Renacet 475mg tablet

1. Name Of The Medicinal Product

Renacet 475 mg, film-coated tablets

2. Qualitative And Quantitative Composition

Active substance: Calcium acetate

Each film-coated tablet contains:

475 mg calcium acetate (anhydrous) equivalent to 120.25 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, round, convex film-coated tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Hyperphosphatemia associated with chronic renal insufficiency in patients undergoing dialysis.

4.2 Posology And Method Of Administration

Dosage should be effected individually. Unless a different dose has been prescribed, adults should take no more than 14 Renacet 475 mg film-coated tablets daily.

To achieve optimal efficacy, Renacet 475 mg should be taken during or immediately after meals

The usual dose is:

with breakfast:	1 to 2 film-coated tablets Renacet 475 mg,
with a snack:	1 to 2 film-coated tablets Renacet 475 mg,
with a main meal:	2 to 6 film-coated tablets Renacet 475 mg,
with supper:	2 to 4 film-coated tablets Renacet 475 mg.

Renacet 475 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 475 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 475 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 475 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 475 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 475 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 475 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

This medicinal product does not require any special storage conditions.

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 Hüttenberg

Germany

Phone: +49 (0) 64 03 9 21 60

Fax: +49 (0) 64 03 9 21 63

E-mail: mail@renacare.com

8. Marketing Authorisation Number(S)

PL 36032/0001

9. Date Of First Authorisation/Renewal Of The Authorisation

30/06/2010

10. Date Of Revision Of The Text

30/06/2010

Risperidone 3mg Film-coated Tablets

1. Name Of The Medicinal Product

Risperidone 3mg Film-coated Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 3 mg of the active substance risperidone.

Excipient: 183.75mg lactose monohydrate per tablet.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Film coated Tablet

White, 11 x 6.5 mm oval biconvex, scored, coated tablet, marking "T3".

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 bd 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 requirements.

7. Marketing Authorisation Holder

Actavis Group PTC ehf

Reykjavíkurvegi 76-78

220 Hafnarfjordur

Iceland.

8. Marketing Authorisation Number(S)

PL 30306/0093

9. Date Of First Authorisation/Renewal Of The Authorisation

01/04/2008

10. Date Of Revision Of The Text

17^th February 2010

11 DOSIMETRY

(IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

(IF APPLICABLE)

ISMN Genericon

ISMN Genericon may be available in the countries listed below.

Ingredient matches for ISMN Genericon

Isosorbide Mononitrate

Isosorbide Mononitrate is reported as an ingredient of ISMN Genericon in the following countries:

• Austria


• Croatia (Hrvatska)

International Drug Name Search

Raporsin XL 4mg Prolonged-release Tablets

1. Name Of The Medicinal Product

Raporsin XL 4mg Prolonged-release Tablets

2. Qualitative And Quantitative Composition

Each prolonged-release tablet contains: 4 mg doxazosin (as mesilate)

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Prolonged-release tablet.

White, round, biconvex tablets with bossing "DL".

4. Clinical Particulars

4.1 Therapeutic Indications

- Essential hypertension

- Symptomatic treatment of benign prostatic hyperplasia.

4.2 Posology And Method Of Administration

Oral use.

Raporsin XL, prolonged-release tablets can be taken with or without food. The tablets must be swallowed whole with a sufficient amount of liquid. The prolonged-release tablets should not be chewed, divided or crushed.

The maximum recommended dose is 8 mg doxazosin once daily.

Essential hypertension:

Adults: Usually 4 mg doxazosin once daily. If necessary, the dosage may be increased to 8 mg doxazosin once daily.

It may take up to 4 weeks to reach optimal effect.

Raporsin XL, prolonged-release tablets can be used as sole agent or in combination with another medicinal product e.g. a thiazide diuretic, beta-adrenoceptor blocking agent, calcium antagonist or an ACE-inhibitor.

Symptomatic treatment of prostatic hyperplasia:

Adults: Usually 4 mg doxazosin once daily. If necessary, the dosage may be increased to 8 mg doxazosin once daily.

Raporsin XL, prolonged-release tablets may be used in benign prostatic hyperplasia (BPH) patients who are either hypertensive or normotensive, as the blood pressure changes in normotensive patients are clinically insignificant. In hypertensive patients both conditions are treated concomitantly.

Elderly: Same dosage as for adults.

Patients with renal impairment: Since there is no change in pharmacokinetics in patients with impaired renal function, and since there are no signs that doxazosin aggravates existing renal impairment, the usual dose can be used in these patients.

Patients with hepatic impairment: Doxazosin should be given with particular caution to patients with evidence of impaired liver function. In patients with severe hepatic impairment clinical experience is lacking and therefore the use of doxazosin is not recommended. (See section 4.4).

Children and adolescents: Raporsin XL, prolonged-release tablets are not recommended for patients under the age of 18 years.

4.3 Contraindications

Doxazosin is contraindicated in

(1) Patients with a known hypersensivity to quinazolines (e.g.prazosin, terazosin, doxazosin) or any of the excipients.

(2) Patients with a history of orthostatic hypotension

(3) Patients with benign prostatic hyperplasia and concomitant congestion of the upper urinary tract, chronic urinary tract infection or bladder stones.

(4) Patients with a history of gastro-intestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastro-intestinal tract ¹

(5) During lactation (please see section 4.6) ²

(6) Patients with hypotension ³

¹ For patients taking the sustained release tablets only.

² For the hypertension indication only

³ For the benign prostatic hyperplasia indication only

Doxazosin is contraindicated as monotherapy in patients with either overflow bladder or anuria with or without progressive renal insufficiency.

4.4 Special Warnings And Precautions For Use

Doxazosin is not appropriate for first-line treatment for essential hypertension. It may be used as monotheraphy in patients who have failed to respond to or have contraindications to other agents. Alternatively, use should be limited to second- or third-line treatment in combination with other antihypertensives.

Information to be given to the Patient: Patients should be informed that doxazosin tablets should be swallowed whole. Patients should not chew, divide or crush the tablets.

Abnormally short transit times through the gastrointestinal tract (e.g. following surgical resection) could result in incomplete absorption. In view of the long half life of doxazosin the clinical significance of this is unclear.

Initiation of Therapy: In relation with the alpha-blocking properties of doxazosin, patients may experience postural hypotension evidenced by dizziness and weakness, or rarely loss of consciousness (syncope), particularly with the commencement of therapy. Therefore, it is prudent medical practice to monitor blood pressure on initiation of therapy to minimise the potential for postural effects. The patient should be cautioned to avoid situations where injury could result should dizziness or weakness occur during the initiation of doxazosin therapy.

Use in patients with Acute Cardiac Conditions: As with any other vasodilatory anti-hypertensive agent it is prudent medical practice to advise caution when administering doxazosin to patients with the following acute cardiac conditions:

- pulmonary oedema due to aortic or mitral stenosis

- heart failure at high output

- right-sided heart failure due to pulmonary embolism or pericardial effusion

- left ventricular heart failure with low filling pressure.

Use in Hepatically Impaired Patients: As with any drug wholly metabolised by the liver, doxazosin should be administered with particular caution to patients with evidence of impaired hepatic function. Since there is no clinical experience in patients with severe hepatic impairment use in these patients is not recommended.

Use with PDE-5 inhibitors: Concomitant use of phosphodiesterase-5-inhibitors (eg sildenafil, tadalafil, and vardenafil) and doxazosin may lead to symptomatic hypotension in some patients. In order to minimise the risk for developing postural hypotension the patient should be stable on alpha-blocker therapy before initiating use of phosphodiesterase-5-inhibitors.

Use in patients undergoing cataract surgery: The 'Intraoperative Floppy Iris Syndrome' (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with tamsulosin. Isolated reports have also been received with other alpha-1 blockers and the possibility of a class effect cannot be excluded. As IFIS may lead to increased procedural complications during the cataract operation current or past use of alpha-1 blockers should be made known to the ophthalmic surgeon in advance of surgery.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of Phosphodiesterase-5-inhubitors (e.g. sildenafil, tadalafil, vardenafil) and doxazosin may lead to symptomatic hypotension in some patients (see section 4.4.). No studies have been conducted with doxazosin prolonged release formulations.

Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin or indometacin.

Conventional doxazosin has been administered without any adverse drug interaction in clinical experience with thiazide diuretics, furosemide, beta-blockers, non-steroidal anti-inflammatory drugs, antibiotics, oral hypoglycaemic drugs, uricosuric agents, and anticoagulants. However, data from formal drug/drug interaction studies are not present.

Doxazosin potentiates the blood pressure lowering activity of other alpha-blockers and other antihypertensives.

In an open-label, randomized, placebo-controlled trial in 22 healthy male volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a four-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin, and no statistically significant changes in mean Cmax and mean half-life of doxazosin. The 10% increase in the mean AUC for doxazosin with cimetidine is within intersubject variation (27%) of the mean AUC for doxazosin with placebo.

4.6 Pregnancy And Lactation

For the hypertension indication:

As there are no adequate and well controlled studies in pregnant women, the safety of doxazosin during pregnancy has not been established. Accordingly, during pregnancy, doxazosin should be used only if the potential benefit outweighs the risk. Although no teratogenic effects were seen in animal testing, reduced foetal survival was observed in animals at high doses (see Section 5.3: Preclinical Safety Data).

Doxazosin is contraindicated during lactation as the drug accumulates in milk of lactating rats and there is no information about the excretion of the drug into the milk of lactating women.

Alternatively, mothers should stop breast-feeding when treatment with doxazosin is necessary (Please see section 5.3).

For the benign prostatic hyperplasia indication:

This section is not applicable.

4.7 Effects On Ability To Drive And Use Machines

The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating therapy.

4.8 Undesirable Effects

Frequencies used are as follows: Very common

MedDRA System Organ Class	Frequency	Undesirable Effects
Infections and infestations	Common	Respiratory tract infection, urinary tract infection
Blood and lymphatic system disorders	Very Rare	Leukopenia, thrombocytopenia
Immune System Disorders	Uncommon	Allergic drug reaction
Metabolism and Nutrition Disorders	Uncommon	Anorexia, gout, increased appetite
Psychiatric Disorders	Uncommon	Anxiety, depression, insomnia
	Very Rare	Agitation, nervousness
Nervous System Disorders	Common	Dizziness, headache, somnolence
	Uncommon	Cerebrovascular accident, hypoesthesia, syncope, tremor
	Very Rare	Dizziness postural, paresthesia
Eye Disorders	Very Rare	Blurred vision
	Unknown	Introperative floppy iris syndrome (see Section 4.4)
Ear and Labyrinth Disorders	Common	Vertigo
	Uncommon	Tinnitus
Cardiac Disorders	Common	Palpitation, tachycardia
	Uncommon	Angina pectoris, myocardial infarction
	Very Rare	Bradycardia, cardiac arrhythmias
Vascular Disorders	Common	Hypotension, postural hypotension
	Very Rare	Flush
Respiratory, Thoracic and Mediastinal Disorders	Common	Bronchitis, cough, dyspnea, rhinitis
	Uncommon	Epistaxis
	Very Rare	Bronchospasm
Gastrointestinal Disorders	Common	Abdominal pain, dyspepsia, dry mouth, nausea
	Uncommon	Constipation, diarrhoea, flatulence, vomiting, gastroenteritis
	Unknown	Taste disturbances
Hepatobiliary Disorders	Uncommon	Abnormal liver function tests
	Very Rare	Cholestasis, hepatitis, jaundice
Skin and Subcutaneous Tissue Disorders	Common	Pruritus
	Uncommon	Skin rash
	Very Rare	Alopecia, purpura, urticaria
Musculoskeletal and Connective Tissue Disorders	Common	Back pain, myalgia
	Uncommon	Arthralgia
	Very Rare	Muscle cramps, muscle weakness
Renal and Urinary Disorders	Common	Cystitis, urinary incontinence
	Uncommon	Dysuria, hematuria, micturition frequency
	Very Rare	Micturition disorder, nocturia, polyuria, increased diuresis
Reproductive System and Breast Disorders	Uncommon	Impotence
	Very Rare	Gynecomastia, priapism
	Unknown	Retrograde ejaculation
General Disorders and Administration Site Conditions	Common	Asthenia, chest pain, influenza-like symptoms, peripheral oedema
	Uncommon	Pain
	Very Rare	Fatigue, malaise, facial oedema
Investigations	Uncommon	Weight increase

4.9 Overdose

Should overdosage lead to hypotension, the patient should be immediately placed in a supine, head down position. Other supportive measures should be performed if thought appropriate in individual cases. Since doxazosin is highly protein bound, dialysis is not indicated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Alpha-adrenoceptor antagonists

ATC code: C02CA04

Hypertension:

Administration of Raporsin XL, prolonged-release tablets in hypertensive patients causes a clinically significant reduction in blood pressure as a result of a reduction in systemic vascular resistance. This effect is thought to result from selective blockade of the alpha-1-adrenoceptors located in the vasculature. With once daily dosing, clinically significant reductions in blood pressure are present throughout the day and at 24-hours post dose. The majority of patients are controlled on the initial dose of 4 mg Raporsin XL, prolonged-release tablets. In patients with hypertension, the decrease in blood pressure during treatment with Raporsin XL, prolonged-release tablets was similar in both the sitting and standing position.

Patients treated with immediate release doxazosin tablets against hypertension can be transferred to Raporsin XL, prolonged-release tablets and the dose titrated upwards as needed, while maintaining effect and tolerability.

Habituation has not been observed during long-term treatment with doxazosin. Increase in plasma renin activity and tachycardia have rarely been seen during long-term treatment.

Doxazosin has a beneficial effect on blood lipids with significant increase of HDL/total cholesterol ratio (app. 4-13% of base line values), and significant reduction in total glycerides and total cholesterol. The clinical relevance of these findings is still unknown.

Treatment with doxazosin has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation as well as enhanced capacity of tissue plasminogen-activator. The clinical relevance of these findings is still uncertain. Additionally, doxazosin improves insulin sensitivity in patients with impaired sensitivity to insulin, but also concerning this finding the clinical relevance is still uncertain.

Doxazosin has shown to be free of metabolic adverse effects and is suitable for treatment of patients with coexistent asthma, diabetes, left ventricular dysfunction or gout.

Prostatic hyperplasia:

Administration of Raporsin XL, prolonged-release tablets to patients with prostatic hyperplasia results in a significant improvement in urodynamics and symptoms as a result of a selective blockade of alpha-adrenoceptors located in the prostatic muscular stroma, capsule and bladder neck.

Most of the patients with prostatic hyperplasia are controlled with the initial dose.

Doxazosin has shown to be an effective blocker of 1A subtype of alpha-adrenoceptors which make up more than 70% of the adrenergic subtypes in prostate.

Throughout the recommended dosage range, Raporsin XL, prolonged-release tablets have only a minor or no effect on blood pressure in normotensive benign prostatic hyperplasia (BPH) patients.

5.2 Pharmacokinetic Properties

Absorption:

After oral administration of therapeutic doses, doxazosin in Raporsin XL, prolonged-release tablets is well absorbed with peak blood levels gradually reached at 6 to 8 hours after dosing. Peak plasma levels are approximately one third of those of the same dose of immediate release doxazosin tablets. Trough levels at 24 hours are, however, similar. The pharmacokinetic properties of doxazosin in Raporsin XL, prolonged-release tablets lead to a minor variation in plasma levels. Peak/trough ratio of Raporsin XL, prolonged-release tablets is less than half that of immediate release doxazosin tablets.

At steady-state, the relative bioavailability of doxazosin from Raporsin XL, prolonged-release tablets compared to immediate release form was 54% at the 4 mg dose and 59% at the 8 mg dose.

Distribution:

App. 98% of doxazosin is protein-bound in plasma.

Biotransformation:

Doxazosin is extensively metabolised with <5% excreted as unchanged product. Doxazosin is primarily metabolised by O-demethylation and hydroxylation.

Elimination:

The plasma elimination is biphasic with the terminal elimination half-life being 22 hours and hence this provides the basic for once daily dosing

Elderly:

Pharmacokinetic studies with doxazosin in the elderly have shown no significant altera-tions compared to younger patients.

Renal impairment:

Pharmacokinetic studies with doxazosin in patients with renal impairment also showed no significant alterations compared to patients with normal renal function.

Liver impairment:

There are only limited data in patients with liver impairment and on the effects of medicinal products known to influence hepatic metabolism (e.g. cimetidine). In a clinical study in 12 subjects with moderate hepatic impairment, single dose administration of doxazosin resulted in an increase of AUC of 43% and a decrease in oral clearance of app. 40%. Doxazosin therapy in patients with hepatic impairment should be performed with caution (see section 4.4.).

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity. Studies in pregnant rabbits and rats at daily doses resulting in plasma concentrations 4 and 10 times the human exposure (C_max and AUC), respectively, revealed no evidence of harm to the foetus. A dosage regime of 82 mg/kg/day (8 times the human exposure) was associated with reduced foetal survival.

Studies in lactating rats given a single oral dose of radioactive doxazosin gave an accumulation in the breast milk with a maximum concentration of about 20 times greater than the maternal plasma concentration. Radioactivity was found to cross the placenta following oral administration of labelled doxazosin to pregnant rats.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Polyethylene oxide

Cellulose, microcrystalline

Povidone K 29-32

Butylhydroxytoluene (E321)

All-rac-α-Tocopherol

Silica, colloidal anhydrous

Sodium stearyl fumarate

Tablet coat:

Methacrylic acid - ethyl acrylate copolymer (1:1) Dispersion 30 per cent

Silica, colloidal anhydrous

Macrogol 1300-1600

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

4 years.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

PVC/PVDC/aluminium blister.

Pack sizes: 10, 28, 30, 50, 90, 98 and 100 prolonged-release tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Actavis Group PTC ehf

Reykjavikurvegur 76-78

220 Hafnarfjordur

Iceland

8. Marketing Authorisation Number(S)

PL 30306/0219

9. Date Of First Authorisation/Renewal Of The Authorisation

12.02.2009

10. Date Of Revision Of The Text

26/06/11

11. DOSIMETRY (IF APPLICABLE)

Not applicable.

12. INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

Not applicable.

Ranitidine 300mg Tablets (Goldshield plc)

1. Name Of The Medicinal Product

Ranitidine 300mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains Ranitidine hydrochloride Ph.Eur. equivalent to Ranitidine 300 mg

3. Pharmaceutical Form

Oblong, biconvex, white to yellowish film-coated biconvex tablet. Tablet size: 8.2 x 17mm.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults:

Goldshield Ranitidine tablets are indicated in the treatment of ulcers of the duodenum and of benign gastric ulcers, including those associated with use of non-steroidal anti-inflammatory agents (NSAID's) and/or prevention of NSAID induced duodenal ulcers.

Goldshield Ranitidine tablets may also be used in conditions where reduction of gastric secretion and acid output may be beneficial, such as: prophylaxis of gastrointestinal haemorrhage arising from stress ulceration in seriously ill patients; prophylaxis of recurring haemorrhage associated with bleeding peptic ulcers; before general anaesthesia in patients considered to be at risk of acid aspiration (Mendelson's syndrome) for example in obstetric patients during labour.

Other indications include the treatment of Zollinger-Ellison syndrome, gastro-oesophageal reflux disease (including the long-term management of healed oesophagitis) and post-operative ulcer. Patients with chronic episodic dyspepsia, characterised by pain (epigastric or retrosternal) which disturbs sleep or is related to meals but is not associated with the preceding conditions may also benefit from treatment with Goldshield Ranitidine.

Children (3 to 18 years)

- Short term treatment of peptic ulcer

- Treatment of gastro-oesophageal reflux, including reflux oesophagitis and symptomatic relief of gastro-oesophageal reflux disease.

4.2 Posology And Method Of Administration

Adults and the elderly:

Treatment of ulcers

The normal starting dose is Goldshield Ranitidine 150 mg twice daily, morning and evening. Absorption is not affected by the presence of food.

Patients with duodenal ulceration. gastric ulceration or gastro-oesophageal reflux disease may be treated with a single dose of 300 mg at bedtime. In duodenal ulcer it has been reported that use of 300 mg twice daily for 4 weeks results in healing rates which are higher than those at 4 weeks with ranitidine 150mg twice daily or 300 mg nocte. without an associated increase in the incidence of adverse reactions.

In most cases of duodenal ulcer, benign gastric ulcer and post-operative ulcer, healing occurs in four weeks. A further four week course of treatment may be necessary in those patients whose ulcers have not fully healed after the initial course of therapy; healing normally takes place following the second course of treatment.

NSAID associated ulcers

In ulcers following NSAID therapy or associated with continued NSAID's, eight weeks' treatment may be necessary to induce healing.

For the prevention of NSAID associated duodenal ulcers, Goldshield Ranitidine 150mg twice daily may be given with NSAID therapy.

Maintenance treatment of ulcers

Maintenance treatment at a reduced dosage of 150 mg at bedtime is recommended for patients who have responded to short-term therapy, particularly those with a history of recurrent ulcer.

Oesophageal Reflux Disease

In the management of oesophageal reflux disease, the recommended course of treatment is either 150 mg twice daily or 300mg at bedtime for up to 8 or 12 weeks.

In patients with moderate to severe gastro-oesophagitis, the dosage of ranitidine may be increased to 150 mg four times daily for up to twelve weeks. The increased dose has not been associated with an increased incidence of adverse reactions.

The recommended adult oral dose is 150 mg twice daily for the long-term treatment of healed oesophagitis. Long-term treatment is not indicated in the management of patients with unhealed oesophagitis.

Mendelson's Syndrome

Goldshield Ranitidine tablets 150 mg can be given orally 2 hours before induction of general anaesthesia, and if possible, an additional dose of 150 mg the previous evening, in patients regarded to be at risk of acid aspiration syndrome.

At onset of labour, an oral dose of 150 mg Goldshield Ranitidine may be given to obstetric patients followed by a further 150 mg every six hours. Since gastric emptying and drug absorption are delayed during labour, it is recommended that any patient requiring emergency general anaesthesia should also be given a non-particulate antacid (e.g. sodium citrate) prior to induction of anaesthesia. The usual precautions to avoid acid aspiration should also be taken.

Zollinger-Ellison syndrome

In patients with Zollinger-Ellison syndrome, the recommended starting dose is 150 mg three times daily, which may be increased as necessary. Doses increasing to 6 g per day have been used in patients with this syndrome and it has been reported that these doses have been well tolerated.

Chronic episodic dyspepsia

The recommended course of treatment in such cases is 150 mg twice daily for up to six weeks. Further investigations should be carried out in non-responding patients.

Children

Children from 3 to 11 years and over 30 kg of weight

See Section 5.2 Pharmacokinetic Properties - Special Patient Populations.

Peptic Ulcer Acute Treatment

The recommended oral dose for the treatment of peptic ulcer in children is 4 mg/kg/day to 8 mg/kg/day administered as two divided doses to a maximum of 300 mg ranitidine per day for a duration of 4 weeks. For those patients with incomplete healing, another 4 weeks of therapy is indicated, as healing usually occurs after eight weeks of treatment.

Gastro-Oesophageal Reflux

The recommended oral dose for the treatment of gastro-oesophageal reflux in children is 5 mg/kg/day to 10 mg/kg/day administered as two divided doses in a maximum dose of 600 mg (the maximum dose is likely to apply to heavier children or adolescents with severe symptoms).

Safety and efficacy in new-born patients has not been established.

4.3 Contraindications

Goldshield Ranitidine tablets are contra-indicated in patients hypersensitive to any ingredient of the preparation.

4.4 Special Warnings And Precautions For Use

Treatment with H₂ - antagonists such as ranitidine may mask symptoms associated with carcinoma of the stomach. In order to avoid delays in diagnosis of this condition, in patients of middle age and over with new or recently changed dyspeptic symptoms, or where Gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with Goldshield Ranitidine Tablets commences.

A large epidemiological study showed an increased risk of developing community acquired pneumonia in current users of H2 receptor antagonists versus those who had stopped treatment, with an observed adjusted relative risk increase of 1.82 (95% CI, 1.26 -2.64). This increased risk was mainly observed in patients with pulmonary diseases, diabetes, heart failure and in immunocompromised patients.

Current evidence shows that Ranitidine only protects against NSAID associated ulceration in the duodenum, not in the stomach. Regular supervision of all patients, but especially the elderly, who are taking NSAID's concomitantly with Ranitidine is recommended.

Clinical reports of acute intermittent porphyria associated with Ranitidine administration have been rare and inconclusive. However, Ranitidine should be avoided in patients with a history of this condition.

As Ranitidine is excreted via the kidney, plasma levels of the drug are increased in patients with severe renal impairment. It is therefore recommended that a reduced starting dose of Goldshield Ranitidine is utilised in such patients ie.150 mg at night for 4 to 8 weeks. The same dose should be used for maintenance treatment if deemed necessary. If an ulcer has not healed after treatment the standard dosage regimen of 150 mg twice daily may be commenced, followed, if necessary, by maintenance treatment of 150mg at night.

Use in renal transplants

Ranitidine has been used successfully in patients with renal transplants.

Use in elderly patients

Similar rates of healing of ulcers and adverse reaction profiles have been observed in patients aged 65 and over compared to younger patients.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ranitidine has the potential to affect the absorption, metabolism or renal excretion of other drugs. The altered pharmacokinetics may necessitate dosage adjustment of the affected drug or discontinuation of treatment

Interactions occur by several mechanisms including:

1) Inhibition of cytochrome P450-linked mixed function oxygenase system: Ranitidine at usual therapeutic doses does not potentiate the actions of drugs which are inactivated by this enzyme system such as diazepam, lidocaine, phenytoin, propanolol and theophylline.

There have been reports of altered prothrombin time with coumarin anticoagulants (e.g. warfarin). Due to the narrow therapeutic index, close monitoring of increased or decreased prothrombin time is recommended during concurrent treatment with ranitidine.

2) Competition for renal tubular secretion:

Since ranitidine is partially eliminated by the cationic system, it may affect the clearance of other drugs eliminated by this route. High doses of ranitidine (e.g. such as those used in the treatment of Zollinger-Ellison syndrome) may reduce the excretion of procainamide and N-acetylprocainamide resulting in increased plasma level of these drugs.

3) Alteration of gastric pH:

The bioavailability of certain drugs may be affected. This can result in either an increase in absorption (e.g. triazolam, midazolam, glipizide) or a decrease in absorption (e.g. ketoconazole, atazanavir, delaviridine, gefitnib).

There is no evidence of an interaction between ranitidine and metronidazole or amoxycillin.

4.6 Pregnancy And Lactation

Like other drugs, Goldshield Ranitidine tablets should only be used during pregnancy and nursing if considered essential by the physician. Ranitidine is excreted in human breast milk.

Ranitidine crosses the placenta but therapeutic doses administered to obstetric patients in labour or undergoing caesarean section at the recommended dosage (see sections 4.1 & 4.2) have been without any adverse effect on labour, delivery or subsequent neonatal progress.

4.7 Effects On Ability To Drive And Use Machines

Ranitidine may cause dizziness and the patient should be warned not to drive or to operate machinery if affected.

4.8 Undesirable Effects

The following convention has been utilised for the classification of undesirable effects: very common (

Blood & Lymphatic System Disorders

Unknown: Blood count changes (leucopenia, thrombocytopenia). These are usually reversible. Agranulocytosis or pancytopenia, sometimes with marrow hypoplasia or marrow aplasia.

Immune System Disorders

Uncommon: Hypersensitivity reactions (urticaria, angioneurotic oedema, fever, bronchospasm, hypotension and chest pain).

Unknown: Anaphylactic shock

These events have been reported after a single dose.

Psychiatric Disorders

Very Rare: Depression.

Unknown: Reversible mental confusion, depression and hallucinations.

These have been reported predominantly in severely ill and elderly patients.

Nervous System Disorders

Common: Headache (sometimes severe) and dizziness

Unknown: Reversible involuntary movement disorders.

Eye Disorders

Uncommon: Reversible blurred vision.

There have been reports of blurred vision, which is suggestive of a change in accommodation.

Cardiac Disorders

Unknown: As with other H₂ receptor antagonists bradycardia and A-V Block.

Vascular Disorders

Unknown: Vasculitis.

Gastrointestinal Disorders

Common: Diarrhoea

Unknown: Acute pancreatitis.

Hepatobiliary Disorders

Very Rare: Transient and reversible changes in liver function tests.

Unknown: Hepatitis (hepatocellular, hepatocanalicular or mixed) with or without jaundice, these were usually reversible.

Skin and Subcutaneous Tissue Disorders

Uncommon: Skin Rash.

Unknown: Erythema multiforme, alopecia.

Musculoskeletal and Connective Tissue Disorders

Unknown: Musculoskeletal symptoms such as arthralgia and myalgia.

Renal and Urinary Disorders

Unknown: Acute interstitial nephritis.

Reproductive System and Breast Disorders

Unknown: Reversible impotence. Breast symptoms and breast conditions (such as gynaecomastia and galactorrhea).

The safety of ranitidine has been assessed in children aged 0 to 16 years with acid-related disease and was generally well tolerated with an adverse event profile resembling that in adults. There are limited long term safety data available, in particular regarding growth and development.

4.9 Overdose

No specific antidote is available. However, no particular problems are expected following overdosage due to the specificity of action of ranitidine. Symptomatic and supportive therapy should be given as appropriate. Ranitidine may be removed from the plasma by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ranitidine is a specific, rapidly acting histamine H₂ -antagonist. It inhibits both basal and stimulated secretion of gastric acid, thereby reducing both the volume and the acid and pepsin content of gastric secretions. Ranitidine has a relatively long duration of action. A single dose effectively suppresses gastric acid secretion for up to twelve hours.

5.2 Pharmacokinetic Properties

Absorption of ranitidine after oral administration is rapid and peak plasma concentrations are usually achieved 2-3 hours after administration. Absorption is not significantly impaired by food or antacids. Oral bioavailability is approximately 50%.

Ranitidine is approximately 15% protein bound.

Metabolism of ranitidine is not extensive, and elimination of the drug is primarily by tubular secretion. The elimination half-life of ranitidine is 2-3 hours. In balance studies with 150 mg 3H-ranitidine 60-70% of an oral dose was excreted in urine and 26% in faeces. 35% of the oral dose was eliminated unchanged in the urine in the first 24 hours after dosing. Approximately 6% of the dose is excreted as the N-oxide, 2% as the S-oxide, 2% as desmethyl ranitidine and 1-2% as the furoic acid analogue.

Special Patient Populations

Children (3 years and above)

Limited pharmacokinetic data have shown that there are no significant differences in half-life (range for children 3 years and above: 1.7 - 2.2 h) and plasma clearance (range for children 3 years and above: 9 - 22 ml/min/kg) between children and healthy adults receiving oral ranitidine when correction is made for body weight.

5.3 Preclinical Safety Data

There was no indication of tumourigenic or carcinogenic effects in life-span studies in mice and rats at dosages up to 2,000 mg/kg per day.

Ranitidine was not mutagenic in standard bacterial tests (Salmonella, Escherichia coli) for mutagenicity at concentrations up to the maximum recommended for these assays.

In a dominant lethal assay, a single oral dose of 1,000 mg/kg to male rats was without effect on the outcome of two matings per week for the next nine weeks.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Croscarmellose sodium Ph.Eur

Magnesium stearate Ph.Eur.

Microcrystalline cellulose Ph.Eur.

Hydroxypropylmethylcellulose Ph.Eur.

Titanium dioxide Ph.Eur.

Talc Ph.Eur.

Polyethylene glycol 6000 Ph Eur

Polymethylmethacrylic acid copolymer (Eudragit E)

6.2 Incompatibilities

None known.

6.3 Shelf Life

2 years (unopened).

6.4 Special Precautions For Storage

Store below 25°C in a dry place.

6.5 Nature And Contents Of Container

Carton of 30 tablets, packed in A1/A1 blisters.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

ADMINISTRATIVE DATA

7. Marketing Authorisation Holder

Goldshield Pharmaceuticals Ltd.

NLA Tower, 12-16 Addiscombe Road

Croydon,

CR0 0XT

United Kingdom.

8. Marketing Authorisation Number(S)

PL 12762/0012

9. Date Of First Authorisation/Renewal Of The Authorisation

27 October 1997

10. Date Of Revision Of The Text

01/03/2010