Pericyazine 10mg / 5ml Syrup

1. Name Of The Medicinal Product

Pericyazine 10mg/5ml Syrup

2. Qualitative And Quantitative Composition

Pericyazine 10mg/5ml

3. Pharmaceutical Form

Syrup for oral administration

4. Clinical Particulars

4.1 Therapeutic Indications

a) In adults with schizophrenia or other psychoses, for the treatment of symptoms or prevention of relapse.

b) In anxiety, psychomotor agitation, violent or dangerously impulsive behaviour. Pericyazine is used as an adjunct to the short-term management of these conditions.

c) In children with behaviour disorders or schizophrenia

4.2 Posology And Method Of Administration

Route of administration: oral

Dosage requirement varies with the individual and the severity of the condition being treated. Initial dosage should be low with progressive increases until the desired response is obtained, after which dosage should be adjusted to maintain control of the symptoms.

Severe conditions

Indications (a) or (c)

Adults

Initially 75mg per day in divided doses. Dosage should be increased by 25mg per day at weekly intervals until the optimum effect is achieved. Maintenance therapy would not normally be expected to exceed 300mg per day.

Elderly

Initially 15-30mg per day in divided doses. If this is well tolerated the dosage may be increased if necessary for optimum control of behaviour.

Children

The initial daily dose should be calculated on bodyweight. A child weighing 10kg should receive 0.5 milligram and this initial dose should be increased by 1mg for each additional 5kg of bodyweight up to a total daily dose of 10mg daily. This dosage may be gradually increased until the desired effect is achieved, but the daily maintenance dose should not exceed twice the initial amount.

Pericyazine is not recommended for use in children below 1 year of age.

Mild or moderate conditions

Anxiety, psychmotor agitation, violent or dangerously impulsive behaviour.

Adults

Initially 15-30mg daily, divided into two portions with a larger dose being given in the evening.

Elderly

5 - 10mg per day is suggested as a starting dose. It may be divided so that a larger portion is given in the evening. Half or quarter the normal adult dose may be sufficient for maintenance therapy.

Children

Not recommended for children.

4.3 Contraindications

Known hypersensitivity to pericyazine or to any of the other ingredients.

4.4 Special Warnings And Precautions For Use

Neuroleptics should be avoided in patients with liver or renal dysfunction, Parkinson's disease, hypothyroidism, cardiac failure, phaeochromocytoma, myasthenia gravis, prostrate hypertrophy. It should be avoided in patients known to be hypersensitive to phenothiazines or with a history of narrow angle glaucoma or agranulocytosis. It should be used with caution in the elderly, particularly during very hot or very cold weather (risk of hyper-hypothermia).

Close monitoring is required in patients with epilepsy or a history of seizures, as phenothiazines may lower the seizure threshold.

As agranulocytosis may occur rarely, regular monitoring of the complete blood count is recommended.

It is imperative that treatment be discontinued in the event of unexplained fever, as this may be a sign of neuroleptic malignant syndrome (pallor, hyperthermia, autonomic dysfunction, altered consciousness, muscle rigidity). Signs of autonomic dysfunction, such as sweating and arterial instability, may precede the onset of hyperthermia and serve as early warning signs. Although neuroleptic malignant syndrome may be idiosyncratic in origin, dehydration and organic brain disease are predisposing factors.

The occurrence of unexplained infections or fever may be evidence of blood dyscrasia (see section 4.8 below), and requires immediate haematological investigation.

Acute withdrawal symptoms, including nausea, vomiting and insomnia, have very rarely been reported following the abrupt cessation of high doses of neuroleptics. Relapse may also occur, and the emergence of extrapyramidal reactions has been reported. Therefore, gradual withdrawal is advisable.

In schizophrenia, the response to neuroleptic treatment may be delayed. If treatment is withdrawn, the recurrence of symptoms may not become apparent for some time.

Neuroleptic phenothiazines may potentiate QT interval prolongation which increases the risk of onset of serious ventricular arrhythmias of the torsade de pointes type, which is potentially fatal (sudden death). QT prolongation is exacerbated, in particular, in the presence of bradycardia, hypokalaemia, and congenital or acquired (i.e. drug induced) QT prolongation. The risk-benefit should be fully assessed before pericyazine treatment is commenced. If the clinical situation permits, medical and laboratory evaluations (e.g. biochemical status and ECG) should be performed to rule out possible risk factors (e.g. cardiac disease; family history of QT prolongation; metabolic abnormalities such as hypokalaemia, hypocalcaemia or hypomagnesaemia; starvation; alcohol abuse; concomitant therapy with other drugs known to prolong the QT interval) before initiating treatment with pericyazine and during the initial phase of treatment, or as deemed necessary during the treatment (see also sections 4.5 & 4.8).

Avoid concomitant treatment with other neuroleptics (see section 4.5).

Stroke: In randomised clinical trials versus placebo performed in a population of elderly patients with dementia and treated with certain atypical antipsychotic drugs, a 3-fold increase of the risk of cerebrovascular events has been observed. The mechanism of such risk increase is not known. An increase in the risk with other antipsychotic drugs or other populations of patients cannot be excluded. Pericyazine should be used with caution in patients with stroke risk factors.

As with all antipsychotic drugs, pericyazine should not be used alone where depression is predominant. However, it may be combined with antidepressant therapy to treat those conditions in which depression and psychosis coexist.

Because of the risk of photosensitisation, patients should be advised to avoid exposure to direct sunlight.

In those frequently handling preparations of phenothiazines, the greatest care must be taken to avoid contact of the drug with the skin, since contact skin sensitisation occurs rarely.

Hyperglycaemia or intolerance to glucose has been reported in patients with pericyazine.

Patients with an established diagnosis of diabetes mellitus or with risk factors for the development of diabetes who are started on pericyazine, should get appropriate glycaemic monitoring during treatment (see section 4.8).

Increased Mortality in Elderly people with Dementia

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

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

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The CNS depressant actions of neuroleptic agents may be intensified (additively) by alcohol, barbiturates and other sedatives. Respiratory depression may occur.

The hypotensive effect of most antihypertensive drugs, especially alpha adrenoceptor blocking agents may be exaggerated by neuroleptics.

There is an increased risk of arrhythmias when neuroleptics are used with concomitant QT prolonging drugs (including certain antiarrhythmics, antidepressants, and other antipsychotics) and drugs causing electrolyte imbalance (see sections 4.4 and 4.8).

The mild anticholinergic effect of neuroleptics may be enhanced by other anticholinergic drugs, possibly leading to constipation, heat stroke, etc.

The action of some drugs may be opposed by neuroleptics; these include amfetamine, levodopa, clonidine, guanethidine, adrenaline.

Where treatment for neuroleptic-induced extrapyramidal symptoms is required, anticholinergic antiparkinsonian agents should be used in preference to levodopa, since neuroleptics antagonise the antiparkinsonian action of dopaminergics.

Anticholinergic agents may reduce the antipsychotic effect of neuroleptics.

Some drugs interfere with absorption of neuroleptic agents: antacids, and anti-Parkinson drugs, lithium. Increases or decreases in the plasma concentrations of a number of drugs, eg: propanolol, phenobarbital have been observed but were not of clinical significance.

High doses of neuroleptics may reduce the response to hypoglycaemic agents the dosage of which might have to be raised.

In patients treated concurrently with neuroleptics and lithium, there have been rare reports of neurotoxicity

Adrenaline must not be used in patients overdosed with neuroleptics.

Simultaneous administration of desferrioxamine and prochlorperazine has been observed to induce a transient metabolic encephalopathy characterised by loss of consciousness for 48-72 hours. It is possible this may occur with Pericyazine since it shares many of the pharmacological properties of prochlorperazine

There is an increased risk of agranulocytosis when neuroleptics are used concurrently with drugs with myelosuppressive potential, such as carbamazepine or certain antibiotics and cytotoxics.

4.6 Pregnancy And Lactation

There is inadequate evidence of the safety of pericyazine in human pregnancy. There is evidence with some neuroleptics of harmful effects in animals. Like other drugs pericyazine should be avoided in pregnancy unless the physician considers it essential. It may occasionally prolong labour and at such a time should be withheld until the cervix is dilated 3-4cm. Possible adverse effects on the foetus include lethargy or paradoxical hyperexcitability, tremor and low Apgar score.

Phenothiazines may be excreted in milk, therefore breastfeeding should be suspended during treatment.

4.7 Effects On Ability To Drive And Use Machines

Patients should be warned about drowsiness during early days of treatment, and advised not to drive or operate machinery. The elderly are particularly susceptible to postural hypotension.

4.8 Undesirable Effects

Liver function: Jaundice occurs in a very small percentage of patients taking neuroleptics. A premonitory sign may be a sudden onset of fever after one to three weeks of treatment followed by the development of jaundice. Neuroleptic jaundice has the biochemical and other characteristics of obstructive (cholestatic) jaundice and is associated with obstruction of the canaliculi by bile thrombi; the frequent presence of an accompanying eosinophilia indicates the allergic nature of this phenomenon. Liver injury has been reported very rarely in patients treated with pericyazine. Treatment should be withheld on the development of jaundice.

Cardiorespiratory: hypotension, usually postural, commonly occurs. Elderly or volume depleted subjects are particularly susceptible.

ECG changes, include QT prolongation (as with other neuroleptics), ST depression, U-Wave and T-Wave changes. Cardiac arrhythmias, including ventricular arrhythmias and atrial arrhythmias, a-v block, ventricular tachycardia, which may result in ventricular fibrillation or cardiac arrest have been reported during neuroleptic phenothiazine therapy, possibly related to dosage. Pre-existing cardiac disease, old age, hypokalaemia and concurrent tricyclic antidepressants may predispose.

There have been isolated reports of sudden death, with possible cases of cardiac origin (see section 4.4, above), as well as cases of unexplained sudden death, in patients receiving neuroleptic phenothiazines.

Respiratory depression is possible in susceptible patients.

Blood picture: A mild leukopenia occurs in up to 30% of patients on prolonged high dosage of neuroleptics: Agranulocytosis may occur rarely; it is not dose related.

Extrapyramidal: acute dystonias or dyskinesias, usually transitory are commoner in children and young adults, and usually occur within the first four days of treatment or after dosage increases.

• akathisia characteristically occurs after large initial doses.

• parkinsonism is commoner in adults and the elderly. It usually develops after weeks or months of treatment. One or more of the following may be seen: tremor, rigidity, akinesia, or other features of parkinsonism. Commonly just tremor.

• tardive dyskinesia: if this occurs it is usually, but not necessarily after prolonged or high dosage. It can even occur after treatment has been stopped. Dosage should therefore be kept low whenever possible.

Skin and eyes: Contact skin sensitisation may occur rarely in those frequently handling preparations of phenothiazines (see Section 4.4 above).

Skin rashes of various kinds may also be seen in patients treated with the drug. Patients on high dosage should be warned that they may develop photosensitivity in sunny weather and should avoid exposure to direct sunlight.

Endocrine: hyperprolactinaemia which may result in galactorrhoea, gynaecomastia, amenorrhoea; impotence.

Priapism has been reported very rarely in patients treated with pericyazine.

Neuroleptic malignant syndrome (hyperthermia, rigidity autonomic dysfunction and altered consciousness) may occur with any neuroleptic.

Minor side effects are nasal stuffiness, dry mouth, insomnia, agitation.

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs (see also section 4.4).

Intolerance to glucose, hyperglycaemia (see section 4.4).

4.9 Overdose

Symptoms of neuroleptic overdosage include drowsiness or loss of consciousness, hypotension, tachycardia, ECG changes, ventricular arrhythmias and hypothermia. Severe extra-pyramidal dyskinesias may occur.

If the patient is seen sufficiently soon (up to 6 hours) after ingestion of a toxic dose, gastric lavage may be attempted. Pharmacological induction of emesis is unlikely to be of any use. Activated charcoal should be given. There is no specific antidote. Treatment is supportive.

Generalised vasodilatation may result in circulatory collapse; raising the patient's legs may suffice, in severe cases, volume expansion by intravenous fluids may be needed; infusion fluids should be warmed before administration in order not to aggravate hypothermia.

Positive inotropic agents such as dopamine may be tried if fluid replacement is insufficient to correct the circulatory collapse. Peripheral vasoconstrictor agents are not generally recommended; avoid the use of adrenaline.

Ventricular or supraventricular tachy-arrhythmias usually respond to restoration of normal body temperature and correction of circulatory or metabolic disturbances. If persistent or life threatening, appropriate anti-arrhythmic therapy may be considered. Avoid lidocaine, and as far as possible long acting, anti-arrhythmic drugs.

Pronounced central nervous system depression requires airway maintenance or, in extreme circumstances, assisted respiration. Severe dystonic reactions usually respond to procyclidine (5-10mg) or orphenedrine (20-40mg) administered intramuscularly or intravenously. Convulsions should be treated with intravenous diazepam.

Neuroleptic malignant syndrome should be treated with cooling. Dantrolene sodium may be tried.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pericyazine is a neuroleptic with cardiovascular and antihistamine effects similar to those of chlorpromazine, but it has a stronger antiserotonin effect and a powerful central sedative effect.

5.2 Pharmacokinetic Properties

Kinetics: There is little information about plasma concentrations, distribution and excretion in humans. The rate of metabolism and excretion of phenothiazines decreases in old age.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sucrose, Caramel, Spearmint Oil, Peppermint Oil, Fruit cup 868, Polysorbate 20, Citric acid anhydrous, Sodium citrate, Sodium sulphite anhydrous (E221), Sodium metabisulphite (E223), Ascorbic acid, Sodium benzoate (E211), Purified water.

6.2 Incompatibilities

None known

6.3 Shelf Life

24 months unopened, 1 month after opening

6.4 Special Precautions For Storage

Protect from light

6.5 Nature And Contents Of Container

Amber glass bottle containing 1000ml or 100ml. HDPE/polypropylene child resistant cap with tamper evident band. or rolled on pilfer proof aluminium cap and a PVDC emulsion coated wad.

6.6 Special Precautions For Disposal And Other Handling

Care must be taken to avoid contact of the drug with the skin. Contact skin sensitisation is a serious but rare complication in those frequently handling preparations of phenothiazines.

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS, UK

8. Marketing Authorisation Number(S)

PL 17780/0461

9. Date Of First Authorisation/Renewal Of The Authorisation

1^st October 2009

10. Date Of Revision Of The Text

6^th April 2010

Legal status

POM

Pantoprazole 40 mg, powder for solution for injection

1. Name Of The Medicinal Product

Pantoprazole 40 mg, powder for solution for injection.

2. Qualitative And Quantitative Composition

Each vial contains 40 mg of pantoprazole (as sodium sesquihydrate)

Excipients

Each vial contains 5.0 mg of sodium citrate dihydrate and sodium hydroxide

q.s.

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. is essentially “sodium free”.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Powder for solution for injection.

White or almost white, uniform porous cake.

For the solution reconstituted with 10 ml of 0.9% NaCl solution the pH is approximately 10 and the osmolality is approximately 382 mOsm/Kg

For the solution reconstituted with a further 100 ml of 0.9% NaCl solution or 5% glucose solution the pH is approximately 9 and 8.5, respectively

4. Clinical Particulars

4.1 Therapeutic Indications

- Reflux oesophagitis

- Gastric and duodenal ulcer

- Zollinger – Ellison Syndrome and other pathological hypersecretory conditions.

4.2 Posology And Method Of Administration

This medicine should be administered by a healthcare professional and under appropriate medical supervision.

The intravenous administration of pantoprazole is recommended only if oral application is not appropriate. Data are available on intravenous use for up to 7 days. Therefore as soon as oral therapy is possible, treatment with pantoprazole i.v. should be discontinued and 40 mg pantoprazole p.o. should be administered instead.

Recommended dose:

Gastric and duodenal ulcer, reflux oesophagitis

The recommended intravenous dose is one vial of pantoprazole (40 mg) per day.

Zollinger-Ellison Syndrome and other pathological hypersecretory conditions

For the long-term management of Zollinger-Ellison Syndrome and other pathological hypersecretory conditions patients should start their treatment with a daily dose of 80 mg of pantoprazole i.v. Thereafter, the dosage can be titrated up or down as needed using measurements of gastric acid secretion to guide. With doses above 80 mg daily, the dose should be divided and given twice daily. A temporary increase of the dosage above 160 mg pantoprazole is possible but should not be applied longer than required for adequate acid control.

In case a rapid acid control is required, a starting dose of 2 x 80 mg of pantoprazole i.v. is sufficient to manage a decrease of acid output into the target range (<10 mEq/h) within one hour in the majority of patients.

Special populations

Paediatric patients:

The experience in children is limited. Therefore, pantoprazole i.v. is not recommended for use in patients below 18 years of age until further data become available.

Hepatic impairment:

A daily dose of 20 mg pantoprazole (half a vial of 40 mg pantoprazole) should not be exceeded in patients with severe liver impairment (see section 4.4).

Renal impairment:

No dose adjustment is necessary in patients with impaired renal function

Elderly

No dose adjustment is necessary in elderly patients

Method of administration :

A ready-to-use solution is prepared in 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. For instructions for preparation see section 6.6. The prepared solution may be administered directly or may be administered after mixing it with 100 ml of 9 mg/ml (0.9%) sodium chloride injection, or 50 mg/ml glucose (5% ) solution for injection.

After preparation the solution must be used within 12 hours. (See section 6.3).

The medicinal product should be administered intravenously over 2 – 15 minutes.

4.3 Contraindications

Hypersensitivity to the active substance, substituted benzimidazoles, or to any of the excipients

4.4 Special Warnings And Precautions For Use

In presence of alarm symptoms

In the presence of any alarm symptom (e. g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis.

Further investigation is to be considered if symptoms persist despite adequate treatment.

Hepatic impairment

In patients with severe liver impairment liver enzymes should be monitored during therapy. In case of a rise in the liver enzymes, pantoprazole i.v. should be discontinued. (See also section 4.2)

Co-administration with atazanavir

Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir. A pantoprazole dose of 20 mg per day should not be exceeded.

Gastrointestinal infections caused by bacteria

Pantoprazole, like all proton pump inhibitors (PPIs), might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract. Treatment with pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria (e.g. Salmonella and Campylobacter).

Sodium

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially “sodium-free”

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effect of Pantoprazole on the absorption of other medicinal products

Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may reduce the absorption of drugs with a gastric pH dependant bioavailability, e.g. some azole antifungals such as ketoconazole, intraconazole, posaconazole and other medicines such as erlotinib.

HIV medications (atazanavir)

Co-administration of atazanavir and other HIV medications whose absorption is pH-dependent with proton pump inhibitors might result in a substantial reduction in the bioavailability of these HIV medications and might have an impact on the efficacy of these medicines. Therefore, the co-administration of proton pump inhibitors with atazanavir and is not recommended (see section 4.4).

Coumarin anticoagulants (phenprocoumon or warfarin)

Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in International Normalised Ratio (INR) have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated with coumarin anticoagulants (e.g. phenprocoumon or warfarin), monitoring of prothrombin time/INR is recommended after initiation, termination or during irregular use of pantoprazole.

Other interactions studies

Pantoprazole is extensively metabolised in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by CYP3A4.

Interaction studies with drugs also metabolised with these pathways, like carbamazepine, diazepam, glibenclamide, nifedipine and an oral contraceptive containing levonorgestrel and ethinyl oestradiol did not reveal clinically significant interactions.

Results from a range of interaction studies demonstrate that Pantoprazole does not effect the metabolism of active substances metabolised by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol) or does not interfere with p-glycoprotein related absorption digoxin.

There were also no interactions with concomitantly administered antacids.

Interaction studies have been performed administering pantoprazole concomitantly with the respective antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically relevant interactions were found.

4.6 Pregnancy And Lactation

Pregnancy:

There are no adequate data from the use of pantoprazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Pantoprazole should not be used during pregnancy unless clearly necessary.

Lactation:

Animal studies have shown excretion of pantoprazole in breast milk. Excretion into human milk has been reported. Therefore a decision on whether to continue/discontinue breast-feeding or to continue/discontinue treatment with pantoprazole should be made taking into account the benefit of breast-feeding to the child and the benefit of pantoprazole therapy to women.

4.7 Effects On Ability To Drive And Use Machines

Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8). If affected, patients should not drive or operate machines.

4.8 Undesirable Effects

Approximately 5% of patients can be expected to experience adverse drug reactions (ADRs). The most commonly reported ADRs are diarrhoea and headache, both occurring in approximately 1% of patients.

The table below lists adverse reactions reported with pantoprazole, ranked under the following frequency classification:

Very common (

Within each frequency, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions with pantoprazole in clinical trials and post-marketing experience

Frequency	Common	Uncommon	Rare	Very rare	Not known
System organ class
Blood and lymphatic system disorders				Thrombocytopenia: Leukopenia
Immune system disorders			Hypersensitivity (including anaphylactic reactions and anaphylactic shock)
Metabolism and nutrition disorders			Hyperlipidaemia and lipid increases (triglycerides, cholesterol); Weight changes		Hyponatraemia
Psychiatric disorders		Sleep disorders	Depression (an all aggravations)	Disorientation (and all aggravations)	Hallucination: Confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in case of pre-existence)
Nervous system disorders		Headache; Dizziness
Eye disorders			Disturbances in vision/blurred vision
Gastrointestinal disorders		Diarrhoea; Nausea/vomiting; Abdominal distension and bloating; Constipation; Dry mouth; Abdominal pain and discomfort.
Hepatobiliary disorders		Liver enzymes increased (transaminases, γ-GT)	Bilirubin increased		Hepatocellular injury; Jaundice; Hepatocellular failure
Skin and sub-cutaneous tissue disorders		Rash/ exanthema/ eruption; Pruritus	Urticaria; Angioedema		Stevens-Johnson syndrome; Lyell syndrome; Erythema multiforme;Photosensitivity
Musculo-skeletal and connective tissue disorders			Arthralgia; Myalgia
Renal and urinary disorders					Interstitial nephritis
Reproductive system and breast disorders			Gynaecomastia
General disorders and administration site conditions	Injection site thrombo-phlebitis	Asthenia, fatigue and malaise	Body temperature increased; Oedema peripheral

4.9 Overdose

There are no known symptoms of overdose in man.

Systemic exposure with up up to 240 mg administered intravenously over 2 minutes were well tolerated. As pantoprazole is extensively protein bound, it is not readily dialysable.

In case of overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC02.

Mechanism of action

Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells.

Pantoprazole is converted to its active form in the acidic environment in the parietal cells where it inhibits the H⁺/K⁺-ATPase enzyme i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, freedom from symptoms is achieved within 2 eeks. As with other proton pump inhibitors and H₂ receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and thereby an increase in gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the cell receptor level, the substance can affect hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is given orally or intravenously.

The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term treatment (similar to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursosrs (atypical hyperplasia) or gastric carcinoids as were found in animal experiments (see section 5.3) have not been observed in humans.

An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid according to results in animal studies.

5.2 Pharmacokinetic Properties

General Pharmacokinetics

Pharmacokinetics do not vary after single or repeated administration. In the dose range of 10 to 80 mg the plasma kinetics of pantoprazole are linear after both oral and intravenous administration.

Distribution

Pantoprazole's plasma protein binding is about 98%. Volume of distribution is about 0.15 l/kg.

Elimination

The substance is almost exclusively metabolised in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulphate conjugation, other metabolic pathways include oxidation by CYP3A4. Terminal half-life is about 1 hour and clearance is about 0.1 l/h/kg. There were few cases of subjects with delayed elimination. Because of specific binding of pantoprazole to the proton pumps of the parietal cell the elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion).

Renal elimination represents the major route of excretion (about 80%) for the metabolites of pantoprazole; the rest are excreted in the faeces. The main metabolite in both the plasma and urine is desmethylpantoprazole which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 hours) is not much longer than that of pantoprazole.

Characteristics in patients/special groups of subjects:

Approximately 3% of the European population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of pantoprazole is probably mainly catalysed by CYP3A4. After a single dose administration of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60%. These findings have no implications for the posology of pantoprazole.

No dose reduction is required when pantoprazole is administered to patients with impaired kidney function (including dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very small amounts of pantoprazole are dialysed. Although the main metabolite has a moderately delayed half-life (2-3 hours), excretion is still rapid and thus accumulation does not occur.

Although for patients with hepatic cirrhosis (classes A and B according to Child) the half-life values increased to between 7 and 9 hours and the AUC values increased by a factor of 5 to 7, the maximum plasma concentration only increased slightly by a factor of 1.5 compared with healthy subjects.

A slight increase in AUC and Cmax in elderly volunteers compared with younger counterparts is also not clinically relevant.

Children

Following administration of single intravenous doses of 0.8 or 1.6 mg/kg pantoprazole to children aged 2 – 16 years there was no significant association between pantoprazole clearance and age or weight. AUC and volume of distribution were in accordance with data from adults.

5.3 Preclinical Safety Data

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

In the 2-year carcinogenicity study in rats neuroendocrine neoplasms were found. In addition, squamous cell papillomas were found in the forestomach of rats. The mechanism leading to the formation of gastric carcinoids by substituted benzimidazoles has been carefully investigated and allows the conclusion that it is a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during treatment. In the two-year rodent studies an increased number of liver tumours was observed in rats and female mice and was interpreted as being due to pantoprazole's high metabolic rate in the liver.

A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest dose (200 mg/kg). The occurrence of these neoplasms is associated with the pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no side effects to the thyroid glands are expected.

In animal reproduction studies, signs of slight fetotoxicity were observed at does above 5 mg/kg. Investigations revealed no evidence of impaired fertility or teratogenic effects.

Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, the concentration of pantoprazole in the foetus is increased shortly before birth.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol

Sodium citrate dihydrate

Sodium hydroxide (for pH adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

As packaged for sale: 2 years

After reconstitution, or reconstitution and dilution, chemical and physical in-use stability has been demonstrated for 12 hours at 25ºC.

From a microbiological point of view, the product should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special Precautions For Storage

Do not store above 25ºC. Keep the vial in the outer carton to protect from light.

For storage conditions of the reconstituted and diluted medicinal product see section 6.3.

6.5 Nature And Contents Of Container

15 ml, type I, colourless glass vial, sealed with a grey chlorobutyl stopper and an aluminium flip-off cap, containing 40 mg powder for solution for injection.

Pack sizes: 1, 5, 10 and 20 vials

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

A ready-to-use intravenous solution is prepared by injecting 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into the vial containing the lyophilised powder. The reconstituted solution should be clear and colourless. This solution may be administered directly or may be administered after mixing it with 100 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for injection. Glass or plastic containers should be used for dilution

Pantoprazole 40 mg, powder for solution for injection should not be prepared or mixed with solvents other than those stated.

This medicine should be administered intravenously over 2- 15 minutes.

The content of the vial is for single use only. Any product that has remained in the container or the visual appearance of which has changed (e.g. if cloudiness or precipitation is observed) should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Actavis Group PTC ehf

Reykjavikurvegur 76-78

Hafnarfjordur

IS-220

8. Marketing Authorisation Number(S)

PL 30306/0135

9. Date Of First Authorisation/Renewal Of The Authorisation

21/04/2010

10. Date Of Revision Of The Text

21/04/2010

11 DOSIMETRY

IF APPLICABLE

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

IF APPLICABLE

Phorpain Gel 5%

1. Name Of The Medicinal Product

Ibuprofen 5% gel,

Fenbid gel,

Phorpain Gel

Flexigel,

Boots Ibuprofen Gel, Ibuprofen Pain Relief Gel

Nurofen 5% gel,

Morrison's Ibuprofen pain relief 5% w/w gel

Ibucalm Ibuprofen Pain Relief Gel 5 % w/w

Ibuprofen Pain relief gel 5% w/w

Bell's Healthcare Ibuprofen 5% gel

2. Qualitative And Quantitative Composition

5% w/w ibuprofen Ph. Eur.

3. Pharmaceutical Form

Gel for topical application

4. Clinical Particulars

4.1 Therapeutic Indications

Pharmacy only indication:

Topical analgesic and anti-inflammatory for backache, pain of non-serious arthritic conditions, muscular pain, sprains, strains, sports injuries and neuralgia.

General Sales List indication:

Topical analgesic and anti-inflammatory for backache, rheumatic and muscular pain, sprains, strains and sports injuries.

4.2 Posology And Method Of Administration

Strength 5% maximum

Method of administration

For topical application to the skin

Dosage:

Adults, the elderly and children over 14 years: Squeeze 50 to 125mg (4 to 10cm) of the gel from the tube and lightly rub into the affected area until absorbed.

The dose should not be repeated more frequently than every four hours and no more than 4 times in any 24 hour period.

Wash hands after each application. Do not exceed the stated dose. Review treatment after 2 weeks, especially if the symptoms worsen or persist.

Children under 14 years: Do not use on children under 14 years of age except on the advice of a doctor.

4.3 Contraindications

Hypersensitivity to any of the constituents. Hypersensitivity to aspirin, or other non-steroidal anti-inflammatory drugs, asthma, rhinitis or urticaria.

4.4 Special Warnings And Precautions For Use

Apply with gentle massage only. Avoid contact with eyes, mucous membranes and inflamed or broken skin.

Discontinue if rash develops.

Hands should be washed immediately after use.

Not for use with occlusive dressings.

The label will state:

Do not exceed the stated dose

Keep out of reach of chilrden

For external use only

If symptoms persist consult your doctor or pharmacist

Do not use if you are allergic to Ibuprofen or any of the ingredients, aspirin, or any other painkillers.

Consult your doctor before use if:

-you are taking aspirin or any other pain relieving medication.

-you are pregnant.

Not recommended for children under 14 years.

Oral NSAIDs, including ibuprofen, can sometimes be associated with renal impairment, aggravation of active peptic ulcers, and can induce allergic bronchial reactions in susceptible asthmatic patients. Although the systemic absorption of topically applied ibuprofen is less than for oral dosage forms, these complications can occur in rare cases. For these reasons, patients with an active peptic ulcer, a history of kidney problems, asthma or intolerance to aspirin or ibuprofen taken orally should seek medical advice before using Ibuprofen gel.

Patients should be advised against excessive exposure to sunlight of area treated in order to avoid possibility of photosensitivity.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Non-steroidal anti-inflammatory drugs may interact with blood pressure lowering drugs, and may possibly enhance the effects of anticoagulants, although the chance of either of these occurring with a topically administered preparation is extremely remote. Concurrent aspirin or other NSAIDS may result in an increased incidence of adverse reactions.

4.6 Pregnancy And Lactation

Whilst no teratogenic effects have been demonstrated in animal experiments, Ibuprofen should be avoided during pregnancy. The onset of labour may be delayed and duration of labour increased. Ibuprofen appears in breast milk in very low concentration and is unlikely to affect the breast fed infant adversely.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of (a) non-specific allergic reaction and anaphylaxis (b) respiratory tract reactivity comprising of asthma, aggrevated asthma, brochospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritis, urticaria, purpura, angiodema and less commonly, bullous dermatoses (including epidermal necrolysis and erythrema muliforme).

Gastro-intestinal:abdominal pain, dyspepsia.

4.9 Overdose

In children ingestion of more than 400 mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.

Symptoms

Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible.

In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma.

Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/ INR may be prolonged, probably due to interference with the actions of circulating clotting factors.

Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Management

Management should be symptomatic and supportive and include the maintainance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ibuprofen is a non-steroidal anti-inflammatory drug which has been tested and proved to be effective as an analgesic, anti-pyretic and anti-inflammatory after systemic administration. When administered as a topical preparation, ibuprofen has been shown to be an effective topical analgesic and antiinflammatory for the relief of rheumatic and muscular pain, backache, pain of non-serious arthritic conditions, sprains, strains, lumbago and fibrositis by virtue of percutaneous absorption.

5.2 Pharmacokinetic Properties

The gel product containing ibuprofen diffuses through the skin as a function of time and after 24 hours an application to human skin shows that the dose administered is present in the epidermis and dermis. Percutaneous absorption of this Fenbid gel is approximately 5% that of oral ibuprofen. Therapeutic concentrations are reached locally; but not systemically.

5.3 Preclinical Safety Data

There is no new data published on the active ingredient.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Ethylhydroxycellulose EP

Sodium Hydroxide EP

Benzyl alcohol EP

Isopropyl alcohol BP

Purified water EP

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

Aluminium tube with internal epoxy phenolic coating containing 15g (trial size/starter pack) and 30/35/50/100g of Fenbid Gel. The 100g pack size is restricted to “Pharmacy” only.

6.6 Special Precautions For Disposal And Other Handling

None

Administrative Data

7. Marketing Authorisation Holder

Goldshield Group Limited

(trading as Goldshield Pharmaceuticals)

NLA Tower

12-16 Addiscombe Road

Croydon CR0 0XT

8. Marketing Authorisation Number(S)

PL 10972/0045

9. Date Of First Authorisation/Renewal Of The Authorisation

26 April 1996

10. Date Of Revision Of The Text

06/09/2010

Parlodel 2.5mg Tablets

1. Name Of The Medicinal Product

PARLODEL 2.5mg Tablets

2. Qualitative And Quantitative Composition

Active substance: Ergotaman-3`, 6`, 18-trione, 2-bromo-12`-hydroxy-2`-(1-methylethyl-5`-(2-methylpropyl)-, (5`alpha)-mono-methanesulphonate.

Bromocriptine mesilate Ph. Eur 2.87mg, equivalent to 2.5mg of bromocriptine base.

For a full list of excipients see section 6.1

3. Pharmaceutical Form

Tablet: Each tablet is round, white, flat, with a bevelled edge, angle-scored and coded with “2.5 MG” on the upper side.

4. Clinical Particulars

4.1 Therapeutic Indications

Inhibition of lactation for medical reasons

The inhibition or suppression of puerperal lactation where medically indicated such as after intrapartum loss or neonatal death.

PARLODEL is not recommended for the routine suppression of lactation or for the relief of symptoms of post-partum pain and engorgement which can be adequately treated with simple analgesics and breast support.

Hyperprolactinaemia

The treatment of hyperprolactinaemia in men and women with hypogonadism and/or galactorrhoea.

Menstrual cycle disorders and female infertility

Amenorrhoea and oligomenorrhoea, with or without galactorrhoea.

Drug-induced hyperprolactinaemic disorders.

Polycystic ovary syndrome.

Some infertile women with oligomenorrhoea or amenorrhoea and galactorrhoea may be unduly sensitive to prolactin. PARLODEL has been used successfully in the treatment of a number of infertile women with galactorrhoea who do not have demonstrable hyperprolactinaemia.

Prolactinomas

To reduce tumour size, particularly in those at risk of optic nerve compression.

Acromegaly

PARLODEL has been used in a number of specialised units, as an adjunct to surgery and/or radiotherapy to reduce circulating growth hormone in the management of acromegalic patients.

Parkinson's Disease

In the treatment of idiopathic Parkinson's Disease, PARLODEL has been used both alone and in combination with Levodopa in the management of previously untreated patients and those disabled by 'on-off' phenomena. PARLODEL has been used with occasional benefit in patients who do not respond to or are unable to tolerate Levodopa and those whose response to Levodopa is declining.

Premenstrual symptoms and benign breast disease (see section 4.4 Special warnings and precautions for use).

4.2 Posology And Method Of Administration

PARLODEL should always be taken with food.

A number of disparate conditions are amenable to treatment with PARLODEL and for this reason, the recommended dosage regimens are variable.

In most indications, irrespective of the final dose, the optimum response with the minimum of side effects is best achieved by gradual introduction of PARLODEL. The following scheme is suggested: Initially, 1mg to 1.25mg at bed time, increasing after 2 to 3 days to 2mg to 2.5mg at bed time. Dosage may then be increased by 1mg at 2 to 3 day intervals, until a dosage of 2.5mg twice daily is achieved. Further dosage increments, if necessary, should be added in a similar manner.

Prevention of Lactation

2.5mg on the day of delivery, followed by 2.5mg twice daily for 14 days. Treatment should be instituted within a few hours of parturition once vital signs have been stabilised. Gradual introduction of PARLODEL is not necessary in this indication.

Suppression of Lactation for Medical Reasons

2.5mg on first day, increasing after 2 to 3 days to 2.5mg twice daily for 14 days. Gradual introduction of PARLODEL is not necessary in this indication.

Hypogonadism/Galactorrhea syndromes/Infertility

Introduce PARLODEL gradually according to the suggested scheme.

Most patients with hyperprolactinaemia have responded to 7.5mg daily, in divided doses, but doses of up to 30mg daily have been used. In infertile patients without demonstrably elevated serum prolactin levels, the usual dose is 2.5mg twice daily.

Prolactinomas

Introduce PARLODEL gradually according to the suggested scheme. Dosage may then be increased by 2.5mg daily at 2 to 3 day intervals, as follows:- 2.5mg eight hourly, 2.5mg six hourly, 5mg six hourly. Daily doses should not exceed 30 mg.Acromegaly

Acromegaly

Introduce PARLODEL gradually, according to the suggested scheme.

Dosage may then be increased by 2.5mg at 2 to 3 day intervals as follows: - 2.5mg eight-hourly, 2.5mg six-hourly, 5mg six-hourly.

Parkinson's Disease

Introduce PARLODEL gradually, as follows: Week 1: 1mg to 1.25mg at bed time. Week 2: 2mg to 2.5mg at bed time. Week 3: 2.5mg twice daily. Week 4: 2.5mg three times daily. Thereafter take three times a day increasing by 2.5mg every 3 to 14 days, depending on the patient's response. Continue until the optimum dose is reached. This will usually be between 10mg and 30mg daily. Daily doses should not exceed 30 mg. In patients already receiving Levodopa the dosage of this drug may gradually be decreased, while the dosage of PARLODEL is increased until the optimum balance is determined.

Use in Children

Administration of PARLODEL is not appropriate for children less than 15 years old.

Use in Elderly

There is no clinical evidence that PARLODEL poses a special risk to the elderly.

Use in Patients with Hepatic Impairment

In patients with impaired hepatic function, the speed of elimination may be retarded and plasma levels may increase, requiring dose adjustment.

4.3 Contraindications

Hypersensitivity to bromocriptine or to any of the excipients of PARLODEL (see Section 2 Qualitative and Quantitative composition and 6.1 List of excipients) or other ergot alkaloids.

Uncontrolled hypertension, hypertensive disorders of pregnancy (including eclampsia, pre-eclampsia or pregnancy-induced hypertension), hypertension post partum and in the puerperium.

PARLODEL is contraindicated for use in the suppression of lactation or other non-life threatening indications in patients with a history of coronary artery disease, or other severe cardiovascular conditions, or symptoms / history of severe psychiatric disorders.

Patients with these underlying conditions taking PARLODEL for the indication of macro-adenomas should only take it if the perceived benefits outweigh the potential risks (see Section 4.4 Special Warnings and Precautions).

For long-term treatment: Evidence of cardiac valvulopathy as determined by pre-treatment echocardiography.

4.4 Special Warnings And Precautions For Use

PARLODEL is contraindicated for use in the suppression of lactation or other non-life threatening indications in patients with severe coronary artery disease, or symptoms and/or a history of serious mental disorders (see Section 4.3 Contraindications).

Other

There is insufficient evidence of efficacy of Parlodel in the treatment of premenstrual symptoms and benign breast disease. The use of Parlodel in patients with these conditions is therefore not recommended.

In rare cases, serious adverse events, including hypertension, myocardial infarction, seizures, stroke or psychiatric disorders have been reported in postpartum women treated with PARLODEL for inhibition of lactation. In some patients the development of seizures or stroke was preceded by severe headache and/or transient visual disturbances (see Section 4.8, Undesirable Effects).

Patients with severe cardiovascular disorders or psychiatric disorders taking PARLODEL for the indication of macro-adenomas should only take it if the perceived benefits outweigh the potential risks (see Section 4.3 Contraindications).

Blood pressure should be carefully monitored, especially during the first days of therapy. Particular caution is required in patients who are on concomitant therapy with, or have recently been treated with drugs that can alter blood pressure. Concomitant use of bromocriptine with vasoconstrictors such as sympathomimetics or ergot alkaloids including ergometrine or methylergometrine during the puerperium is not recommended.

If hypertension, unremitting headache, or any signs of CNS toxicity develop, treatment should be discontinued immediately.

Hyperprolactinaemia may be idiopathic, drug-induced, or due to hypothalamic or pituitary disease. The possibility that hyperprolactinaemic patients may have a pituitary tumour should be recognised and complete investigation at specialised units to identify such patients is advisable. PARLODEL will effectively lower prolactin levels in patients with pituitary tumours but does not obviate the necessity for radiotherapy or surgical intervention where appropriate in acromegaly.

Since patients with macro-adenomas of the pituitary might have accompanying hypopituitarism due to compression or destruction of pituitary tissue, one should make a complete evaluation of pituitary functions and institute appropriate substitution therapy prior to administration of PARLODEL. In patients with secondary adrenal insufficiency, substitution with corticosteroids is essential.

The evolution of tumour size in patients with pituitary macro-adenomas should be carefully monitored and if evidence of tumour expansion develops, surgical procedures must be considered.

If in adenoma patients, pregnancy occurs after the administration of PARLODEL, careful observation is mandatory. Prolactin-secreting adenomas may expand during pregnancy. In these patients, treatment with PARLODEL often results in tumour shrinkage and rapid improvement of the visual fields defects. In severe cases, compression of the optic or other cranial nerves may necessitate emergency pituitary surgery.

Visual field impairment is a known complication of macroprolactinoma. Effective treatment with PARLODEL leads to a reduction in hyperprolactinaemia and often to resolution of the visual impairment. In some patients, however, a secondary deterioration of visual fields may subsequently develop despite normalised prolactin levels and tumour shrinkage, which may result from traction on the optic chiasm which is pulled down into the now partially empty sella. In these cases the visual field defect may improve on reduction of bromocriptine dosage while there is some elevation of prolactin and some tumour re-expansion. Monitoring of visual fields in patients with macroprolactinoma is therefore recommended for an early recognition of secondary field loss due to chiasmal herniation and adaptation of drug dosage.

In some patients with prolactin-secreting adenomas treated with Parlodel, cerebrospinal fluid rhinorrhea has been observed. The data available suggest that this may result from shrinkage of invasive tumours.

Bromocriptine has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with bromocriptine. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines (see Section 4.7 Effects on ability to drive and use machines). Furthermore, a reduction of dosage or termination of therapy may be considered.

When women of child-bearing age are treated with PARLODEL for conditions not associated with hyperprolactinaemia the lowest effective dose should be used. This is in order to avoid suppression of prolactin to below normal levels, with consequent impairment of luteal function.

Gynaecological assessment, preferably including cervical and endometrial cytology, is recommended for women receiving PARLODEL for extensive periods. Six monthly assessment is suggested for post-menopausal women and annual assessment for women with regular menstruation.

A few cases of gastrointestinal bleeding and gastric ulcer have been reported. If this occurs, PARLODEL should be withdrawn. Patients with a history of evidence of peptic ulceration should be closely monitored when receiving the treatment.

Since, especially during the first few days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercised when driving a vehicle or operating machinery.

Among patients on Parlodel, particularly on long-term and high-dose treatment, pleural and pericardial effusions, as well as pleural and pulmonary fibrosis and constrictive pericarditis have occasionally been reported. Patients with unexplained pleuropulmonary disorders should be examined thoroughly and discontinuation of Parlodel therapy should be contemplated.

In a few patients on Parlodel, particularly on long-term and high-dose treatment, retroperitoneal fibrosis has been reported. To ensure recognition of retroperitoneal fibrosis at an early reversible stage it is recommended that its manifestations (e.g. back pain, oedema of the lower limbs, impaired kidney function) should be watched in this category of patients. Parlodel medication should be withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected.

Attention should be paid to the signs and symptoms of

Appropriate investigations such as erythrocyte sedimentation rate, chest X-ray and serum creatinine measurements should be performed if necessary to support a diagnosis of a fibrotic disorder. It is also appropriate to perform baseline investigations of erythrocyte sedimentation rate or other inflammatory markers, lung function/chest X-ray and renal function prior to initiation of therapy.

These disorders can have an insidious onset and patients should be regularly and carefully monitored while taking PARLODEL for manifestations of progressive fibrotic disorders. PARLODEL should be withdrawn if fibrotic or serosal inflammatory changes are diagnosed or suspected.

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

Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson's disease, including PARLODEL.

Elderly

Clinical studies for PARLODEL did not include sufficient numbers of subjects ages 65 and above to determine whether the elderly respond differently from younger subjects. However, other reported clinical experiences, including post-marketing reporting of adverse events have identified no differenced in response or tolerability between elderly and younger patients.

Even though no variation in efficacy or adverse reaction profile in elderly patients taking Parlodel has been observed, greater sensitivity in some elderly individuals cannot be categorically ruled out. In general, dose selection for an elderly patient should be cautious, starting at the lower end of the dose range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy in this population.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Tolerance to PARLODEL may be reduced by alcohol.

Caution is required in patients who are on concomitant therapy with, or have recently been treated with drugs that can alter blood pressure.

Although there is no conclusive evidence of an interaction between PARLODEL and other ergot alkaloids concomitant use of bromocriptine with these medications during the puerperium is not recommended (see also Section 4.4, Special Warnings and Precautions).

The concomitant use of erythromycin and other macrolide antibiotics may increase bromocriptine plasma levels.

Bromocriptine is both a substrate and an inhibitor of CYP3A4 (see Section 5.2 Pharmacokinetic properties). Caution should therefore be used when co-administering drugs which are strong inhibitors and/or substrates of this enzyme (azole antimycotics, HIV protease inhibitors). The concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma levels of bromocriptine.

Dopamine antagonists such as antipsychotics (phenothiazines, butyrophenones and thioxanthenes) may reduce the prolactin-lowering and antiparkinsonian effects of bromocriptine. Metoclopramide and domperidone may reduce the prolactin-lowering effect.

4.6 Pregnancy And Lactation

Pregnancy

If pregnancy occurs it is generally advisable to withdraw PARLODEL after the first missed menstrual period.

Rapid expansion of pituitary tumours sometimes occurs during pregnancy and this may also occur in patients who have been able to conceive as a result of PARLODEL therapy.

As a precautionary measure, patients should be monitored to detect signs of pituitary enlargement so that PARLODEL may be reintroduced if necessary. Based on the outcome of more than 2,000 pregnancies, the use of PARLODEL to restore fertility has not been associated with an increased risk of abortion, premature delivery, multiple pregnancy or malformation in infants. Because this accumulated evidence suggests a lack of teratogenic or embryopathic effects in humans, maintenance of PARLODEL treatment during pregnancy may be considered where there is a large tumour or evidence of expansion.

Lactation

Since PARLODEL inhibits lactation, it should not be administered to mothers who elect to breast-feed.

Women of child-bearing potential

Fertility may be restored by treatment with Parlodel. Women of childbearing age who do not wish to conceive should therefore be advised to practice a reliable method of contraception.

4.7 Effects On Ability To Drive And Use Machines

Hypotensive reactions may be disturbing in some patients during the first few days of treatment and particular care should be exercised when driving vehicles or operating machinery.

Patients being treated with bromocriptine and presenting with somnolence and/or sudden sleep episodes must be advised not to drive or engage in activities where impaired alertness may put themselves or others at risk of serious injury or death (eg. Operating machines) until such recurrent episodes and somnolence have resolved (see also Section 4.4 Special Warnings and Precautions).

4.8 Undesirable Effects

The occurrence of side-effects can be minimised by gradual introduction of the dose or a dose reduction followed by a more gradual titration. If necessary, initial nausea and/or vomiting may be reduced by taking PARLODEL during a meal and by the intake of a peripheral dopamine antagonist, such as domperidone, for a few days, at least one hour prior to the administration of PARLODEL.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (

Nervous System Disorders

Common: Headache, drowsiness

Uncommon: Dizziness, dyskinesia

Rare: Somnolence, paresthesia

Very Rare: Excess daytime somnolence and sudden sleep onset

Psychiatric Disorders

Uncommon: Confusion, psychomotor agitation, hallucinations

Rare: Psychotic disorders, insomnia

Gastrointestinal Disorders

Common: Nausea, constipation

Uncommon: Vomiting, dry mouth

Rare: Diarrhoea, abdominal pain, retroperitoneal fibrosis, gastrointestinal ulcer, gastrointestinal haemorrhage

Vascular Disorders

Uncommon: Hypotension including orthostatic hypotension (which may in very rare instances lead to collapse)

Very Rare: Reversible pallor of fingers and toes induced by cold (especially in patients who have a history of Raynaud's phenomenon)

Cardiac Disorders

Rare: Tachycardia, bradycardia, arrhthymia

Very rare: Cardiac valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion).

Respiratory, thoracic and mediastinal disorders

Common: Nasal congestion

Rare: Pleural effusion, pleural and pulmonary fibrosis, pleuritis, dyspneoa

Musculoskeletal and connective tissue disorders

Uncommon: Leg cramps

Skin and subcutaneous tissue disorders

Uncommon: Allergic skin reactions, hair loss

General disorders and administration site conditions

Uncommon: Fatigue

Rare: Peripheral oedema

Very Rarely: A syndrome resembling Neuroleptic Malignant Syndrome has been reported on withdrawal of PARLODEL.

Eye Disorders

Rare: Visual disturbances, vision blurred

Ear and Labyrinth Disorders

Rare: Tinnitus

Post-partum women

In extremely rare cases (in postpartum women treated with PARLODEL for the prevention of lactation) serious adverse events including hypertension, myocardial infarction, seizures, stroke or mental disorders have been reported, although the causal relationship is uncertain. In some patients the occurrence of seizures or stroke was preceded by severe headache and/or transient visual disturbances (see Section 4.4 Special warnings and precautions for use).

Class effects

Patients treated with dopamine agonists for treatment with Parkinson's disease, including PARLODEL, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation.

4.9 Overdose

Signs and Symptoms

Overdosage with PARLODEL is likely to result in vomiting and other symptoms which could be due to over stimulation of dopaminergic receptors and might include nausea, dizziness, hypotension, postural hypotension, tachycardia, drowsiness, somnolence, lethargy, confusion and hallucinations. General supportive measures should be undertaken to remove any unabsorbed material and maintain blood pressure if necessary.

Overdose management

In the case of overdose, administration of activated charcoal is recommended and in the case of very recent oral intake, gastric lavage may be considered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Dopamine agonist (ATC code N04B C01), prolactin inhibitor (ATC code G02C B01)

PARLODEL, active ingredient bromocriptine, is an inhibitor of prolactin secretion and a stimulator of dopamine receptors. The areas of application of PARLODEL are divided into endocrinological and neurological indications. The pharmacological particulars will be discussed under each indication.

Endocrinological indications

PARLODEL inhibits the secretion of the anterior pituitary hormone prolactin without affecting normal levels of other pituitary hormones. However, PARLODEL is capable of reducing elevated levels of growth hormone (GH) in patients with acromegaly. These effects are due to stimulation of dopamine receptors.

In the puerperium prolactin is necessary for the initiation and maintenance of puerperal lactation. At other times increased prolactin secretion gives rise to pathological lactation (galactorrhoea) and/or disorders of ovulation and menstruation.

As a specific inhibitor of prolactin secretion, PARLODEL can be used to prevent or suppress physiological lactation as well as to treat prolactin-induced pathological states. In amenorrhoea and/or anovulation (with or without galactorrhoea), PARLODEL can be used to restore menstrual cycles and ovulation.

The customary measures taken during lactation suppression, such as the restriction of fluid intake are not necessary with PARLODEL. In addition, PARLODEL does not impair the puerperal involution of the uterus and does not increase the risk of thromboembolism.

PARLODEL has been shown to arrest the growth or to reduce the size of prolactin-secreting pituitary adenomas (prolactinomas).

In acromegalic patients - apart from lowering the plasma levels of growth hormone and prolactin - PARLODEL has a beneficial effect on clinical symptoms and on glucose tolerance.

PARLODEL improves the clinical symptoms of the polycystic ovary syndrome by restoring a normal pattern of LH secretion.

Neurological Indications

Because of its dopaminergic activity, PARLODEL, in doses usually higher than those for endocrinological indications, is effective in the treatment of Parkinson's Disease, which is characterised by a specific nigrostriatal dopamine deficiency. The stimulation of dopamine receptors by PARLODEL can in this condition restore the neurochemical balance within the striatum.

Clinically, PARLODEL improves tremor, rigidity, bradykinesia and other Parkinsonian symptoms at all stages of the disease. Usually the therapeutic effect lasts over years (so far, good results have been reported in patients treated up to eight years). PARLODEL can be given either alone or - at early as well as advanced stages - combined with other anti-Parkinsonian drugs. Combination with Levodopa treatment results in enhanced anti-Parkinsonian effects, often making possible a reduction of the Levodopa dose. PARLODEL offers particular benefit to patients on Levodopa treatment exhibiting a deteriorating therapeutic response or complications such as abnormal involuntary movements (choreoatoid dykinesia and/or painful dystonia), end-of-dose failure, and 'on-off' phenomenon.

PARLODEL improves the depressive symptomatology often observed in Parkinsonian patients. This is due to its inherent antidepressant properties as substantiated by controlled studies in non-Parkinsonian patients with endogenous or psychogenic depression.

5.2 Pharmacokinetic Properties

Following oral administration, PARLODEL (bromocriptine) is rapidly and well absorbed. Peak plasma levels are reached within 1-3 hours. An oral dose of 5mg of bromocriptine results in a C_max of 0.465ng/ml. The prolactin-lowering effect occurs 1-2 hours after ingestion, reaches its maximum within about 5 hours and lasts for 8-12 hours.

The substance is extensively metabolised in the liver. The elimination of parent drug from plasma occurs biphasically, with a terminal half-life of about 15 hours. Parent drug and metabolites are almost completely excreted via the liver, with only 6% being eliminated via the kidney. Plasma protein-binding amounts to 96%.

There is no evidence that the pharmacokinetic properties and tolerability of PARLODEL are directly affected by advanced age. However, in patients with impaired hepatic function, the speed of elimination may be retarded and plasma levels may increase, requiring dose adjustment.

Biotransformation

Bromocriptine undergoes extensive first-pass biotransformation in the liver, reflected by complex metabolite profiles and by almost complete absence of parent drug in urine and faeces. It shows a high affinity for CYP3A and hydroxylations at the proline ring of the cyclopeptide moiety constitute a main metabolic pathway. Inhibitors and/or potent substrates for CYP3A4 might therefore be expected to inhibit the clearance of bromocriptine and lead to increased levels. Bromocriptine is also a potent inhibitor of CYP3A4 with a calculated IC50 value of 1.69 µM. However, given the low therapeutic concentrations of free bromocriptine in patients, a significant alteration of the metabolism of a second drug whose clearance is mediated by CYP3A4 should not be expected.

5.3 Preclinical Safety Data

Pre-clinical data for PARLODEL (bromocriptine) reveal no special hazard for humans based on conventional studies of single and repeat dose toxicity, genotoxicity, mutagenicity, carcinogenic potential or toxicity to reproduction.

Endometrial carcinomas were observed in pre-clinical rat studies at high dosages only. They are considered to be due to the species-specific sensitivity of the test animals to the pharmacological activity of bromocriptine.

Other effects in pre-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Silica, colloidal anhydrous

Disodium edetate

Magnesium stearate

Maleic acid

Maize starch

Lactose monohydrate

6.2 Incompatibilities

None.

6.3 Shelf Life

Opaque white PVC/PVDC blister strip:	24 months
Amber glass bottles:	36 months

6.4 Special Precautions For Storage

Store below 25°C. Store in the original package in order to protect from light.

6.5 Nature And Contents Of Container

Opaque white PVC/PVDC blister strip containing 30 PARLODEL 2.5 mg tablets.

Amber glass bottles with a tamper resistant closure containing 100 and 500 PARLODEL 2.5 mg tablets.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Meda Pharmaceuticals Ltd

249 West George Street

Glasgow

G2 4RB

Trading as: Meda Pharmaceuticals

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

8. Marketing Authorisation Number(S)

PL 15142/0051

9. Date Of First Authorisation/Renewal Of The Authorisation

14 January 1976 / 21 April 1998

10. Date Of Revision Of The Text

17 October 2011