Drugs associated with Rhinorrhea

The following drugs and medications are in some way related to, or used in the treatment of Rhinorrhea. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.



Definition of Rubella: Rubella is a contagious viral infection with mild symptoms associated with a rash.

Drugs associated with Rubella

The following drugs and medications are in some way related to, or used in the treatment of Rubella. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

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1. Name Of The Medicinal Product

Remegel Summer Fruit.

2. Qualitative And Quantitative Composition

Each tablet contains 800mg Calcium Carbonate USP.

3. Pharmaceutical Form

Soft, pink, raspberry-flavoured, chewable square tablets.

4. Clinical Particulars 4.1 Therapeutic Indications

Remegel Summer Fruit are indicated for the relief of acid indigestion, heartburn and associated stomach upsets (dyspepsia).

4.2 Posology And Method Of Administration

Route of administration: oral

Adults and children 12 years and over: One or two tablets of Remegel Summer Fruit to be chewed as symptoms occur. Repeat hourly as necessary. Maximum dose: 12 tablets in 24 hours.

Children under 12 years of age: Not recommended

The elderly: As for adults, see above

Hepatic Dysfunction: There is no specific information relating to the use of Remegel Summer Fruit in hepatic impairment. Normal adult dosage is appropriate.

Renal Dysfunction: Remegel Summer Fruit should be used with caution in subjects with moderate to severe renal impairment. Current use of calcium carbonate as a phosphate binder should be taken into account to prevent hypercalcaemia.

4.3 Contraindications

Hypersensitivity to any of the components. Hypercalcaemia.

4.4 Special Warnings And Precautions For Use

This product should be taken with care by subjects on a low phosphate diet (e.g. the malnourished), as it may lead to a phosphate depletion syndrome, (see Undesirable Effects).

This product should be used with caution in renal dysfunction, (see Posology and Method of Administration).

This product contains sucrose and glucose syrup and as such, care is required in patients with diabetes mellitus.

If symptoms persist, a pharmacist or doctor should be consulted.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In common with other antacids, calcium carbonate may form complexes with certain drugs such as tetracyclines and digoxin, leading to their reduced absorption. This should be taken into account when concomitant administration is considered.

4.6 Pregnancy And Lactation

There is no information relating to the use of Remegel Summer Fruit in pregnancy.

Calcium carbonate antacids have been used during pregnancy for many years without apparent ill consequence, although as with other antacids, this product should be administered with care in the first trimester.

There is no information relating to the excretion of Remegel Summer Fruit in breast milk. However, no problems would be anticipated from the use of this product during lactation.

4.7 Effects On Ability To Drive And Use Machines

No special comment – unlikely to produce an effect.

4.8 Undesirable Effects

Calcium carbonate may cause constipation. Eructation (due to carbon dioxide production in the stomach) may occur in come patients.

4.9 Overdose

Excessive ingestion of calcium carbonate can lead to hypercalcaemia (characterised by gastro-intestinal pain, nausea and vomiting), metabolic alkalosis and reversible renal failure, sometimes presenting as the milk-alkali syndrome. Treatment should be symptomatic and supportive. Haemodialysis and other therapeutic measures, such as saline diuresis, have been used to successfully treat excessive ingestion of calcium carbonate antacid.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Calcium carbonate is a potent antacid, neutralising gastric acid when taken orally.

Calcium carbonate neutralises gastric acid to provide fast relief from indigestion and heartburn.

5.2 Pharmacokinetic Properties

Absorption: Calcium carbonate is converted to calcium chloride by gastric acid (hydrochloric acid) in the stomach, with the resulting formation of carbon dioxide and water. Some of the calcium is absorbed from the intestines but the majority is reconverted into insoluble calcium salts such as carbonate and stearate, which is excreted in the faeces.

Distribution, Metabolism and Elimination: Once absorbed from the stomach, physiological concentrations of calcium are tightly controlled, principally through the effects of parathyroid hormone, vitamin D and its metabolites, and calcitonin. These control mechanisms are well documented in standard texts.

5.3 Preclinical Safety Data

Pre-clinical safety data does not add anything of further significance to the prescriber.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sugar solution; Glucose syrup (41o baume); Purified water; Hyfoama DS (hydrolysed milk protein); Gelatin 200 Bloom; Cornflour Starch; Sorbitol (crystalline); Glycerol; Titanium dioxide (E171); Allure Red (E129); Paramount C (hydrogenated vegetable fat); Amerfond Fondant Sugar; Raspberry flavour; Butylated hydroxyanisole; Talc

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25oC.

6.5 Nature And Contents Of Container

Each tablet in stickpacks is wrapped in printed silicone paper and overwrapped in hermetically sealed aluminium foil stickpack. 8 piece stickpack

6.6 Special Precautions For Disposal And Other Handling

None applicable.

7. Marketing Authorisation Holder

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

8. Marketing Authorisation Number(S)

PL 11314/0131.

9. Date Of First Authorisation/Renewal Of The Authorisation

03/01/2006

10. Date Of Revision Of The Text

03/01/2006



Drugs associated with Radionuclide Myocardial Perfusion Study

The following drugs and medications are in some way related to, or used in the treatment of Radionuclide Myocardial Perfusion Study. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.



1. Name Of The Medicinal Product

Risperidone 1mg Film-coated Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 1mg of the active substance risperidone.

Excipient: 61.25mg lactose monohydrate per tablet.

For a full list of excipients see section 6.1

3. Pharmaceutical Form

Film coated Tablet

White 8 x 5mm, oval biconvex, scored, coated tablet, marking "T1".

The tablet can be divided into equal halves.

4. Clinical Particulars 4.1 Therapeutic Indications

Risperidone tablets are indicated for the treatment of acute and chronic schizophrenic psychoses, and other psychotic conditions, in which positive symptoms (such as hallucinations, delusions, thought disturbances, hostility, suspiciousness), and/or negative symptoms (such as blunted affect, emotional and social withdrawal, poverty of speech) are prominent. Risperidone tablets also alleviate affective symptoms (such as depression, guilt feelings, anxiety) associated with schizophrenia.

Risperidone tablets are also effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.

Risperidone tablets are indicated for the treatment of mania in bipolar disorder. These episodes are characterized by symptoms such as elevated, expansive or irritable mood, inflated self-esteem, decreased need for sleep, pressured speech, racing thoughts, distractibility, or poor judgment, including disruptive or aggressive behaviours.

Risperidone tablets are not licensed for the treatment of behavioural symptoms of dementia (see section 4.4).

4.2 Posology And Method Of Administration

4.2. a Schizophrenia:

Switching from other antipsychotics: where medically appropriate, gradual discontinuation of the previous treatment while Risperidone therapy is initiated is recommended. Where medically appropriate when switching patients from depot antipsychotics, consider initiating Risperidone therapy in place of the next scheduled injection. The need for continuing existing antiparkinson medication should be re-evaluated periodically.

Adults

Risperidone tablets may be given once or twice daily. All patients, whether acute or chronic, should start with 2 mg/day Risperidone tablets. The dosage may be increased to 4 mg/day on the second day. Some patients, such as first episode patients, may benefit from a slower rate of titration. From then on the dosage can be maintained unchanged, or further individualised, if needed. Most patients will benefit from daily doses between 4 and 6 mg/day although in some, an optimal response may be obtained at lower doses.

Doses above 10 mg/day generally have not been shown to provide additional efficacy to lower doses and may increase the risk of extrapyramidal symptoms. Doses above 10 mg/day should only be used in individual patients if the benefit is considered to outweigh the risk. Doses above 16 mg/day have not been extensively evaluated for safety and therefore should not be used.

Elderly

A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.

Children

Use of Risperidone tablets for schizophrenia in children aged less than 15 years has not been formally evaluated.

Renal and liver disease

A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.

Risperidone tablets should be used with caution in this group of patients until further experience is gained.

4.2. b Bipolar Mania:

Adults

Risperidone should be administered on a once daily schedule, starting with 2 mg. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments of 1 mg per day. A dosing range between 1 and 6 mg per day is recommended.

As with all symptomatic treatments, the continued use of Risperidone tablets must be evaluated and justified on an ongoing basis.

Elderly

A starting dose of 0.5 mg is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.

Renal and liver disease

A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.

Risperidone tablets should be used with caution in this group of patients until further experience is gained.

Combined use with mood stabilisers

There is limited information on the combined use of Risperidone tablets with carbamazepine in bipolar mania. Carbamazepine has been shown to induce the metabolism of risperidone producing lower plasma levels of the antipsychotic fraction of Risperidone tablets (see Section 4.5). It is therefore not recommended to co-administer Risperidone tablets with carbamazepine in bipolar mania patients until further experience is gained. The combined use with lithium or valproate does not require any adjustment of the dose of Risperidone tablets.

Method of administration

Oral use.

4.3 Contraindications

Risperidone tablets are contraindicated in patients with a known hypersensitivity to risperidone or any other ingredients in the product.

4.4 Special Warnings And Precautions For Use

Elderly patients with dementia

Elderly patients with dementia treated with atypical antipsychotic drugs had an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including risperidone. In placebo-controlled trials with risperidone in this population, the incidence of mortality was 4.0% for risperidone–treated patients compared to 3.1% for placebo-treated patients. The mean age (range) of patients who died was 86 years (67-100).

In these trials treatment with furosemide plus risperidone was associated with a higher incidence of mortality compared to treatment with risperidone or furosemide alone, however, the mechanism for an interaction is unclear. Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings.

No consistent pattern for cause of death observed. Nevertheless caution should be exercised and the risks and benefits of the combination of risperidone and furosemide or co-medication with other potent diuretics considered prior to the decision to use. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.

Cerebrovascular Adverse Events (CAE)

Risperidone tablets are not recommended for the treatment of behavioural symptoms of dementia because of an increased risk of cerebrovascular adverse events (including cerebrovascular accidents and transient ischaemic attacks). Treatment of acute psychoses in patients with a history of dementia should be limited to short term only and should be under specialist advice.

Data from randomised clinical trials conducted in elderly >65 years) patients with dementia indicate that there is an approximately 3-fold increased risk of cerebrovascular adverse events (including cerebrovascular accidents and transient ischaemic attacks) with risperidone, compared with placebo. Cerebrovascular adverse events occurred in 3.3% (33/989) of patients treated with risperidone and 1.2% (8/693) of patients treated with placebo. The Odds Ratio (95% exact confidence interval) was 2.96 (1.33, 7.45).

Physicians should consider carefully the risk of cerebrovascular adverse events with Risperidone tablets (given the observations in elderly patients with dementia detailed above) before treating any patient with a previous history of CVA/TIA. Consideration should also be given to other risk factors for cerebrovascular disease including hypertension, diabetes, current smoking, atrial fibrillation, etc.

Alpha-blocking activity

Due to the alpha-blocking activity of Risperidone tablets, orthostatic hypotension can occur, especially during the initial dose-titration period. A dose reduction should be considered if hypotension occurs.

Risperidone tablets should be used with caution in patients with known cardiovascular disease including those associated with prolongation of the QT interval and the dose should be gradually titrated. In clinical trials, Risperidone was not associated with an increase in QTc intervals. As with other antipsychotics, caution is advised when prescribing with medications known to prolong the QT interval.

If further sedation is required, an additional drug (such as a benzodiazepine) should be administered rather than increasing the dose of Risperidone tablets.

Tardive Dyskinesia/Extrapyramidal Symptoms (TD/EPS)

Drugs with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia, characterised by rhythmical involuntary movements, predominantly of the tongue and/or face. It has been reported that the occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotic drugs should be considered.

Neuroleptic Malignant Syndrome (NMS)

Neuroleptic malignant syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated CPK levels, has been reported to occur with neuroleptics. In this event all antipsychotic drugs including risperidone should be discontinued.

It is recommended to halve both the starting dose and the subsequent dose increments in geriatric patients and in patients with renal or liver insufficiency.

Caution should also be exercised when prescribing Risperidone tablets to patients with Parkinson's disease since, theoretically, it may cause a deterioration of the disease.

Hyperglycaemia

Hyperglycaemia or exacerbation of pre-existing diabetes has been reported in very rare cases during treatment with Risperdal. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus (see also section 4.8 Undesirable effects).

Venous thromboembolism (VTE)

Cases of venous thrombolembolism (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 risperidone and preventative measures undertaken.

Other

Classical neuroleptics are known to lower the seizure threshold. Caution is recommended when treating patients with epilepsy.

As with other antipsychotics, patients should be advised of the potential for weight gain.

Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia have very rarely been described after abrupt cessation of high doses 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. Therefore, gradual withdrawal is advisable.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Possible interactions of Risperidone tablets with other drugs have not been systematically evaluated. Given the primary CNS effects of risperidone, it should be used with caution in combination with other centrally acting drugs including alcohol.

Risperidone tablets may antagonise the effect of levodopa and other dopamine-agonists.

Carbamazepine has been shown to decrease the plasma levels of the antipsychotic fraction of Risperidone tablets. A similar effect might be anticipated with other drugs which stimulate metabolising enzymes in the liver. On initiation of carbamazepine or other hepatic enzyme-inducing drugs, the dosage of Risperidone tablets should be re-evaluated and increased if necessary. Conversely, on discontinuation of such drugs, the dosage of Risperidone tablets should be re-evaluated and decreased if necessary.

Phenothiazines, tricyclic antidepressants and some beta-blockers may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction. Fluoxetine and paroxetine, CYP2D6 inhibitors, may increase the plasma concentration of risperidone but less so of the active antipsychotic fraction. When concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of Risperidone. Based on in vitro studies, the same interaction may occur with haloperidol. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction. Cimetidine and ranitidine increase the bioavailability of risperidone, but only marginally that of the active antipsychotic fraction. Erythromycin, a CYP 3A4 inhibitor, does not change the pharmacokinetics of risperidone and the active antipsychotic fraction. The cholinesterase inhibitor galantamine does not show a clinically relevant effect on the pharmacokinetics of risperidone and the active antipsychotic fraction. A study of donepezil in non-elderly healthy volunteers also showed no clinically relevant effect on the pharmacokinetics of risperidone and the antipsychotic fraction.When Risperidone tablets are taken together with other highly protein-bound drugs, there is no clinically relevant displacement of either drug from the plasma proteins.

See section 4.4 (Special warnings and special precautions for use) regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide.

Risperidone does not show a clinically relevant effect on the pharmacokinetics of valproate or topiramate. The potential for reduced toleration of the combination treatment should be taken into consideration when co-administering risperidone and topiramate.

In patients on long-term lithium and older/typical neuroleptic therapy, no significant change occurred in the pharmacokinetics of lithium after substitution of the concomitant neuroleptic with risperidone.

Food does not affect the absorption of risperidone.

4.6 Pregnancy And Lactation

Pregnancy

Although, in experimental animals, risperidone did not show direct reproductive toxicity, some indirect, prolactin- and CNS-mediated effects were observed, typically delayed oestrus and changes in mating and nursing behaviour in rats. No teratogenic effect of risperidone was noted in any study. The safety of Risperidone tablets for use during human pregnancy has not been established. Reversible extrapyramidal symptoms in the neonate were observed following postmarketing use of risperidone during the last trimester of pregnancy. Therefore, Risperidone should only be used during pregnancy if the benefits outweigh the risks.

Lactation

In animal studies, risperidone and 9-hydroxyrisperidone are excreted in the milk. It has been demonstrated that risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving Risperidone should not breast feed.

4.7 Effects On Ability To Drive And Use Machines

Risperidone may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.

4.8 Undesirable Effects

Risperidone tablets are generally well tolerated and in many instances it has been difficult to differentiate adverse events from symptoms of the underlying disease. Adverse events observed in association with the use of Risperidone tablets include:

Common: insomnia, agitation, anxiety, headache.

Less common: somnolence, fatigue, dizziness, impaired concentration, constipation, dyspepsia, nausea/vomiting, abdominal pain, blurred vision, priapism, erectile dysfunction, ejaculatory dysfunction, orgasmic dysfunction, urinary incontinence, rhinitis, rash and other allergic reactions.

Cerebrovascular accidents have been observed during treatment with risperidone. (see Section 4.4 Special warnings and precautions for use).

Hyperglycaemia and exacerbation of pre-existing diabetes have been reported in very rare cases during risperidone treatment.

The incidence and severity of extrapyramidal symptoms are significantly less than with haloperidol. However, in some cases the following extrapyramidal symptoms may occur: tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia. If acute in nature, these symptoms are usually mild and are reversible upon dose reduction and/or administration of antiparkinson medication, if necessary. In clinical trials in patients with acute mania risperidone treatment resulted in an incidence of EPS>10%. This is lower than the incidence observed in patients treated with classical neuroleptics.

Occasionally, orthostatic dizziness, hypotension including orthostatic, tachycardia including reflex tachycardia and hypertension have been observed following administration of Risperidone tablets.

Risperidone tablets can induce a dose-dependent increase in plasma prolactin concentration. Possible associated manifestations are: galactorrhoea, gynaecomastia, disturbances of the menstrual cycle and amenorrhoea.

Weight gain, oedema and increased hepatic enzyme levels have been observed during treatment with Risperidone tablets.

A decrease in neutrophil and/or thrombocyte count has been reported.

As with classical neuroleptics, rare cases of the following have been reported in schizophrenic patients: water intoxication with hyponatraemia, either due to polydipsia or to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH); tardive dyskinesia, body temperature dysregulation and seizures.

Benign pituitary adenomas have been reported very rarely in risperidone users during postmarketing surveillance. No causal association has been established.

Very rare cases of angioedema have been reported in postmarketing experience.

Sedation has been reported more frequently in children and adolescents than in adults. In general, sedation is mild and transient.

Withdrawal reactions have been reported in association with antipsychotic drugs (see section 4.4 Special warnings and special precautions for use).

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

4.9 Overdose

In general, reported signs and symptoms have been those resulting from an exaggeration of the drug's known pharmacological effects. These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. In overdose, rare cases of QT-prolongation have been reported. In case of acute overdosage, the possibility of multiple drug involvement should be considered.

Establish and maintain a clear airway, and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

There is no specific antidote to Risperidone tablets. Therefore appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other antipsychotics

ATC code: N05AX

Risperidone is a novel antipsychotic belonging to a new class of antipsychotic agents, the benzisoxazole-derivatives.

Risperidone is a selective monoaminergic antagonist with a high affinity for both serotonergic 5-HT2 and dopaminergic D2 receptors. Risperidone binds also to alpha1-adrenergic receptors and, with lower affinity, to H1-histaminergic and alpha2-adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, that is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy than classical neuroleptics. Balanced central serotonin and dopamine antagonism may reduce the tendency to cause extrapyramidal side effects, and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.

5.2 Pharmacokinetic Properties

Risperidone is completely absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours. The absorption of risperidone is not affected by food .

The most important route of metabolism of risperidone is hydroxylation by cytochrome CYP 2D6 to 9-hydroxy-risperidone which has a similar pharmacological activity to risperidone. This hydroxylation is subject to debrisoquine-type genetic polymorphism but this does not affect the active antipsychotic fraction since this consists of risperidone and its active metabolite 9-hydroxyrisperidone. After oral administration, the elimination half-life of the active antipsychotic fraction is 24 hours.

A single-dose study showed higher active plasma concentrations and a slower elimination of risperidone in the elderly and in patients with renal insufficiency. Risperidone plasma concentrations were normal in patients with liver insufficiency.

Topiramate modestly reduces the bioavailability of risperidone, but not that of the active antipsychotic fraction. Therefore, this interaction is unlikely to be of clinical significance. The bioavailability of topiramate is slightly decreased when administered in combination with risperidone. This interaction is not likely to be clinically significant.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber other than those already provided in other sections of the SPC.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Lactose anhydrous

Cellulose, microcrystalline

Starch pregelatinised

Magnesium stearate

Hypromellose 6

Macrogol 6000

Titanium dioxide (E171)

6.2 Incompatibilities

No incompatibilities known.

6.3 Shelf Life

2 years (bottle) or 3 years (blister)

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Blister pack: PVC-PVDC / Al foil. Pack sizes 14, 20, 28, 30, 42, 56 or 60 film coated tablets

HDPE Container with LDPE Cap. Pack sizes 20, 40, 60 or 100 film coated tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special precautions for storage.

7. Marketing Authorisation Holder

Actavis Group PTC ehf

Reykjav?kurvegi 76-78

220 Hafnarfjordur

Iceland.

8. Marketing Authorisation Number(S)

PL 30306/0091

9. Date Of First Authorisation/Renewal Of The Authorisation

01 /04/2008

10. Date Of Revision Of The Text

17th February 2010

11 DOSIMETRY

IF APPLICABLE

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

IF APPLICABLE



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.

Rifamycin derivatives are antibiotics that work by binding to and inhibiting the mycobacterial DNA dependent RNA polymerase. These antibiotics are bacteriocidal and therefore extremely effective antituberculosis agents, but resistance can develop rapidly if used as a single agent. They easily penetrate into cells, body fluids and cerebrospinal fluid so can be used against organisms in the extracellular component and those that may be present in cells such as macrophages. Rifamycin antibiotics should be used throughout the course of tuberculosis treatment, which can be between nine months to a year.

See also

Medical conditions associated with rifamycin derivatives:

Bartonellosis Endocarditis Haemophilus influenzae Prophylaxis Legionella Pneumonia Leprosy Leprosy, Borderline Leprosy, Tuberculoid Meningitis Meningococcal Meningitis Prophylaxis Mycobacterium avium-intracellulare, Prophylaxis Mycobacterium avium-intracellulare, Treatment Nasal Carriage of Staphylococcus aureus Tuberculosis, Active Tuberculosis, HIV Positive Tuberculosis, Latent Tuberculosis, Prophylaxis Drug List: Rifadin Mycobutin Priftin Rifadin-Iv Rimactane



1. Name Of The Medicinal Product

Ramipril 10mg Tablets

2. Qualitative And Quantitative Composition

10 mg ramipril.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet

White to almost white, oblong tablets with a score-line.

Upper stamp: HMO/HMO

Lower stamp: anonymous

4. Clinical Particulars 4.1 Therapeutic Indications

- Treatment of hypertension.

- Cardiovascular prevention: reduction of cardiovascular morbidity and mortality in patients with:

o manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or

o diabetes with at least one cardiovascular risk factor (see section 5.1).

- Treatment of renal disease:

o Incipient glomerular diabetic nephropathy as defined by the presence of microalbuminuria,

o Manifest glomerular diabetic nephropathy as defined by macroproteinuria in patients with at least one cardiovascular risk factor (see section 5.1),

o Manifest glomerular non diabetic nephropathy as defined by macroproteinuria

- Treatment of symptomatic heart failure.

- Secondary prevention after acute myocardial infarction: reduction of mortality from the acute phase of myocardial infarction in patients with clinical signs of heart failure when started> 48 hours following acute myocardial infarction.

4.2 Posology And Method Of Administration

Oral use.

It is recommended that RAMIPRIL is taken each day at the same time of the day.

RAMIPRIL can be taken before, with or after meals, because food intake does not modify its bioavailability (see section 5.2).

RAMIPRIL has to be swallowed with liquid. It must not be chewed or crushed.

Adults

Diuretic-Treated patients

Hypotension may occur following initiation of therapy with RAMIPRIL; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.

If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with RAMIPRIL (see section 4.4).

In hypertensive patients in whom the diuretic is not discontinued, therapy with RAMIPRIL should be initiated with a 1.25 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of RAMIPRIL should be adjusted according to blood pressure target.

Hypertension

The dose should be individualised according to the patient profile (see section 4.4) and blood pressure control.

RAMIPRIL may be used in monotherapy or in combination with other classes of antihypertensive medicinal products.

Starting dose

RAMIPRIL should be started gradually with an initial recommended dose of 2.5 mg daily.

Patients with a strongly activated renin-angiotensin-aldosterone system may experience an excessive drop in blood pressure following the initial dose. A starting dose of 1.25 mg is recommended in such patients and the initiation of treatment should take place under medical supervision (see section 4.4).

Titration and maintenance dose

The dose can be doubled at interval of two to four weeks to progressively achieve target blood

pressure; the maximum permitted dose of RAMIPRIL is 10 mg daily. Usually the dose is administered once daily.

Cardiovascular prevention

Starting dose

The recommended initial dose is 2.5 mg of RAMIPRIL once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose should be gradually increased. It is recommended to double the dose after one or two weeks of treatment and - after another two to three weeks - to increase it up to the target maintenance dose of 10 mg RAMIPRIL once daily.

See also posology on diuretic treated patients above.

Treatment of renal disease

In patients with diabetes and microalbuminuria:

Starting dose:

The recommended initial dose is 1.25 mg of RAMIPRIL once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

In patients with diabetes and at least one cardiovascular risk

Starting dose:

The recommended initial dose is 2.5 mg of RAMIPRIL once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 5 mg RAMIPRIL after one or two weeks and then to 10 mg RAMIPRIL after a further two or three weeks is recommended. The target daily dose is 10 mg.

In patients with non- diabetic nephropathy as defined by macroproteinuria

Starting dose:

The recommended initial dose is 1.25 mg of RAMIPRIL once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

Symptomatic heart failure

Starting dose

In patients stabilized on diuretic therapy, the recommended initial dose is 1.25 mg daily.

Titration and maintenance dose

RAMIPRIL should be titrated by doubling the dose every one to two weeks up to a maximum daily dose of 10 mg. Two administrations per day are preferable.

Secondary prevention after acute myocardial infarction and with heart failure

Starting dose

After 48 hours, following myocardial infarction in a clinically and haemodynamically stable patient, the starting dose is 2.5 mg twice daily for three days. If the initial 2.5 mg dose is not tolerated a dose of 1.25 mg twice a day should be given for two days before increasing to 2.5 mg and 5 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day the treatment should be withdrawn.

See also posology on diuretic treated patients above.

Titration and maintenance dose

The daily dose is subsequently increased by doubling the dose at intervals of one to three days up to the target maintenance dose of 5 mg twice daily.

The maintenance dose is divided in 2 administrations per day where possible.

If the dose cannot be increased to 2.5 mg twice a day treatment should be withdrawn. Sufficient experience is still lacking in the treatment of patients with severe (NYHA IV) heart failure immediately after myocardial infarction. Should the decision be taken to treat these patients, it is recommended that therapy be started at 1.25 mg once daily and that particular caution be exercised in any dose increase.

Special populations

Patients with renal impairment

Daily dose in patients with renal impairment should be based on creatinine clearance (see section 5.2):

- if creatinine clearance is

- if creatinine clearance is between 30-60 ml/min, it is not necessary to adjust the initial dose (2.5 mg/day); the maximal daily dose is 5 mg;

- if creatinine clearance is between 10-30 ml/min, the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg;

- in haemodialysed hypertensive patients: ramipril is slightly dialysable; the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg; the medicinal product should be administered few hours after haemodialysis is performed.

Patients with hepatic impairment (see section 5.2)

In patients with hepatic impairment, treatment with RAMIPRIL must be initiated only under close medical supervision and the maximum daily dose is 2.5 mg RAMIPRIL.

Elderly

Initial doses should be lower and subsequent dose titration should be more gradual because of greater chance of undesirable effects especially in very old and frail patients. A reduced initial dose of 1.25 mg ramipril should be considered.

Paediatric population

RAMIPRIL is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

4.3 Contraindications

- Hypersensitivity to the active substance, to any of the excipients or any other ACE (Angiotensin Converting Enzyme) inhibitors (see section 6.1)

- History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs)

- Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5)

- Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney

- 2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6)

- Ramipril must not be used in patients with hypotensive or haemodynamically unstable states.

4.4 Special Warnings And Precautions For Use

Special populations

Pregnancy: ACE inhibitors such as ramipril, or Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE inhibitor/ AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/ AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Patients at particular risk of hypotension

Patients with strongly activated renin-angiotensin-aldosterone system:

Patients with strongly activated renin-angiotensin-aldosterone system are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or at first dose increase.

Significant activation of renin-angiotensin-aldosterone system is to be anticipated and medical supervision including blood pressure monitoring is necessary, for example in:

- patients with severe hypertension

- patients with decompensated congestive heart failure

- patients with haemodynamically relevant left ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve)

- patients with unilateral renal artery stenosis with a second functional kidney

- patients in whom fluid or salt depletion exists or may develop (including patients with diuretics)

- patients with liver cirrhosis and/or ascites

- patients undergoing major surgery or during anaesthesia with agents that produce hypotension.

Generally, it is recommended to correct dehydration, hypovolaemia or salt depletion before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed out against the risk of volume overload).

Transient or persistent heart failure post MI

Patients at risk of cardiac or cerebral ischemia in case of acute hypotension

The initial phase of treatment requires special medical supervision.

Elderly patients

See section 4.2.

Surgery

It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.

Monitoring of renal function

Renal function should be assessed before and during treatment and dosage adjusted especially in the initial weeks of treatment. Particularly careful monitoring is required in patients with renal impairment (see section 4.2). There is a risk of impairment of renal function, particularly in patients with congestive heart failure or after a renal transplant.

Angioedema

Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see

section 4.8).

In case of angioedema, RAMIPRIL must be discontinued.

Emergency therapy should be instituted promptly. Patient should be kept under observation for at least 12 to 24 hours and discharged after complete resolution of the symptoms.

Intestinal angioedema has been reported in patients treated with ACE inhibitors including RAMIPRIL (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting).

Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of RAMIPRIL should be considered prior to desensitization.

Hyperkalaemia

Hyperkalaemia has been observed in some patients treated with ACE inhibitors including RAMIPRIL. Patients at risk for development of hyperkalaemia include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium retaining diuretics and other plasma potassium increasing active substances, or conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been rarely seen and bone marrow depression has also been reported. It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma), and all those treated with other medicinal products that can cause changes in the blood picture (see sections 4.5 and 4.8).

Ethnic differences

ACE inhibitors cause higher rate of angioedema in black patients than in non black patients.

As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black people than in non black patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Contra-indicated combinations

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Precautions for use

Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin): Hyperkalaemia may occur, therefore close monitoring of serum potassium is required.

Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g.nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated (see section 4.2 for diuretics)

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of RAMIPRIL: Blood pressure monitoring is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions (see section 4.4).

Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium level must be monitored.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Blood glucose monitoring is recommended.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of RAMIPRIL is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalaemia.

4.6 Pregnancy And Lactation

RAMIPRIL is not recommended during the first trimester of pregnancy (see section 4.4) and contraindicated during the second and third trimesters of pregnancy (see section 4.3).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. ACE inhibitor/ Angiotensin II Receptor Antagonist (AIIRA) therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also 5.3 'Preclinical safety data'). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia (see also sections 4.3 and 4.4).

Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), ramipril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects On Ability To Drive And Use Machines

Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).

This can happen especially at the start of treatment, or when changing over from other preparations. After the first dose or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.

4.8 Undesirable Effects

The safety profile of ramipril includes persistent dry cough and reactions due to hypotension. Serious adverse reactions include angioedema, hyperkalaemia, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Adverse reactions frequency is defined using the following convention:

Very common (

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

 

 

Common

Uncommon

Rare

Very rare

Not known

Cardiac disorders

 

 

Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral

 

 

 

 

 

 

Blood and lymphatic system disorders

 

 

 

Eosinophilia

White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased

 

 

Bone marrow failure, pancytopenia, haemolytic anaemia

Nervous system disorders

 

Headache, dizziness

Vertigo, paraesthesia, ageusia, dysgeusia,

Tremor, balance disorder

 

 

Cerebral ischaemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia

Eye disorders

 

 

 

Visual disturbance including blurred vision

Conjunctivitis

 

 

 

 

Ear and labyrinth disorders

 

 

 

 

Hearing impaired, tinnitus

 

 

 

 

Respiratory, thoracic and mediastinal disorders

 

Non-productive tickling cough, bronchitis, sinusitis, dyspnoea

Bronchospasm including asthma aggravated, nasal congestion

 

 

 

 

 

 

Gastrointestinal disorders

 

 

Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting

Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth

Glossitis

 

 

Aphtous stomatitis

Renal and urinary disorders

 

 

 

Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased

 

 

 

 

 

 

 

Skin and subcutaneous tissue disorders

 

Rash in particular maculo-papular

Angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis

Exfoliative dermatitis, urticaria, onycholysis,

Photosensitivity reaction

Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia

Musculoskeletal and connective tissue disorders

 

Muscle spasms, myalgia

Arthralgia

 

 

 

 

 

 

Metabolism and nutrition disorders

 

Blood potassium increased

Anorexia, decreased appetite,

 

 

 

 

Blood sodium decreased

Vascular disorders

 

Hypotension, orthostatic blood pressure decreased, syncope

Flushing

Vascular stenosis, hypoperfusion, vasculitis

 

 

Raynaud's phenomenon

General disorders and administration site conditions

 

Chest pain, fatigue

Pyrexia

Asthenia

 

 

 

 

Immune system disorders

 

 

 

 

 

 

 

 

 

Anaphylactic or anaphylactoid reactions, antinuclear antibody increased

Hepatobiliary disorders

 

 

Hepatic enzymes and/or bilirubin conjugated increased,

Jaundice cholestatic, hepatocellular damage

 

 

Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).

Reproductive system and breast disorders

 

 

Transient erectile impotence, libido decreased

 

 

 

 

 

Gynaecomastia

Psychiatric disorders

 

 

Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence

 

Confusional state

 

 

Disturbance in attention

4.9 Overdose

Symptoms associated with overdosage of ACE inhibitors may include excessive peripheral

vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: ACE Inhibitors, plain, ATC code C09AA05.

Mechanism of action

Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In plasma and tissue this enzyme catalyses the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

Pharmacodynamic effects

Antihypertensive properties:

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.

In most patients the onset of the antihypertensive effect of a single dose becomes apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.

The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years.

Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

Heart failure:

In addition to conventional therapy with diuretics and optional cardiac glycosides, ramipril has been shown to be effective in patients with functional classes II-IV of the New-York Heart Association. The drug had beneficial effects on cardiac haemodynamics (decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index). It also reduced neuroendocrine activation.

Clinical efficacy and safety

Cardiovascular prevention/Nephroprotection;

A preventive placebo-controlled study (the HOPE-study), was carried out in which ramipril was added to standard therapy in more than 9,200 patients. Patients with increased risk of cardiovascular disease following either atherothrombotic cardiovascular disease (history of coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol level, low high-density lipoprotein cholesterol level or cigarette smoking) were included in the study.

The study showed that ramipril statistically significantly decreases the incidence of myocardial infarction, death from cardiovascular causes and stroke, alone and combined (primary combined events).

The HOPE Study: Main Results;

 

 

Ramipril

Placebo

relative risk

(95% confidence interval)

p-value

 

 

%

%

 

 

 

 

All patients

n=4,645

N=4,652

 

 

Primary combined events

14.0

17.8

0.78 (0.70-0.86)

<0.001

Myocardial infarction

9.9

12.3

0.80 (0.70-0.90)

<0.001

Death from cardiovascular causes

6.1

8.1

0.74 (0.64-0.87)

<0.001

Stroke

3.4

4.9

0.68 (0.56-0.84)

<0.001

 

 

 

 

 

 

 

 

 

 

Secondary endpoints

 

 

 

 

Death from any cause

10.4

12.2

0.84 (0.75-0.95)

0.005

Need for Revascularisation

16.0

18.3

0.85 (0.77-0.94)

0.002

Hospitalisation for unstable angina

12.1

12.3

0.98 (0.87-1.10)

NS

Hospitalisation for heart failure



1. Name Of The Medicinal Product

Ralgex Cream.

2. Qualitative And Quantitative Composition

Glycol Monosalicylate DAB 10.0% w/w; Methyl Nicotinate BP 1.0% w/w; Capsicum Oleoresin BPC 1973 0.12% w/w.

3. Pharmaceutical Form

Cream.

4. Clinical Particulars 4.1 Therapeutic Indications

Symptomatic relief of muscular pain and stiffness, including backache, sciatica, lumbago, fibrositis and rheumatic pain.

4.2 Posology And Method Of Administration

Adults and children aged 12 years and over: After trial use, rub into the skin until absorbed. To be applied as required to the affected area. Repeat as necessary up to four times a day. Not to be used on children under 12 years except on medical advice. The elderly: The normal adult directions for use can be followed.

4.3 Contraindications

Known hypersensitivity to salicylates or to any of the ingredients of the cream. Injuries involving broken skin.

4.4 Special Warnings And Precautions For Use

Some people experience stronger effects with Ralgex than others; the product should be tried on a small area first. Do not apply near the eyes, mouth or on sensitive body areas. Day-to-day variation may occur in the sensitivity of the skin, which is more sensitive after a hot bath or in hot weather.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

No evidence of safety of this product has been determined in pregnancy. It is not necessary to contraindicate this product in pregnancy and lactation provided caution is exercised and the directions for use are followed. However, as with all medicines, the advice of a doctor should be sought before the product is used.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Mild irritation of the skin (reddening, burning sensations and rarely swelling) have been reported, which may become more severe. Rashes have also been rarely reported.

4.9 Overdose

Overuse would probably cause localised redness, swelling and burning sensations of the skin owing to the counter-irritant effect of the product. Rashes may also develop. These should subside on withdrawal of the product, but occasionally may require treatment. Where this is indicated, relief would be obtained from gently swabbing the area with gauze or white lint soaked in vegetable oil. Rarely the application of a cream or ointment containing corticosteroid may be necessary. It is most unlikely that even the most excessive use of this product would lead to sufficient percutaneous absorption of active ingredients to cause systemic effects. In the case of accidental oral ingestion, the advice of a doctor should be sought.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: other topical products for joint and muscular pain, ATC code: M02A.

Methyl nicotinate has a counter-irritant effect by a rubefacient action. It readily penetrates the cutaneous barrier to produce vasodilatation and elevation of skin temperature. Capsicum oleoresin has a counter-irritant effect by producing irritation and a transient feeling of warmth. Glycol monosalicylate provides the anti-inflammatory and analgesic action. Clinical data demonstrate that Ralgex Cream provides rapid warming relief for muscular aches and pains.

5.2 Pharmacokinetic Properties

Glycol monosalicylate and methyl nicotinate are readily absorbed percutaneously.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Polawax; Arlacel 165; Oleyl Alcohol; Dimethicone; Methylhydroxybenzoate; Butylhydroxybenzoate; Goliath Perfume SE 83.0502; Neutralaire D7; Deionised water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Two years.

6.4 Special Precautions For Storage

Store below 25oC.

6.5 Nature And Contents Of Container

Flexible aluminium tubes containing either 40g or 100g of product, internally lacquered and having a white polypropylene screw cap. The tubes are contained in a boxboard carton.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

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

8. Marketing Authorisation Number(S)

PL 17905/0052

9. Date Of First Authorisation/Renewal Of The Authorisation

10/12/96, 09/01/02

10. Date Of Revision Of The Text

September 2006



1. Name Of The Medicinal Product

REPEVAX®, suspension for injection, in pre-filled syringe

Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine (adsorbed, reduced antigen(s) content)

2. Qualitative And Quantitative Composition

1 dose (0.5 mL) contains:

Diphtheria Toxoid........................................................... Not less than 2 IU* (2 Lf)

Tetanus Toxoid ........................................................... Not less than 20 IU* (5 Lf)

Pertussis Antigens

Pertussis Toxoid.............................................................................. 2.5 micrograms

Filamentous Haemagglutinin...........................................................5 micrograms

Pertactin.......................................................................................... 3 micrograms

Fimbriae Types 2 and 3................................................................... 5 micrograms

Poliovirus (Inactivated)**

Type 1.......................................................................................... 40 D antigen units

Type 2............................................................................................ 8 D antigen units

Type 3.......................................................................................... 32 D antigen units

Adsorbed on aluminium phosphate....................................................... 1.5 mg (0.33 mg aluminium)

* As lower confidence limit (p = 0.95) of activity measured according to the assay described in the European Pharmacopoeia.

** Produced in Vero cells.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Suspension for injection in pre-filled syringe

REPEVAX appears as a uniform, cloudy, white suspension.

4. Clinical Particulars 4.1 Therapeutic Indications

REPEVAX is indicated for active immunization against diphtheria, tetanus, pertussis and poliomyelitis in persons from 3 years of age as a booster following primary immunization.

The use of REPEVAX should be determined on the basis of official recommendations.

4.2 Posology And Method Of Administration

Posology

A single injection of one (0.5 mL) dose is recommended in all indicated age groups.

REPEVAX may be administered from the age of three years onwards. The use of REPEVAX in children aged 3 to 5 years is based upon studies in which REPEVAX was given as the fourth dose (first booster) of diphtheria, tetanus, pertussis and poliomyelitis vaccines.

REPEVAX is a vaccine containing low-dose diphtheria toxoid plus tetanus toxoid in combination with pertussis and polio antigens for booster vaccinations. When administering the vaccine, indications and dosing intervals according to the official recommendations should be considered for all antigens contained in the vaccine.

Individuals with an incomplete, or no history of a primary series of diphtheria and tetanus toxoids or polio vaccine should not be vaccinated with REPEVAX.

REPEVAX is not precluded in persons with an incomplete, or no history of previous pertussis vaccination. However, a booster response will only be elicited in individuals who have been previously primed by vaccination or by natural infection.

There are currently no data upon which to base a recommendation for the optimal interval for administering subsequent booster doses with REPEVAX.

Method of Administration

A single injection of one dose (0.5 mL) of REPEVAX should be administered intramuscularly. The preferred site is into the deltoid muscle.

Do not administer REPEVAX intravascularly. After insertion of the needle, aspirate to ensure that the needle has not entered a blood vessel.

REPEVAX should not be administered into the gluteal area; intradermal or subcutaneous routes should not be used (in exceptional cases the subcutaneous route may be considered, see section 4.4).

4.3 Contraindications

• REPEVAX should not be administered to persons with known hypersensitivity

- to diphtheria, tetanus, pertussis or poliomyelitis vaccines

- to any other component of the vaccine (see Section 6.1)

- to any residual substances carried over from manufacture (formaldehyde, glutaraldehyde, streptomycin, neomycin, polymyxin B and bovine serum albumin), which may be present in undetectable trace amounts.

• REPEVAX should not be administered to persons who experienced an encephalopathy of unknown origin within 7 days of previous immunization with a pertussis-containing vaccine.

• As with other vaccines, administration of REPEVAX should be postponed in persons suffering from an acute severe febrile illness. The presence of a minor infection (e.g., mild upper respiratory infection) is not a contraindication.

4.4 Special Warnings And Precautions For Use

REPEVAX should not be used for primary immunization.

Regarding the interval between a booster dose of REPEVAX and preceding booster doses of diphtheria and/or tetanus containing vaccines, the official recommendations should generally be followed. Clinical data in adults have demonstrated that there was no clinically relevant difference in rates of adverse reactions associated with administration of REPEVAX as early as 4 weeks, compared to at least 5 years after a preceding dose of tetanus and diphtheria-containing vaccine.

Prior to Immunization

Vaccination should be preceded by a review of the person's medical history (in particular previous vaccinations and possible adverse events). In persons who have a history of serious or severe reaction within 48 hours of a previous injection with a vaccine containing similar components, administration of REPEVAX vaccine must be carefully considered.

As with all injectable vaccines, appropriate medical treatment and supervision should be readily available for immediate use in case of a rare anaphylactic reaction following the administration of the vaccine.

If Guillain-Barr? syndrome or brachial neuritis has occurred following receipt of prior vaccine containing tetanus toxoid, the decision to give any vaccine containing tetanus toxoid should be based on careful consideration of the potential benefits and possible risks.

REPEVAX should not be administered to individuals with a progressive or unstable neurological disorder, uncontrolled epilepsy or progressive encephalopathy until a treatment regimen has been established and the condition has stabilized.

The rates and severity of adverse events in recipients of tetanus toxoid antigen are influenced by the number of prior doses and level of pre-existing antitoxins.

The immunogenicity of the vaccine could be reduced by immunosuppressive treatment or immunodeficiency. It is recommended to postpone the vaccination until the end of such disease or treatment if practical. Nevertheless, vaccination of HIV infected persons or persons with chronic immunodeficiency, such as AIDS, is recommended even if the antibody response might be limited.

Administration Precautions

Intramuscular injections should be given with care in patients on anticoagulant therapy or suffering from coagulation disorders because of the risk of haemorrhage. In these situations and following official recommendations the administration of REPEVAX by deep subcutaneous injection may be considered, although there is a risk of increased local reactions.

Other Considerations

As with any vaccine, a protective immune response may not be elicited in all vaccinees (see section 5.1).

A persistent nodule at the site of injection may occur with all adsorbed vaccines, particularly if administered into the superficial layers of the subcutaneous tissue.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

REPEVAX may be administered concurrently with a dose of hepatitis B vaccine.

REPEVAX may be administered concurrently with a dose of recombinant Human Papillomavirus with no significant interference with antibody response to any of the components of either vaccine. However, a trend of lower anti-HPV GMTs was observed in the concomitant group. The clinical significance of this observation is not known. This is based on the results from a clinical trial in which REPEVAX was administered concomitantly with the first dose of Gardasil (see section 4.8).

Separate limbs must be used for the site of injection. Interaction studies have not been carried out with other vaccines, biological products or therapeutic medications. However, in accordance with commonly accepted immunization guidelines, since REPEVAX is an inactivated product it may be administered concomitantly with other vaccines or immunoglobulins at separate injection sites.

In the case of immunosuppressive therapy please refer to Section 4.4.

4.6 Pregnancy And Lactation

The effect of REPEVAX on embryo-foetal development has not been assessed. No teratogenic effect of vaccines containing diphtheria or tetanus toxoids, or inactivated poliovirus has been observed following use in pregnant women. Data on the use of vaccines containing acellular pertussis antigens in pregnant women are not available.

The use of this combined vaccine is not recommended during pregnancy.

It is not known whether the active substances included in REPEVAX are excreted in human milk. The effect on breast-fed infants of the administration of REPEVAX to their mothers has not been studied.

The risks and benefits of vaccination should be assessed before making the decision to immunize a nursing woman.

The effect of administration of REPEVAX during lactation has not been assessed. Nevertheless, as REPEVAX contains toxoids or inactivated antigens, no risk to the breastfed infant should be expected. The benefits versus the risk of administering REPEVAX to breastfeeding women should be evaluated by the health-care providers.

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.

4.8 Undesirable Effects

Clinical Trials

In clinical trials REPEVAX was given to a total of 1,384 children, adolescent and adults. Most commonly reported reactions following vaccination included local reactions at the injection site (pain, redness and swelling). These signs and symptoms usually were mild in intensity and occurred within 48 hours following vaccination. They all resolved without sequelae.

Adverse reactions are ranked under headings of frequency using the following convention:

Very common

(

Common

(

Uncommon

(

Rare

(

Very Rare

(<1/10,000), including individual cases

Not Known

cannot be estimated from the available data

Children

In a clinical study, 240 children were primed at 3, 5 and 12 months of age with a DTaP vaccine with no additional dose in the second year of life. These children received REPEVAX at 5 to 6 years of age.

The rates of general symptoms after the first day but within 10 days after vaccination were low; only fever (

One hundred and fifty children primed at 2, 3, and 4 months of age with a DTwP vaccine (with no additional dose in the second year of life) received REPEVAX at 3 to 5 years of age

Adverse Events

Children 3 to 5 years (150 Persons)

Children 5 to 6 years (240 Persons)

Gastrointestinal Disorders

   

Diarrhoea

Common

Uncommon

Vomiting

   

Nausea

NR

 

General Disorders and Administration Site Conditions

   

Fatigue

Very Common

 

Fever**

Very Common

Common

Irritability

NR

 

Arthralgia/joint swelling

Common

NR

Injection site reactions

   

pain

Very Common

 

swelling

   

erythema

Very Common

Common

dermatitis

Common

NR

pruritus

NR

Common

bruising

Common

NR

Skin and Subcutaneous System Disorders

   

Rash

Common

NR

**Fever was measured as temperature

NR: Not Reported

Adolescents (11 years of age and older) and Adults

There was a trend for higher rates of local and systemic reactions in adolescents than in adults. In both age groups, injection site pain was the most common adverse reaction.

Late-onset local adverse reactions (i.e. a local adverse reaction which had an onset or increase in severity 3 to 14 days post-immunization), such as injection site pain, erythema and swelling occurred in less than 1.2%. Most of the reported adverse reactions occurred within 24 hours after the vaccination.

Adverse Events

Adolescents and Adults (994 Persons)

Nervous System Disorders

 

Headache

Very Common

Gastrointestinal Disorders

 

Nausea

Very Common

Vomiting

Common

Diarrhoea

 

Musculoskeletal and Connective Tissue Disorders

 

Arthralgia/joint swelling

Very Common

 

Myalgia

 

General Disorders and Administration Site Conditions

 

Asthenia

Very Common

Chills

 

Fever

Common

Injection site reactions

 

pain

Very Common

 

swelling

 

erythema

 

In a clinical trial of 843 healthy adolescent males and females 11-17 years of age, administration of the first dose of Gardasil concomitantly with REPEVAX showed that there was more injection-site swelling and headache reported following concomitant administration. The differences observed were < 10% and in the majority of subjects, the adverse events were reported as mild to moderate in intensity.

Data from Post-Marketing Experience

The following additional adverse events have been spontaneously reported during the post-marketing use of REPEVAX worldwide. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. Therefore, the frequency category “Not Known” is assigned to these adverse events.

Blood and Lymphatic Disorders

Lymphadenopathy

Immune System Disorders

Anaphylactic reactions, such as urticaria, face oedema and dyspnea

Nervous System Disorders

Convulsions, vasovagal syncope, Guillain-Barr? syndrome, facial palsy, myelitis, brachial neuritis, transient paresthesia / hypoesthesia of vaccinated limb, dizziness.

Musculoskeletal and Connective Tissue Disorders

Pain in vaccinated limb

General Disorders and Administrative Site Conditions

Extensive limb swelling which may extend from the injection site beyond one or both joints and is frequently associated with erythema, and sometimes with blisters has been reported following administration of REPEVAX. The majority of these reactions appeared within 48 hours of vaccination and spontaneously resolved over an average of 4 days without sequelae.

The risk appears to be dependent on the number of prior doses of d/DtaP vaccine, with a greater risk following the 4th and 5th doses.

Malaise, pallor, injection site induration

4.9 Overdose

Not-applicable.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Vaccine against diphtheria, tetanus, pertussis and poliomyelitis

ATC Code: J07CA02

Clinical Trials

The immune responses of adults, adolescents and children 3 to 6 years of age one-month after vaccination with REPEVAX are shown in the table below.

Table 1: Immune Responses 4 Weeks after Vaccination

Antigen

Criteria

Adults and Adolescents *

(n = 994)

Children

5-6 years old †

(n = 240)

Children

3-5 years old ‡

(n = 148)

Diphtheria

92.8%

99.4%

100%

Tetanus

100%

99.5%

100%

Pertussis

Pertussis Toxoid

Filamentous Haemagglutinin

Pertactin

Fimbriae Types 2 and 3

 

 

99.7%

99.9%

99.6%

99.8%

 

91.2%

99.1%

100%

99.5%

 

99.3%

99.3%

100%

100%

Polio 1

Polio 2

Polio 3

99.9%

100%

100%

100%

100%

100%

100%

100%

100%

* From the age of 10 years onwards

† Primed with DTaP at 3 and 5 months with a booster at 12 months of age

‡ Primed with DTwP at 2, 3 and 4 months of age

§ Measured by ELISA

** EU = ELISA units: Antibody levels of>5 EU/mL were postulated as possible surrogate markers for protection against pertussis by Storsaeter J. et al, Vaccine 1998; 16:1907-16.

The safety and immunogenicity of REPEVAX in adults and adolescents was shown to be comparable to that observed with a single booster dose of Td adsorbed or Td Polio adsorbed vaccines containing a similar amount of tetanus and diphtheria toxoids and inactivated poliovirus types 1, 2 and 3.

The lower response to diphtheria toxoid in adults probably reflected the inclusion of some participants with an uncertain or incomplete immunization history.

Serological correlates for protection against pertussis have not been established. On comparison with data from the Sweden I pertussis efficacy trials conducted between 1992 and 1996, where primary immunization with Sanofi Pasteur Limited's acellular pertussis infant DTaP formulation confirmed a protective efficacy of 85% against pertussis disease, it is considered that REPEVAX had elicited protective immune responses.

In a subsequent study, robust immune responses were observed following a single dose of REPEVAX in UK children 3.5 to 4.0 years of age previously primed with either an acellular pertussis combination vaccine (DTaP-IPV-Hib) or whole cell pertussis combination vaccine (DTwP//Hib) and OPV.

Serology follow-up studies were conducted in children adolescents and adults immunized with a single booster dose of REPEVAX.

At the 5-year follow-up time point, seroprotective antibody levels (

For poliovirus, the seroprotective levels (

GMTs for all pertussis antigens at 5 years remained several fold higher than pre-immunization levels, indicating a sustained long-term immune response for all age groups.

5.2 Pharmacokinetic Properties

Evaluation of pharmacokinetic properties is not required for vaccines.

5.3 Preclinical Safety Data

Non-clinical data revealed no special hazard for humans based on conventional studies of repeated doses toxicity.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Phenoxyethanol

Polysorbate 80

Water for injections

6.2 Incompatibilities

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

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store in a refrigerator at 2°C to 8°C.

Do not freeze. Discard the vaccine if it has been frozen.

Keep the container in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

0.5 mL of suspension in pre-filled syringe (type I glass) with a plunger stopper (chlorobromobutyl elastomer), without attached needle, with a tip-cap (chlorobromobutyl elastomer) - pack size of 1, 10 or 20.

0.5 mL of suspension in pre-filled syringe (type I glass) with a plunger stopper (chlorobromobutyl elastomer), without attached needle, with a tip-cap (chlorobromobutyl elastomer) and 1 or 2 separate needles - pack size of 1 or 10.

0.5 mL of suspension in pre-filled syringe (type I glass) with a plunger stopper (chlorobromobutyl elastomer) with attached needle and needle guard (elastomer) - pack size of 1, 10 or 20.

0.5 mL of suspension in pre-filled syringe (type I glass) with a plunger stopper (chlorobromobutyl elastomer) with attached needle and needle guard (translucent polypropylene rigid safeshield and polyisoprene) - pack size of 1, 10 or 20.

The stoppers, plunger stoppers and caps for all presentations of REPEVAX are latex-free.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Instructions for Use

Parenteral products should be inspected visually for extraneous particulate matter and/or discoloration prior to administration. In the event of either being observed, discard the medicinal product.

The normal appearance of the vaccine is a uniform cloudy, white suspension which may sediment during storage. Shake the prefilled syringe well to uniformly distribute the suspension before administering the vaccine.

For needle free syringes, the needle should be pushed firmly on to the end of the prefilled syringe and rotated through 90 degrees.

Disposal

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

Needles should not be recapped.

7. Marketing Authorisation Holder

Sanofi Pasteur MSD Ltd

Mallards Reach

Bridge Avenue

Maidenhead, Berkshire

SL6 1QP

8. Marketing Authorisation Number(S)

PL 06745/121

9. Date Of First Authorisation/Renewal Of The Authorisation

02 November 2001 / 15 December 2006

10. Date Of Revision Of The Text

06 /2011



Rapamune 1mg/ml oral solution.

Sirolimus

Please read all of this leaflet carefully before you start taking this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects get serious, or if you notice any other effects not mentioned in this leaflet, please tell your doctor or pharmacist. In this leaflet:

1. What Rapamune is and what it is used for



1. Name Of The Medicinal Product

Radian B Liniment/Radian B Muscle Lotion/Radian B Sport Muscle Lotion/ Radian B Winter Sport Muscle Lotion/ Cura Heat Pain Relief Lotion

2. Qualitative And Quantitative Composition

Menthol

1.4

%w/v

Camphor

0.6

%w/v

Aspirin

1.2

%w/v

Equivalent to ammonium salicylate

1.0

%w/v

Methyl Salicylate

0.6

%w/v

Equivalent to salicylic acid

(as Methyl and Ethyl Esters)

0.54

%w/v

3. Pharmaceutical Form

Liniment for topical application to human beings.

4. Clinical Particulars 4.1 Therapeutic Indications

For symptomatic relief of muscular aches and pains, including fibrositis, sciatica, lumbago, sprained ligaments, bruises, muscle stiffness, strains, tennis elbow, golf shoulder.

4.2 Posology And Method Of Administration

Posology: For external application.

For Adults and Children Over 12 Years:

Apply the lotion on the affected part once or twice, leaving 10-15 minutes between applications. Smooth in or massage if preferred. If necessary, repeat application up to three times daily, reducing to morning and evening when acute symptoms subside.

When convenient, use after a warm bath.

Children Under 12: Not recommended for children under 12.

Elderly: The adult dose is appropriate.

4.3 Contraindications

Not to be used on children under 12 years old. Do not apply to skin abrasions. Do not apply to irritated skin. Not to be used by persons who are sensitive to any of the ingredients. If irritation develops, use of the product should be discontinued. Pregnancy and lactation.

4.4 Special Warnings And Precautions For Use

Keep away from eyes and other sensitive areas. If symptoms persist, consult a doctor. Flammable: Do not use near naked flame. Should not be placed on or used near polished or painted surfaces.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There have been reports that topical salicylates may potentiate the anticoagulant effects of warfarin.

4.6 Pregnancy And Lactation

Use of the product during pregnancy and lactation is not recommended.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

If used on tender skin do not cover immediately after application. If an adverse reaction occurs, discontinue use immediately. Known side effects of menthol - contact dermatitis or eczema, hypersensitivity reactions characterised by urticaria, flushing and headache.

4.9 Overdose

When used externally as directed, overdose is unlikely.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Radian B is manufactured using the following active ingredients; Menthol, camphor, aspirin and methyl salicylate. The finished product contains menthol, camphor, ammonium salicylate and a mixture of methyl and ethyl esters of salicylic acid. The product provides salicylate ions which have analgesic properties. Methyl and ethyl salicylate are readily absorbed through the skin and have counter-irritant properties. Menthol relieves itching, dilates the vessels causing a sensation of coldness followed by an analgesic effect. Camphor acts as a rubefacient and mild analgesic and is employed as a counter-irritant.

5.2 Pharmacokinetic Properties

The active ingredients are well-documented pharmacopoeial ingredients. The extent of percutaneous absorption in human volunteers of (14C) acetyl salicylic acid from Radian B was studied and estimated by measurement of blood and urinary concentrations of radioactivity. Significant absorption through the skin was indicated by the excretion of almost 10% of the applied radioactivity in the urine within 5 days with approximately 5.5% in the first 24 hours.

5.3 Preclinical Safety Data

None

6. Pharmaceutical Particulars 6.1 List Of Excipients

Industrial Methylated Spirit 95

Glycerol

Citronella oil

Ammonia '880'

Water (purified)

6.2 Incompatibilities

None known

6.3 Shelf Life

60 months

6.4 Special Precautions For Storage

Store below 25°C

6.5 Nature And Contents Of Container

Ribbed oval glass bottle with polypropylene insert and plastic cap. Polythene bottle and plastic cap. Pack sizes 50 and 100ml.

White HDPE bottle with red urea cap and wad. Pack sizes: 30, 125 and 250ml oval bottles and 500 and 2000ml round bottles.

Boston round silver HDPE bottle and silver polypropylene cap without wad. Pack size 500ml.

Silver HDPE bottle with silver coloured, black urea cap and wad and LDPE insert. Pack sizes: 125 and 250ml oval bottle.

Silver HDPE bottle with LDPE plug insert and warm red coloured, spigot seal polypropylene cap. Pack sizes: 125, 250ml and 500ml oval bottle.

White polypropylene bottle with an angled neck containing an applicator, consisting of polypropylene plug, ring and spring, encasing a red polyurethane foam, with a red polypropylene cap. Pack size 80ml.

6.6 Special Precautions For Disposal And Other Handling

No special precautions necessary

7. Marketing Authorisation Holder

Thornton & Ross Limited

Linthwaite

Huddersfield

West Yorkshire

HD7 5QH

United Kingdom

8. Marketing Authorisation Number(S)

PL 00240/0359

9. Date Of First Authorisation/Renewal Of The Authorisation

30 April 2002

10. Date Of Revision Of The Text

04/03/2008



Drugs associated with Rubella Prophylaxis

The following drugs and medications are in some way related to, or used in the treatment of Rubella Prophylaxis. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.



1. Name Of The Medicinal Product

Radian B Muscle Rub or Askit Muscle Rub or Radian Massage Cream or Radian B Sport Muscle Rub.

2. Qualitative And Quantitative Composition

Menthol

2.54% w/w

Camphor

1.41% w/w

Methyl Salicylate

0.42% w/w

Camphor Oil, White

0.32%w/w

Oleoresin Capsicum 500,000 Water soluble (equivalent to 0.000125% capsaicin)

0.005% w/w

Camphor and Camphor Oil, White are collectively declared as: Camphor BP

1.43% w/w

3. Pharmaceutical Form

Cream

4. Clinical Particulars 4.1 Therapeutic Indications

For the symptomatic relief of muscular and rheumatic aches and pains, including; muscular stiffness, bruising, sprains, fibrositis.

4.2 Posology And Method Of Administration

For external use application.

Adult and children over 6

Apply to the affected parts and slowly massage well into the skin. For muscular strains and stiffness it is best used after a hot bath.

Elderly

The adult dose is appropriate

Children

Not recommended for children under 6.

4.3 Contraindications

Not to be used on children under 6 years old.

Do not apply to skin abrasions.

Do not apply to irritated skin

4.4 Special Warnings And Precautions For Use

Keep away from eyes and sensitive areas. If symptoms persist consult a doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There have been reports that topical salicylates may potentiate the anticoagulant effects of warfarin.

4.6 Pregnancy And Lactation

There is no, or inadequate evidence of safety in human pregnancy. Use in pregnancy only when there is no safer alternative. Use in lactation is acceptable.

4.7 Effects On Ability To Drive And Use Machines

Not applicable

4.8 Undesirable Effects

Use sparingly on tender skin and do not cover immediately after application. If an adverse reaction occurs discontinue use immediately. Known side effects of menthol - contact dermatitis or eczema, hypersensitivity reactions characterised by urticaria, flushing and headache.

4.9 Overdose

When used externally as directed, overdose is unlikely.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Radian Massage Cream is a smooth, off-white cream which incorporates menthol, camphor, methyl salicylate, capsicine and white camphor oil as active ingredients and glycerol as emollient.

Menthol relieves itching, dilates the vessels causing a sensation of coldness followed by an analgesic effect. Camphor acts as a rubefacient and mild analgesic and is employed as a counter-irritant. Methyl salicylate has the actions of the salicylates. It is readily absorbed through the skin and has counter-irritant properties. Capsicine has counter-irritant properties and white camphor oil is a rubefacient and mild counter-irritant.

5.2 Pharmacokinetic Properties

None available

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars 6.1 List Of Excipients

Argobase S.1

(contains: Lanolin, Lanolin alcohol, Cetostearyl alcohol, Liquid paraffin)

Emulsifying Wax

White Petroleum Jelly

2,4-dichlorobenzyl alcohol

Imidurea

Industrial Mehtylated Spirit 95

Purified Water

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

Lacquered aluminium tube and plastic cap. White plastic screw-cap jar. Pack sizes: 15, 25, 40, 70, 100, 650gm.

6.6 Special Precautions For Disposal And Other Handling

No special precautions necessary.

7. Marketing Authorisation Holder

Thornton & Ross Limited

Linthwaite

Huddersfield

West Yorkshire

HD7 5QH

United Kingdom

8. Marketing Authorisation Number(S)

PL 00240/0360

9. Date Of First Authorisation/Renewal Of The Authorisation

30th April 2002

10. Date Of Revision Of The Text

December 2003



REDUCTIL 10mg & 15mg Capsules

(sibutramine)

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 give it to others. If any of the side effects get serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What REDUCTIL is and what it is used for 2. Before you take REDUCTIL 3. How to take REDUCTIL 4. Possible side effects 5. How to store REDUCTIL 6. Further information What Reductil Is And What It Is Used For

Reductil, which contains sibutramine is a medicine to help you lose weight if your doctor has determined you are obese, or over-weight with additional risk factors for obesity such as diabetes and/or elevated lipids. Your doctor may start you on Reductil if diet and exercise for three months didn’t help you lose enough weight. This medicine makes you feel full sooner so you eat less food. By eating less you should be able to lose and control your weight. This medicine is part of your weight loss plan you set up with your doctor.

This medicine should be used together with a low calorie diet and an increase in your physical activity. The combination will also help you lose weight. Your doctor will guide you with your weight loss program and will give you regular check-ups.

Before You Take Reductil Do Not Take REDUCTIL if you have obesity that is not related to overeating if your blood pressure is above 145/90 mmHg whether or not you take blood pressure medicines. if you have, or have had in the past, an eating disorder, such as anorexia or bulimia. if you are allergic to sibutramine or any of the other ingredients of Reductil (please refer to Section 6 or the list of ingredients for this medicine) if you have a mental illness such as manic depression (bipolar disorder) if you are currently using or have used in the past 2 weeks MAOI medicines (to treat depression or Parkinson’s disease) or you have used other medicines to treat depression, psychosis or weight loss or tryptophan to treat sleep disorders. These medicines can affect the amount of the chemical called serotonin in your brain. This can be a problem if you also use Reductil at the same time. if you have Tourette’s syndrome if you have or have ever had heart problems, a raised heart rate, an uneven heart beat, heart failure, hardening of the arteries or strokes if you have an overactive thyroid gland if you have severe kidney disease, are on dialysis or have severe liver disease. if you are a male patient and you notice problems with your prostate. An enlarged prostate may make it hard to empty your bladder even if you feel an urge to urinate. if you have a certain kind of tumours on the adrenal glands (phaeochromocytoma) if you have an eye problem called narrow angle glaucoma. if you abuse drugs, medicines or alcohol or have done so in the past if you are pregnant or planning to become pregnant or if you are breastfeeding. if you are under 18 or over 65 years old. Take Special Care with REDUCTIL

Your doctor will check your progress regularly, measuring your weight, blood pressure and pulse rate to be sure that this medicine is the right treatment for you.

Talk to your doctor: if your blood pressure or heart rate goes up or gets too high. It is very important to have your blood pressure checked if you have a sleeping problem called sleep apnoea. if you experience symptoms such as shortness of breath, chest pain and swollen ankles due to pulmonary hypertension. if you have epilepsy (seizures). if you have kidney or liver problems if you have a family history of tics. if you have depression. if you have a condition that makes you prone to bleeding or if you are taking any medicines that may thin your blood or may increase bleeding. if you have an eye problem called wide angle glaucoma (increase of pressure in your eyes) or if you are at risk because you have a relative who has had this condition.

Your doctor will decide if you should continue taking this medicine.

Important information about some of the ingredients of REDUCTIL

Reductil contains lactose. If you have been told by your doctor that you are have an intolerance to some sugars, tell your doctor taking this medicinal product.

Using Other Medicines

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

Several medicines can cause unwanted reactions if used with Reductil. Ask your doctor or pharmacist for advice before taking this medicine. In particular tell your doctor if you are using any of the following medicines:

if you are currently using or have used in the past 2 weeks MAOI medicines (to treat depression or Parkinson’s disease) or you have used other medicines to treat depression, psychosis or weight loss or tryptophan to treat sleep disorders (see Do Not Take REDUCTIL). medicines to treat migraine headaches e.g. sumatriptan, ergot (dihydroergotamine) some kinds of strong pain-killers: for example, fentanyl and pethidine, pentazocine. certain medicines that can increase blood pressure, such as cold or allergy medications e.g. dextromethorphan, ephedrine, pseudoephedrine. cimetidine (a medicine used to treat ulcers) some medicines to treat infections including antibiotics, such as rifampicin, erythromycin, troleandomycin and clarithromycin, or antifungal medicines, such as itraconazole and ketoconazole. Talk to your doctor if you are using any medicine to treat an infection. some epilepsy (seizure) medicines: carbamazepine, phenobarbitone and phenytoin. some medicines called steroids and medicines that affect your body’s ability to fight disease: such as dexamethasone and cyclosporin. Taking REDUCTIL with Food and Drink It doesn’t matter if you have eaten or not when you take this medicine. This medicine should be swallowed whole with a full glass of water. Pregnancy and Breast-feeding

You shouldn’t use Reductil if you are pregnant or planning to become pregnant. Take measures to avoid becoming pregnant while using this medicine. Do not breast-feed if you are taking this medicine. Ask your doctor or pharmacist for advice before taking any medicine.

Driving and Using Machines

If you find that this medicine affects your judgment, your thinking or your coordination, you should not drive or use tools or machinery.

How To Take Reductil

Always take this medicine exactly as your doctor has told you. If you are not sure, you should check with your doctor.

The starting dose is one 10mg capsule of Reductil every morning, swallowed whole with a glass of water. Do not chew or break open the capsule. It doesn’t matter if you have eaten or not when you take this medicine.

If you haven’t lost about four pounds (two kilograms) of weight during the first four weeks you take Reductil, your doctor may want to increase your dose of this medicine to one 15 mg capsule taken once a day. Reductil must be taken as prescribed by your doctor.

If you take more REDUCTIL than you should

If you took more Reductil than you should, immediately tell your doctor or pharmacist. Taking too much Reductil may make you feel dizzy. Your heart may beat faster and your blood pressure may increase. You may also get a headache.

If you forget to take REDUCTIL

If you do forget to take a dose, just skip it. Do not take a double dose to make up for the one you have missed. Talk to your doctor or pharmacist if you have any questions about how to take this medicine.

If you stop taking REDUCTIL

If you stop taking this medicine, you might get a headache or want to eat more. If this happens, talk to your doctor.

Possible Side Effects

Like all medicines, Reductil can cause side effects, although not everyone gets them. Most side effects occur during the first four weeks of treatment. Most of these are not serious, occur less often and became less marked over time or go away when this medicine is stopped.

The following side effects have been seen with Reductil. Some of these may become serious. You should talk to your doctor and/or pharmacist if you notice any of the following.

An increase in blood pressure or heart rate. An irregular heart beat such as a fluttering of the heart A rare but serious problem called serotonin syndrome. This is a combination of symptoms that can include feeling confused, sweating, shaking, nausea, hallucinations, sudden jerking of the muscles or a fast heart beat. This may occur when people take other medicines that affect a brain chemical called serotonin along with this medicine. If you get breathing problems, chest pains or swollen ankles. Unusual bleeding or unusual bruising, or if it takes you longer than usual to stop bleeding. If you get a rash or hives, trouble breathing, fainting and swelling of the face and throat. You may be having an allergic reaction which may need emergency treatment. If you get any of these symptoms, stop taking this medicine and talk to your doctor right away.

Very common side effects (in more than 1 in 10 patients taking this medicine in clinical trials) include:

trouble sleeping, constipation, dry mouth

Common side effects (in less than 1 in 10 patients taking this medicine in clinical trials) include:

a fast heart beat, increased blood pressure, awareness of the heart beat (palpitations), nausea, headache, anxiety, a “pins-and-needles” feeling, dizziness, hot flushes or sweating. If you have haemorrhoids (piles), they could become worse.

Foods and drinks may taste different than they used to or you may have a different taste in your mouth.

Other side effects include (less common or with an unknown frequency): seizures, trouble remembering things, blurred vision, diarrhoea, vomiting, thinning hair, erectile dysfunction/abnormal orgasms, menstrual disorders, bleeding into the skin with joint pain, feeling agitated or depressed, bleeding in the stomach, kidney problems, inability to empty the bladder and increases in certain liver tests.

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 Reductil

Keep out of the reach and sight of children.

Do not store above 25°C. Store in the original package in order to protect from moisture.

Do not use this medicine if you notice the capsules are damaged or don’t look right in some other way.

Do not use this medicine after the expiry date which is stated on the blister strip and the carton after EXP. The expiry date refers to the last day of that month.

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

Further Information What REDUCTIL Contains

The active substance is sibutramine, as sibutramine hydrochloride monohydrate.

Reductil Capsules also contain the following non active ingredients: Lactose monohydrate, magnesium stearate, microcrystalline cellulose, colloidal anhydrous silica.

Capsule shell and markings contain: Indigo carmine (E132), titanium dioxide (E171), gelatin, sodium lauryl sulphate, dimethicone, propylene glycol, iron oxide black (E172), shellac glaze, lecithin (E322).

Reductil 10 mg capsules also contain quinilone yellow (E104).

What REDUCTIL looks like and contents of the pack

Reductil 10mg Capsules are immediate release hard gelatin capsules with a blue cap and yellow body

Reductil 15mg Capsules are immediate release hard gelatin capsules with a blue cap and white body

Reductil capsules are available in a PVC/PVDC blister strip calendar packs.

Calendar packs containing 28 capsules (4 weeks), 56 capsules (8 weeks) and 98 capsules (14 weeks) Hospital packs (calendar packs) containing 28 capsules and 280 (10 x 28) capsules Marketing Authorisation Holder and Manufacturer Abbott Laboratories Ltd. Queenborough Kent ME11 5EL United Kingdom

Reductil is made by

Abbott GmbH & Co. KG Knollstrasse 67061 Ludwigshafen Germany

This leaflet was last approved in November 2007



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.

Recombinant human erythropoietins, act like endogenous erythropoietin to stimulate erythropoiesis, the process of red blood cell production. Endogenous erythropoietin is a hormone that is secreted by particular cells in the kidneys in response to reduced levels of oxygen reaching the tissues in the kidneys.

Recombinant human erythropoietins are given to patients with kidney failure to treat anemia.

See also

Medical conditions associated with recombinant human erythropoietins:

Anemia Anemia Associated with Chronic Renal Failure Anemia Prior to Surgery Anemia, Chemotherapy Induced Anemia, Drug Induced Drug List: Aranesp Epogen Mircera Procrit



1. Name Of The Medicinal Product

Renacet 950 mg, film-coated tablets

2. Qualitative And Quantitative Composition

Active substance: Calcium acetate

Each film-coated tablet contains:

950 mg calcium acetate (anhydrous) equivalent to 240.50 mg calcium.

Excipients: Contains sucrose, see section 4.4.

For a full list of excipients see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

white, oval, convex film-coated tablets scored on both sides.

4. Clinical Particulars 4.1 Therapeutic Indications

Hyperphosphatemia associated with chronic renal insufficiency in patients undergoing dialysis.

4.2 Posology And Method Of Administration

The tablet can be divided into equal halves. Dosage should be effected individually. Unless a different dose has been prescribed, adults should take no more than 7 Renacet 950 mg film-coated tablets daily.

To achieve optimal efficacy, Renacet 950 mg should be taken during or immediately after meals.

The usual dose is:

with breakfast:

? to 1 film-coated tablet Renacet 950 mg,

with a snack:

? to 1 film-coated tablet Renacet 950 mg,

with a main meal:

1 to 3 film-coated tablets Renacet 950 mg,

with supper:

1 to 2 film-coated tablets Renacet 950 mg.

Renacet 950 mg film-coated tablets should be taken with some liquid during or immediately after meals and must not be chewed.

Experience with children is not available.

4.3 Contraindications

Renacet 950 mg must not be used in patients with:

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

Hypophosphatemia, severe hypophosphatemia, hypercalcemia, hypercalciuria associated with calcium-containing kidney stones, decalcifying tumors and skeletal metastases; severe renal failure without dialysis treatment; constipation; known stenosis of the large intestine, osteoporosis due to immobilisation.

4.4 Special Warnings And Precautions For Use

Treatment with Renacet 950 mg film-coated tablets requires regular measurement of the serum calcium and serum phosphate levels. Under no circumstances should the calcium concentration multiplied by the phosphate concentration exceed 5.3 mmol/l since the frequency of extraosseous calcification increases if this value is exceeded.

To avoid an increase in serum calcium level beyond the normal range the intake of Renacet 950 mg film-coated tablets should be monitored regularly when patients are already on preparations which contain calcium.

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant intake of Renacet 950 mg film-coated tablets with other medicinal products may impair their absorption.

For numerous anionic medicinal agents, e.g. tetracyclines and doxycycline, quinolones (gyrase inhibitors), biphosphonates, fluorides and anticholinergics changes in absorption may occur. Interaction may also occur with vitamin D preparations.Therefore it is recommended that there should be an interval of 1-2 hours between the intake of Renacet 950 mg film-coated tablets and other medicinal products.

An increased effect may occur with cardiac glycosides, a reduced effect may occur with calcium antagonists.

Concomitant administration of thiazides results in an increased risk of hypercalcemia. If the calcium level is increased, use of adrenaline may lead to severe cardiac arrhythmia.

Intake of larger quantities of calcium salts may cause a precipitation of fatty or bile acids as calcium soaps. This may impair the absorption of ursodeoxycholic acid and chenodeoxycholic acid as well as fats and fat soluble vitamins.

4.6 Pregnancy And Lactation

Harmful effects on humans due to calcium taken during pregnancy and lactation have not been reported.

However, the likelihood of hypercalcaemia is increased in pregnant women in whom calcium and vitamin D are co-administered.

4.7 Effects On Ability To Drive And Use Machines

Renacet 950 mg has no effect on the ability to drive or use machines.

4.8 Undesirable Effects

The following definitions apply to the incidence of undesirable effects:

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

General disorders:

 

Uncommon:

Soft tissue calcification (e.g in the fatty tissue under the skin) usually occurring only after many years of intake and frequently associated with increased blood calcium levels.

Cardiac/vascular disorders:

 

Uncommon:

Hypercalcemia, especially following overdosage.

Gastrointestinal disorders:

 

Rare:

Gastrointestinal disorders such as nausea and constipation, especially in case of too high dosages.

 

If gastrointestinal side effects occur, treatment should be changed to calcium carbonate as appropriate.

4.9 Overdose

Overdose would not be expected to cause gross hypercalcaemia except in patients taking excessive doses of vitamin D.

Measures in case of overdose: Discontinuation of the medicinal product and symptomatic treatment including lowering calcium levels e.g. administration of oral phosphates and non-saline laxatives such as lactulose.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group:

Drug for treatment of hyperphosphatemia

ATC-Code:

A12AA12

Calcium is an endogenous ion of the body essential for the maintenance of a number of physiologic processes. It participates as an integral factor in the maintenance of the functional integrity of the nervous system, in the contractile mechanisms of muscle tissue, in the clotting of blood, and in the formation of the major structural material of the skeleton.

A dynamic equilibrium occurs between blood calcium and skeletal calcium, homeostasis being mainly regulated by the parathyroid hormone, by calcitonin and by vitamin D.

Variations in the concentration of ionised calcium are responsible for the symptoms of hyper/hypocalcaemia. Soluble calcium salts are commonly used in the treatment of calcium deficiency.

5.2 Pharmacokinetic Properties

The pharmacokinetics of calcium and its salts are well known. Bioavailability of calcium acetate depends on the dissolution rate which is normally completed after 15 minutes. After 15 minutes the calcium acetate is released. The serum concentration of phosphate may decrease after interaction with calcium resulting in the formation of the less soluble calcium phosphate salts.

5.3 Preclinical Safety Data

Preclinical studies with calcium acetate are very limited and reveal no special additional risks to those already mentioned in other sections of the SPC. Preclinical effects were observed only at doses considered in excess of the maximum human dose.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Tablet core

Maize starch

Sucrose

Gelatin

Sodium starch glycolate (Type A)

Croscarmellose sodium

Magnesium stearate

Film coat

Hypromellose

Refined castor oil

Saccharin sodium

Talc

Orange flavour

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 30 °C.

6.5 Nature And Contents Of Container

Pack sizes:

100 film-coated tablets

200 film-coated tablets

PVDC-coated PVC / aluminium foil blisters

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

RenaCare NephroMed GmbH

Werrastr. 1 a

35625 H?ttenberg

Germany

 

Phone:

Fax:

E-mail:

+49 (0) 64 03 9 21 60

+49 (0) 64 03 9 21 63

[email protected]

8. Marketing Authorisation Number(S)

PL 36032/0002

9. Date Of First Authorisation/Renewal Of The Authorisation

30/06/2010

10. Date Of Revision Of The Text

30/06/2010



There are currently no drugs listed for "Retinal Vasculitis". See Retinal Disorders.



There are currently no drugs listed for "Refsum's Disease".

Definition of Refsum's Disease: A genetic disorder of the fatty acid phytanic acid which accumulates and causes a number of progressive problems including polyneuritis (inflammation of numerous nerves), diminishing vision (due to retinitis pigmentosa), and wobbliness (ataxia) caused by damage to the cerebellar portion of the brain (cerebellar ataxia).



1. Name Of The Medicinal Product

Rythmodan 150mg Capsules.

2. Qualitative And Quantitative Composition

Capsule containing Disopyramide 150mg.

For excipients, see 6.1.

3. Pharmaceutical Form

Capsule.

4. Clinical Particulars 4.1 Therapeutic Indications

Rythmodan is used in the treatment of cardiac arrhythmias as follows:-

1. The prevention and treatment of arrhythmias occurring after myocardial infarction.

2. Maintenance of normal rhythm following electroconversion eg atrial fibrillation, atrial flutter.

3. Persistent ventricular extrasystoles.

4. Control of arrhythmias following the use of digitalis or similar glycosides.

5. Suppression of arrhythmias during surgical procedures eg cardiac catheterisation.

6. The prevention of paraxysmal supraventricular tachycardia.

7. Other types of arrhythmias e.g. atrial extrasystoles, Wolff-Parkinson-White Syndrome.

4.2 Posology And Method Of Administration

Route of administration

Oral

300 mg to 800mg daily in divided doses.

Children :

Not recommended as insufficient data available.

Elderly

A dose reduction due to reduced renal and hepatic function in the elderly (especially elderly non-smokers) should be considered (see section 4.4)

4.3 Contraindications

Disopyramide is contra–indicated in un–paced second or third degree atrioventricular block; bundle–branch block associated with first–degree atrioventricular block ; unpaced bifasicular block; pre-existing long QT syndromes; severe sinus node dysfunction ; severe heart failure, unless of secondary to cardiac arrhythmia ; hypersensitivity to disopyramide. It is also contra–indicated in concomitant administration with other anti–arrhythmics or other drugs liable to provoke ventricular arrythmias, especially Torsade de Pointes (see section 4.5). The sustained release formulation is contra–indicated in patients with renal or hepatic impairment.

4.4 Special Warnings And Precautions For Use

Antiarrhythmic drugs belonging to the class 1c (Vaughan Williams Classification) were included in the Cardiac Arrhythmia Suppression Trial (CAST), a long term multicentre randomised, double blind study in patients with asymptomatic non life–threatening ventricular arrhythmia who have had a myocardial infarction more than six days but less than two years previously. A significant increase in mortality and non–fatal cardiac arrest rate was seen in patients treated with class 1c antiarrhythmic drugs when compared with a matched placebo group. The applicability of the CAST results to other antiarrhythmics and other populations (eg. those without recent infarction) is uncertain. At present, it is best to assume that the risk extends to other antiarrhythmic agents for patients with structural heart disease.

There is no evidence that prolonged suppression of ventricular premature contractions with antiarrhythmic drugs prevents sudden death. For this reason, antiarrhythmic drugs should not be prescribed for the treatment of patients with asymptomatic ventricular premature contractions.

All antiarrhythmic drugs can produce unwanted effects when they are used to treat symptomatic but not life threatening arrhythmia; the expected benefits should be balanced against their risks.

In patients with structural heart disease, proarrhythmia and cardiac decompensation are special risks associated with antiarrhythmic drugs. Special caution should be exercised when prescribing in this context.

Disopyramide should not be used in patients with uncompensated congestive heart failure, unless this heart failure is secondary to cardiac arrhythmia. If disopyramide is to be given under these circumstances, special care and monitoring are essential.

Life-threatening and haemodynamically significant arrhythmias are difficult to treat and affected patients have a high mortality risk. Treatment of these arrhythmias, by whatever modality, must be initiated in hospital.

Owing to its negative inotropic effect, disopyramide should be used with caution in patients suffering from significant cardiac failure.This group may be specially sensitive to the negative inotropic properties of disopyramide. Such patients should be fully digitalised or controlled with other therapy before treatment with disopyramide is commenced.

Aggravation of existing arrhythmia, or emergence of a new type of arrhythmia, demands urgent review of disopyramide treatment.

Similarly, if an atrioventricular block or a bifascicular block occurs during treatment, the use of disopyramide should be reviewed.

There have been reports of ventricular tachycardia, ventricular fibrillation and Torsade de Pointes in patients receiving disopyramide. These have usually, but not always, been associated with significant widening of the QRS complex or prolonged QT interval. The QT interval and QRS duration must be monitored and disopyramide should be stopped if these are increased by more than 25%. If these changes or arrhythmias develop the drug should be discontinued. Disopyramide should be used only with caution in patients with atrial flutter or atrial tachycardia with block as conversion of a partial AV block to a 1:1 response may occur, leading to a potentially more serious tachyarrhythmia.

The occurrence of hypotension following disopyramide administration requires prompt discontinuation of the drug. This has been observed especially in patients with cardiomyopathy or uncompensated congestive heart failure. Any resumption of therapy should be at a lower dose with close patient monitoring. Disopyramide should be used with caution in the treatment of digitalis intoxication.

Potassium imbalance: Antiarrhythmic drugs may be hazardous in patients with potassium imbalance, as potassium abnormalities can induce arrhythmias.

During treatment with disopyramide, potassium levels should be checked regularly. Patients treated with diuretics or stimulant laxatives are at particular risk of hypokalaemia.

Renal insufficiency: In renal insufficiency, the dosage of disopyramide should be reduced by adjusting the interval between administrations.

Hepatic insufficiency: Hepatic impairment causes an increase in the plasma half–life of Rythmodan and a reduced dosage may be required.

Hypoglycaemia:  Hypoglycaemia has been reported in association with disopyramide administration. The risk of hypoglycaemia, sometimes severe, occurs particularly in elderly or malnourished subjects, treated diabetics and patients with renal insufficiency or cardiac failure. Blood sugar levels should be monitored in all patients. Strict adherence to the dosing recommendations is advised. If hypoglycaemia occurs then treatment with disopyramide should be stopped.

Hypoglycaemia may be associated with interactions with drugs metabolised by hepatic CYP3A (see Section 4.5 Interactions with other medicinal products and other forms of interaction).

Atropine–like effects: There is a risk of :

– ocular hypertension in patients with narrow–angle glaucoma

– acute urinary retention in patients with prostatic enlargement

– aggravation of myasthenia gravis

– cognitive disorders, especially in elderly patients (see also section 4.8).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Combination with other antiarrhythmic drugs: Combinations of antiarrhythmic drugs are not well researched and their effect may be unpredictable. Thus, antiarrhythmic combination should be avoided except under certain circumstances, eg. beta–blockers for angina pectoris ; digoxin with beta–blocker and verapamil for the control of atrial fibrillation, when defined as effective for an individual.

Interaction with drugs associated with risk of Torsade de Pointes, such as

– tricyclic and tetracyclic antidepressants

– All macrolide antibiotics (e.g. erythromycin, clarithromycin, azithromycin etc)

– astemizole ; cisapride ; pentamidine ; pimozide ; sparfloxacin ; terfenadine and thioridazone.

Phosphodiesterase Type 5 Inhibitors:

There is evidence that phosphodiesterase Type 5 inhibitors may be potentially associated with a risk of QT prolongation. Concomitant administration of disopyramide with such drugs may potentially enhance this QT prolongation effect and is not recommended.

The concomitant use of these medications whilst undergoing treatment with disopyramide increases the chance of cardiac arrhythmia.

There is some evidence that disopyramide is metabolised by hepatic CYP3A. Concomitant administration of significant inhibitors of this isozyme (e.g. certain macrolide or azole antifungal antibiotics) may therefore increase the serum levels of disopyramide. On the other hand, inducers of CYP3A (e.g. rifampicin and certain anticonvulsants such as phenytoin, primidone and phenobarbital) may reduce disopyramide and increase MN–disopyramide serum levels. Since the magnitude of such potential effects is not foreseeable, such drug combinations are not recommended.

When prescribing a drug metabolised by CYP3A [such as theophylline, HIV protease inhibitors (e.g. ritonavir, indinavir, saquinavir), ciclosporin A, warfarin] it should be kept in mind that disopyramide is probably also a substrate of this isozyme and thus competitive inhibition of metabolism might occur, possibly increasing serum levels of these drugs.

Interactions with hypokalaemia inducing drugs: Concomitant use with drugs can induce hypokalaemia such as : diuretics, amphotericin B, tetracosactide (corticotropin analogue), gluco and mineralo–corticoids may reduce the action of the drug, or potentiate proarrhythmic effects. Stimulant laxatives are not recommended to be given concomitantly, due to their potassium lowering potential.

Other drug interactions:

Atropine and other anticholinergic drugs, including phenothiazines, may potentiate the atropine–like effects of disopyramide.

4.6 Pregnancy And Lactation

Pregnancy: Although Rythmodan has undergone animal tests for teratogenicity without evidence of any effect on the developing foetus, its safety in human pregnancy has not been established. Rythmodan has been reported to stimulate contractions of the pregnant uterus. The drug should only be used during pregnancy if benefits clearly outweigh the possible risks to the mother and foetus.

Lactation: Studies have shown that oral Rythmodan is secreted in breast milk, although no adverse effects to the infant have been noted. However, clinical experience is limited and Rythmodan should only be used in lactation if, in the clinician's judgement, it is essential for the welfare of the patient. The infant should be closely supervised, particularly for anticholinergic effects and drug levels determined if necessary. Ideally, if the drug is considered essential, an alternative method of feeding should be used.

4.7 Effects On Ability To Drive And Use Machines

Some adverse reactions may impair the patients ability to concentrate and react, and hence the ability to drive or operate machinery. (See section 4.8).

4.8 Undesirable Effects

Cardiac: It is accepted that the arrhythmogenic potential of disopyramide is weak. However, as with all antiarrhythmic drugs, disopyramide may worsen or provoke arrhythmias. This proarrhythmic effect is more likely to occur in the presence of hypokalemia with the associated use of antiarrhythmic drugs, in patients with severe structural heart disease with prolongation of the QT interval.

Intra–cardiac conduction abnormalities may occur: QT interval prolongation, widening of the QRS complex, atrioventricular block and bundle–branch block.

Other types of arrhythmia have been reported: Bradycardia, sinus block, ventricular fibrillation, ventricular tachycardia and torsades de pointes.

Episodes of severe heart failure or even cardiogenic shock have also been described particularly in patients with severe structural heart disease. The resulting low cardiac output can cause hypotension, renal insufficiency and/or acute hepatic ischemia.

Other adverse reactions include:

Atropine-like effects (see also section 4.4):

urinary: dysuria; acute urinary retention, especially in prostatism

ocular: disorders of accommodation; diplopia

gastrointestinal: dry mouth; abdominal pain; nausea, vomiting, anorexia, diarrhoea; constipation

impotence

cognitive disorders

Psychiatric disorders.

Skin reactions: very rarely, rashes.

Rarely: hypoglycaemia, sometimes severe (see Section 4.4 Special warnings and precautions for use). In some cases, severe hypoglycaemia resulted in coma.

Very rarely: cholestatic jaundice, headache, dizzy sensation, neutropenia.

Rapid infusion may cause profuse sweating.

4.9 Overdose

There is no specific antidote for disopyramide. Prostigmine derivatives can be used to treat anticholinergic effects. Symptomatic supportive measures may include : early gastric lavage ; administration of a cathartic followed by activated charcoal by mouth or stomach tube ; IV administration of isoprenaline, other vasopressors and/or positive inotropic agents ; if needed - infusion of lactate and/or magnesium, electro–systolic assistance, cardioversion, insertion of an intra–aortic balloon for counterpulsion and mechanically assisted ventilation. Haemodialysis, haemofiltration or haemoperfusion with activated charcoal has been employed to lower the serum concentrations of the drug.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Class 1 anti-arrhythmic agent.

It decreases membrane responsiveness, prolongs the effective refractory period (ERP) and slows automaticity in cells with augmented automaticity. Effective refractory period of the atrium is lengthened, ERP of the A-V node is shortened and conduction in accessory pathways is prolonged.

Disopyramide is a myocardial depressant and has anti-cholinergic effects.

5.2 Pharmacokinetic Properties

Elimination phase of plasma t1/2: 5-8 hours. Increased in hepatic impairment, cardiac and hepatic disease.

Protein binding: 50 - 60%. Saturable and concentration dependent.

Volume of distribution: Variable according to method of determination.

Metabolism: Approximately 25% of a dose metabolised to a mono-N-dealkylated derivative. Additional 10% as other metabolites.

Excretion: 75% unchanged drug via urine, remainder in faeces mono-N-dealkylated metabolite 25% in urine, 64% via faeces.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Maize starch,

Magnesium stearate,

STA-RX 1500 (pregelatinised starch)

Talc.

Capsule shell:

Gelatin

Indigo carmine

Iron oxide

Titanium dioxide (E171)

6.2 Incompatibilities

Not known.

6.3 Shelf Life

PVC Blister :                    36 months

6.4 Special Precautions For Storage

Do not store above 25°C

6.5 Nature And Contents Of Container

PVC/PVdC blister strips in cardboard cartons containing 84 capsules.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 04425/0608

9. Date Of First Authorisation/Renewal Of The Authorisation

12 February 2009

10. Date Of Revision Of The Text

24 February 2010

LEGAL STATUS

POM



See also cardiac stressing agents radiologic conjugating agents Drug List:



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