects on the neonate such as hypothermia, hypotonia and moderate respiratory depression can be expected owing to the pharmacological action of the compound.

Infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

Since benzodiazepines are found in the breast milk, benzodiazepines should not be given to breast feeding mothers.

4.7 Effects On Ability To Drive And Use Machines

The side-effects of diazepam, such as sedation and impaired muscle function, may adversely affect the ability to drive or use machines. Insufficient sleep may also increase the likelihood of impaired alertness. (see also interactions, Section 4.5)

4.8 Undesirable Effects

Diazepam may cause drowsiness, sedation, blurring of vision, unsteadiness and ataxia. These may occur after single as well as repeated doses and persist to the following day. Less common effects include vertigo, headache, confusion, slurred speech, visual disturbance, tremor, change in libido, skin rashes and gastro-intestinal upset. Jaundice or blood dyscrasias have been reported rarely. High doses may be associated with respiratory depression or hypotension.

Abnormal psychological reactions to benzodiazepines have been reported. Rare behavioural adverse effects including paradoxical aggressive outbursts, excitement, confusion and the uncovering of depression with suicidal tendencies.

4.9 Overdose

Symptoms

Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Coma, hypotension and respiratory depression occasionally occur but are seldom serious if these drugs are taken alone. Coma usually lasts only a few hours but in elderly people it may be more protracted and cyclical. Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic respiratory disease.

Benzodiazepines potentiate the effects of other central nervous system depressants, including alcohol.

Management

Consider activated charcoal in adults or children who have taken more than 1 mg/kg within 1 hour, provided they are not too drowsy. Gastric lavage is unnecessary if these drugs have been taken alone. Patients who are asymptomatic at four hours are unlikely to develop symptoms. Institute supportive measures as indicated by the patient's clinical state.

If CNS depression is severe consider the use of flumazenil (Anexate), a benzodiazepine antagonist. This should rarely be required. It has a short half-life (about an hour) and should NOT TO BE USED IN MIXED OVERDOSE OR AS A "DIAGNOSTIC" TEST. It is contraindicated in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants).

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Diazepam has potent anxiolytic anti-convulsant and central muscle relaxant properties, these effects are probably mediated through special areas of the CNS. Diazepam has little autonomic activity.

5.2 Pharmacokinetic Properties

The following results were obtained following a pharmacokinetic study with healthy volunteers

 

 

Diazepam 5mg/5ml Syrup (Lagap)

cmax (mean ± S.D.)

275 ± 73

tmax (mean)

1 hour

5.3 Preclinical Safety Data

None stated

6. Pharmaceutical Particulars 6.1 List Of Excipients

Glycerin, sucrose, microcrystalline cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, alcohol (96%), sodium carboxymethylcellulose, Flavouring Agent (Framboise/raspberry 50969A), Ponceau 4R (E124), potassium sorbate and purified water.

6.2 Incompatibilities

None Known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Store below 25?C. Protect from light.

6.5 Nature And Contents Of Container

Amber glass bottles with screw caps and plastic inserts.

Pack sizes: 50ml, 100ml, 150ml, 200ml, 250ml, 300ml and 500ml

6.6 Special Precautions For Disposal And Other Handling

Shake well before use.

7. Marketing Authorisation Holder

Sandoz Ltd

Woolmer Way

Bordon

Hampshire

GU35 9QE

8. Marketing Authorisation Number(S)

PL 4416/0067

9. Date Of First Authorisation/Renewal Of The Authorisation

16th April 1984 / 30th January 1995

10. Date Of Revision Of The Text

6 July 2005



Address Dr. Reddy's Laboratories Inc.,



1. Name Of The Medicinal Product

Depixol Injection

Depixol® Conc. Injection

2. Qualitative And Quantitative Composition

Depixol Injection:

20 mg/mL (2% w/v) cis(Z)-flupentixol decanoate in thin vegetable oil.

Ampoules 1mL and 2 mL, Syringes 1 mL and 2 mL and Vial 10 mL.

Depixol Conc Injection:

100 mg/mL (10%w/v) cis (Z)-flupentixol decanoate in thin vegetable oil.

Ampoules 0.5 mL and 1 mL and Vial 5 mL.

3. Pharmaceutical Form

Oily solution for deep intramuscular injection.

4. Clinical Particulars 4.1 Therapeutic Indications

The treatment of schizophrenia and other psychoses.

Use of Depixol should be restricted to those stabilised on oral therapy.

4.2 Posology And Method Of Administration

Route of administration

Deep intramuscular injection into the upper outer buttock or lateral thigh.

Dosage and dosage interval should be adjusted according to the patients' symptoms and response to treatment.

Note: As with all oil-based injections it is important to ensure, by aspiration before injection, that inadvertent intravascular entry does not occur.

Adults

The usual dosage of flupentixol decanoate lies between 50 mg every 4 weeks and 300 mg every 2 weeks, but some patients may require up to 400 mg weekly. Other patients may be adequately maintained on dosages of 20-40 mg flupentixol decanoate every 2-4 weeks. In patients who have not previously received depot antipsychotic, treatment is usually started with a small dose (e.g. 20 mg) to assess tolerability. An interval of at least one week should be allowed before the second injection is given at a dose consistent with the patients' condition.

Depixol Injection 20 mg/ml is not intended for use in patients requiring doses of greater than 60 mg (3 mL) of flupentixol. Injection volumes of 2 – 3 mL should be distributed between two injection sites.

More concentrated solutions of flupentixol decanoate (Depixol Conc Injection or Depixol Low Volume Injection) should be used if doses greater than 3 mL (60 mg) are required.

The injection volumes selected for Depixol Conc Injection or Depixol Low Volume Injection should not exceed 2 mL.

Adequate control of severe psychotic symptoms may take up to 4 to 6 months at high enough dosage. Once stabilised lower maintenance doses may be considered, but must be sufficient to prevent relapse.

Elderly

In accordance with standard medical practice, initial dosage may need to be reduced to a quarter or half the normal starting dose in the frail or elderly.

Children

Depixol is not indicated for children.

Reduced renal function

Flupentixol has not been studied in renal impairment. Increased cerebral sensitivity to antipsychotics has been noted in severe renal impairment (see section 4.4).

Reduced hepatic function

Flupentixol has not been studied in hepatic impairment. It is extensively metabolised by the liver and particular caution should be used in this situation and serum level monitoring is advised (see section 4.4). Depixol should be initiated at low doses orally to check for tolerability before switching to the depot formulation.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see section 6.1). Circulatory collapse, depressed level of consciousness due to any cause (e.g. intoxication with alcohol, barbiturates or opiates), coma.

Not recommended for excitable or agitated patients.

4.4 Special Warnings And Precautions For Use

Caution should be exercised in patients having: liver disease; cardiac disease or arrhythmias; severe respiratory disease; renal failure; epilepsy (and conditions predisposing to epilepsy e.g. alcohol withdrawal or brain damage); Parkinson's disease; narrow angle glaucoma; prostatic hypertrophy; hypothyroidism; hyperthyroidism; myasthenia gravis; phaeochromocytoma and patients who have shown hypersensitivity to thioxanthenes or other antipsychotics.

The elderly require close supervision because they are specially prone to experience such adverse effects as sedation, hypotension, confusion and temperature changes.

The possibility of development of neuroleptic malignant syndrome (hyperthermia, muscle rigidity, fluctuating consciousness, instability of the autonomous nervous system) exists with any neuroleptic. The risk is possibly greater with the more potent agents. Patients with pre-existing organic brain syndrome, mental retardation, and opiate and alcohol abuse are overrepresented among fatal cases.

Treatment: Discontinuation of the neuroleptic. Symptomatic treatment and use of general supportive measures. Dantrolene and bromocriptine may be helpful.

Symptoms may persist for more than a week after oral neuroleptics are discontinued and somewhat longer when associated with the depot forms of the drugs.

Blood dyscrasias, including thrombocytopenia, have been reported rarely. Blood counts should be carried out if a patient develops signs of persistent infection.

As described for other psychotropics flupentixol may modify insulin and glucose responses calling for adjustment of the antidiabetic therapy in diabetic patients.

Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia have been described after abrupt cessation of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. The plasma concentrations of the Depixol Injection gradually decrease over several weeks which makes gradual dosage tapering unnecessary.

When transferring patients from oral to depot antipsychotic treatment, the oral medication should not be discontinued immediately, but gradually withdrawn over a period of several days after administering the first injection.

An approximately 3-fold increased risk of cerebrovascular adverse events have been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations.

Flupentixol should be used with caution in patients with risk factors for stroke.

As with other drugs belonging to the therapeutic class of antipsychotics, flupentixol may cause QT prolongation. Persistently prolonged QT intervals may increase the risk of malignant arrhythmias. Therefore, flupentixol should be used with caution in susceptible individuals (with hypokalaemia, hypomagnesia or genetic predisposition) and in patients with a history of cardiovascular disorders, e.g. QT prolongation, significant bradycardia (<50 beats per minute), a recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Depixol and preventive measures undertaken.

Concomitant treatment with other antipsychotics should be avoided (see section 4.5).

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs.

It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Other psychiatric conditions for which flupentixol is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders. Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Increased Mortality in Elderly people with Dementia

Data from two large observational studies showed that elderly people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.

Depixol is not licensed for the treatment of dementia-related behavioural disturbances.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In common with other antipsychotics, flupentixol enhances the response to alcohol the effects of barbiturates and other CNS depressants. Flupentixol may potentiate the effects of general anaesthetics and anticoagulants and prolong the action of neuromuscular blocking agents.

The anticholinergic effects of atropine or other drugs with anticholinergic properties may be increased. Concomitant use of drugs such as metoclopramide, piperazine or antiparkinson drugs may increase the risk of extrapyramidal effects such as tardive dyskinesia. Combined use of antipsychotics and lithium or sibutramine has been associated with an increased risk of neurotoxicity.

Antipsychotics may enhance the cardiac depressant effects of quinidine; the absorption of corticosteroids and digoxin. The hypotensive effect of vasodilator antihypertensive agents such as hydralazine and ?-blockers (e.g. doxazosin), or methyl-dopa may be enhanced.

Increases in the QT interval related to antipsychotic treatment may be exacerbated by the co-administration of other drugs known to significantly increase the QT interval.

Co-administration of such drugs should be avoided. Relevant classes include:

• class Ia and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide)

• some antipsychotics (e.g. thioridazine)

• some macrolides (e.g. erythromycin)

• some antihistamines

• some quinolone antibiotics (e.g. moxifloxacin)

The above list is not exhaustive and other individual drugs known to significantly increase QT interval (e.g. cisapride, lithium) should be avoided.

Drugs known to cause electrolyte disturbances such as thiazide diuretics (hypokalaemia) and drugs known to increase the plasma concentration of flupentixol should also be used with caution as they may increase the risk of QT prolongation and malignant arrythmias (see section 4.4).

Antipsychotics may antagonise the effects of adrenaline and other sympathomimetic agents, and reverse the antihypertensive effects of guanethidine and similar adrenergic-blocking agents. Antipsychotics may also impair the effect of levodopa, adrenergic drugs and anticonvulsants.

The metabolism of tricyclic antidepressants may be inhibited and the control of diabetes may be impaired.

4.6 Pregnancy And Lactation

As the safety of this drug during pregnancy has not been established, use during pregnancy, especially the first and last trimesters, should be avoided, unless the expected benefit to the patient outweighs the potential risk to the foetus.

Flupentixol is excreted into the breast milk. If the use of Depixol is considered essential, nursing mothers should be advised to stop breast feeding.

The newborn of mothers treated with antipsychotics in late pregnancy, or labour, may show signs of intoxication such as lethargy, tremor and hyperexcitability, and have a low Apgar score.

4.7 Effects On Ability To Drive And Use Machines

Alertness may be impaired, especially at the start of treatment, or following the consumption of alcohol; patients should be warned of this risk and advised not to drive or operate machinery until their susceptibility is known. Patients should not drive if they have blurred vision.

4.8 Undesirable Effects

Cases of suicidal ideation and suicidal behaviours have been reported during flupentixol therapy or early after treatment discontinuation (see section 4.4).

Undesirable effects are for the majority dose dependent. The frequency and severity are most pronounced in the early phase of treatment and decline during continued treatment.

Extrapyramidal reactions may occur, especially in the early phase of treatment. In most cases these side effects can be satisfactorily controlled by reduction of dosage and/or use of antiparkinsonian drugs. The routine prophylactic use of antiparkinsonian drugs is not recommended. Antiparkinsonian drugs do not alleviate tardive dyskinesia and may aggravate them. Reduction in dosage or, if possible, discontinuation of flupentixol therapy is recommended. In persistent akathisia a benzodiazepine or propranolol may be useful.

Cardiac disorders

Tachycardia, palpitations.

Electrocardiogram QT prolonged.

Blood and lymphatic system disorders

Thrombocytopenia, neutropenia, leukopenia, agranulocytosis

Nervous system disorders

Somnolence, akathisia, hyperkinesia, hypokinesia.

Tremor, dystonia, dizziness, headache, disturbance in attention.

Tardive dyskinesia, dyskinesia, parkinsonism, speech disorder, convulsion.

Neuroleptic malignant syndrome.

Eye disorders

Accommodation disorder, vision abnormal.

Oculogyration.

Respiratory, thoracic and mediastinal disorders

Dyspnoea.

Gastrointestinal disorders

Dry mouth.

Salivary hypersecretion, constipation, vomiting, dyspepsia, diarrhoea.

Abdominal pain, nausea, flatulence.

Renal and urinary disorders

Micturition disorder, urinary retention.

Skin and subcutaneous tissue disorders

Hyperhidrosis, pruritus.

Rash, photosensitivity reaction, dermatitis.

Musculoskeletal and connective tissue disorder

Myalgia.

Muscle rigidity.

Endocrine disorder

Hyperprolactinaemia.

Metabolism and nutrition disorders

Increased appetite, weight increased.

Decreased appetite.

Hyperglycaemia, glucose tolerance abnormal.

Vascular disorders

Hypotension, hot flush.

General disorders and administration site conditions

Asthenia, fatigue.

Injection site reaction1.

Immune system disorders

Hypersensitivity, anaphylactic reaction.

Hepatobiliary disorders

Liver function test abnormal.

Jaundice

Reproductive system and breast disorders

Ejaculation failure, erectile dysfunction.

Gynaecomastia, galactorrhoea, amenorrhoea.

Psychiatric disorders

Insomnia, depression, nervousness, agitation, libido decreased.

Confusional state.

1For injectable flupentixol presentations.

As with other drugs belonging to the therapeutic class of antipsychotics, rare cases of QT prolongation, ventricular arrhythmias - ventricular fibrillation, ventricular tachycardia, Torsade de Pointes and sudden unexplained death have been reported for flupentixol (see section 4.4).

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs- Frequency unknown.

Abrupt discontinuation of flupentixol may be accompanied by withdrawal symptoms. The most common symptoms are nausea, vomiting, anorexia, diarrhoea, rhinorrhoea, sweating, myalgias, paraesthesias, insomnia, restlessness, anxiety, and agitation. Patients may also experience vertigo, alternate feelings of warmth and coldness, and tremor. Symptoms generally begin within 1 to 4 days of withdrawal and abate within 7 to 14 days.

4.9 Overdose

Overdosage may cause somnolence or even coma, extrapyramidal symptoms, convulsions, hypotension, shock, hyper or hypothermia. ECG changes, QT prolongation, Torsade de Pointes, cardiac arrest and ventricular arrhythmias have been reported when administered in overdose together with drugs known to affect the heart.

Treatment is symptomatic and supportive, with measures aimed at supporting the respiratory and cardiovascular systems. The following specific measures may be employed if required.

- Anticholinergic antiparkinson drugs if extrapyramidal symptoms occur

- Sedation (with benzodiazepines) in the unlikely event of agitation or excitement or convulsions

- Noradrenaline in saline intravenous drip if the patient is in shock. Adrenaline must not be given.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Flupentixol is a non-sedating antipsychotic drug of the thioxanthene group. Its primary pharmacological action is dopamine blockade. Flupentixol has a high affinity for D1 and D2 receptors. Depixol Injection contains the deconoic ester of flupentixol in thin vegetable oil.

5.2 Pharmacokinetic Properties

After intramuscular injection, the ester is slowly released from the oil depot and is rapidly hydrolysed to release flupentixol. Flupentixol is widely distributed in the body and extensively metabolized in the liver. Peak circulating levels occur around 7 days after administration.

5.3 Preclinical Safety Data

Nil of relevance

6. Pharmaceutical Particulars 6.1 List Of Excipients

Thin vegetable oil "Viscoleo" (fractionated coconut oil).

6.2 Incompatibilities

This product may be mixed in the same syringe with other products in the Depixol Injection range. It should not be mixed with any other injection fluids.

6.3 Shelf Life

Depixol Injection:

Ampoules 1 mL and 2 mL : 4 years

Syringes 1 mL and 2 mL : 2 years

Vial 10 mL : 3 years (shelf-life after opening : 1 day)

Depixol Conc Injection:

Ampoule 0.5 mL : 2 years

Ampoule 1 mL : 4 years

Vial 5 mL : 3 years

6.4 Special Precautions For Storage

Store at or below 25°C. Protect from light.

6.5 Nature And Contents Of Container

Depixol Injection:

Ampoules containing 1 mL and 2 mL of 20 mg/mL (2% w/v) cis (Z)-flupentixol decanoate in thin vegetable oil. Pack size = 10 ampoules per box.

Syringes containing 1 mL and 2 mL of 20 mg/mL (2%w/v) cis (Z)-flupentixol decanoate in thin vegetable oil. Pack size = 5 syringes per box.

Vial containing 10 mL of 20 mg/mL (2%w/v) cis (Z)-flupentixol decanoate in thin vegetable oil. Pack size = 1 vial per box.

Depixol Conc Injection:

Ampoules containing 0.5 mL and 1 mL of 100 mg/ml (10% w/v) cis(Z)-flupentixol decanoate in thin vegetable oil. Pack size = 10 ampoules per box.

Vial containing 5 mL of 100 mg/ml (10%) cis(Z)- flupentixol decanoate in thin vegetable oil. Pack size = 1 vial per box.

6.6 Special Precautions For Disposal And Other Handling

Nil.

7. Marketing Authorisation Holder

Lundbeck Ltd

Lundbeck House

Caldecotte Lake Business Park

Milton Keynes

Buckinghamshire

MK7 8LF

United Kingdom

8. Marketing Authorisation Number(S)

Depxiol Injection - PL 0458/0007R

Depixol Conc Injection - PL 00458/0015R

9. Date Of First Authorisation/Renewal Of The Authorisation

28 January 1987 / 17 March 2002

10. Date Of Revision Of The Text

02/012/2010



1. Name Of The Medicinal Product

Diprobase Cream

2. Qualitative And Quantitative Composition

No pharmacologically active components.

3. Pharmaceutical Form

Cream

4. Clinical Particulars 4.1 Therapeutic Indications

Diprobase Cream is an emollient, moisturising and protective cream for the follow-up treatment with topical steroids or in spacing such treatment. It may also be used as diluent for topical steroids. Diprobase Cream is recommended for the symptomatic treatment of red inflamed, damaged, dry or chapped skin, the protection of raw skin areas and as a pre-bathing emollient for dry/eczematous skin to alleviate drying areas.

4.2 Posology And Method Of Administration

Adults and Children:

The cream should be applied to the dry skin areas as often as is required and rubbed well into the skin.

4.3 Contraindications

There are no absolute contraindications to the use of the cream other than hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

None stated.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None stated.

4.6 Pregnancy And Lactation

None stated.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Skin reactions including pruritus, rash, erythema, skin exfoliation, burning sensation, hypersensitivity, pain, dry skin and bullous dermatitis have been reported with product use.

4.9 Overdose

None stated.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Diprobase Cream contains no active ingredients and has no pharmacological action. The ingredients provide emollient, moisturising action on dry or chapped skin.

5.2 Pharmacokinetic Properties

Not applicable due to topical administration and direct action on the skin.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Chlorocresol

Macrogol Cetostearyl Ether (Cetomacrogol)

Cetostearyl alcohol

Liquid paraffin

White soft paraffin

Phosphoric acid

Sodium dihydrogen phosphate

Sodium hydroxide

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

15, 50 and 100gm aluminium tubes - 60 months

500gm pump presentations – 36 months

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

50, 100 and 15gm aluminium epoxy lined membrane tubes with plastic caps.

500gm polypropylene piston pack with polyethylene cap and daplen pump, disc and tube or PVC cap, polypropylene pump, polyolefin disc and HDPE tube or

500gm polypropylene jar (container) with a polypropylene dispenser head and cover, the pump system consists of a polyethylene follower plate, a polypropylene pump cylinder, a polyethylene piston with a glass and a polypropylene valve.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU, UK

8. Marketing Authorisation Number(S)

PL 00025/0575

9. Date Of First Authorisation/Renewal Of The Authorisation

12 April 1996 / 12 April 2001

10. Date Of Revision Of The Text

21 March 2011

11 LEGAL CATEGORY

GSL

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

DipCrm/UK/03-11/7



Dispersible Aspirin Tablets 75mg

Please read this leaflet carefully before you start to take your medicine. It gives you important information about your medicine. If you want to know more, or you are not sure about anything, ask your pharmacist or doctor. Keep the leaflet until you have finished the medicine. What’S In Your Medicine

Dispersible Aspirin Tablets are white, uncoated tablets which contain 75mg of the active ingredient Aspirin.

The tablets also contain: citric acid, lactose, maize starch, saccharin sodium, calcium carbonate (E170).

Dispersible Aspirin Tablets are available in a pack size of 28.

Dispersible Aspirin Tablets is one of a group of medicines which have analgesic (pain relief ), anti-inflammatory (reduce swelling) and antipyretic (reduce temperature) properties. Aspirin also acts on the blood helping to prevent the formation of blood clots.

MA holder/Manufacturer: Actavis Barnstaple EX32 8NS UK About Your Medicine

The name of your medicine is Dispersible Aspirin Tablets which is the generic (common) name. Your doctor may have given you this medicine before from another company or you may have purchased it and it may have looked slightly different. Either brand will have the same effect.

Dispersible Aspirin may be used to help prevent heart attacks and stroke in patients who have previously suffered such events, in patients who have unstable angina and following by-pass surgery.

Before Taking Your Medicine

There is a possible association between aspirin and Reye’s syndrome when given to children. Reye’s syndrome is a very rare disease, which can be fatal. For this reason aspirin should not be given to children aged under 16 years, unless on the advice of a doctor.

Make sure you talk to your doctor before you start long-term treatment with aspirin. Also tell your doctor if you:

are pregnant, plan to become pregnant or are breast feeding. Aspirin should be avoided in the last three months of pregnancy and during breast feeding. are sensitive to aspirin, other ingredients in the product, salicylates or non-steroidal anti-inflammatory drugs (NSAIDs). You may have developed difficulty breathing, a runny nose, itchy skin or swelling after taking aspirin or a NSAID previously. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product, as it contains lactose. have a stomach ulcer or a history of stomach ulcers or indigestion. have haemophilia or other blood clotting disorder. are anaemic or suffer from a deficiency of the enzyme glucose-6-phosphate dehydrogenase, this can cause episodes of anaemia after eating certain foods such as fava beans (favism). have asthma, or suffer from allergies. have nasal polyps. have heart, liver or kidney problems. have an overactive thyroid gland. have gout. are dehydrated. have systemic lupus erythematosus (SLE) or other connective tissue disease. are taking other medicines such as anticoagulants (medicines to stop blood clotting eg warfarin and heparin), water tablets (diuretics eg spironolactone, frusemide, acetazolamide), medicines which make your urine more alkaline (eg antacids, citrates), medicines to treat gout (eg probenecid, sulphinpyrazone), methotrexate, antidiabetics, corticosteroids, metoclopramide, domperidone, mifepristone, dipyridamole, anti-epileptic medicines (eg phenytoin, sodium valproate), other non-steroidal anti-inflammatory medicines - NSAIDs (eg ibuprofen or naproxen), medicines which can cause hearing problems (eg vancomycin) and any that you may have bought without a prescription. alcohol may increase the risk of side effects. Avoid alcohol whilst taking aspirin.

If you need to have an operation including having teeth removed tell your doctor or dentist that you are taking aspirin. Aspirin may interfere with some laboratory tests such as urine tests.

Taking Your Medicine

The usual dosage(s) are described below:

Your doctor’s advice should be sought before starting long-term aspirin treatment.

Adults: The usual dose for long-term use is 1-2 tablets (75-150mg) once daily. In some circumstances a higher dose may be appropriate, especially in the short-term, and up to 4 tablets (300mg) a day may be used on the advice of a doctor.

Children: Not recommended.

These tablets should be dissolved or mixed with water before taking with or after food. Swallow the tablets immediately after dispersing them in water. If symptoms persist you should consult your doctor.

If you forget to take a dose, take another as soon as you remember and then your next dose at the usual time. NEVER take two doses at the same time.

If you take more tablets than recommended above, contact your nearest hospital casualty department, or tell your doctor, immediately. Take any remaining tablets and the container with you.

After Taking Your Medicine

Like many medicines, Dispersible Aspirin may occasionally cause side-effects in some patients, particularly when you first start taking it. Effects may include:

Allergic Reactions - runny nose, itchy skin, swelling and worsening of asthma.

Effects on the gastrointestinal system - stomach ulcers or bleeding which can be severe (you may develop bloody or black tarry stools, severe stomach pain and vomit blood), stomach irritation (mild stomach pain, heartburn and feeling sick) and inflammation of the liver.

Effects on the blood - anaemia, changes in numbers and types of blood cells. If you have an increase in number of nose bleeds or notice that you bruise more easily or have more infections talk to your doctor.

Effects on the ear - ringing or buzzing in the ear.

Salicylism - if you take large doses for a long time you may develop symptoms of salicylism, these include: dizziness, ringing or buzzing in the ear, deafness, sweating, feeling or being sick, headache and confusion.

If you are concerned about any side-effects or have any other unusual effects, tell your doctor immediately and seek advice.

Storing Your Medicine

Do not use the tablets after the expiry date shown on the product packaging. Keep the tablets stored below 25°C in a dry place and in the original packaging. KEEP THEM IN A SECURE PLACE WHERE CHILDREN CANNOT GET AT OR SEE THEM. REMEMBER, this medicine is for YOU only. NEVER give it to anyone else. It may harm them, even if their symptoms are the same as yours.

Give any medicines you no longer need to your pharmacist for safe disposal.

Date of last revision: March 2007.

Actavis Barnstaple EX32 8NS UK

50106989



DOXAZOSIN 1 MG TABLETS

DOXAZOSIN 2 MG TABLETS

DOXAZOSIN 4 MG TABLETS

(as mesilate)

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 further questions, please ask your doctor or your pharmacist. This medicine has been prescribed for you personally and you should not pass it onto others. It may harm them, even if their symptoms are the same as yours. In this leaflet: 1. What DOXAZOSIN is and what it is used for 2. Before you take DOXAZOSIN 3. How to take DOXAZOSIN 4. Possible side effects 5. Storing DOXAZOSIN 6. Further information

The name of your medicine is DOXAZOSIN 1 mg Tablets, DOXAZOSIN 2 mg Tablets, DOXAZOSIN 4 mg Tablets (referred to as DOXAZOSIN throughout this leaflet).

What Doxazosin Is And What It Is Used For

Doxazosin is one of a group of medicines called alpha-blockers.

DOXAZOSIN tablets are used to treat high blood pressure (hypertension) or the symptoms caused by enlargement of the prostate gland in men.

In patients taking DOXAZOSIN to treat high blood pressure (hypertension) DOXAZOSIN works by relaxing blood vessels so that blood passes through them more easily. This helps to lower blood pressure.

In patients with enlargement of the prostate gland, DOXAZOSIN is taken to treat frequent and/or poor passing of urine. This is common in patients with enlargement of the prostate gland. DOXAZOSIN works by relaxing muscle around the bladder exit and prostate gland so urine is passed more easily.

Before You Take Doxazosin Do not take DOXAZOSIN if you: have ever had an allergic reaction (hypersensitivity) to doxazosin or any of the other ingredients of DOXAZOSIN tablets.

This may have been itching, reddening of the skin or difficulty in breathing.

are breastfeeding. are aged under 16 years of age Take special care with DOXAZOSIN: If you have liver disease tell your doctor before you start taking your tablets. If you are pregnant or trying to become pregnant tell your doctor before you start taking your tablets.

If you are undergoing eye surgery because of cataract (cloudiness of the lens) please inform your eye specialist before the operation that you are using or have previously used DOXAZOSIN. This is because DOXAZOSIN may cause complications during the surgery which can be managed if your specialist is prepared in advance.

When you start to take DOXAZOSIN you may experience faintness or dizziness caused by low blood pressure, when getting up from sitting or lying down. If you feel faint or dizzy, you should sit or lie down until you feel better and avoid situations where you might fall or hurt yourself.

Taking other medicines:

Some patients who take alpha-blocker therapy for the treatment of high blood pressure or prostate enlargement may experience dizziness or light headedness, which may be caused by low blood pressure upon sitting or standing up quickly. Certain patients have experienced these symptoms when taking drugs for erectile dysfunction (impotence) with alpha-blockers. In order to reduce the likelihood that these symptoms occur, you should be on a regular daily dose of your alpha-blocker before you start drugs for erectile dysfunction.

Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not prescribed.

Driving and using machines:

Take care if you drive or operate machinery. Your tablets may affect your ability to drive or operate machinery safely, particularly when you first start to take them. They may make you feel weak or dizzy. If affected, do not drive or operate machinery and contact your doctor immediately.

Important information about some of the ingredients of DOXAZOSIN:

This medicine contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

How To Take Doxazosin Adults and Elderly:

Always take DOXAZOSIN exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are unsure.

DOXAZOSIN is usually taken once daily. DOXAZOSIN may be taken in the morning or the evening.

You can take your tablets before or after food.

You should take your tablets at the same time each day with a small amount of water.

The initial dose of DOXAZOSIN is 1mg once daily. Thereafter the dose may be gradually increased (within 1-2 weeks interval) to the usual dose (2mg or 4mg daily).

In some circumstances the dose may be increased to a maximum of 8mg daily if you are being treated for prostate enlargement, or to a maximum of 16mg if you are being treated for high blood pressure.

Children:

This medicine is not recommended for children.

You have been given a calendar pack that will help you remember to take your tablets. If you are taking more than one tablet a day, you must ignore the marking for the day, printed on the back of the blister.

Because high blood pressure is treated in order to prevent problems from arising, you may have no symptoms at all while taking DOXAZOSIN. Even if this is so and you feel well, you should not stop taking your blood pressure medication unless instructed to by your doctor.

Don't change the dose or stop taking the tablets without first checking with your doctor.

Don't wait until your tablets are finished before seeing your doctor.

If you have impression that the effect of DOXAZOSIN is too strong or too weak, talk to your doctor or pharmacist.

If you forget to take DOXAZOSIN:

If you miss a dose just carry on with the next one as normal. Do not take a double dose to make up for the missed one.

If you take more DOXAZOSIN than you should:

Too many tablets at once may make you unwell. If several tablets are taken it may be dangerous.

Tell your doctor immediately or go to your nearest hospital casualty department.

Possible Side Effects

Like all medicines, DOXAZOSIN can have side effects but not everybody gets them.

Most undesirable effects are usually mild and tend to wear off as treatment goes on. It is important to tell your doctor if any unwanted effect causes you concern, including those which may not be listed below.

Problems DOXAZOSIN may cause are:

allergic reaction, with symptoms such as skin rash, itching, which may be accompanied by shortness of breath, difficulty breathing, swelling of the face, tongue and throat. If any of these symptoms occur, STOP taking DOXAZOSIN and seek medical attention immediately. The following events have been reported in patients with high blood pressure being treated with doxazosin, but these may be due to the underlying disease rather than the medicine: chest pain, angina, a feeling of increased, decreased or irregular heart beat, palpitations, heart attack or stroke. Contact your doctor immediately if any of these occur. low white blood cells (which may result in increasing frequency of infection, sore throat, mouth ulcer, high temperature or stomach upset); low blood platelets [which may result in bruising or bleeding easily, nose bleeds (epistaxis)].

If any of these occur contact your doctor.

Other side effects

generally feeling unwell, weakness, tirednesssleepiness, swelling of feet or lower legs (oedema), weight gain

headache , dizziness or faintness, especially on getting up from a sitting or lying position, tremor, tingling or altered sensitivity of the hands and feet vertigo, ringing in the ears (tinnitus) digestive system complaints, including stomach/abdominal pains, constipation, diarrhoea, feeling/being sick, heartburn and wind, dry mouth nasal stuffiness, runny nose and/or sneezing (rhinitis), wheeze, cough painful persistent erection of the penis, erection difficulties (when a man cannot get, or keep a hard, erect penis suitable for sexual activity), discomfort or enlargement of the breasts in men (gynaecomastia), cloudy urine following sexual climax, little or no semen ejaculated at sexual climax painful joints, painful muscles, muscle cramps, muscle weakness, back pain or general pain low blood pressure, hot flushes agitation, anxiety, depression or nervousness, sleeplessness hair loss loss of appetite liver enzyme increases, jaundice (yellowing of the skin or whites of the eyes), hepatitis or bile disorder blurred vision urinary incontinence, urinary disorder or blood in urine

If any of the side - effects become serious, or you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist.

Storing Doxazosin

There are no special precautions for storage. Keep out of the reach and sight of children.

Check the expiry date on the label. Do not use the tablets if the expiry date has passed.

Further Information What DOXAZOSIN contains

The active substance is: doxazosin. Each tablet contains 1mg, 2mg, or 4mg of doxazosin (as mesilate).

The other ingredients are: Lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulphate, sodium starch glycolate (type A) and colloidal anhydrous silica.

What DOXAZOSIN looks like and contents of the pack

DOXAZOSIN comes in three different strengths:

Doxazosin 1 mg tablet is a round white to off-white tablet scored on one side.

Doxazosin 2 mg tablet is a white to off-white capsule shaped tablet scored on one side.

Doxazosin 4 mg tablet is a white to off-white capsule shaped tablet, scored on both sides, with embossement "D4" on one side.

Doxazosin 1 mg, 2 mg and 4 mg tablets are available in calendar packs of 28 tablets in foil blister strips.

The manufacturer / holder of the marketing authorization is: Dexcel-Pharma Ltd. 1 Cottesbrooke Park Heartlands Business Park Daventry Northamptonshire NN11 8YL England

This leaflet was last approved in October 2009.

1217420114-E



1. Name Of The Medicinal Product

Daktarin Aktiv Cream

2. Qualitative And Quantitative Composition

Miconazole nitrate 2.0% w/w

(Each gram of cream contains 20mg of miconazole nitrate)

For excipients, see Section 6.1

3. Pharmaceutical Form

Cream

White homogeneous cream

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of athlete's foot.

4.2 Posology And Method Of Administration

For all ages.

Apply the cream twice daily to the lesions. Treatment should be prolonged for 10 days after all lesions have disappeared to prevent relapse.

Method of administration: Cutaneous application.

4.3 Contraindications

Daktarin Aktiv Cream is contraindicated in individuals with a known hypersensitivity to miconazole or another ingredient in this product.

4.4 Special Warnings And Precautions For Use

Daktarin Aktiv Cream must not come into contact with the eyes.

If a reaction suggesting sensitivity or irritation should occur, the treatment should be discontinued.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Miconazole administered systemically is known to inhibit CYP3A4/2C9. Due to the limited systemic availability after topical application, clinically relevant interactions are rare. However, in patients on oral anticoagulants, such as warfarin, caution should be exercised and anticoagulant effect should be monitored.

4.6 Pregnancy And Lactation

Pregnancy

In animals, miconazole nitrate has shown no teratogenic effects but is foetotoxic at high oral doses. Only small amounts of miconazole nitrate are absorbed following topical administration. However, as with other imidazoles, miconazole nitrate should be used with caution during pregnancy.

Lactation

Topically applied miconazole is minimally absorbed into the systemic circulation, and it is not known whether miconazole is excreted in human breast milk. Caution should be exercised when using topically applied miconazole products during lactation.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience with Daktarin that meet threshold criteria are included. The adverse drug reactions are ranked by frequency, using the following convention:

Very common > 1/10

Common > 1/100 and < 1/10

Uncommon > 1/1,000 and < 1/100

Rare > 1/10,000, < 1/1,000

Very rare < 1/10,000, including isolated reports

The frequencies provided below reflect reporting rates for adverse drug reactions from spontaneous reports, and do not represent more precise estimates of incidence that might be obtained in clinical or epidemiological studies.

Immune system disorders

Very rare: anaphylactic reaction, hypersensitivity, angioneurotic edema.

Skin and subcutaneous tissue disorders

Very rare: urticaria, contact dermatitis, rash, erythema, pruritus, skin burning sensation.

General disorders and administration site conditions

Rare: application site reactions, including application site irritation.

4.9 Overdose

Symptoms

Cutaneous use: Excessive use can result in skin irritation, which usually disappears after discontinuation of therapy.

Treatment

Daktarin Aktiv Cream is intended for cutaneous use, not for oral use. If accidental ingestion of large quantities of the product occurs, an appropriate method of gastric emptying may be used if considered necessary.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic classification: (Antifungals for dermatological/topical use; imidazole derivative) ATC code: D01A C02.

Miconazole is an imidazole antifungal agent and may act by interfering with the permeability of the fungal cell membrane. It possesses a wide antifungal spectrum and has some antibacterial activity.

5.2 Pharmacokinetic Properties

Absorption: There is little absorption through skin or mucous membranes when miconazole nitrate is applied topically.

Distribution: Absorbed miconazole is bound to plasma proteins (88.2%) and red blood cells (10.6%).

Metabolism and Excretion: The small amount of miconazole that is absorbed is eliminated predominantly in faeces as both unchanged drug and metabolites.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of local irritation, single and repeated dose toxicity, genotoxicity, and toxicity to reproduction.

6. Pharmaceutical Particulars 6.1 List Of Excipients

PEG-6, PEG 32 and glycol stearate

Oleoyl macroglycerides

Liquid paraffin

Benzoic acid (E210)

Butylated hydroxyanisole (E320)

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Aluminium tube lined with epoxyphenol resin. Cap made of white polypropylene for the 15, 30 and 70g sizes. Cap for 5g size made of high density polyethylene.

Daktarin Aktiv Cream may be supplied in packs of 5, 15, 30 and 70g.

*Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire

SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0304

9. Date Of First Authorisation/Renewal Of The Authorisation

01 July 2008

10. Date Of Revision Of The Text

10 July 2008



A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

Anticonvulsants are drugs that prevent or reduce the severity and frequency of seizures in various types of epilepsy. The different types of anticonvulsants may act on different receptors in the brain and have different modes of action.

Two mechanisms that appear to be important in anticonvulsants are enhancement of GABA action and inhibition of sodium channel activity. Other mechanisms are inhibition of calcium channels and glutamate receptors.

See also

Medical conditions associated with dibenzazepine anticonvulsants:

Anxiety Bipolar Disorder Diabetic Nerve Damage Dystonia Epilepsy Lennox-Gastaut Syndrome Peripheral Neuropathy Reflex Sympathetic Dystrophy Syndrome Schizoaffective Disorder Seizures Trigeminal Neuralgia Vulvodynia Drug List: Banzel Tegretol-Xr-Sustained-Release-Tablets Carbatrol-Sustained-Release-Capsules Epitol Trileptal Tegretol Equetro



1. Name Of The Medicinal Product

Drapolene Cream

2. Qualitative And Quantitative Composition

Drapolene contains:

Benzalkonium chloride solution 0.02% w/w

Equivalent to benzalkonium chloride 0.01% w/w

Cetrimide 0.2% w/w

3. Pharmaceutical Form

Cream for topical application.

4. Clinical Particulars 4.1 Therapeutic Indications

Drapolene is indicated for the relief of nappy rash and for use as an adjunct to baby care hygiene for the prevention of nappy rash.

Drapolene is indicated for the relief of urinary dermatitis in adults, and as an adjunct to patient care hygiene for the prevention of urinary dermatitis.

Drapolene is indicated for the symptomatic relief of minor burns, limited sunburn and the effects of weather.

4.2 Posology And Method Of Administration

Route of administration:

Topical

Dosage:

Babies: The nappy area should be washed then dried thoroughly at each change of nappy. Drapolene Cream should be applied, paying particular attention to folds in the skin.

Adults: The affected area (or the area of application) should be washed and dried thoroughly before applying Drapolene. Regular routine application is advised.

Drapolene should be applied as required for minor burns, limited sunburn and the effects of weather.

Use in the Elderly

No special comment

4.3 Contraindications

It is inadvisable to apply Drapolene Cream to a baby or adult who has an established hypersensitivity to benzalkonium chloride, cetrimide or lanolin. Use should be discontinued if an allergic hypersensitivity reaction is suspected.

4.4 Special Warnings And Precautions For Use

The packs carry the following additional warnings:

Store below 25°C

For external use only

Keep out of the reach of children

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

When used in accordance with the specified indications, systemic absorption of the specified components is not envisaged and so there are no special precautions/warnings appropriate to pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

Allergic hypersensitivity reactions may occur in individuals who are sensitive to one or several components of Drapolene Cream.

Hypersensitivity to lanolin is recognised but is rare.

In a few individuals, benzalkonium chloride, used as a preservative in ophthalmic solutions, was associated with oedema and conjunctivitis. Dermatitis as a result of contact allergy to benzalkonium chloride in plaster of Paris has also been reported.

Hypersensitivity to cetrimide is also known to occur, presenting as a localised contact dermatitis. In severe cases the rash may be generalised.

4.9 Overdose

There are no reports of adverse events resulting from excessive application or accidental ingestion of Drapolene Cream.

In cases of accidental ingestion, symptomatic treatment is appropriate.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Benzalkonium chloride and cetrimide are both quaternary ammonium disinfectants with properties typical of cationic surfactants. This preparation is useful in the treatment of and prevention of nappy rash, acting to suppress the development of ammonia producing organisms usually associated with this condition.

5.2 Pharmacokinetic Properties

No data is available on the pharmacokinetics of the active ingredients of Drapolene Cream, when used for the specified indications. Systemic absorption of the active ingredients is not envisaged.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars 6.1 List Of Excipients

White soft paraffin

Wool fat (purified lanolin)

Cetyl alcohol

Polawax

Chlorocresol

Amaranth

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

Tube - 36 months unopened.

Other packs - 36 months unopened.

6.4 Special Precautions For Storage

Store below 25° C.

6.5 Nature And Contents Of Container

25, 75, 150, 200 or 300 g - white pigmented polypropylene containers with white-pigmented LDPE snap-fit caps or white-pigmented polypropylene containers with white pigmented LDPE/HDPE snap-fit caps.

500 g polypropylene pots with PVDC faced wad and polypropylene screw caps.

100 g polyolefin/foil/polyolefin laminate tubes with polypropylene caps.

6.6 Special Precautions For Disposal And Other Handling

None applicable.

7. Marketing Authorisation Holder

Chefaro UK Ltd.

4th Floor,Hamilton House

Mabledon Place,Bloomsbury

LONDON,WC1H 9BB

United Kingdom

8. Marketing Authorisation Number(S)

PL 02855/0016

9. Date Of First Authorisation/Renewal Of The Authorisation

17th January 2005

10. Date Of Revision Of The Text

14th November 2010



1. Name Of The Medicinal Product

Didronel 200mg Tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 200mg of Etidronate Disodium, USP.

3. Pharmaceutical Form

White rectangular tablets marked with 'P&G' on one face and '402' on the other.

4. Clinical Particulars 4.1 Therapeutic Indications

Paget's disease of bone:

Effectiveness has been demonstrated primarily in patients with polyostotic Paget's disease with symptoms of pain and with clinically significant elevations of urinary hydroxyproline and serum alkaline phosphatase. In other circumstances in which there is extensive involvement of the skull or the spine with the prospect of irreversible neurological damage, or when a weight-bearing bone may be involved, the use of Didronel may also be considered.

4.2 Posology And Method Of Administration

5mg/kg/day to 20mg/kg/day as detailed below.

Didronel should be given on an empty stomach. It is recommended that patients take the therapy with water, at the mid point of a four hour fast (ie. two hours before and two after food).

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of risedronate on an individual patient basis, particularly after 5 or more years of use.

Adults and Elderly:

The recommended initial dose of Didronel for most patients is 5mg/kg body weight/day, for a period not exceeding six months. Doses above 10mg/kg should be reserved for use when there is an overriding requirement for suppression of increased bone turnover associated with Paget's disease or when the patient requires more prompt reduction of elevated cardiac output. Treatment with doses above 10mg/kg/day should be approached cautiously and should not exceed three months duration. Doses in excess of 20mg/kg/day are not recommended.

Re-treatment should be undertaken only after a drug-free period of at least three months and after it is evident that reactivation of the disease has occurred and biochemical indices of the disease have become substantially re-elevated or approach pretreatment values (approximately twice the upper limit of normal or 75% of pre-treatment value). In no case should duration of treatment exceed the maximum duration of the initial treatment. Premature re-treatment should be avoided. In clinical trials the biochemical improvements obtained during drug therapy have generally persisted for a period of three months to 2 years after drug withdrawal.

Daily Dosage Guide

Body Weight

Required Daily Regimen of 200mg Tablets

     

Kilogrames

Stones

5mg/kg*

10mg/kg*

20mg/kg+

50

8

1

3

5

60

9.5

2

3

6

70

11

2

4

7

80

12.5

2

4

8

90

14

2

5

9

*Course of therapy - 6 months

+Course of therapy - 3 months

Children:

Disorders of bone in children, referred to as juvenile Paget's disease, have been reported rarely. The relationship to adult Paget's disease has not been established. Didronel has not been studied in children for Paget's disease.

4.3 Contraindications

Known hypersensitivity to etidronate disodium or any of the other ingredients in the product (see Section 6.1 List of Excipients). Clinically overt osteomalacia.

4.4 Special Warnings And Precautions For Use

In Pagetic patients the physician should adhere to the recommended dose regimen in order to avoid over- treatment with Didronel. The response to therapy may be of slow onset and may continue even for months after treatment with the drug has been discontinued. Dosage should not be increased prematurely nor should treatment be resumed before there is clear evidence of reactivation of the disease process. Re-treatment should not be initiated until the patient has had at least a three-month drug-free interval.

Etidronate disodium is not metabolized and is excreted intact via the kidney. Due to the lack of clinical experience the treatment of patients with impaired renal function should be undertaken with due caution. The use of etidronate disodium is discouraged in patients with severely impaired kidney function.

Caution should be taken in patients with a history of renal stone formation. In patients with impaired renal function or a history of renal stone formation, serum and urinary calcium should be monitored regularly.

It is recommended that serum phosphate, serum alkaline phosphatase and urinary hydroxyproline be measured before commencing medication and at three month intervals during treatment. If after three months of medication the pre-treatment levels have not been reduced by at least 25%, the patient may be relatively resistant to therapy. If the serum phosphate level is unchanged in the "resistant" patient, consideration should be given to increasing the dose since the absorption of pharmacologically active amounts of Didronel is typically accompanied by a rise in serum phosphate. This rise usually correlates with reductions in the biochemical indices of disease activity. If after three or more months of medication elevations of serum phosphate above the upper limit of normal are not accompanied by clinical or biochemical evidence of reduced activity, resistance of the disease to the action of Didronel is probable and termination of Didronel medication should be considered. Etidronate disodium suppresses bone turnover and may retard mineralisation of osteoid laid down during the bone accretion process. These effects are dose and time dependent. Osteoid, which may accumulate noticeably at doses of 10-20 mg/kg/day, mineralises normally post-therapy. Patients in whom serum phosphate elevations are high and reductions of disease activity are low may be particularly prone to retarded mineralisation of new osteoid. In those cases where 200mg per day (a single tablet) may be excessive, doses may be administered less frequently.

Patients with Paget's disease of bone should maintain an adequate intake of calcium and vitamin D. Patients with low vitamin D and calcium intake may be particularly sensitive to drugs that affect calcium homeostasis and should be closely monitored during Didronel therapy.

Etidronate disodium does not adversely affect serum levels of parathyroid hormone or calcium.

Hyperphosphataemia has been observed in patients receiving etidronate disodium, usually in association with doses of 10-20mg/kg/day. No adverse effects have been traced to this, and it does not constitute grounds for discontinuing therapy. It is apparently due to a drug-related increase in renal tubular reabsorption of phosphate. Serum phosphate levels generally return to normal 2-4 weeks post therapy.

Patients with significant chronic diarrhoeal disease may experience increased frequency of bowel movements and diarrhoea, particularly at higher doses.

Increased or recurrent bone pain at existing Pagetic sites and/or the appearance of pain at sites previously asymptomatic have been reported at a dose of 5mg/kg/day.At higher doses, the incidence rises to approximately 20%. When therapy continues, pain resolves in some patients but persists in others.

Fractures are recognised as a common feature in patients with Paget's disease. There has been no evidence of increased risk of fractures at the recommended dose of 5mg/kg/day for six months. At doses of 20mg/kg/day in excess of three months' duration, mineralisation of newly formed osteoid may be impaired and the risk of fracture may be increased. The risk of fracture may also be greater in patients with extensive and severe disease, a history of multiple fractures, and/or rapidly advancing osteolytic lesions. It is therefore recommended that the drug is discontinued when fractures occur and therapy not reinstated until the fracture healing is complete.

Patients with predominantly lytic lesions should be monitored radiographically and biochemically to permit termination of etidronate disodium in those patients unresponsive to treatment.The incidence of osteogenic sarcoma is known to be increased in Paget's disease. Pagetic lesions, with or without therapy, may appear by X-ray to progress markedly, possibly with some loss of definition of periosteal margins. Such lesions should be evaluated carefully to differentiate these from osteogenic sarcoma.

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 bisphosphonates.

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

While on treatment, these patients should avod 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 risk of osteonecrosis of the jaw.

Clinical judgement 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

Food in the stomach or upper portions of the small intestine, particularly materials with a high calcium content such as milk, may reduce absorption of etidronate disodium. Vitamins with mineral supplements such as iron, calcium supplements, laxatives containing magnesium, or antacids containing calcium or aluminium should not be taken within two hours of dosing etidronate disodium.

The diagnostic utility of bone-imaging agents may be impaired by current or recent etidronate use.

There have been isolated reports of patients experiencing changes in their prothrombin times when etidronate was added to warfarin therapy. The majority of these reports concerned variable elevations in prothrombin times without clinically significant sequelae. Although the relevance of these reports and any mechanism of coagulation alterations is unclear, patients on warfarin should have their prothrombin time monitored.

4.6 Pregnancy And Lactation

The safety of this medicinal product for use in human pregnancy has not been established. Reproductive studies have shown skeletal abnormalities in rats. It is therefore recommended that Didronel should not be used in women of childbearing potential unless adequate contraceptive measures are taken.

It is not known whether this drug passes into breast milk. It should therefore not be used during lactation period.

4.7 Effects On Ability To Drive And Use Machines

Etidronate disodium does not interfere with the ability to drive or use machines.

4.8 Undesirable Effects

Gastro-intestinal

The most common effects reported are diarrhoea and nausea. Reports of exacerbation of peptic ulcer with complications in a few patients.

Dermatological/hypersensitivity

Hypersensitivity reactions, including angio-oedema/urticaria, rash and/or pruritus, have been reported rarely.

Nervous System

Paresthesia, peripheral neuropathy , confusion, have been reported rarely.

Haematological

In patients receiving etidronate disodium, there have been rare reports of leucopenia, agranulocytosis and pancytopenia.

Musculoskeletal and connective tissue disorders

osteonecrosis of the jaw (see section 4.4 special warnings and precautions of use)

Other

Less common effects believed to be related to therapy include arthropathies (arthralgia and arthritis), and rarely burning of the tongue, alopecia, erythema multiforme and exacerbation of asthma.

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

Overdose would manifest as the signs and symptoms of hypocalcaemia. Treatment should involve cessation of therapy and correction of hypocalcaemia with administration of Ca2+ intravenously.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Etidronate acts primarily on bone. It can inhibit the formation, growth and dissolution of hydroxyapatite crystals and amorphous precursors by chemisorption to calcium phosphate surfaces. Inhibition of crystal resorption occurs at lower doses than are required for the inhibition of crystal growth. Both effects increase as dose increases.

5.2 Pharmacokinetic Properties

Etidronate is not metabolised. Absorption averages about 1% of an oral dose of 5mg/kg body weight/day. This increases to about 1.5% at 10mg/kg/day and 6% at 20mg/kg/day. Most of the drug is cleared from the blood within 6 hours. Within 24 hours about half of the absorbed dose is excreted in the urine. The remainder is chemically absorbed to bone, especially to areas of elevated osteogenesis, and is slowly eliminated. Unabsorbed drug is excreted in the faeces.

5.3 Preclinical Safety Data

In long term studies in mice and rats, there was no evidence of carcinogenicity with etidronate disodium. All in vitro and in vivo assays conducted to assess the mutagenic potential of etidronate disodium have been negative.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Starch, magnesium stearate and microcrystalline cellulose.

6.2 Incompatibilities

See section 4.5 Interactions with other medicaments and other forms of interaction.

6.3 Shelf Life

Four years.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Supplied in high density polypropylene bottles or blister packs of 60 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Warner Chilcott UK Limited

Old Belfast Road,

Millbrook,

Larne,

County Antrim,

BT40 2SH

8. Marketing Authorisation Number(S)

PL 10947/0018

9. Date Of First Authorisation/Renewal Of The Authorisation

26th November 1987

10. Date Of Revision Of The Text

September 2011



1. Name Of The Medicinal Product

Daktarin Cream.

2. Qualitative And Quantitative Composition

Miconazole nitrate 2% w/w.

(Each gram of cream contains 20mg of miconazole nitrate)

For excipients, see Section 6.1

3. Pharmaceutical Form

Cream

White homogeneous cream.

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of mycotic infections of the skin and nails and superinfections due to Gram-positive bacteria.

4.2 Posology And Method Of Administration

Route of administration:

Cutaneous use.

Recommended dosage:

For all ages:

Skin infections: Apply the cream twice daily to the lesions. Treatment should be prolonged for 10 days after all lesions have disappeared to prevent relapse.

Nail infections: Apply the cream once or twice daily to the lesions. Treatment should be prolonged for 10 days after all lesions have disappeared to prevent relapse.

4.3 Contraindications

Daktarin Cream is contraindicated in individuals with a known hypersensitivity to miconazole or another ingredient in this product.

4.4 Special Warnings And Precautions For Use

Daktarin Cream must not come into contact with the eyes.

If a reaction suggesting sensitivity or irritation should occur, the treatment should be discontinued.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Miconazole administered systemically is known to inhibit CYP3A4/2C9. Due to the limited systemic availability after topical application, clinically relevant interactions are rare. However, in patients on oral anticoagulants, such as warfarin, caution should be exercised and anticoagulant effect should be monitored.

4.6 Pregnancy And Lactation

Pregnancy

In animals miconazole nitrate has shown no teratogenic effects but is foetotoxic at high oral doses. Only small amounts of miconazole nitrate are absorbed following topical administration. However, as with other imidazoles, miconazole nitrate should be used with caution during pregnancy.

Lactation

Topically applied miconazole is minimally absorbed into the systemic circulation, and it is not known whether miconazole is excreted in human breast milk. Caution should be exercised when using topically applied miconazole products during lactation.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience with Daktarin that meet threshold criteria are included. The adverse drug reactions are ranked by frequency, using the following convention:

Very common

Common

Uncommon

Rare

Very rare <1/10,000, including isolated reports

The frequencies provided below reflect reporting rates for adverse drug reactions from spontaneous reports, and do not represent more precise estimates of incidence that might be obtained in clinical or epidemiological studies.

Immune system disorders

Very rare: anaphylactic reaction, hypersensitivity, angioneurotic edema

Skin and subcutaneous tissue disorders

Very rare: urticaria, contact dermatitis, rash, erythema, pruritus, skin burning sensation

General disorders and administration site conditions

Rare: application site reactions, including application site irritation

4.9 Overdose

Symptoms

Cutaneous use: Excessive use can result in skin irritation, which usually disappears after discontinuation of therapy.

Treatment

Daktarin Cream is intended for cutaneous use, not for oral use. If accidental ingestion of large quantities of the product occurs, an appropriate method of gastric emptying may be used if considered necessary.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic classification: (Antifungals for dermatological/topical use; imidazole derivative) ATC code: D01A C02.

Miconazole nitrate is an imidazole antifungal agent and may act by interfering with the permeability of the fungal cell membrane. It possesses a wide antifungal spectrum and has some antibacterial activity.

5.2 Pharmacokinetic Properties

Absorption: There is little absorption through skin or mucous membranes when miconazole nitrate is applied topically.

Distribution: Absorbed miconazole is bound to plasma proteins (88.2%) and red blood cells (10.6%).

Metabolism and Excretion: The small amount of miconazole that is absorbed is eliminated predominantly in faeces as both unchanged drug and metabolites.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of local irritation, single and repeated dose toxicity, genotoxicity, and toxicity to reproduction.

6. Pharmaceutical Particulars 6.1 List Of Excipients

PEG-6, PEG-32 and glycol stearate

Oleoyl macroglycerides

Liquid paraffin

Benzoic acid (E210)

Butylated hydroxyanisole (E320)

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Aluminium tube inner lined with heat polymerised epoxy-phenol resin with a white polypropylene cap containing 15 g, 30 g or 70 g* of cream, or aluminium tube inner lined with heat polymerised epoxy-phenol resin with a high density polyethylene cap containing 5 g of cream.

*Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Janssen-Cilag Ltd,

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8. Marketing Authorisation Number(S)

PL 00242/0016

9. Date Of First Authorisation/Renewal Of The Authorisation

13 May 1974 / 08 December 2008

10. Date Of Revision Of The Text

08 December 2008



1. Name Of The Medicinal Product

DITHROCREAM™

2. Qualitative And Quantitative Composition

Dithranol 0.1%, 0.25%, 0.5%, 1.0% or 2.0% w/w.

3. Pharmaceutical Form

Yellow aqueous cream.

4. Clinical Particulars 4.1 Therapeutic Indications

For the topical treatment of subacute and chronic psoriasis including psoriasis of the scalp.

4.2 Posology And Method Of Administration

Dithranol therapy customarily involves titrating the concentration applied to skin to suit individual patient's circumstances. Dithrocream is, therefore, available in five strengths. The different packs are colour coded as follows:

0.1%

pale blue

0.25%

red

0.5%

purple

1.0%

brown

2.0%

yellow

For adults and the elderly: It is important to determine each patient's optimal treatment strength, as too high a strength may induce a burning sensation. Where the response to Dithrocream has not previously been established, always commence with Dithrocream 0.1%, continuing for at least one week and then, if necessary, increase to the 0.25% followed by the 0.5%, the 1.0% and finally the 2.0% strength. The aim should be to build up gradually over approximately 4 weeks to the highest tolerated strength to produce the optimum therapeutic effect. This optimum concentration will depend upon such factors as the thickness and location of the psoriatic plaques, as well as the variation between individual patients in their reaction to dithranol.

Dithrocream should be applied sparingly, and only to the affected areas, once every 24 hours, at any convenient time of the day or evening. Rub the cream gently and carefully into the skin until completely absorbed. For use on the scalp, first comb the hair to remove scalar debris and, after suitably parting, rub the cream well into the affected areas. Remove by washing off the skin or scalp, usually no more than one hour after application (Short Contact Therapy). Alternatively, it may be applied at night before retiring and washed off in the morning.

Treatment should be continued until the skin is entirely clear, i.e. when there is nothing to feel with the fingers and the texture is normal. By gradually increasing the strength of cream applied, it should be possible to clear psoriasis patches within 4 to 6 weeks.

For children No additional special precautions necessary. However, use cautiously as described above for adults and the elderly, with regular supervision.

4.3 Contraindications

Not to be used on the face, or for acute or pustular psoriasis.

Not to be used in cases of sensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Dithrocream 0.5%, Dithrocream 1.0% and Dithrocream 2.0% should only be used for those patients who have failed to respond to lower strengths of dithranol. Dithrocream 1.0% and 2.0% should normally only be applied for 'short contact' periods.

Dithrocream 0.5%, Dithrocream 1.0% and Dithrocream 2.0% should always be used under medical supervision.

It is most important to avoid applying an excessive amount of the cream, which may cause unnecessary soiling and staining of the clothing and/or bed linen. After each period of treatment, a bath/shower should be taken to remove any residual cream. To prevent the possibility of discolouration, particularly where Dithrocream 1.0% or 2.0% has been used, always rinse the bath/shower with hot water immediately after washing/showering and then use a suitable cleanser to remove any deposit on the surface of the bath/shower.

After use on the scalp, a shampoo may be used to remove the Dithrocream residue. Great care must be taken when washing out the shampoo (which may contain some Dithrocream residue), to ensure that it does not get into the eyes or on the face. This is particularly important when the higher strengths of Dithrocream have been used.

Although a feeling of warmth at the application site is normal, if this amounts to a burning sensation, or if the lesions spread, treatment should be stopped at once, and the dosage re-evaluated by a doctor.

Dithrocream is not normally recommended for use on areas of folded skin such as the groin and beneath the breasts. Do not use high strengths on these sites.

Keep away from the eyes and mucous membranes.

Always wash the hands after use.

As long term use of topical corticosteroids is known to destabilise psoriasis, and withdrawal may give rise to a rebound phenomenon, an interval of at least one week should be allowed between the discontinuance of such steroids and the commencement of Dithrocream therapy. A suitably bland emollient may usefully be applied in the intervening period.

The excipients, chlorocresol and cetostearyl alcohol may on rare occasions give rise to allergic or local skin reactions (eg. contact dermatitis) in sensitive people.

Contact with fabrics, plastics and other materials may cause permanent staining and should be avoided.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Although there is no experimental evidence to support the safety of the drug in pregnancy or during lactation, no adverse effects have been reported.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Some skin irritation and/or a feeling of warmth at the site of application is normally associated with dithranol therapy. Dithrocream applied at too high a strength or left in contact with the skin for too long may induce a burning sensation.

Dithrocream may cause temporary staining of the skin and/or hair.

4.9 Overdose

Dithranol is a cathartic (laxative) and if accidentally swallowed, it should be removed by gastric lavage.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Dithranol has been used in the treatment of sub-acute and chronic psoriasis for over 70 years and, during that time, it has become established as a safe and effective form of therapy. Its precise mode of action is still to be confirmed, although it has been shown to inhibit DNA replication, cellular respiration and key cellular enzymes eg glucose-6-phosphate dehydrogenase.

Because dithranol causes staining and irritation, it is now widely used in short contact therapy where the preparation is washed off the skin after periods of one hour or less. For this purpose, Dithrocream is particularly suitable, as it is convenient to apply and washes off easily in a bath or shower.

5.2 Pharmacokinetic Properties

The traditional formulations of dithranol are based on soft paraffin from which it is effectively released into the skin. In Dithrocream, during manufacture, the oily paraffin phase of the cream is heated until the dithranol entirely dissolves so that, on cooling, it is retained solely within the paraffin phase and does not spread into the aqueous phase. After application of Dithrocream to the skin, the water is lost through absorption and evaporation, leaving the oily phase which then acts in the same way as a dithranol ointment. However, since the cream may be rubbed into the skin more effectively than the ointment, it is convenient to apply and, owing to the presence of the emulsifying components, is easier to wash off.

The availability of the dithranol has now been confirmed in numerous publications detailing the results of clinical trials.

5.3 Preclinical Safety Data

No special information.

6. Pharmaceutical Particulars 6.1 List Of Excipients

White Soft Paraffin; Cetostearyl Alcohol; Salicylic Acid; Ascorbic Acid; Sodium Laurilsulfate; Chlorocresol; Purified Water.

Dithrocream 2.0% also contains Liquid Paraffin.

6.2 Incompatibilities

None known.

6.3 Shelf Life

48 months.

6.4 Special Precautions For Storage

Do not store above 25°C. Replace cap tightly after use.

6.5 Nature And Contents Of Container

All strengths of Dithrocream are supplied in collapsible tubes containing 50 g. These are supplied as original packs (OP).

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Dermal Laboratories

Tatmore Place, Gosmore

Hitchin, Herts SG4 7QR, UK.

8. Marketing Authorisation Number(S)

Dithrocream 0.1%

00173/0029

Dithrocream 0.25%

00173/0028

Dithrocream 0.5%

00173/0027

Dithrocream 1.0%

00173/0039

Dithrocream 2.0%

00173/0045

9. Date Of First Authorisation/Renewal Of The Authorisation

31 July 2008.

10. Date Of Revision Of The Text

October 2006.



1. Name Of The Medicinal Product

DISIPAL TABLETS

2. Qualitative And Quantitative Composition

Orphenadrine hydrochloride BP 50 mg

3. Pharmaceutical Form

Tablet

4. Clinical Particulars 4.1 Therapeutic Indications

Anti-cholinergic, for the treatment of all forms of Parkinsonism, including drug-induced extrapyramidal symptoms (neuroleptic syndrome).

4.2 Posology And Method Of Administration

For Adults, and the Elderly:

Initially 150 mg daily in divided doses, increasing by 50 mg every two or three days until maximum benefit is obtained. Optimal dosage is usually 250 - 300 mg daily in divided doses in idiopathic and post-encephalitic Parkinsonism, 100 - 300 mg daily in divided doses in the neuroleptic syndrome. Maximal dosage, 400 mg daily in divided doses. The elderly may be more susceptible to side-effects at doses which are clinically optimal.

For children:

A dosage for children has not been established.

4.3 Contraindications

Contraindicated in patients with tardive dyskinesia, glaucoma, or prostatic hypertrophy, untreated urinary retention, gastro-intestinal obstruction, porphyria.

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

4.4 Special Warnings And Precautions For Use

Use with caution in patients with micturition difficulties, in pregnancy and breast feeding, and in the presence of cardiovascular disease and hepatic or renal impairment. Use in caution in the elderly (see 4.2). Avoid abrupt discontinuation of treatment. For some patients, orphenadrine may be a drug of abuse.

Patients with rare hereditary problems of fructose and galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

The colours sunset yellow (E110), tartrazine (E102) and amaranth (E123) may cause allergic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of other antimuscarinic drugs can lead to an increase in side effects such as dry mouth and urine retention.

4.6 Pregnancy And Lactation

No recommendations; if considered necessary, it should be used with caution, see 4.4.

4.7 Effects On Ability To Drive And Use Machines

Patients must be advised to exercise caution while driving or operating machinery or whilst carrying out other skilled tasks.

4.8 Undesirable Effects

System Organ Class

Common

>1/100

<1/10

Uncommon

>1/1000

<1/100

Rare

>1/10,000

<1/1000

Immune system disorder

 

 

Hypersensitivity

 

 

Nervous system disorder

Dizziness

Sedation, confusion, nervousness, hallucinations, convulsions, insomnia, euphoria

Memory disturbances

Eye disorders

Accommodation disorders

 

 

 

 

Cardiac disorders

 

 

Tachycardia

 

 

Gastrointestinal disorders

Dry mouth, gastrointestinal disturbances

 

 

 

 

Renal and urinary disorders

 

 

Urinary retention

 

 

4.9 Overdose

Toxic effects are anti-cholinergic in nature and the treatment is gastric lavage, cholinergics such as carbachol, anticholinesterases such as physostigmine, and general non-specific treatment.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Orphenadrine, which is a congener of diphenhydramine without sharing its soporific effect, is an antimuscarinic agent. It also has weak antihistaminic and local anaesthetic properties.

Orphenadrine is used as the hydrochloride in the symptomatic treatment of Parkinsonism. It is also used to alleviate the extrapyramidal syndrome induced by drugs such as the phenothiazine derivatives, but is of no value in tardive dyskinesia, which may be exacerbated.

5.2 Pharmacokinetic Properties

Orphenadrine is readily absorbed from the gastro-intestinal tract, and very readily absorbed following intramuscular injection. It is rapidly distributed in tissues and most of a dose is metabolised and excreted in the urine along with a small proportion of unchanged drug. A half life of 14 hours has been reported.

5.3 Preclinical Safety Data

No relevant pre-clinical safety data has been generated

6. Pharmaceutical Particulars 6.1 List Of Excipients

Lactose

Sucrose

Acacia

Maize starch

Tribasic calcium phosphate

Stearic acid

Magnesium stearate

Opaseal P-17-0200 (containing IMS, polyvinylacetate phthalate and stearic acid)

Calcium carbonate

Talc

Kaolin

Titanium dioxide

Gelatin

Opalux yellow AS 3026 (containing sucrose, titanium dioxide, tartrazine E102, sunset yellow E110, povidone, amaranth E123 and sodium benzoate E211)

Opaglos 6000 (containing ethanol, shellac, beeswax and yellow carnuba wax)

Black printing ink Opacode black S-1-27794 (containing shellac, IMS, black iron oxide E172, N-butyl alcohol, propylene glycol E1520, isopropyl alcohol)

6.2 Incompatibilities

None

6.3 Shelf Life

Three years

6.4 Special Precautions For Storage

Store at room temperature (15°C - 25°C)

6.5 Nature And Contents Of Container

Amber glass click-lock bottles and/or securitainers and/or plastic lid-seal containers, containing 100, 250, 1,000, or 10,000 tablets.

6.6 Special Precautions For Disposal And Other Handling

None

Administrative Data 7. Marketing Authorisation Holder

Astellas Pharma Ltd

Lovett House

Lovett Road

Staines

TW18 3AZ

United Kingdom

8. Marketing Authorisation Number(S)

PL 0166/5001R

9. Date Of First Authorisation/Renewal Of The Authorisation

6 May 1987; renewed March 2003.

10. Date Of Revision Of The Text

12th June 2009

11. Legal Category

POM



1. Name Of The Medicinal Product

Diocalm Tablets

2. Qualitative And Quantitative Composition

Morphine Hydrochloride 0.395mg

Activated Attapulgite 312.5mg

Attapulgite 187.5mg

For excipients, see 6.1.

3. Pharmaceutical Form

Tablet.

4. Clinical Particulars 4.1 Therapeutic Indications

For the relief of occasional diarrhoea and its associated pain and discomfort.

4.2 Posology And Method Of Administration

Directions for use:

The tablets should be chewed and then followed by a drink of water. As well as using Diocalm, it is important to replace body fluids lost during diarrhoea.

Recommended dose:

Adults and children aged 12 years and over: 2 tablets.

Children aged 6 to under 12 years: 1 tablet.

The recommended dose should be taken every two to four hours as required according to the severity of the symptoms.

Do not take more than six doses in 24 hours.

Not to be given to children under 6 years.

Elderly: as the adult dose.

4.3 Contraindications

Patients with impaired renal function.

Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Labelling:

Warning: Do not exceed the stated dose.

Keep out of reach of children.

If symptoms persist for more than 24 hours, consult your doctor.

As well as taking Diocalm, it is important to replace body fluids lost during diarrhoea.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None.

4.6 Pregnancy And Lactation

There are no known contraindications to the use of the product during pregnancy and lactation, but as with all medicines caution should be exercised.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

None.

4.9 Overdose

Overdosage is considered a theoretical possibility but, in practice, not a significant hazard with the small level of morphine in the product (40 tablets contain 15.8mg of morphine hydrochloride, an analgesic dose). Larger doses would cause nausea, vomiting, constipation, drowsiness and confusion. Convulsions may occur in infants and children. Morphine dependence is not considered to be a likely problem with the low doses of morphine present in the product.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Morphine, combinations, ATC code: A07DA52

Morphine acts by antimotility and antisecretory mechanisms on the gastrointestinal tract and is used in the symptomatic treatment of diarrhoea.

Attapulgite and activated attapulgite are effective gastrointestinal adsorbents.

5.2 Pharmacokinetic Properties

Morphine salts are absorbed from the gastrointestinal tract. Conjugation to morphine 3- and 6-glucoronides occurs in the liver. About 10% of a dose of morphine is excreted through the bile into the faeces and the remainder is excreted in the urine, mainly as conjugates.

Attapulgite and activated attapulgite have a local action in the gastrointestinal tract. They are insoluble and remain unabsorbed.

5.3 Preclinical Safety Data

Preclinical safety data on these active ingredients in the literature have not revealed any pertinent and conclusive findings which are of relevance to the recommended dosage and use of the product.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Icing Sugar

Paregoric Essence

Magnesium Stearate.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Blister strips made of PVC/PVDC coated plastic with aluminium foil backing. Each strip contains 10 tablets. Two or four strips are contained in a boxboard carton.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

SSL International PLC. Venus, 1 Old Park Lane, Trafford Park, Manchester, M41 7HA.

8. Marketing Authorisation Number(S)

PL 17905/0048

9. Date Of First Authorisation/Renewal Of The Authorisation

31/01/06

10. Date Of Revision Of The Text

23/01/07



1. Name Of The Medicinal Product

Dovobet 50 microgram/g + 0.5 mg/g ointment

2. Qualitative And Quantitative Composition

One gram of ointment contains 50 micrograms of calcipotriol (as monohydrate) and 0.5 mg of betamethasone (as dipropionate).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Ointment.

Off-white to yellow.

4. Clinical Particulars 4.1 Therapeutic Indications

Topical treatment of stable plaque psoriasis vulgaris amenable to topical therapy in adults.

4.2 Posology And Method Of Administration

Posology

Dovobet ointment should be applied to the affected area once daily.

The recommended treatment period is 4 weeks. There is experience with repeated courses of Dovobet up to 52 weeks. If it is necessary to continue or restart treatment after 4 weeks, treatment should be continued after medical review and under regular medical supervision.

When using calcipotriol containing medicinal products, the maximum daily dose should not exceed 15 g. The body surface area treated with calcipotriol containing medicinal products should not exceed 30 % (see section 4.4).

Special populations

Renal and hepatic impairment

The safety and efficacy of Dovobet ointment in patients with severe renal insufficiency or severe hepatic disorders have not been evaluated.

Paediatric population

The safety and efficacy of Dovobet ointment in children below 18 years have not been established. No data are available.

Method of administration

Dovobet ointment should be applied to the affected area. In order to achieve optimal effect, it is not recommended to take a shower or bath immediately after application of Dovobet ointment.

4.3 Contraindications

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

Dovobet ointment is contraindicated in erythrodermic, exfoliative and pustular psoriasis.

Due to the content of calcipotriol Dovobet ointment is contra-indicated in patients with known disorders of calcium metabolism.

Due to the content of corticosteroid Dovobet ointment is contraindicated in the following conditions: Viral (e.g. herpes or varicella) lesions of the skin, fungal or bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis or syphilis, perioral dermatitis, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers, wounds, perianal and genital pruritus.

4.4 Special Warnings And Precautions For Use

Effects on endocrine system

Dovobet ointment contains a potent group III steroid and concurrent treatment with other steroids must be avoided. Adverse reactions found in connection with systemic corticosteroid treatment, such as adrenocortical suppression or impact on the metabolic control of diabetes mellitus may occur also during topical corticosteroid treatment due to systemic absorption. Application under occlusive dressings should be avoided since it increases the systemic absorption of corticosteroids. Application on large areas of damaged skin and under occlusive dressings or on mucous membranes or in skin folds should be avoided since it increases the systemic absorption of corticosteroids (see section 4.8).

In a study in patients with both extensive scalp and extensive body psoriasis using a combination of high doses of Dovobet gel (scalp application) and high doses of Dovobet ointment (body application), 5 of 32 patients showed a borderline decrease in cortisol response to adrenocorticotropic hormone (ACTH) challenge after 4 weeks of treatment (see section 5.1).

Effects on calcium metabolism

Due to the content of calcipotriol, hypercalcaemia may occur if the maximum daily dose (15 g) is exceeded. Serum calcium is, however, quickly normalised when treatment is discontinued. The risk of hypercalcaemia is minimal when the recommendations relevant to calcipotriol are followed. Treatment of more than 30 % of the body surface should be avoided (see section 4.2).

Local adverse reactions

Skin of the face and genitals are very sensitive to corticosteroids. The medicinal product should not be used in these areas. The patient must be instructed in correct use of the medicinal product to avoid application and accidental transfer to the face, mouth and eyes. Hands must be washed after each application to avoid accidental transfer to these areas.

Concomitant skin infections

When lesions become secondarily infected, they should be treated with antimicrobiological therapy. However, if infection worsens, treatment with corticosteroids should be stopped.

Discontinuation of treatment

When treating psoriasis with topical corticosteroids there may be a risk of generalised pustular psoriasis or of rebound effects when discontinuing treatment. Medical supervision should therefore continue in the post-treatment period.

Long-term use

With long-term use there is an increased risk of local and systemic corticosteroid adverse reactions. The treatment should be discontinued in case of adverse reactions related to long-term use of corticosteroid (see section 4.8).

Unevaluated uses

There is no experience for the use of Dovobet ointment in guttate psoriasis.

Concurrent treatment and UV exposure

There is no experience for the use of this medicinal product on the scalp. Dovobet ointment for body psoriasis lesions has been used in combination with Dovobet gel for scalp psoriasis lesions, but there is no experience of combination of Dovobet with other topical anti-psoriatic products at the same treatment area, other anti-psoriatic medicinal products administered systemically or with phototherapy.

During Dovobet ointment treatment, physicians are recommended to advise patients to limit or avoid excessive exposure to either natural or artificial sunlight. Topical calcipotriol should be used with UVR only if the physician and patient consider that the potential benefits outweigh the potential risks (see section 5.3).

Dovobet ointment contains butylhydroxytoluene (E321). This may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of Dovobet ointment in pregnant women. Studies in animals with glucocorticoids have shown reproductive toxicity (see section 5.3), but a number of epidemiological studies have not revealed congenital anomalies among infants born to women treated with corticosteroids during pregnancy. The potential risk for humans is uncertain. Therefore, during pregnancy, Dovobet ointment should only be used when the potential benefit justifies the potential risk.

Breastfeeding

Betamethasone passes into breast milk but risk of an adverse effect on the infant seems unlikely with therapeutic doses. There are no data on the excretion of calcipotriol in breast milk. Caution should be exercised when prescribing Dovobet ointment to women who breast feed. The patient should be instructed not to use Dovobet ointment on the breast when breast feeding.

Fertility

Studies in rats with oral doses of calcipotriol or betamethasone dipropionate demonstrated no impairment of male and female fertility.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

The trial programme for Dovobet ointment has so far included more than 2,500 patients and has shown that approximately 10 % of patients can be expected to experience a non-serious undesirable effect.

These reactions are usually mild and cover mainly various skin reactions like rash, pruritus and burning sensation. Pustular psoriasis has been reported rarely. Rebound effect after end of treatment has been reported but the frequency of this is not known.

Based on data from clinical trials and postmarket use the following adverse reactions are listed for Dovobet ointment.

The adverse reactions are listed by MedDRA System Organ Class, and the individual adverse reactions are listed starting with the most frequently reported. Within each frequency grouping, the adverse reactions are listed in order of decreasing seriousness.

The following terminologies have been used in order to classify the frequencies of adverse reactions:

Very common

Common

Uncommon

Rare

Very rare

<1/10,000

Not known (cannot be estimated from the available data)

 

Skin and subcutaneous tissue disorders

 

Common

Pruritus

Rash

Burning sensation of skin

Uncommon

Exacerbation of psoriasis

Skin pain or irritation

Dermatitis

Erythema

Folliculitis

Application site pigmentation changes

Rare

Pustular psoriasis

General disorders and administration site conditions

 

Not known

Rebound effect - included in section 4.4

The following adverse reactions are considered to be related to the pharmacological classes of calcipotriol and betamethasone, respectively:

Calcipotriol

Adverse reactions include application site reactions, pruritus, skin irritation, burning and stinging sensation, dry skin, erythema, rash, dermatitis, eczema, psoriasis aggravated, photosensitivity and hypersensitivity reactions including very rare cases of angioedema and facial oedema.

Systemic effects after topical use may appear very rarely causing hypercalcaemia or hypercalciuria (see section 4.4).

Betamethasone (as dipropionate)

Local reactions can occur after topical use, especially during prolonged application, including skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, depigmentation and colloid milia. When treating psoriasis there may be a risk of generalised pustular psoriasis.

Systemic reactions due to topical use of corticosteroids are rare in adults, however they can be severe. Adrenocortical suppression, cataract, infections, impact on the metabolic control of diabetes mellitus and increase of intra-ocular pressure can occur, especially after long term treatment. Systemic reactions occur more frequently when applied under occlusion (plastic, skin folds), when applied on large areas and during long term treatment (see section 4.4).

4.9 Overdose

Use above the recommended dose may cause elevated serum calcium which should rapidly subside when treatment is discontinued.

Excessive prolonged use of topical corticosteroids may suppress the pituitary-adrenal functions resulting in secondary adrenal insufficiency which is usually reversible. In such cases symptomatic treatment is indicated.

In case of chronic toxicity the corticosteroid treatment must be discontinued gradually.

It has been reported that due to misuse one patient with extensive erythrodermic psoriasis treated with 240 g of Dovobet ointment weekly (corresponding to a daily dose of approximately 34 g) for 5 months (maximum recommended dose 15 g daily) developed Cushing's syndrome and pustular psoriasis after abruptly stopping treatment.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antipsoriatics. Other antipsoriatics for topical use, Calcipotriol, combinations. ATC Code: D05AX52

Calcipotriol is a vitamin D analogue. In vitro data suggests that calcipotriol induces differentiation and suppresses proliferation of keratinocytes. This is the proposed basis for its effect in psoriasis.

Like other topical corticosteroids, betamethasone dipropionate has anti-inflammatory, antipruritic, vasoconstrictive and immunosuppresive properties, however, without curing the underlying condition. Through occlusion the effect can be enhanced due to increased penetration of the stratum corneum. The incidence of adverse events will increase because of this. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear.

A safety study in 634 psoriasis patients has investigated repeated courses of Dovobet ointment used once daily as required, either alone or alternating with Dovonex, for up to 52 weeks, compared with Dovonex used alone for 48 weeks after an initial course of Dovobet ointment. Adverse drug reactions were reported by 21.7 % of the patients in the Dovobet ointment group, 29.6 % in the Dovobet ointment/Dovonex alternating group and 37.9 % in the Dovonex group. The adverse drug reactions that were reported by more than 2 % of the patients in the Dovobet ointment group were pruritus (5.8 %) and psoriasis (5.3 %). Adverse events of concern possibly related to long-term corticosteroid use (e.g. skin atrophy, folliculitis, depigmentation, furuncle and purpura) were reported by 4.8 % of the patients in the Dovobet ointment group, 2.8 % in the Dovobet ointment/Dovonex alternating group and 2.9 % in the Dovonex group.

Adrenal response to ACTH was determined by measuring serum cortisol levels in patients with both extensive scalp and body psoriasis, using up to 106 g per week combined Dovobet gel and Dovobet ointment. A borderline decrease in cortisol response at 30 minutes post ACTH challenge was seen in 5 of 32 patients (15.6 %) after 4 weeks of treatment and in 2 of 11 patients (18.2 %) who continued treatment until 8 weeks. In all cases, the serum cortisol levels were normal at 60 minutes post ACTH challenge. There was no evidence of change of calcium metabolism observed in these patients. With regard to HPA suppression, therefore, this study shows some evidence that very high doses of Dovobet gel and ointment may have a weak effect on the HPA axis.

5.2 Pharmacokinetic Properties

Clinical studies with radiolabelled ointment indicate that the systemic absorption of calcipotriol and betamethasone from Dovobet ointment is less than 1 % of the dose (2.5 g) when applied to normal skin (625 cm2) for 12 hours. Application to psoriasis plaques and under occlusive dressings may increase the absorption of topical corticosteroids. Absorption through damaged skin is approx. 24 %.

Following systemic exposure, both active ingredients – calcipotriol and betamethasone dipropionate – are rapidly and extensively metabolised. Protein binding is approx. 64 %. Plasma elimination half-life after intravenous application is 5-6 hours. Due to the formation of a depot in the skin elimination after dermal application is in order of days. Betamethasone is metabolised especially in the liver, but also in the kidneys to glucuronide and sulphate esters. The main route of excretion of calcipotriol is via faeces (rats and minipigs) and for betamethasone dipropionate it is via urine (rats and mice). In rats, tissue distribution studies with radiolabelled calcipotriol and betamethasone dipropionate, respectively, showed that the kidney and liver had the highest level of radioactivity.

Calcipotriol and betamethasone dipropionate were below the lower limit of quantification in all blood samples of 34 patients treated for 4 or 8 weeks with both Dovobet gel and Dovobet ointment for extensive psoriasis involving the body and scalp. One metabolite of calcipotriol and one metabolite of betamethasone dipropionate were quantifiable in some of the patients.

5.3 Preclinical Safety Data

Studies of corticosteroids in animals have shown reproductive toxicity (cleft palate, skeletal malformations). In reproduction toxicity studies with long-term oral administration of corticosteroids to rats, prolonged gestation and prolonged and difficult labour were detected. Moreover, reduction in offspring survival, body weight and body weight gain was observed. There was no impairment of fertility. The relevance for humans is unknown.

A dermal carcinogenicity study with calcipotriol in mice revealed no special hazard to humans.

Photo(co)carcinogenicity studies in mice suggest that calcipotriol may enhance the effect of UVR to induce skin tumours.

No carcinogenicity or photocarcinogenicity studies have been performed with betamethasone dipropionate.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Liquid paraffin

Polyoxypropylene-15 stearyl ether

All-rac-?-tocopherol

White soft paraffin

Butylhydroxytoluene (E321)

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

2 years.

After first opening: 1 year.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Aluminium/epoxyphenol tubes with polyethylene screw cap.

Tube sizes: 3 (sample), 15, 30, 60, 100 and 120 g.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

LEO Pharmaceutical Products Ltd. A/S

Industriparken 55

DK-2750 Ballerup

Denmark

8. Marketing Authorisation Number(S)

PL 05293/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

15 March 2006

10. Date Of Revision Of The Text

April 2011



1. Name Of The Medicinal Product

Dacarbazine for Injection BP 600mg

2. Qualitative And Quantitative Composition

Each vial contains 600mg of dacarbazine. When reconstituted each ml of solution contains 10mg of dacarbazine.

For excipients, see Section 6.1.

3. Pharmaceutical Form

Powder for solution for injection

A white or pale yellow powder or plug.

4. Clinical Particulars 4.1 Therapeutic Indications

1. Metastatic malignant melanoma

2. Sarcoma

3. Hodgkin's disease.

In addition, dacarbazine has been shown, when used in combination with other cytotoxic agents, to be of use in the treatment of other malignant diseases including: carcinoma of the colon, ovary, breast, lung, testicular teratoma, and solid tumours in children.

4.2 Posology And Method Of Administration

Dosage

Standard dose: The following dosage schedules are recommended:

1. 2.0-4.5mg/kg/day for 10 days, which may be repeated at 4 week

intervals.

2. 250mg/m?/day for five days, which may be repeated at 3 week intervals.

3. A further alternative is to administer the total schedule dose on the first day.

Other schedules may be used at the discretion of the prescribing physician.

Children:

The dosage for children is calculated on a mg/kg or mg/m? basis as per the standard dosage. There is no indication that children require a different dosage range or metabolise or react differently to the drug.

Geriatric:

As for paediatric use.

With Impaired Hepatic Function

As the drug partly undergoes metabolism in the liver, impairment of liver function is likely to necessitate a reduction in dosage.

With Impaired Renal Function

As the drug is excreted 50% unchanged in the urine by tubular secretion, impairment of renal function is likely to necessitate a reduction in dosage.

Administration

Administration is by the intravenous route only.

Dacarbazine 600mg vials should be reconstituted with 59.1ml of Water for Injections BP. The resulting solution contains the equivalent of 10mg/ml of dacarbazine and has a pH of 3 to 4. The resultant solution should be injected intravenously over one to two minutes.

If desired the reconstituted solution can be further diluted with 125-250ml of Dextrose Injection BP 5% or Sodium Chloride Injection BP 0.9% and administered by intravenous infusion over 15-30 minutes.

4.3 Contraindications

Dacarbazine is contraindicated in patients who have demonstrated a hypersensitivity to Dacarbazine in the past.

Dacarbazine should not be administered to patients who are pregnant or may become pregnant or breast feeding mothers.

Patients who have previously had severe myelosuppression.

4.4 Special Warnings And Precautions For Use

Warnings

Haemopoietic depression is the most common toxic side-effect of dacarbazine and involves primarily the leucocytes and platelets, although mild anaemia may sometimes occur. Leucopenia and thrombocytopenia may be severe enough to cause death. Possible bone marrow depression requires careful monitoring of white blood cells, red blood cells and platelet levels. Such toxicity may necessitate temporary suspension or cessation of therapy.

Hepatic toxicity, accompanied by hepatic vein thrombosis and hepatocellular necrosis resulting in death, have been reported. The incidence of such reactions has been low. This toxicity has been observed mostly when dacarbazine has been administered concomitantly with other anti-neoplastic drugs; however, it has also been reported in some patients treated with dacarbazine alone.

Precautions

The drug can produce severe and possibly fatal, haematologic or hepatic toxicity and severe GI reactions and should be administered to patients preferably within the hospital setting, where they can be observed frequently during and after therapy, particularly with regards to the haemopoietic toxicity.

It is recommended that dacarbazine be administered by physicians experienced in the use of cytotoxic therapy. Laboratory facilities should be available for blood monitoring.

Restriction of food and oral fluids intake for 4-6 hours prior to treatment may reduce the severity of the nausea and vomiting which occurs in most patients particularly during the first two days of treatment. Administration of an anti-emetic may also reduce the severity of these effects.

Impairment of renal and liver function: See dosage in impaired renal and liver function.

Care must be taken to avoid extravasation during intravenous administration as this may cause tissue damage and severe pain.

Care should be taken to avoid contact with the skin and eyes when reconstituting or administering dacarbazine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Microsomal liver enzyme inducer e.g. barbiturates, rifampicin, phenytoin may theoretically hasten the activation of dacarbazine to aminoimidazole-carboxamide.

Mercaptopurine, azathioprine, allopurinol: dacarbazine inhibits xanthine oxidase and may theoretically potentiate the activity of these drugs.

Patients receiving Dacarbazine should not receive immunisation with live vaccines. Dacarbazine may impair the immunological response to the vaccine with the development of a generalised vaccinia.

4.6 Pregnancy And Lactation

Studies have demonstrated that this agent is carcinogenic and teratogenic when administered to animals. Dacarbazine therefore should not be administered to pregnant or lactating women unless the benefit clearly justifies the potential risk to the foetus.

4.7 Effects On Ability To Drive And Use Machines

Dacarbazine in appropriate doses should not impair the ability to drive. However, rare adverse reactions affecting the nervous system may cause blurred vision, seizures, headache, confusion, malaise and lethargy. Patients affected by these adverse effects should not drive or operate machinery.

4.8 Undesirable Effects

Common Reactions

Symptoms of anorexia, nausea, and vomiting are the most frequent side-effects. Vomiting may last for 1-12 hours.. Nausea and vomiting rarely necessitate discontinuation of therapy. Diarrhoea is a rarer side-effect of Dacarbazine therapy.

It is suggested that restriction of the patient's oral fluid intake and food 4-6 hours prior to treatment may be helpful. The rapid toleration of these symptoms suggests a central nervous system mechanism, and usually these symptoms subside after the first 1-2 days.

Haematological: Bone marrow depression, leucocytopenia, thrombocytopenia and occasionally anaemia.

Haemopoietic toxicity may warrant temporary suspension or cessation of Dacarbazine therapy.

Less Common Reactions:

Cardiovascular: Facial flushing

Dermatological: Transient rash, alopecia

General: Infrequently some patients have experienced an influenza type syndrome of fever, myalgias and malaise. This syndrome usually occurs after large single doses and approximately seven days after treatment with dacarbazine and lasts 7-21 days, and may reoccur with successive treatments.

Hepatic: Increases in transaminases (AST, ALT), alkaline phosphatase, LDH. Levels usually return to normal within two weeks; hepatic toxicity accompanied by hepatic vein thrombosis and hepatocellular necrosis,(Budd-Chiari Syndrome) resulting in death.

Nervous System: Blurred vision, seizures, headache, facial paraesthesia, confusion, malaise, and lethargy.

Anaphylaxis can occur very rarely following administration of Dacarbazine.

Photosensitivity reactions may occur rarely.

4.9 Overdose

Signs and Symptoms:

Severe bone marrow depression and gastrointestinal effects such as nausea, vomiting and diarrhoea may be expected.

Treatment:

Cease dacarbazine administration and institute supportive measures, e.g. appropriate transfusions for bone marrow suppression.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Dacarbazine is an imidazole dimethyltriazene with reproducible activity in patients with metastatic melanoma. The structure of Dacarbazine bears a striking resemblance to the metabolite 5-aminoimidazole-4-carboxamide (AIC) which is converted to inosinic acid by enzymes involved in purine synthesis.

It was therefore initially thought to act as an antimetabolite, by inhibiting purine metabolism and nucleic acid synthesis. However the similarity of structure is of little relevance since Dacarbazine is extensively metabolised by the cytochrome P450 system in the liver by N-demethylation reaction. The monomethyl derivative then spontaneously cleaves to yield AIC and an intermediate compound, probably diazomethane, which decomposes to produce the methyl carbonium ion. This ion attached to nucleophilic groups on nucleic acids and other macromolecules, thus acting as an alkylating agent. The 7-position of guanine on DNA is especially susceptible to alkylation.

Dacarbazine is thought to act as an alkylating agent in man. It interferes with the synthesis of DNA, RNA and proteins but its cytotoxicity is not specific for any phase of the cell cycle. In general, it is most effective in inhibiting synthesis of RNA. Dacarbazine kills cells slowly and no immunosuppressive action has been shown in man. There are no systemic studies of dose-response effects but one anecdotal report has suggested that there may be an increased chance of response as the dose increases.

Dacarbazine undergoes spontaneous photodegradation in light, decomposing into 5-diazoimidazole-4-carboxamide and dimethylamine. 5-Diazoimidazole-4-carboxamide can attack nucleophilic groups of DNA and also undergoes structural rearrangement to form 2-azahypoxanthine. However, the products of photodegradation of dacarbazine probably do not contribute greatly to its cytotoxicity, although they may be implicated in the local burning pain on intravenous injection and systemic problems associated with the drug.

5.2 Pharmacokinetic Properties

The volume of distribution of dacarbazine exceeds body water content, suggesting localisation in some body tissues, probably the liver. Dacarbazine is only slightly (approximately 5%) bound to plasma proteins. Its plasma half-life after intravenous administration is approximately 35 minutes. In animal studies, approximately 46% of radio-labelled dose was recovered from the urine after 6 hours. Of this 46%, almost half, was unchanged dacarbazine and a similar quantity was amino-imidazole carboxamide, a metabolite. Dacarbazine is subject to renal tubular secretion rather than glomerular filtration.

Dacarbazine crosses the blood-brain barrier to a limited extent; CSF concentrations are reported to be about 14% of plasma concentrations. It is not known if dacarbazine crosses the placenta or distributes into milk.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Citric Acid, Mannitol, Sodium Hydroxide.

6.2 Incompatibilities

Dacarbazine is incompatible with hydrocortisone sodium succinate in solution, forming an immediate precipitate.

It has been reported to be incompatible with heparin, although only with concentrated solutions (25mg/ml).

6.3 Shelf Life

The shelf life of the product as packaged for sale is 36 months.

The physical and chemical in use stability of reconstituted solutions has been demonstrated for 96 hours at 2-8°C. Solutions diluted with 5% dextrose or 0.9% sodium chloride have demonstrated physical and chemical in use stability for 24 hours at 2-8°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at

2 to 8°C, unless reconstitution / dilution has taken place in controlled and validated aseptic conditions.

Dacarbazine is photosensitive with exposure to light causing a colour change from pale yellow to pink. The product or reconstituted solution should not be used if it appears pink in colour.

6.4 Special Precautions For Storage

Store at 2-8°C. Keep vial in the outer carton.

The reconstituted and diluted solutions should be protected from light.

6.5 Nature And Contents Of Container

20mm West Type 1816 S87J freeze-drying rubber closure (Type 1 as defined by the Ph.Eur).

100ml amber Type1 glass vials with or without Onco-Tain™ shrink wrapping

Aluminium cap with plastic 'flip-off' top.

6.6 Special Precautions For Disposal And Other Handling

Cytotoxic Handling Guidelines

Dacarbazine for Injection should only be prepared for administration by professionals who have been trained in the safe use of the preparation. Preparation should only be carried out in an aseptic cabinet or suite dedicated for the assembly of cytotoxics.

In the event of spillage, operators should put on gloves and mop up the spilled material with an absorbent material kept in the area for that purpose. The procedure should be repeated and the area rinsed with water. Repeat if necessary. All contaminated material must be transferred to a cytotoxic spillage bag or bin and sealed for incineration.

Preparation Guidelines

All operations such as reconstitution should be carried out only under aseptic conditions in a suite or cabinet dedicated for the assembly of cytotoxics.

Dacarbazine solutions should be prepared immediately before use. Dacarbazine is sensitive to light exposure.

Aseptically transfer 59.1ml of water for injections into the Dacarbazine 600mg vial and shake until a solution is obtained. The solution should be clear, colourless and free from visible particles. The resultant solution should be injected intravenously over one to two minutes.

If desired the reconstituted solution can be further diluted with 125-250ml of Dextrose Injection 5% or Sodium Chloride Injection 0.9% and administered by intravenous infusion over 15-30 minutes. During administration, the infusion set should be protected from exposure to daylight e.g. by using light-resistant PVC infusion sets. If normal infusion sets are used, then these should be covered to protect from light.

Disposal

Vials, materials that have been utilised for dilution, and any other contaminated material should be placed in a thick plastic bag or other impervious container and incinerated.

Administrative Data 7. Marketing Authorisation Holder

Mayne Pharma Plc

Queensway

Royal Leamington Spa

Warwickshire

CV31 3RW

United Kingdom

8. Marketing Authorisation Number(S)

PL 04515/0122

9. Date Of First Authorisation/Renewal Of The Authorisation

29 November 2000

10. Date Of Revision Of The Text

15th May 2003



1. Name Of The Medicinal Product

Diprosalic Scalp Application

2. Qualitative And Quantitative Composition

Betamethasone Dipropionate 0.064% w/w*

(* equivalent to 0.05% Betamethasone)

Salicylic Acid 2.00% w/w

3. Pharmaceutical Form

Lotion

4. Clinical Particulars 4.1 Therapeutic Indications

Betamethasone Dipropionate is a synthetic fluorinated corticosteroid. It is active topically and produces a rapid and sustained response in those inflammatory dermatoses that are normally responsive to topical corticosteroid therapy, and it is also effective in the less responsive conditions, such as psoriasis of the scalp.

Topical salicylic acid softens keratin, loosens cornified epithelium and desquamates the epidermis.

Diprosalic presentations are therefore indicated for the treatment of hyperkeratotic and dry corticosteroid-responsive dermatoses where the cornified epithelium may resist penetration of the steroid. The salicylic acid constituent of Diprosalic preparations, as a result of its descaling action, allows access of the dermis more rapidly than by applying steroid alone.

4.2 Posology And Method Of Administration

Adults :

Once to twice daily. In most cases a thin film should be applied to the affected areas twice daily and massaged gently and thoroughly into the skin.

For some patients adequate maintenance therapy may be achieved with less frequent application.

It is recommended that Diprosalic preparations are prescribed for two weeks, and that treatment is reviewed at that time. The maximum weekly dose should not exceed 60g.

Children :

Dosage in children should be limited to 5 days.

4.3 Contraindications

Rosacea, acne, perioral dermatitis, perianal and genital pruritus. Hypersensitivity to any of the ingredients of the Diprosalic presentations contra-indicates their use as does tuberculous and most viral lesions of the skin, particularly herpes simplex, vacinia, varicella. Diprosalic should not be used in napkin eruptions, fungal or bacterial skin infections without suitable concomitant anti-infective therapy.

4.4 Special Warnings And Precautions For Use

Occlusion must not be used, since under these circumstances the keratolytic action of salicylic acid may lead to enhanced absorption of the steroid.

Local and systemic toxicity is common, especially following long continuous use on large areas of damaged skin, in flexures or with polythene occlusion. If used in children or on the face courses should be limited to 5 days. Long term continuous therapy should be avoided in all patients irrespective of age.

Topical corticosteroids may be hazardous in psoriasis for a number of reasons, including rebound relapses following development of tolerance, risk of generalised pustular psoriasis and local systemic toxicity due to impaired barrier function of the skin. Careful patient supervision is important.

It is dangerous if Diprosalic presentations come into contact with the eyes. Avoid contact with the eyes and mucous membranes.

The systemic absorption of betamethasone dipropionate and salicylic acid may be increased if extensive body surface areas or skin folds are treated for prolonged periods or with excessive amounts of steroids. Suitable precautions should be taken in these circumstances, particularly with infants and children.

If irritation or sensitisation develops with the use of Diprosalic, treatment should be discontinued.

Any side effects that are reported following systemic use of corticosteroids, including adrenal suppression, may also occur with topical corticosteroids, especially in infants and children.

If excessive dryness or increased skin irritation develops, discontinue use of this preparation.

Paediatric Use: Paediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced hypothalamic-pituary-adrenal (HPA) axis suppression and to exogenous corticosteroid effects than mature patients because of greater absorption due to a large skin surface area to body weight ratio.

HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include a bulging fontanelle, headaches and bilateral papilledema.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None stated

4.6 Pregnancy And Lactation

Since safety of topical corticosteroid use in pregnant women has not been established, drugs of this class should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Drugs of this class should not be used extensively in large amounts or for prolonged periods of time in pregnant patients.

Since it is not known whether topical administration of corticosteroids can result in sufficient systemic absorption to produce detectable quantities in breast milk, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Diprosalic skin preparations are generally well tolerated and side-effects are rare.

Continuous application without interruption may result in local atrophy of the skin, striae and superficial vascular dilation, particularly on the face.

Adverse reactions that have been reported with the use of topical corticosteroids include: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis and allergic contact dermatitis.

The following may occur more frequently with the use of occlusive dressings: maceration of the skin, secondary infection, skin atrophy, striae and miliaria.

In addition, prolonged use of salicylic acid preparations may cause dermatitis.

4.9 Overdose

Excessive prolonged use of topical corticosteroids can suppress pituitary-adrenal functions resulting in secondary adrenal insufficiency, and produce manifestations of hypercorticism, including Cushing's disease.

Treatment: Appropriate symptomatic treatment is indicated. Acute hypercorticoid symptoms are usually reversible. Treat electrolyte imbalance, if necessary. In case of chronic toxicity, slow withdrawal of corticosteroids is advised.

With topical preparations containing salicylic acid excessive prolonged use may result in symptoms of salicyclism. Treatment is symptomatic. Measures should be taken to rid the body rapidly of salicylate. Adminster oral sodium bicarbonate to alkalinize the urine and force diuresis.

The steroid content of each tube is so low as to have little or no toxic effect in the unlikely event of accidental oral ingestion.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Diprosalic preparations contain the dipropionate ester of betamethasone which is a glucocorticoid exhibiting the general properties of corticosteroids, and salicylic acid which has keratolytic properties.

Salicylic acid is applied topically in the treatment of hyperkeratotic and scaling conditions where its keratolytic action facilitates penetration of the corticosteroid.

In pharmacological doses, corticosteroids are used primarily for their anti-inflammatory and/or immune suppressive effects.

Topical corticosteroids such as betamethasone dipropionate are effective in the treatment of a range of dermatoses because of their anti-inflammatory, anti-pruritic and vasoconstrictive actions. However, while the physiologic, pharmacologic and clinical effects of the corticosteroids are well known, the exact mechanisms of their action in each disease are uncertain.

5.2 Pharmacokinetic Properties

Salicylic acid exerts only local action after topical application.

The extent of percutaneous absorption of topical corticosteroids is determined by many factors including vehicle, integrity of the epidermal barrier and the use of occlusive dressings.

Topical corticosteroids can be absorbed through intact, normal skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption.

Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids.

Once absorbed through the skin, topical corticosteroids enter pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees, are metabolised primarily in the liver and excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted in the bile.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Disodium edetate

Hydroxypropyl methylcellulose

Sodium hydroxide

Isopropyl alcohol

Purified water

6.2 Incompatibilities

None Stated.

6.3 Shelf Life

18 months

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

30ml or 100ml polyethylene containers with polypropylene closures

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

UK

8. Marketing Authorisation Number(S)

PL 00025/0569

9. Date Of First Authorisation/Renewal Of The Authorisation

30 July 1997

10. Date Of Revision Of The Text

February 2011

11. LEGAL CATEGORY

Prescription Only Item

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

Diprosalic-SA/UK/02-11/8



Dulcolax Suppositories 10 mg

Dulcolax Suppositories for Children 5 mg

bisacodyl

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

This medicine is available without prescription. You need to use DULCOLAX Suppositories as instructed in this leaflet to get the best results from it.

Keep this leaflet. You may need to read it again Ask your pharmacist if you need more information or advice You must contact your pharmacist or doctor if your symptoms worsen or do not improve after 5 days of treatment If a side effect occurs and gets troublesome, or seems serious to you, or if you experience any side effect not listed in this leaflet, please tell your pharmacist or doctor In this leaflet: 1. What DULCOLAX Suppositories are and what they are used for 2. Before you use DULCOLAX Suppositories 3. How to use DULCOLAX Suppositories 4. Possible side effects 5. How to store DULCOLAX Suppositories 6. Further information What Dulcolax Suppositories Are And What They Are Used For

DULCOLAX Suppositories contain a medicine called bisacodyl. This belongs to a group of medicines called laxatives.

DULCOLAX Suppositories are used for relief of constipation DULCOLAX Suppositories are also used in hospitals to clear the bowel before surgery, X-rays or other tests DULCOLAX Suppositories stimulate the muscles of the bowel (large intestine), helping to return the body to its natural rhythm. They have a laxative effect usually within 30 minutes What is constipation?

Normal and regular bowel movement is important for most people. However, what is “normal and regular” varies from person to person. Some may have a bowel movement every day, others less often. Whatever it is like for you, it is best that your bowel movement has a regular pattern.

Constipation is an occasional problem for some people; for others, it may happen more often It happens when the normal muscle actions in the bowel (large intestine) slow down. This can mean that the material is not easily eliminated from the body

The cause of constipation is often not known. It can be associated with:

Sudden change of diet A diet with not enough fibre Loss of ‘tone’ of the bowel muscles in older people Pregnancy Medicines such as morphine or codeine Having to stay in bed for a long time Lack of exercise

Whatever the cause, constipation is uncomfortable. It may make you feel bloated and heavy, or generally “off colour”. Sometimes it causes headaches.

These healthy tips are recommended to try and prevent constipation happening:

Eat a balanced diet including fresh fruit and vegetables Drink enough water so that you do not become dehydrated Keep up your exercise and stay fit Make time to empty your bowels when your body tells you Before You Use Dulcolax Suppositories Do not use DULCOLAX Suppositories if: You are allergic (hypersensitive) to bisacodyl or hard fat You have severe dehydration You have a bowel condition called “ileus” (in the small intestine) You have a serious abdominal condition such as appendicitis You have severe abdominal pain with nausea and vomiting You have a blocked bowel (intestinal obstruction) You have inflammation of the bowel (small or large intestine) You have cracking of the skin around your back passage (anal fissures) You have inflammation or ulcers around your back passage (ulcerative proctitis)

Do not use DULCOLAX Suppositories if any of the above applies to you. If you are not sure, talk to your pharmacist or doctor before using this medicine.

Taking other medicines

Please tell your pharmacist or doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This includes herbal medicines. This is because DULCOLAX Suppositories can affect the way some other medicines work. Also, some other medicines can affect the way DULCOLAX Suppositories work.

In particular, tell your pharmacist or doctor if you are taking any of the following medicines:

Water tablets (diuretics) such as bendrofluazide or furosemide (frusemide) Steroid medicines such as prednisolone

Before using DULCOLAX Suppositories, tell your pharmacist or doctor if you are not sure if any of the above applies to you.

Pregnancy and breast-feeding

Talk to your pharmacist or doctor before using DULCOLAX Suppositories if you are pregnant, planning to become pregnant or are breast-feeding.

How To Use Dulcolax Suppositories

If this medicine is from your doctor or pharmacist, do exactly as they have told you. Otherwise, follow the instructions below. If you do not understand the instructions, or if you are not sure, ask your pharmacist or doctor.

As with all laxatives, DULCOLAX Suppositories should not be used every day for more than 5 days. If you need laxatives every day, or if you have abdominal pain which does not go away, you should see your doctor.

How to use the suppositories

The suppositories should only be used in your back passage.

1. Take off the foil wrapping 2. Lie on one side and pull your knees up towards your chest. Keep one leg drawn up more than the other 3. Use your first finger (index finger) or middle finger to push in the suppository 4. Gently push the suppository as far as possible into your back passage, pointed end first 5. Once it is as far as it will go, push it side-ways to make sure it touches the wall of the bowel 6. Lower your legs to a comfortable position whilst the suppository is retained in place 7. Keep the suppository inside you for at least 30 minutes If you feel the suppository might come out straight away: You may not have put it in high enough. Push it in as far as possible Try to keep it in for 30 minutes, even if you feel like you urgently need to go to the toilet. This is how long it takes to work How much to use

For constipation

Adults and children over 10 years

Put one 10 mg suppository into the back passage for immediate effect. Only use one suppository per day

Children under 10 years

DULCOLAX Suppositories for Children 5 mg should only be used if recommended by a doctor. The usual dose is:

Put one 5 mg suppository into the back passage for immediate effect. Only use one suppository per day

For bowel clearance before surgery, X-rays or other tests

In hospitals, when patients are being prepared for surgery, X-rays or other tests, DULCOLAX Suppositories and DULCOLAX Tablets are both used. This helps to get complete bowel clearance.

Adults and children over 10 years

Take two tablets in the morning and two tablets in the evening and use one 10 mg suppository on the following morning

Children 4 -10 years

Give one tablet in the evening and one 5 mg suppository (DULCOLAX Suppositories for Children) on the following morning If you use more DULCOLAX Suppositories than you should

If you use more of this medicine than you should, talk to a doctor or go to a hospital straight away. Take the medicine pack with you. This is so the doctor knows what you have used.

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

Possible Side Effects

Like all medicines, DULCOLAX Suppositories can cause side effects, although not everybody gets them. The following side effects may happen with this medicine:

Common side effects (affect less than 1 in 10 people) Abdominal cramps or pain Nausea Diarrhoea Uncommon side effects (affect less than 1 in 100 people) Vomiting Abdominal discomfort Blood in the stools (usually mild and self-limiting) Discomfort inside and around the back passage Rare side effects (affect less than 1 in 1000 people) Allergic reactions which may cause a skin rash or itching Unknown – incidence of side effect cannot be estimated from the available data Colitis (inflammation of the large intestine which causes abdominal pain or diarrhoea) Dehydration which can make you feel thirsty and produce less urine. If you are dehydrated drink plenty of liquid. Serious allergic reactions which may cause swelling of the face or throat and difficulty in breathing or dizziness. If you have a severe allergic reaction, stop taking this medicine and see a doctor straight away.

If a side effect occurs and gets troublesome or seems serious to you, or if you experience any side effect not listed in this leaflet, please tell your pharmacist or doctor.

How To Store Dulcolax Suppositories Keep this medicine out of the sight and reach of children Do not use DULCOLAX Suppositories after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month. Do not store above 25°C The suppositories should be protected from light. Keep them in the outer carton 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 protect the environment Further Information What DULCOLAX Suppositories contain DULCOLAX Suppositories 10 mg contain 10 mg of the active ingredient bisacodyl DULCOLAX Suppositories for Children 5 mg contain 5 mg of the active ingredient bisacodyl Both the suppositories are made from hard fat, which is an ingredient needed to mould the suppository into the correct shape What DULCOLAX Suppositories look like and contents of the pack The suppositories are white and torpedo shaped DULCOLAX Suppositories 10 mg are available in packs of 12 DULCOLAX Suppositories for Children 5 mg are available in packs of 5 Marketing Authorisations are held by: Boehringer Ingelheim Limited Consumer Healthcare Ellesfield Avenue Bracknell Berkshire RG12 8YS United Kingdom DULCOLAX Suppositories are manufactured by: Instituto De Angeli. S.r.I. Localit? Prulli di Sotto n. 103/c Regello (Fl) Italy

This leaflet was revised in May 2010.

Registered trade mark

© Boehringer Ingelheim Limited 2010

XXXXXX/GB/7

20080918



Diurexan 20 mg tablets

Xipamide

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. In this leaflet: 1. What Diurexan is for 2. Before you take Diurexan 3. How to take Diurexan 4. Possible side effects 5. How to store Diurexan 6. Further information What Diurexan is for

Diurexan belongs to the group of medicines known as diuretics. Diuretics are often referred to as water tablets.

Diurexan removes excess water from the body by increasing how often you urinate. It is used to treat high blood pressure (hypertension) and too much fluid in the body (oedema), often caused by heart failure or problems with your liver or kidneys.

Before you use Diurexan Do not take Diurexan if: You are allergic to Xipamide You are allergic to any of the other ingredients of Diurexan (listed in section 6) You have low levels of salts in your blood sometimes caused by severe vomiting or diarrhoea You have liver disease that is causing you to become unconscious You have severe kidney disease You have untreated Addison’s disease – a condition in which your adrenal glands do not produce sufficient levels of natural steroid in the blood You are less than 4 months’ pregnant.

If any of the above applies to you, talk to your doctor or pharmacist.

Check with your doctor before taking Diurexan if: You have gout or have too much uric acid in your urine You have diabetes You have kidney or liver disease You have an enlarged prostate gland or trouble urinating You suffer with coronary or cerebral arteriosclerosis (narrowing of the arteries in the heart or brain) Your body produces too much aldosterone, a hormone which controls salt and water balance (hyperaldosteronism) You have diarrhoea You are malnourished (a severe lack of food) You are being sick You are over 65 years of age. Tell your doctor if you are taking any of the following medicines: Medicines for high blood pressure Medicines called cardiac glycosides such as digoxin for heart problems Insulin or tablets for diabetes Lithium.

Taking these Diurexan at the same time as these medicines may lead to your doctor adjusting the dose you require.

Also tell your doctor if you are taking:

Steroids used to treat many conditions including asthma, arthritis, eczema and dermatitis ACTH which is mainly used to test if your pituitary gland is working properly Carbenoxolone used to treat stomach ulcers and inflammation of the oesophagus Amphotericin used to treat fungal and bacterial infections Laxatives.

These medicines may cause the level of potassium in your blood to fall when used at the same time as Diurexan.

Tell your doctor or pharmacist if you are taking any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

If you are pregnant, trying to become pregnant or breastfeeding ask your doctor or pharmacist for advice before taking Diurexan.

How to take Diurexan

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

Important:

Your doctor will choose the dose that is right for you. Your dose will be shown clearly on the label that your pharmacist puts on your medicine. If it does not, or you are not sure, ask your doctor or pharmacist.

For high blood pressure:

The usual dose is one tablet per day, taken early in the morning.

For excessive fluid retention:

The usual starting dose is two tablets per day, taken early in the morning.

Once your doctor has seen how the medicine is working, they may change your dose. They may reduce it to one tablet per day. If the medicine is not having much effect, your doctor may increase your dose to 3 or 4 tablets per day.

Medical check-ups

Taking Diurexan for a long time can cause you to lose potassium from your blood. Your doctor will check for this and may prescribe you extra potassium especially if you are elderly or getting little potassium in your diet.

If you take more Diurexan than you should

If you accidentally take too much Diurexan immediately go to the nearest hospital casaulty department or your doctor. An overdose may cause the loss of too much fluid from your body.

This can cause hypotension, making you feel faint and change the make-up of your blood.

You may have your stomach washed out and an infusion into your vein to replace lost fluids.

If you forget to take Diurexan

Do not take a double dose to make up for a missed dose. Simply take your dose as planned.

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

Possible side effects

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

These may include:

Slight dizziness Effects on your stomach or intestine such as stomach pain, constipation and diarrhoea Low potassium and sodium levels in blood (hypokalaemia and hyponatraemia respectively) which may cause headaches, muscle cramps and weakness.

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 Diurexan

Keep out of the reach and sight of children.

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

Medicines should not be disposed of via wastewater or household waste. Return any medicine you no longer need to your pharmacist.

Further information What Diurexan contains

The active substance is xipamide. Each tablet contains 20 mg of xipamide.

The other ingredients are maize starch, mannitol, cellulose powder, colloidal silicon dioxide, magnesium stearate and purified water.

What Diurexan looks like

Diurexan tablets are white and round with a notch on one side and an "A" on the other. They are about 6 mm in diameter. They come in blister strips strips of 14 tablets with 10 blister strips in a box.

Marketing Authorisation Holder is: Meda Pharmaceuticals Ltd Skyway House Parsonage Road Takeley Bishop’s Stortford CM22 6PU United Kingdom Manufacturer is: Sidefarma, S.A. Rua da Guin?, n? 26 2689-514 Prior Velho PORTUGAL

This leaflet was last updated on September 2008

If this leaflet is difficult to see or read and you would like it in a different format, please contact

Meda Pharmaceuticals Skyway House Parsonage Road Takeley Bishop’s Stortford CM22 6PU United Kingdom



1. Name Of The Medicinal Product

Dorzolamide/Timolol 20mg/ml + 5mg/ml eye drops, solution

2. Qualitative And Quantitative Composition

Each ml contains 20mg dorzolamide (as Dorzolamide hydrochloride) and 5mg timolol (as timolol maleate).

Excipients: each ml of eye drops solution contains 0.075mg benzalkonium chloride.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Eye drops, solution.

Clear, slightly viscous, colourless aqueous solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Dorzolamide/Timolol is indicated in the treatment of elevated intra-ocular pressure (IOP) in patients with open-angle glaucoma or pseudo-exfoliative glaucoma when topical beta-blocker monotherapy is not sufficient.

4.2 Posology And Method Of Administration

The dose is one drop of Dorzolamide/Timolol in the (conjunctival sac of the) affected eye(s) two times daily.

If another topical ophthalmic medicinal product is being used, the other agent should be administered at least ten minutes apart.

Paediatric population:

Efficacy in paediatric patients has not been established.

Safety in paediatric patients below the age of two years has not been established. (For information regarding safety in paediatric patients

Patients should be instructed to wash their hands before use and avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

In order to secure correct dosage – the dropper tip should not be enlarged.

Patients should also be instructed that ocular solutions, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

Patients should be informed of the correct handling of the ophthalmic Dorzolamide/Timolol.

Usage instructions:

1. The tamper-proof seal on the bottle neck must be unbroken before the product is being used for the first time. A gap between the bottle and the cap is normal for an unopened bottle.

2. The cap of the bottle should be taken off.

3. The patient's head must be tilted back and the lower eyelid must be pulled gently down to form a small pocket between the eyelid and the eye.

4. The bottle should be inverted and squeezed until a single drop is dispensed into the eye. THE EYE OR EYELID MUST NOT BE TOUCHED WITH THE DROPPER TIP.

5. Steps 3 & 4 should be repeated with the other eye if it is necessary.

6. The cap must be put back on and the bottle must be closed straight after it has been used.

4.3 Contraindications

Dorzolamide/Timolol is contra-indicated in patients with:

• reactive airway disease, including bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease

• sinus bradycardia, second- or third-degree atrioventricular block, overt cardiac failure, cardiogenic shock

• severe renal impairment (creatinine clearance < 30ml/min) or hyperchloraemic acidosis

• hypersensitivity to one or both active substances or to any of the excipients.

The above are based on the components and are not unique to the combination.

4.4 Special Warnings And Precautions For Use

Cardiovascular/respiratory reactions

As with other topically-applied ophthalmic agents, this drug may be absorbed systemically. The timolol component is a beta-blocker. Therefore, the same types of adverse reactions found with systemic administration of beta-blockers may occur with topical administration, including worsening of Prinzmetal's angina, worsening of severe peripheral and central circulatory disorders, and hypotension.

Because of the timolol maleate component, cardiac failure should be adequately controlled before beginning therapy with Dorzolamide/Timolol. In patients with a history of severe cardiac disease, signs of cardiac failure should be watched for and pulse rates should be checked.

Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and rarely death in association with cardiac failure, have been reported following administration of timolol maleate.

Hepatic impairment

Dorzolamide/Timolol eye drops solution has not been studied in patients with hepatic impairment and therefore should be used with caution in such patients.

Immunology and hypersensitivity

As with other topically-applied ophthalmic agents, this drug may be absorbed systemically. The dorzolamide component is a sulphonamide. Therefore the same types of adverse reactions found with systemic administration of sulphonamides may occur with topical administration. If signs of serious reactions or hypersensitivity occur, discontinue use of this preparation.

Local ocular adverse effects, similar to those observed with dorzolamide hydrochloride eye drops, have been seen with Dorzolamide/Timolol eye drops solution. If such reactions occur, discontinuation of Dorzolamide/Timolol should be considered.

While taking ?-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to accidental, diagnostic, or therapeutic repeated challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

Concomitant therapy

The following concomitant medication is not recommended:

? dorzolamide and oral carbonic anhydrase inhibitors

? topical beta-adrenergic blocking agents.

Withdrawal of therapy

As with systemic beta-blockers, if discontinuation of ophthalmic timolol is needed in patients with coronary heart disease, therapy should be withdrawn gradually.

Additional effects of beta-blockade

Therapy with beta-blockers may mask certain symptoms of hypoglycaemia in patients with diabetes mellitus or hypoglycaemia.

Therapy with beta-blockers may mask certain symptoms of hyperthyroidism. Abrupt withdrawal of beta-blocker therapy may precipitate a worsening of symptoms.

Therapy with beta-blockers may aggravate symptoms of myasthenia gravis.

Additional effects of carbonic anhydrase inhibition

Therapy with oral carbonic anhydrase inhibitors has been associated with urolithiasis as a result of acid-base disturbances, especially in patients with a prior history of renal calculi. Although no acid-base disturbances have been observed with Dorzolamide/Timolol eye drops solution, urolithiasis has been reported infrequently. Because Dorzolamide/Timolol contains a topical carbonic anhydrase inhibitor that is absorbed systemically, patients with a prior history of renal calculi may be at increased risk of urolithiasis while using Dorzolamide/Timolol.

Other

The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide/Timolol eye drops solution has not been studied in patients with acute angle-closure glaucoma.

Corneal oedema and irreversible corneal decompensation have been reported in patients with pre-existing chronic corneal defects and/or a history of intra-ocular surgery while using dorzolamide. Topical dorzolamide should be used with caution in such patients.

Choroidal detachment concomitant with ocular hypotony have been reported after filtration procedures with administration of aqueous suppressant therapies.

As with the use of other antiglaucoma drugs, diminished responsiveness to ophthalmic timolol maleate after prolonged therapy has been reported in some patients. However, in clinical studies in which 164 patients have been followed for at least three years, no significant difference in mean intra-ocular pressure has been observed after initial stabilisation.

Contact lens use

Dorzolamide/Timolol contains the preservative benzalkonium chloride, which may cause eye irritation. Benzalkonium chloride is known to discolour soft contact lenses. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion.

Paediatric use

See section 5.1.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Specific drug interaction studies have not been performed with Dorzolamide/Timolol eye drops solution.

In clinical studies, Dorzolamide/Timolol eye drops solution was used concomitantly with the following systemic medications without evidence of adverse interactions: ACE-inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory drugs including aspirin, and hormones (e.g. oestrogen, insulin, thyroxine).

However, the potential exists for additive effects and production of hypotension and/or marked bradycardia when timolol maleate ophthalmic solution is administered together with oral calcium channel blockers, catecholamine-depleting drugs or beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, narcotics, and monoamine oxidase (MAO) inhibitors.

Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, SSRIs) and timolol.

The dorzolamide component of Dorzolamide/Timolol is a carbonic anhydrase inhibitor and although administered topically, is absorbed systemically. In clinical studies, dorzolamide hydrochloride ophthalmic solution was not associated with acid-base disturbances. However, these disturbances have been reported with oral carbonic anhydrase inhibitors and have in some instances, resulted in drug interactions (e.g., toxicity associated with high-dose salicylate therapy). Therefore, the potential for such drug interactions should be considered in patients receiving Dorzolamide/Timolol.

Although Dorzolamide/Timolol alone has little or no effect on pupil size, mydriasis resulting from concomitant use of ophthalmic timolol maleate and epinephrine has been reported occasionally.

Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents.

Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.

4.6 Pregnancy And Lactation

Pregnancy

Dorzolamide/Timolol should not be used during pregnancy.

Dorzolamide

No adequate clinical data in exposed pregnancies are available. In rabbits, dorzolamide produced teratogenic effects at maternotoxic doses (see Section 5.3).

Timolol

Well controlled epidemiological studies with systemic beta blockers showed no evidence of teratogenic effects, but some pharmacological effects such as bradycardia were observed in fetuses or neonates. If Dorzolamide/Timolol is administered until delivery, the neonate should be carefully monitored during the first days of life.

Lactation

It is not known whether dorzolamide is excreted in human milk. In lactating rats receiving dorzolamide, decreases in the body weight gain of offspring were observed. Timolol does appear in human milk. Dorzolamide/Timolol should not be used during lactation.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Possible side effects such as blurred vision may affect some patients' ability to drive and/or operate machinery.

4.8 Undesirable Effects

In clinical studies no adverse experiences specific to Dorzolamide/Timolol have been observed; adverse experiences have been limited to those that were reported previously with dorzolamide hydrochloride and/or timolol maleate. In general, common adverse experiences were mild and did not cause discontinuation.

During clinical studies, 1,035 patients were treated with Dorzolamide/Timolol eye drops solution. Approximately 2.4% of all patients discontinued therapy with Dorzolamide/Timolol eye drops solution because of local ocular adverse reactions, approximately 1.2% of all patients discontinued because of local adverse reactions suggestive of allergy or hypersensitivity (such as lid inflammation and conjunctivitis).

The following adverse reactions have been reported with Dorzolamide/Timolol eye drops solution or one of its components either during clinical trials or during post-marketing experience:

[Very Common: (

Nervous system and Psychiatric disorders:

Dorzolamide hydrochloride ophthalmic solution:

Common: headache*

Rare: dizziness*, paresthesia*

Timolol maleate ophthalmic solution:

Common: headache*

Uncommon: dizziness*, depression*

Rare: insomnia*, nightmares*, memory loss, paraesthesia*, increase in signs and symptoms of myasthenia gravis, decreased libido*, cerebrovascular accident*

Eye disorders:

Dorzolamide/Timolol ophthalmic solution:

Very Common: burning and stinging

Common: conjunctival injection, blurred vision, corneal erosion, ocular itching, tearing

Dorzolamide hydrochloride ophthalmic solution:

Common: eyelid inflammation*, eyelid irritation*

Uncommon: iridocyclitis*

Rare: irritation including redness*, pain*, eyelid crusting*, transient myopia (which resolved upon discontinuation of therapy), corneal oedema*, ocular hypotony*, choroidal detachment (following filtration surgery)*

Timolol maleate ophthalmic solution:

Common: signs and symptoms of ocular irritation including blepharitis*, keratitis*, decreased corneal sensitivity, and dry eyes*

Uncommon: visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases)*

Rare: ptosis, diplopia, choroidal detachment (following filtration surgery)*

Ear and labyrinth disorders:

Timolol maleate ophthalmic solution:

Rare: tinnitus*

Cardiac and Vascular disorders:

Timolol maleate ophthalmic solution:

Uncommon: bradycardia*, syncope*

Rare: hypotension*, chest pain*, palpitation*, oedema*, arrhythmia*, congestive heart failure*, heart block*, cardiac arrest*, cerebral ischaemia, claudication, Raynaud's phenomenon*, cold hands and feet*

Respiratory, thoracic, and mediastinal disorders:

Dorzolamide/Timolol ophthalmic solution:

Common: sinusitis

Rare: shortness of breath, respiratory failure, rhinitis

Dorzolamide hydrochloride ophthalmic solution:

Rare: epistaxis*

Timolol maleate ophthalmic solution:

Uncommon: dyspnoea*

Rare: bronchospasm (predominantly in patients with pre-existing bronchospastic disease)*, cough*

Gastro-intestinal disorders:

Dorzolamide/Timolol ophthalmic solution:

Very Common: taste perversion

Dorzolamide hydrochloride ophthalmic solution:

Common: nausea*

Rare: throat irritation, dry mouth*

Timolol maleate ophthalmic solution:

Uncommon: nausea*, dyspepsia*

Rare: diarrhoea, dry mouth*

Skin and subcutaneous tissue disorders:

Dorzolamide/Timolol ophthalmic solution:

Rare: contact dermatitis

Dorzolamide hydrochloride ophthalmic solution:

Rare: rash*

Timolol maleate ophthalmic solution:

Rare: alopecia*, psoriasiform rash or exacerbation of psoriasis*

Musculoskeletal and connective tissue disorders:

Timolol maleate ophthalmic solution:

Rare: systemic lupus erythematosus

Renal and Urinary disorders:

Dorzolamide/Timolol ophthalmic solution:

Uncommon: urolithiasis

Reproductive system and breast disorders:

Timolol maleate ophthalmic solution:

Rare: Peyronie's disease*

General disorders and administration site disorders:

Dorzolamide/Timolol ophthalmic solution:

Rare: signs and symptoms of systemic allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylaxis, rarely bronchospasm

Dorzolamide hydrochloride ophthalmic solution:

Common: asthenia/fatigue*

Timolol maleate ophthalmic solution:

Uncommon: asthenia/fatigue*

*These adverse reactions were also observed with Dorzolamide/Timolol ophthalmic solution during post-marketing experience.

Laboratory findings

Dorzolamide/Timolol eye drops solution was not associated with clinically meaningful electrolyte disturbances in clinical studies.

4.9 Overdose

No data are available in humans in regard to overdosage by accidental or deliberate ingestion of Dorzolamide/Timolol eye drops solution.

There have been reports of inadvertent overdosage with timolol maleate ophthalmic solution resulting in systemic effects similar to those seen with systemic beta

Only limited information is available with regard to human overdosage by accidental or deliberate ingestion of dorzolamide hydrochloride. With oral ingestion, somnolence has been reported. With topical application the following have been reported: nausea, dizziness, headache, fatigue, abnormal dreams, and dysphagia.

Treatment should be symptomatic and supportive. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Studies have shown that timolol does not dialyse readily.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiglaucoma preparations and miotics, Beta-Blocking Agents, Timolol, Combinations.

ATC code: S01E D51

Mechanism of action

Dorzolamide/Timolol eye drops solution is comprised of two components: dorzolamide hydrochloride and timolol maleate. Each of these two components decreases elevated intra-ocular pressure by reducing aqueous humor secretion, but does so by a different mechanism of action.

Dorzolamide hydrochloride is a potent inhibitor of human carbonic anhydrase II.

Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. The precise mechanism of action of timolol maleate in lowering intra-ocular pressure is not clearly established at this time, although a fluorescein study and tonography studies indicate that the predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed. The combined effect of these two agents results in additional intra-ocular pressure reduction compared to either component administered alone.

Following topical administration, Dorzolamide/Timolol eye drops solution reduces elevated intra-ocular pressure, whether or not associated with glaucoma. Elevated intra-ocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.

Dorzolamide/Timolol eye drops solution reduces intra-ocular pressure without the common side effects of miotics such as night blindness, accommodative spasm and pupillary constriction.

Pharmacodynamic effects

Clinical effects:

Adult Patients

Clinical studies of up to 15 months duration were conducted to compare the IOP-lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. (dosed morning and bedtime) to individually- and concomitantly-administered 0.5% timolol and 2.0% dorzolamide in patients with glaucoma or ocular hypertension for whom concomitant therapy was considered appropriate in the trials. This included both untreated patients and patients inadequately controlled with timolol monotherapy. The majority of patients were treated with topical beta-blocker monotherapy prior to study enrollment. In an analysis of the combined studies, the IOP-lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. was greater than that of monotherapy with either 2% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOP-lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. was equivalent to that of concomitant therapy with dorzolamide b.i.d. and timolol b.i.d. The IOP-lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. was demonstrated when measured at various time points throughout the day and this effect was maintained during long-term administration.

Paediatric Population

A three month controlled study, with the primary objective of documenting the safety of 2% dorzolamide hydrochloride ophthalmic solution in children under the age of 6 years has been conducted. In this study, 30 patients under six and greater than or equal to two years of age whose IOP was not adequately controlled with monotherapy by dorzolamide or timolol received Dorzolamide/Timolol eye drops solution in an open label phase. Efficacy in those patients has not been established. In this small group of patients, twice daily administration of Dorzolamide/Timolol eye drops solution was generally well tolerated with 19 patients completing the treatment period and 11 patients discontinuing for surgery, a change in medication, or other reasons.

5.2 Pharmacokinetic Properties

Dorzolamide hydrochloride:

Unlike oral carbonic anhydrase inhibitors, topical administration of dorzolamide hydrochloride allows for the drug to exert its effects directly in the eye at substantially lower doses and therefore with less systemic exposure. In clinical trials, this resulted in a reduction in IOP without the acid-base disturbances or alterations in electrolytes characteristic of oral carbonic anhydrase inhibitors.

When topically applied, dorzolamide reaches the systemic circulation. To assess the potential for systemic carbonic anhydrase inhibition following topical administration, drug and metabolite concentrations in red blood cells (RBCs) and plasma and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates in RBCs during chronic dosing as a result of selective binding to CA-II while extremely low concentrations of free drug in plasma are maintained. The parent drug forms a single N-desethyl metabolite that inhibits CA-II less potently than the parent drug but also inhibits a less active isoenzyme (CA-I). The metabolite also accumulates in RBCs where it binds primarily to CA-I. Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in the urine; the metabolite is also excreted in urine. After dosing ends, dorzolamide washes out of RBCs non-linearly, resulting in a rapid decline of drug concentration initially, followed by a slower elimination phase with a half-life of about four months.

When dorzolamide was given orally to simulate the maximum systemic exposure after long term topical ocular administration, steady state was reached within 13 weeks. At steady state, there was virtually no free drug or metabolite in plasma; CA inhibition in RBCs was less than that anticipated to be necessary for a pharmacological effect on renal function or respiration. Similar pharmacokinetic results were observed after chronic, topical administration of dorzolamide hydrochloride. However, some elderly patients with renal impairment (estimated creatinine clearance 30-60 millilitre/min) had higher metabolite concentrations in RBCs, but no meaningful differences in carbonic anhydrase inhibition and no clinically significant systemic side effects were directly attributable to this finding.

Timolol maleate:

In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined following twice daily topical administration of timolol maleate ophthalmic solution 0.5%. The mean peak plasma concentration following morning dosing was 0.46ng/millilitre and following afternoon dosing was 0.35ng/millilitre.

5.3 Preclinical Safety Data

The ocular and systemic safety profile of the individual components is well established.

Dorzolamide

In rabbits given maternotoxic doses of dorzolamide associated with metabolic acidosis, malformations of the vertebral bodies were observed.

Timolol

Animal studies have not shown a teratogenic effect.

Furthermore, no adverse ocular effects were seen in animals treated topically with dorzolamide hydrochloride and timolol maleate ophthalmic solution or with concomitantly-administered dorzolamide hydrochloride and timolol maleate. In vitro and in vivo studies with each of the components did not reveal a mutagenic potential. Therefore, no significant risk for human safety is expected with therapeutic doses of Dorzolamide/Timolol eye drops solution.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Mannitol (E421)

Hydroxyethyl Cellulose

Sodium Citrate (E331)

Sodium Hydroxide (E524)(for pH adjustment)

Benzalkonium chloride

Water for injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years

After first opening: 28 days

6.4 Special Precautions For Storage

This medicinal product does not require any special temperature storage conditions

6.5 Nature And Contents Of Container

White opaque medium density polyethylene bottle ophthalmic dispenser with a sealed LDPE dropper tip and a HDPE screw cap with tamper proof seal in a cardboard box.

Pack size: 1 bottle of 5ml each

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Pharmathen S.A.

6 Dervenakion str.,

15351 Pallini, Attiki

Greece

8. Marketing Authorisation Number(S)

PL 17277/0243

9. Date Of First Authorisation/Renewal Of The Authorisation

11/03/2011

10. Date Of Revision Of The Text

11/03/2011

LEGAL CATEGORY

POM



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