Modecate Injection 25mg / ml

1. Name Of The Medicinal Product

Modecate Injection 25mg/ml.

2. Qualitative And Quantitative Composition

Each ampoule contains 25mg/ml of the active substance Fluphenazine Decanoate.

Also contains sesame oil (q.s.).

For full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for Injection

Pale yellow clear, oily liquid.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment and maintenance of schizophrenic patients and those with paranoid psychoses.

While Modecate injection has been shown to be effective in acute states, it is particularly useful in the maintenance treatment of chronic patients who are unreliable at taking their oral medication, and also of those who do not absorb their oral phenothiazine adequately.

4.2 Posology And Method Of Administration

Dosage and Administration

Adults

It is recommended that patients be stabilised on the injection in hospital.

Recommended dosage regimes for all indications:

A. Patients without previous exposure to a depot fluphenazine formulation:

Initially 0.5ml ie 12.5mg (0.25 ml ie 6.25mg for patients over 60) by deep intramuscular injection into the gluteal region.

The onset of action generally appears between 24 and 72 hours after injection and the effects of the drug on psychotic symptoms become significant within 48 to 96 hours. Subsequent injections and the dosage interval are determined in accordance with the patient's response. When administered as maintenance therapy, a single injection may be effective in controlling schizophrenic symptoms for up to four weeks or longer.

It is desirable to maintain as much flexibility in the dose as possible to achieve the best therapeutic response with the least side-effects; most patients are successfully maintained within the dose range 0.5ml (12.5mg) to 4.0ml (100mg) given at a dose interval of 2 to 5 weeks.

Patients previously maintained on oral fluphenazine:

It is not possible to predict the equivalent dose of depot formulation in view of the wide variability of individual response.

B. Patients previously maintained on depot fluphenazine:

Patients who have suffered a relapse following cessation of depot fluphenazine therapy may be restarted on the same dose, although the frequency of injections may need to be increased in the early weeks of treatment until satisfactory control is obtained.

Elderly:

Elderly patients may be particularly susceptible to extrapyramidal reactions, sedative and hypotensive effects. In order to avoid this, a reduced maintenance dosage may be required and a smaller initial dose (see above).

Children:

Not recommended for children.

* Where a smaller volume of injection is desirable, patients may be transferred directly to the equivalent dose of Modecate Concentrate injection on the basis that 1ml Modecate Concentrate injection is equivalent to 4ml Modecate injection.

Note:

The dosage should not be increased without close supervision and it should be noted that there is a variability in individual response.

The response to antipsychotic drug treatment may be delayed. If drugs are withdrawn, recurrence of symptoms may not become apparent for several weeks or months.

Route of administration: Intramuscular.

4.3 Contraindications

The product is contraindicated in the following cases.

Comatose states

Marked cerebral atherosclerosis

Phaeochromocytoma

Renal failure

Liver failure

Severe cardiac insufficiency

Severely depressed states

Existing blood dyscrasias

Hypersensitivity to Fluphenazine Decanoate or to any of the excipients

4.4 Special Warnings And Precautions For Use

Caution should be exercised with the following:

Liver disease

Renal impairment

Cardiac arrhythmias, cardiac disease

Thyrotoxicosis

Severe respiratory disease

Epilepsy, conditions predisposing to epilepsy (eg. alcohol withdrawal or brain damage)

Parkinson's disease

Patients who have shown hypersensitivity to other phenothiazines

Personal or family history of narrow angle glaucoma

In very hot weather

The elderly, particularly if frail or at risk of hypothermia

Hypothyroidism

Myasthenia gravis

Prostatic hypertrophy.

Patients with known or with a family history of cardiovascular disease should receive ECG screening, and monitoring and correction of electrolyte balance prior to treatment with fluphenazine.

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 fluphenazine and preventative measures undertaken.

Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia have been described after abrupt cessation of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal is advisable.

Psychotic patients on large doses of phenothiazines who are undergoing surgery should be watched carefully for hypotension. Reduced amounts of anaesthetics or central nervous system depressants may be necessary.

Fluphenazine should be used with caution in patients exposed to organophosphorus insecticides

Neuroleptic drugs elevate prolactin levels, and an increase in mammary neoplasms has been found in rodents after chronic administration. However, studies to date have not shown an association between chronic administration of these drugs and human mammary tumours.

As with any phenothiazine, the physician should be alert to the possibility of “silent pneumonias” in patients receiving long-term fluphenazine.

Increased Mortality in Elderly people with Dementia

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

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The possibility should be borne in mind that phenothiazines may:

1 Increase the central nervous system depression produced by drugs such as alcohol, general anaesthetics, hypnotics, sedatives or strong analgesics.

2 Antagonise the action of adrenaline and other sympathomimetic agents and reverse the blood-pressure lowering effects of adrenergic-blocking agents such as guanethidine and clonidine.

3 Impair: the anti-parkinsonian effect of L-dopa; the effect of anti-convulsants; metabolism of tricyclic antidepressants; the control of diabetes.

4 Increase the effect of anticoagulants and antidepressants.

5 Interact with lithium.

Anticholinergic effects may be enhanced by anti-parkinsonian or other anticholinergic drugs.

Phenothiazines may enhance: the absorption of corticosteroids, digoxin, and neuromuscular blocking agents.

Fluphenazine is metabolised by P450 2D6 and is itself an inhibitor of this drug metabolising enzyme. The plasma concentrations and the effects of fluphenazine may therefore be increased and prolonged by drugs that are either the substrates or inhibitors of this P450 isoform, possibly resulting in severe hypotension, cardiac arrhythmias or CNS side effects. Examples of drugs which are substrates or inhibitors of cytochrome P450 2D6 include anti-arrhythmics, certain antidepressants including SSRIs and tricyclics, certain antipsychotics, β-blockers, protease inhibitors, opiates, cimetidine and ecstasy (MDMA). This list is not exhaustive.

Concomitant use of barbiturates with phenothiazines may result in reduced serum levels of both drugs, and an increased response if one of the drugs is withdrawn.

The effect of fluphenazine on the QT interval is likely to be potentiated by concurrent use of other drugs that also prolong the QT interval. Therefore, concurrent use of these drugs and fluphenazine is contraindicated. Examples include certain anti-arrhythmics, such as those of Class 1A (such as quinidine, disopyramide and procainamide) and Class III (such as amiodarone and sotalol), tricyclic antidepressants (such as amitriptyline); certain tetracyclic antidepressants (such as maprotiline); certain antipsychotic medications (such as phenothiazines and pimozide); certain antihistamines (such as terfenadine); lithium, quinine, pentamidine and sparfloxacin. This list is not exhaustive.

Electrolyte imbalance, particularly hypokalaemia, greatly increases the risk of QT interval prolongation. Therefore, concurrent use of drugs that cause electrolyte imbalance should be avoided.

Concurrent use of MAO inhibitors may increase sedation, constipation, dry mouth and hypotension.

Owing to their adrenolytic action, phenothiazines may reduce the pressor effect of adrenergic vasoconstrictors (i.e. ephedrine, phenylephrine).

Phenylpropanolamine has been reported to interact with phenothiazines and cause ventricular arrhythmias.

Concurrent use of phenothiazines and ACE inhibitors or angiotensin II antagonists may result in severe postural hypotension.

Concurrent use of thiazide diuretics may cause hypotension. Diuretic-induced hypokalaemia may potentiate phenothiazine-induced cardiotoxicity.

Clonidine may decrease the antipsychotic activity of phenothiazines.

Methyldopa increases the risk of extrapyramidal side effects with phenothiazines.

The hypotensive effect of calcium channel blockers is enhanced by concurrent use of antipsychotic drugs.

Phenothiazines may predispose to metrizamide-induced seizures.

Concurrent use of phenothiazines and amfetamine/anorectic agents may produce antagonistic pharmacological effects.

Concurrent use of phenothiazines and cocaine may increase the risk of acute dystonia.

There have been rare reports of acute Parkinsonism when an SSRI has been used in combination with a phenothiazine.

Phenothiazines may impair the action of anti-convulsants. Serum levels of phenytoin may be increased or decreased.

Phenothiazines inhibit glucose uptake into cells, and hence may affect the interpretation of PET studies using labelled glucose.

4.6 Pregnancy And Lactation

Use in pregnancy: The safety for the use of this drug during pregnancy has not been established; therefore, the possible hazards should be weighed against the potential benefits when administering this drug to pregnant patients.

Nursing mothers: Breast feeding is not recommended during treatment with depot fluphenazines, owing to the possibility that fluphenazine may be excreted in the breast milk.

4.7 Effects On Ability To Drive And Use Machines

The use of this drug may impair the mental and physical abilities required for driving a car or operating heavy machinery.

4.8 Undesirable Effects

Side Effects: Acute dystonic reactions occur infrequently, as a rule within the first 24-48 hours, although delayed reactions may occur. In susceptible individuals they may occur after only small doses. These may include such dramatic manifestations as oculogyric crises and opisthotonos. They are rapidly relieved by intravenous administration of an anti-parkinsonian agent such as procyclidine.

Parkinsonian-like states may occur particularly between the second and fifth days after each injection, but often decrease with subsequent injection. These reactions may be reduced by using smaller doses more frequently, or by the concomitant use of anti-parkinsonian drugs such as trihexyphenidyl, benzatropine or procyclidine. Anti-parkinsonian drugs should not be prescribed routinely, because of the possible risks of aggravating anti-cholinergic side effects or precipitating toxic confusional states, or of impairing therapeutic efficacy.

With careful monitoring of the dose the number of patients requiring anti-parkinsonian drugs can be minimised.

Tardive Dyskinesia: As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long term therapy or may occur after drug therapy has been discontinued. The risk seems to be greater in elderly patients on high dose therapy, especially females. The symptoms are persistent and in some patients appear to be irreversible.

The syndrome is characterised by rhythmical involuntary movements of the tongue, face, mouth or jaw (eg protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of the extremities. There is no known effective treatment for tardive dyskinesia: anti-parkinsonian agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, the syndrome may be masked. It has been reported that fine vermicular movements of the tongue may be an early sign of the syndrome and if the medication is stopped at that time, the syndrome may not develop.

Other Undesirable Effects: As with other phenothiazines, drowsiness, lethargy, blurred vision, dryness of the mouth, constipation, urinary hesitancy or incontinence, mild hypotension, impairment of judgement and mental skills, and epileptiform attacks are occasionally seen.

Headache, nasal congestion, vomiting, agitation, excitement, insomnia and hyponatraemia have also been observed during phenothiazine therapy.

Blood dyscrasias have rarely been reported with phenothiazine derivatives. Blood counts should be performed if the patient develops signs of persistent infection. Transient leucopenia and thrombocytopenia have been reported. Antinuclear antibodies and SLE have been reported very rarely.

Jaundice has rarely been reported. Transient abnormalities of liver function tests may occur in the absence of jaundice.

A transient rise in serum cholesterol has been reported rarely in patients on oral fluphenazine.

Abnormal skin pigmentation and lens opacities have sometimes been seen following long-term administration of high doses of phenothiazines.

Phenothiazines are known to cause photosensitivity reactions but this has not been reported for fluphenazine. Skin rashes, hypersensitivity and anaphylactic reactions have occasionally been reported.

Elderly patients may be more susceptible to the sedative and hypotensive effects.

The effects of phenothiazines on the heart are dose-related. ECG changes with prolongation of the QT interval and T-Wave changes have been reported commonly in patients treated with moderate to high dosage; they have been reported to precede serious arrhythmias, including ventricular tachycardia and fibrillation, which have also occurred after overdosage. Sudden, unexpected and unexplained deaths have been reported in hospitalised psychotic patients receiving phenothiazines.

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

Phenothiazines may impair body temperature regulation. Elderly or hypothyroid patients may be particularly susceptible to hypothermia. The hazard of hyperpyrexia may be increased by especially hot or humid weather, or by drugs such as anti-parkinsonian agents, which impair sweating.

Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported in patients on neuroleptic therapy. The syndrome is characterised by hyperthermia, together with some or all of the following: muscular rigidity, autonomic instability (labile blood pressure, tachycardia, diaphoresis), akinesia, and altered consciousness, sometimes progressing to stupor or coma. Leucocytosis, elevated CPK, liver function abnormalities, and acute renal failure may also occur. Neuroleptic therapy should be discontinued immediately and vigorous symptomatic treatment implemented since the syndrome is potentially fatal.

Hormonal effects of phenothiazines include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligomenorrhoea or amenorrhoea. Sexual function may be impaired, and false results may be observed with pregnancy tests. Syndrome of inappropriate anti-diuretic hormone secretion has also been observed.

Oedema has been reported with phenothiazine medication.

4.9 Overdose

Overdosage should be treated symptomatically and supportively, extrapyramidal reactions will respond to oral or parenteral anti-parkinsonian drugs such as procyclidine or benzatropine. In cases of severe hypotension, all procedures for the management of circulatory shock should be instituted, eg vasoconstrictors and/or intravenous fluids. However, only the vasoconstrictors metaraminol or noradrenaline should be used, as adrenaline may further lower the blood pressure through interaction with the phenothiazine.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Psycholeptics; Phenothiazines with piperazine structure, ATC code: N05AB02

Fluphenazine decanoate is an ester of the potent neuroleptic fluphenazine, a phenothiazine derivative of the piperazine type. The ester is slowly absorbed from the intramuscular site of injection and is then hydrolysed in the plasma to the active therapeutic agent, fluphenazine.

Extrapyramidal reactions are not uncommon, but fluphenazine does not have marked sedative or hypotensive properties.

5.2 Pharmacokinetic Properties

Plasma level profiles of fluphenazine following intramuscular injection have shown half-lives of plasma clearance ranging from 2.5-16 weeks, emphasising the importance of adjusting dose and interval to the individual requirements of each patient. The slow decline of plasma levels in most patients means that a reasonably stable plasma level can usually be achieved with injections spaced at 2-4 week intervals.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Benzyl alcohol

Sesame oil

6.2 Incompatibilities

None.

6.3 Shelf Life

2 years.

The in use shelf life for the 10ml vial is 28 days

6.4 Special Precautions For Storage

Store below 25°C. Keep the ampoules in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

Type I Glass ampoules containing 0.5, 1 and 2ml.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 04425/0386

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 21 March 1996

Date of latest renewal: 23 September 2002

10. Date Of Revision Of The Text

8 July 2011

LEGAL CATEGORY

POM

Octreotide 500micrograms / ml solution for injection

1. Name Of The Medicinal Product

Octreotide 500 micrograms/ml solution for injection

2. Qualitative And Quantitative Composition

One ampoule contains octreotide acetate equivalent to 500 micrograms of octreotide (as octreotide acetate).

For full list of excipients, see Section 6.1.

3. Pharmaceutical Form

Solution for injection.

1ml ampoule containing clear colourless solution for injection.

4. Clinical Particulars

4.1 Therapeutic Indications

GEP tumours

For the relief of symptoms associated with functional gastroenteropancreatic endocrine tumours including:

• carcinoid tumours with features of carcinoid syndrome

• VIPomas

• glucagonomas

Octreotide is not antitumour therapy and is not curative in these patients.

Acromegaly

For symptomatic control and reduction of growth hormone and somatomedin c plasma levels in patients with acromegaly:

• in short term treatment, prior to pituitary surgery, or

• in long term treatment in those who are inadequately controlled by pituitary surgery, radiotherapy, or in the interim period until radiotherapy becomes effective.

Octreotide is indicated for acromegalic patients for whom surgery is inappropriate.

Evidence from short term studies demonstrate that tumour size is reduced in some patients (prior to surgery); further tumour shrinkage however cannot be expected as a feature of continued long term treatment.

Prevention of complications following pancreatic surgery

Route of administration

Subcutaneous or intravenous use.

4.2 Posology And Method Of Administration

GEP tumours

Initially 0.05 mg once or twice daily by s.c. injection. Depending on response, dosage can be gradually increased to 0.2 mg three times daily. Under exceptional circumstances, higher doses may be required. Maintenance doses are variable.

The recommended route of administration is subcutaneous, however, in instances where a rapid response is required, e.g. carcinoid crises, the initial recommended dose of octreotide may be administered by the intravenous route, diluted and given as a bolus, whilst monitoring the cardiac rhythm.

In carcinoid tumours, if there is no beneficial effect within a week, continued therapy is not recommended.

Acromegaly

0.1 – 0.2 mg three times daily by s.c. injection. Dosage adjustment should be based on monthly assessment of GH and IGF-1 levels (target: GH less than 2.5ng/ml, 5mU/l; IGF-1 within normal range) and clinical symptoms, and on tolerability. For patients on a stable dose of octreotide, assessment of GH should be made every 12 months. Six-monthly monitoring may be necessary in those patients whose clinical and biochemical control is less adequate.

If no relevant reduction of growth hormone levels and no improvement of clinical symptoms have been achieved within three months of starting treatment, therapy should be discontinued.

For the prevention of complications following pancreatic surgery

0.1 mg three times daily by subcutaneous injection for 7 consecutive days, starting on the day of operation at least one hour before laparotomy.

Use in patients with impaired renal function

Impaired renal function did not affect the total exposure (AUC; area under the curve) to octreotide when administered s.c. therefore, no dose adjustment of octreotide is necessary.

Use in patients with impaired hepatic function

In a study with octreotide administered s.c. and i.v. it was shown that the elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease. In patients with liver cirrhosis, an adjustment of the maintenance dose may therefore be necessary.

Use in the elderly

In elderly patients treated with octreotide, there is no evidence for reduced tolerability or altered dosage requirements.

Use in children

Experience with octreotide in children is very limited.

4.3 Contraindications

Known hypersensitivity to octreotide or to any component of the formulations (see 6.1 List of excipients).

4.4 Special Warnings And Precautions For Use

As growth hormone secreting pituitary tumours may sometimes expand, causing serious complications (e.g. visual field defects), it is essential that all patients be carefully monitored. If evidence of tumour expansion appears, alternative procedures may be advisable.

Sudden escape of gastroenteropancreatic endocrine tumours from symptomatic control by octreotide may occur infrequently, with rapid recurrence of severe symptoms.

Octreotide may increase the depth and duration of hypoglycaemia in patients with insulinoma. This is because it is relatively more potent in inhibiting growth hormone and glucagon secretion than in inhibiting insulin and because its duration of insulin inhibition is shorter. If octreotide is given to a patient with insulinoma, close monitoring is necessary on introduction of therapy and at each change of dosage. Marked fluctuations of blood glucose may be reduced by more frequent administration of octreotide.

Octreotide may reduce insulin or oral hypoglycaemic requirements in patients with type I diabetes mellitus. In non-diabetics and type II diabetics with particularly intact insulin reserves, octreotide administration can result in prandial increases in glycaemia.

Thyroid function should be monitored in patients receiving long-term octreotide therapy.

Octreotide exerts an inhibiting effect on gallbladder motility, bile acid secretion and bile flow and there is an acknowledged association with the development of gallstones. The incidence of gallstone formation with octreotide treatment is estimated to be between 15 - 30 %.

Ultrasonic examination of the gallbladder, before and at about 6 to 12 month intervals during octreotide therapy is therefore recommended. If gallstones do occur, they are usually asymptomatic; symptomatic stones should be treated in the normal manner with due attention to abrupt withdrawal of the drug.

In patients with cirrhosis, dosage adjustment may be necessary (see Section 4.2 Posology and Method of Administration).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Octreotide has been reported to reduce the intestinal absorption of cyclosporin and to delay that of cimetidine.

Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine.

Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolised by CYP3A4 and which have a low therapeutic index should therefore be used with caution (e.g. carbamazepine, digoxin, warfarin and terfenadine).

4.6 Pregnancy And Lactation

Experience with octreotide in pregnant or nursing women is very limited, and they should therefore be given the drug only under compelling circumstances.

Women receiving treatment with octreotide should not breastfeed their infants.

4.7 Effects On Ability To Drive And Use Machines

No data exists on the effects of octreotide on the ability to drive and use machines.

4.8 Undesirable Effects

The main side-effects are local and gastrointestinal.

Body as a whole

Rare: hypersensitivity skin reactions; hair loss and isolated reports of anaphylactic reactions have been observed.

Cardiovascular system

Isolated cases of bradycardia.

Gastrointestinal system

Anorexia, nausea, vomiting, abdominal pain, abdominal bloating, flatulence, loose stools, diarrhoea and steatorrhea. Although measured faecal fate excretion may increase, there is no evidence to date that long-term treatment with octreotide has led to nutritional deficiency due to malabsorption. In rare instances, gastrointestinal side-effects may resemble acute intestinal obstruction with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding. Occurrrence of gastrointestinal side-effects may be reduced by avoiding meals around the time of octreotide administration, that is, by injecting between meals or on retiring to bed.

Hepatobiliary

Prolonged use of octreotide may result in gallstone formation (see 4.4 Special warnings and precautions for use), and there have been isolated cases of biliary colic following the abrupt withdrawal of the drug in acromegalic patients in whom biliary sludge or gallstones had developed.

There have been isolated reports of hepatic dysfunctions associated with octreotide administration. These consist of

• acute hepatitis, without cholestasis, where transaminase values have normalised on withdrawal of octreotide, or

• slow development of hyperbilirubinaemia in association with elevation of alkaline phosphatase, gamma-glutamyl transferase and, to a lesser extent, transaminases.

Pancreas

Because of its inhibitory action on growth hormone, glucagon, and insulin release, octreotide may affect glucose regulation. Postprandial glucose tolerance may be impaired and, in some instances, the state of persistent hyperglycaemia may be induced as a result of chronic administration. Hypoglycaemia has also been observed within the first hours or days of octreotide treatment and resolves on withdrawal of the drug. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term octreotide treatment.

Local reactions

Pain or a sensation of stinging, tingling or burning at the site of s.c. injection, with redness and swelling, rarely lasting more than 15 minutes. Local discomfort may be reduced by allowing the solution to reach room temperature before injection.

4.9 Overdose

Doses of up to 2000 microgrammes octreotide given as subcutaneous tid for several months have been well tolerated.

No life-threatening reactions have been reported after acute overdosage. The maximum single dose given to an adult so far has been 1 mg by intravenous bolus injection. The observed signs and symptoms were a brief drop in heart rate, facial flushing, abdominal cramps, diarrhoea, an empty feeling in the stomach and nausea, which resolved in 24 hours of drug administration.

One patient has been reported to have received an accidental overdosage of octreotide by continuous infusion (250 microgrammes per hour for forty eight hours instead of 25 microgrammes per hour). He experienced no side-effects.

The management of overdosage is symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antigrowth hormones (ATC code H01B C02).

Octreotide is a synthetic octapeptide derivative of naturally occurring somatostatin with similar pharmacological effects, but with a longer duration of action. It inhibits pathologically increased secretion of growth hormone and of peptides and serotonin produced within the gastroenteropancreatic endocrine (GEP) system.

In animals, octreotide is a more potent inhibitor of growth hormone, glucagon and insulin release than somatostatin with greater selectivity for growth hormone and glucagon suppression.

In normal healthy subjects octreotide, like somatostatin, has been shown to inhibit

• release of growth hormone stimulated by arginine, exercise and insulin-induced hypoglycaemia

• postprandial release of insulin, glucagon, gastrin other peptides of the gastroenteropancreatic system; arginine-stimulated release of insulin and glucagon and

• thyrotropin-releasing hormone (TRH) - stimulated release of thyroid stimulating hormone (TSH).

Unlike somatostatin, octreotide inhibits growth hormone preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (i.e. growth hormone in patients with acromegaly).

For patients undergoing pancreatic surgery, the peri and post-operative administration of octreotide reduces the incidence of typical post-operative complications (e.g. pancreatic fistula, abscess and subsequent sepsis, post-operative acute pancreatitis).

In patients with acromegaly, octreotide consistently lowers GH and normalises IGF-1 serum concentrations in the majority of patients. In most patients, octreotide markedly reduces the clinical symptoms of the disease , such as headache, perspiration, paresthesia, fatigue, osteoarthralgia and carpal tunnel syndrome. In individual patients with GH-secreting pituitary adenoma, octreotide was reported to lead to shrinkage of the tumour mass.

For patients with functional tumours of the gastroenteropancreatic endocrine system, treatment with octreotide provides continuous control of symptoms related to the underlying disease. The effects of octreotide in different types of gastroenteropancreatic tumours are as follows:

Carcinoid tumours

Administration of octreotide may result in improvement of symptoms, particularly of flushing and diarrhoea. In many cases, this is accompanied by a falling plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid.

VIPomas

The biochemical characteristic of these tumours is overproduction of vasoactive intestinal peptide (VIP). In most cases, administration of octreotide results in alleviation of the severe secretory diarrhoea typical of the condition, with consequent improvement in quality of life. This is accompanied by an improvement in associated electrolyte abnormalities, e.g. hypokalaemia, enabling enteral and parenteral fluid and electrolyte supplementation to be withdrawn. Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall into the normal reference range.

Glucagonomas

Administration of octreotide results in most cases in substantial improvement of the necrolytic migratory rash which is characteristic of the condition. The effect of octreotide on the state of mild diabetes mellitus which frequently occurs is not marked and, in general, does not result in a reduction of requirements for insulin or oral hypoglycaemic agents. Octreotide produces improvement of diarrhoea, and hence weight gain, in those patients affected. Although administration of octreotide often leads to an immediate reduction in plasma glucagon levels, this decrease is generally not maintained over a prolonged period of administration, despite continued symptomatic improvement.

5.2 Pharmacokinetic Properties

Absorption

After subcutaneous injection, octreotide is rapidly and completely absorbed. Peak plasma concentrations are reached within 30 minutes.

Distribution

The volume of distribution is 0.27 l/kg and the total body clearance 160 ml/min. Plasma protein binding amounts to 65 %. The amount of octreotide bound to blood cells is negligible.

Elimination

The elimination half-life after subcutaneous administrations is 100 minutes. After intravenous injection the elimination is biphasic with half-lives of 10 and 90 minutes respectively. About 32 % is excreted unchanged into the urine.

5.3 Preclinical Safety Data

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

Studies in animals showed transient growth retardation of offspring, possibly consequent upon the specific endocrine profiles of the species tested, but there was no evidence of foetotoxic, teratogenic, or other reproduction effects.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium acetate trihydrate

Glacial acetic acid

Sodium chloride

Water for injections

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

For prolonged storage, ampoules should be stored between 2ºC and 8ºC. For day-to-day use they may be stored at room temperature for up to two weeks. Protect from light. Do not freeze.

6.5 Nature And Contents Of Container

1 ml ampoule of uncoloured glass containing clear colourless solution.

Boxes of 5 ampoules.

6.6 Special Precautions For Disposal And Other Handling

For i.v. use octreotide should be diluted with normal saline to a ratio of not less than 1 vol : 1 vol and not more than 1 vol : 9 vol . Dilution of octreotide with glucose solution is not recommended.

If octreotide has been diluted, the prepared solution may be kept at room temperature but should be administered within 8 hours of preparation.

To reduce local discomfort, let the solution reach room temperature before injection. Avoid multiple injections at short intervals at the same site.

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

7. Marketing Authorisation Holder

Sun Pharmaceuticals UK Ltd

1200 Century Way,

Thorpe Business Park,

Colton,

Leeds,

W Yorkshire,

LS15 8ZA

UK

8. Marketing Authorisation Number(S)

PL 24897/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

12 May 2008

10. Date Of Revision Of The Text

April 2010

Tretin-X Topical

Generic Name: tretinoin (Topical route)

TRET-i-noin

Commonly used brand name(s)

In the U.S.

• Atralin


• Avita


• Refissa


• Renova


• Retin-A


• Retin-A Micro


• Tretin-X

In Canada

• Rejuva-A


• Stieva-A Cream


• Stieva-A Cream Forte


• Stieva-A Gel


• Stieva-A Solution


• Vitamin A Acid

Available Dosage Forms:

• Gel/Jelly


• Solution


• Liquid


• Cream

Therapeutic Class: Dermatological Agent

Chemical Class: Retinoid

Uses For Tretin-X

Tretinoin is used to treat acne. It works partly by keeping skin pores clear.

One of the tretinoin creams is used to treat fine wrinkles, dark spots, or rough skin on the face caused by damaging rays of the sun. It works by lightening the skin, replacing older skin with newer skin, and by slowing down the way the body removes skin cells that may have been harmed by the sun. Tretinoin works best when used within a skin care program that includes protecting the treated skin from the sun. However, it does not completely or permanently erase these skin problems or greatly improve more obvious changes in the skin, such as deep wrinkles caused by sun or the natural aging process.

Tretinoin may also be used to treat other skin diseases as determined by your doctor.

Tretinoin is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although this use is not included in product labeling, tretinoin is used in certain patients with the following medical conditions:

• Keratosis follicularis (skin disorder of small, red bumps)


• Verruca plana (flat warts)

Before Using Tretin-X

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of this medicine in children with use in other age groups. Children are unlikely to have skin problems due to the sun. In older children treated for acne, tretinoin is not expected to cause different side effects or problems than it does in other age groups.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of tretinoin in patients 50 years of age and older with use in other age groups.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aminocaproic Acid


• Aprotinin


• Tetracycline


• Tranexamic Acid

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Fluconazole


• Ketoconazole


• Voriconazole

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Dermatitis, seborrheic or


• Eczema or


• Sunburn—Use of this medicine may cause or increase the irritation associated with these problems

Proper Use of tretinoin

This section provides information on the proper use of a number of products that contain tretinoin. It may not be specific to Tretin-X. Please read with care.

It is very important that you use this medicine only as directed. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. To do so may cause irritation of the skin.

Do not apply this medicine to windburned or sunburned skin or on open wounds.

Do not use this medicine in or around the eyes or lips, or inside of the nose. Spread the medicine away from these areas when applying. If the medicine accidentally gets on these areas, wash with water at once.

This medicine usually comes with patient directions. Read them carefully before using the medicine.

Before applying tretinoin, wash the skin with a mild soap or cleanser and warm water by using the tips of your fingers. Then gently pat dry. Do not scrub your face with a sponge or washcloth. Wait 20 to 30 minutes before applying this medicine to make sure the skin is completely dry. Applying tretinoin to wet skin can irritate the skin.

To use the cream or gel form of this medicine:

• Apply just enough medicine to very lightly cover the affected areas, and rub in gently but well. A pea-sized amount is enough to cover the whole face.

To use the solution form of this medicine:

• Using your fingertips, a gauze pad, or a cotton swab, apply enough tretinoin solution to cover the affected areas. If you use a gauze pad or a cotton swab for applying the medicine, avoid getting it too wet. This will help prevent the medicine from running into areas not intended for treatment.

After applying the medicine, wash your hands to remove any medicine that might remain on them.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For topical dosage forms (cream, gel, or solution):
  
  • For acne:
    
    • Adults and teenagers—Apply to the affected area(s) of the skin once a day, at bedtime.
    
    
  
  


• For cream dosage form (brand name Renova only):
  
  • For fine wrinkles, dark spots, or rough skin caused by the sun:
    
    • Adults up to 50 years of age—Apply to the affected area(s) of the skin once a day, at bedtime.
    
    
    • Adults 50 years of age and older—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

The gel product is flammable and should be kept away from fire or excessive heat.

Precautions While Using Tretin-X

During the first 3 weeks you are using tretinoin, your skin may become irritated. Also, your acne may seem to get worse before it gets better. It may take longer than 12 weeks before you notice full improvement of your acne, even if you use the medicine every day. Check with your health care professional at any time skin irritation becomes severe or if your acne does not improve within 8 to 12 weeks.

You should avoid washing the skin treated with tretinoin for at least 1 hour after applying it.

Avoid using any topical medicine on the same area within 1 hour before or after using tretinoin. Otherwise, tretinoin may not work properly or skin irritation might occur.

Unless your doctor tells you otherwise, it is especially important to avoid using the following skin products on the same area as tretinoin:

• Any other topical acne product or skin product containing a peeling agent (such as benzoyl peroxide, resorcinol, salicylic acid, or sulfur)


• Hair products that are irritating, such as permanents or hair removal products


• Skin products that cause sensitivity to the sun, such as those containing spices or limes


• Skin products containing a large amount of alcohol, such as astringents, shaving creams, or after-shave lotions


• Skin products that are too drying or abrasive, such as some cosmetics, soaps, or skin cleansers

Using these products along with tretinoin may cause mild to severe irritation of the skin. Although skin irritation can occur, some doctors sometimes allow benzoyl peroxide to be used with tretinoin to treat acne. Usually tretinoin is applied at night so that it does not cause a problem with any other topical products that you might use during the day. Check with your doctor before using topical medicines with tretinoin.

During the first 6 months of use, avoid overexposing the treated areas to sunlight, wind, or cold weather. The skin will be more prone to sunburn, dryness, or irritation, especially during the first 2 or 3 weeks. However, you should not stop using this medicine unless the skin irritation becomes too severe. Do not use a sunlamp .

To help tretinoin work properly, regularly use sunscreen or sunblocking lotions with a sun protection factor (SPF) of at least 15. Also, wear protective clothing and hats, and apply creams, lotions, or moisturizers often.

Check with your doctor at any time your skin becomes too dry and irritated. Your health care professional can help you choose the right skin products for you to reduce skin dryness and irritation and may include the following:

• For patients using tretinoin for the treatment of acne:
  
  • Regular use of water-based creams or lotions helps to reduce skin irritation or dryness that may be caused by the use of tretinoin.
  
  


• For patients using tretinoin for the treatment of fine wrinkling, dark spots, and rough skin caused by the sun:
  
  • This medicine should be used as part of an ongoing program to avoid further damage to your skin from the sun. This program includes staying out of the sun when possible or wearing proper clothing or hats to protect your skin from sunlight.
  
  
  • Regular use of oil-based creams or lotions helps to reduce skin irritation or dryness caused by the use of tretinoin.
  
  

Tretin-X Side Effects

In some animal studies, tretinoin has been shown to cause skin tumors to develop faster when the treated area is exposed to ultraviolet light (sunlight or artificial sunlight from a sunlamp). Other studies have not shown the same result and more studies need to be done. It is not known if tretinoin causes skin tumors to develop faster in humans.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

More common

• Burning feeling or stinging skin (severe)


• lightening of skin of treated area, unexpected


• peeling of skin (severe)


• redness of skin (severe)


• unusual dryness of skin (severe)

Rare

• Darkening of treated skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Burning feeling, stinging, or tingling of skin (mild)—lasting for a short time after first applying the medicine


• chapping or slight peeling of skin (mild)


• redness of skin (mild)


• unusual dryness of skin (mild)


• unusually warm skin (mild)

The side effects will go away after you stop using tretinoin. On the rare chance that your skin color changes, this effect may last for several months before your skin color returns to normal.

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Tretin-X Topical side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Tretin-X Topical resources

• Tretin-X Topical Side Effects (in more detail)
• Tretin-X Topical Use in Pregnancy & Breastfeeding
• Tretin-X Topical Drug Interactions
• Tretin-X Topical Support Group
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Mylanta Gas Maximum Strength

Generic Name: simethicone (sye METH i cone)

Brand Names: Alka-Seltzer Anti-Gas, Equalize Gas Relief Drops, Gas Aide, Gas Free Extra Strength, Gas-X, Gas-X Extra Strength, Gas-X Infant Drops, Gas-X Maximum Strength, Gas-X Thin Strips Cinnamon, Gas-X Thin Strips Peppermint, Gas-X Tongue Twisters Thin Strips Children's, Gas-X Ultra Softgels, Genasyme, Infantaire Gas Relief, Little Tummys, Maalox Anti-Gas, Maalox Anti-Gas Extra Strength, Mi-Acid Gas Relief, Mylanta Gas, Mylanta Gas Maximum Strength, Mylicon, Mytab Gas, Phazyme, Phazyme Maximum Strength, Phazyme Ultra, Phazyme-125, Phazyme-95

What is Mylanta Gas Maximum Strength (simethicone)?

Simethicone allows gas bubbles in the stomach and intestines to come together more easily, which allows for easier passage of gas.

Simethicone is used to relieve painful pressure caused by excess gas in the stomach and intestines. Simethicone is for use in babies, children, and adults.

Simethicone may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Mylanta Gas Maximum Strength (simethicone)?

Never use more than the recommended dose of simethicone.

Ask a doctor or pharmacist if it is safe for you to take this medicine if you are allergic to any drugs, or if you have any type of serious illness (especially one that affects your stomach or intestines).

Simethicone works best if you take it after meals and at bedtime.

Simethicone may be only part of a complete program of treatment that may also include a special diet or increased exercise. It is very important to follow the diet and exercise plan created for you by your doctor or nutrition counselor. You should become very familiar with the list of foods you must avoid to help control your condition.

There may be other drugs that can interact with simethicone. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

What should I discuss with my healthcare provider before taking Mylanta Gas Maximum Strength (simethicone)?

You should not use this medication if you are allergic to simethicone.

Ask a doctor or pharmacist if it is safe for you to take this medicine if you are allergic to any drugs, or if you have any type of serious illness (especially one that affects your stomach or intestines).

Simethicone is not expected to harm an unborn baby. It is not known whether simethicone passes into breast milk or if it could harm a nursing baby. Do not use this medication without medical advice if you are breast-feeding a baby.

The liquid form may contain phenylalanine. Talk to your doctor before using this form of simethicone if you have phenylketonuria (PKU).

How should I take Mylanta Gas Maximum Strength (simethicone)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

Do not take more of this medication than is directed.

Simethicone works best if you take it after meals and at bedtime.

The simethicone chewable tablet must be chewed before swallowing.

Measure liquid medicine with a special dose measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose measuring device, ask your pharmacist for one. Clean the medicine dropper after each use. Allow it to air dry.

Simethicone liquid drops can be mixed with water, baby formula, or other liquids to make swallowing easier for an infant or child.

Children should never be given more than the recommended dose of simethicone. Call your doctor if the child's gas symptoms do not improve after treatment with simethicone.

Simethicone may be only part of a complete program of treatment that may also include a special diet or increased exercise. It is very important to follow the diet and exercise plan created for you by your doctor or nutrition counselor. You should become very familiar with the list of foods you must avoid to help control your condition.

Store at room temperature away from moisture, heat, and light. Do not allow the liquid form of this medicine to freeze.

What happens if I miss a dose?

Since simethicone is used on an as needed basis, you are not likely to miss a dose. Do not use more of this medication than is directed.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking Mylanta Gas Maximum Strength (simethicone)?

Ask a doctor or pharmacist before using any other stomach medicine or antacid. Simethicone is contained in many combination medicines. Taking certain products together can cause you to get too much simethicone.

Mylanta Gas Maximum Strength (simethicone) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Mylanta Gas Maximum Strength (simethicone)?

There may be other drugs that can interact with simethicone. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Mylanta Gas Maximum Strength resources

• Mylanta Gas Maximum Strength Side Effects (in more detail)
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• Drug Images
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• Simethicone Professional Patient Advice (Wolters Kluwer)


• Simethicone Monograph (AHFS DI)


• Alka-Seltzer Anti-Gas Advanced Consumer (Micromedex) - Includes Dosage Information


• Bicarsim MedFacts Consumer Leaflet (Wolters Kluwer)


• Gas-X Chewable Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Gas-X Extra Strength MedFacts Consumer Leaflet (Wolters Kluwer)


• Gas-X Infant Drops Liquid Drops MedFacts Consumer Leaflet (Wolters Kluwer)


• Genasyme Suspension MedFacts Consumer Leaflet (Wolters Kluwer)

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• Endoscopy or Radiology Premedication
• Functional Gastric Disorder
• Gas
• Postoperative Gas Pains

Where can I get more information?

• Your pharmacist can provide more information about simethicone.

See also: Mylanta Gas Maximum Strength side effects (in more detail)

Ery Pads

erythromycin

Dosage Form: pledgets, topical solution
Ery 2% Pads

(Erythromycin Pledgets USP, 2%)

Rx Only

For Dermatologic Use Only

Not for Ophthalmic Use

Ery Pads Description

Ery 2% Pads contain erythromycin, USP for topical dermatologic use. Erythromycin is a macrolide antibiotic produced from a strain of Saccaropolyspora erythraea (formerly Streptomyces erythreus). It is a base and readily forms salts with acids.

Chemically, erythromycin is C37H67NO13. It has the following structural formula:

The chemical name for erythromycin is (3R*,4S*,5S*,6R*,7R*,9R*,11R*,12R*,13S*,14R*) - 4 - [(2,6 - Dideoxy - 3 - C - methyl - 3 - O - methyl - α - L - ribo - hexopyranosyl)oxy] - 14 - ethyl - 7,12,13 - trihydroxy - 3,5,7,9,11,13 - hexamethyl - 6 - [[3,4,6 - trideoxy - 3 - (dimethylamino) - β - D - xylo - hexopyranosyl]oxy] oxacyclotetradecane-2,10-dione.

Erythromycin has the molecular weight of 733.94. It is a white or slightly yellow, crystalline powder, slightly soluble in water, soluble in alcohol, in chloroform, and in ether. It is odorless or practically odorless. It has a pH range between 8.0 and 10.5 in a methanol and water solution prepared by diluting 1 volume of a methanol solution, containing 40 mg per mL, with 19 volumes of water.

Each mL of expressible liquid contains 20 mg erythromycin in a base of dehydrated alcohol, propylene glycol and citric acid to adjust pH. Each pledget is filled to contain 0.8 mL of Erythromycin Topical Solution 2%.

Ery Pads - Clinical Pharmacology

The exact mechanism by which erythromycin reduces lesions of acne vulgaris is not fully known; however, the effect appears to be due in part to the antibacterial activity of the drug.

MICROBIOLOGY

Erythromycin acts by inhibition of protein synthesis in susceptible organisms by reversibly binding to 50S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis. Antagonism has been demonstrated in vitro between erythromycin, lincomycin, chloramphenicol, and clindamycin.

Indications and Usage for Ery Pads

Ery 2% Pads are indicated for the topical treatment of acne vulgaris.

Contraindications

Ery 2% Pads are contraindicated in those individuals who have shown hypersensitivity to any of its components.

Warnings

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including erythromycin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic-associated colitis”.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against C. difficile colitis.

Precautions

General -

For topical use only; not for ophthalmic use. Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents.

The use of antibiotic agents may be associated with the overgrowth of antibiotic-resistant organisms. If this occurs, discontinue use and take appropriate measures.

Avoid contact with eyes and all mucous membranes.

Information for Patients -

Patients using Ery 2% Pads should receive the following information and instructions:

1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes, nose, mouth, and all mucous membranes.

2. This medication should not be used for any disorder other than that for which it was prescribed.

3. Patients should not use any other topical acne medication unless otherwise directed by their physician.

4. Patients should report to their physician any signs of local adverse reactions.

Carcinogenesis, Mutagenesis, Impairment of Fertility -

No animal studies have been performed to evaluate the carcinogenic and mutagenic potential or effects on fertility of topical erythromycin. However, long-term (2-year) oral studies in rats with erythromycin ethylsuccinate and erythromycin base did not provide evidence of tumorigenicity. There was no apparent effect on male or female fertility in rats fed erythromycin (base) at levels up to 0.25% of diet.

Pregnancy:

Teratogenic Effects:

Pregnancy Category B -

There was no evidence of teratogenicity or any other adverse effect on reproduction in female rats fed erythromycin base (up to 0.25% diet) prior to and during mating, during gestation and through weaning of two successive litters.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed. Erythromycin has been reported to cross the placental barrier in humans, but fetal plasma levels are generally low.

Nursing Women -

It is not known whether erythromycin is excreted in human milk after topical application. However, erythromycin is excreted in human milk following oral and parenteral erythromycin administration. Therefore, caution should be exercised when erythromycin is administered to a nursing woman.

Pediatric Use -

Safety and effectiveness of this product in pediatric patients have not been established.

Adverse Reactions

The following local adverse reactions have been reported occasionally: peeling, dryness, itching, erythema, and oiliness. Irritation of the eyes and tenderness of the skin have also been reported with topical use of erythromycin. Generalized urticarial reactions, possibly related to the use of erythromycin, which required systemic steroid therapy have been reported.

Ery Pads Dosage and Administration

The Ery 2% Pads should be rubbed over the affected area twice a day (morning and evening) after skin is thoroughly washed with warm water and soap and patted dry. Acne lesions on the face, neck, shoulders, chest, and back may be treated in this manner. Additional pledgets may be used, if needed. Each pledget should be used once and discarded. Wash hands after application. Close jar tightly after each use. Drying and peeling may be controlled by reducing the frequency of applications.

How is Ery Pads Supplied

Ery 2% Pads are available as follows:

A plastic jar containing 60 pledgets (NDC 45802-962-72)

Each pledget is filled to contain 0.8 mL of Erythromycin Topical Solution 2%.

STORAGE

Keep jar tightly closed.

Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature].

Made in Israel

Manufactured by Perrigo

Yeruham 80500, Israel

Rev. 08/11

6E500 RC J4

Principal Display Panel

Rx Only

Ery 2% Pads (Erythromycin Pledgets USP, 2%)

For External Use

Avoid Contact with Eyes

Ery 2% Pads (Erythromycin Pledgets USP, 2%) Label

ERY  erythromycin  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 45802-962 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ERYTHROMYCIN (ERYTHROMYCIN) ERYTHROMYCIN 0.8 mL  in 100 mL

Inactive Ingredients Ingredient Name Strength ALCOHOL   PROPYLENE GLYCOL   CITRIC ACID MONOHYDRATE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 45802-962-72 60 APPLICATOR In 1 JAR contains a APPLICATOR 1 0.8 mL In 1 APPLICATOR This package is contained within the JAR (45802-962-72)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA064126	07/07/2008

Labeler - Perrigo New York Inc (078846912)

Revised: 11/2011Perrigo New York Inc

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• Ery Pads Side Effects (in more detail)
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• Ery Pads Support Group
• 1 Review for Erys - Add your own review/rating

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• Eryderm Solution MedFacts Consumer Leaflet (Wolters Kluwer)


• Romycin Ointment MedFacts Consumer Leaflet (Wolters Kluwer)


• Romycin Advanced Consumer (Micromedex) - Includes Dosage Information


• Romycin eent Monograph (AHFS DI)

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Pericyazine 2.5mg Tablets

1. Name Of The Medicinal Product

Pericyazine 2.5mg Tablets

2. Qualitative And Quantitative Composition

Pericyazine 2.5mg

3. Pharmaceutical Form

Neulactil Tablets 2.5mg: Circular, very pale lime-yellow tablet, with one face impressed 'Neulactil' just inside the perimeter. Break-line on reverse.

Pericyazine 2.5mg Tablets: Circular, very pale lime-yellow tablet, with one face impressed 'S171' just inside the perimeter. Break-line on reverse.

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.

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

Indication (a)

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

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

Mild or moderate conditions

Indication (b)

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

Elderly: 5-10 mg 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.

Pericyazine tablets are not recommended for children.

4.3 Contraindications

See use in pregnancy below. 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.

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.

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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interactions of phenothiazine neuroleptics:

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, anti-Parkinson drugs, lithium. Increases or decreases in the plasma concentrations of a number of drugs, e.g: propranolol, 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. 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 3-4 cm. 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 very rarely been reported 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

Toxicity and treatment of overdosage:

Symptoms of neuroleptic overdosage include drowsiness or loss of consciousness, hypotension, tachycardia, ECG changes, ventricular arrhythmias and hypothermia. Severe extrapyramidal 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 (5-10 mg) or orphenedrine (20-40 mg) 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 preclinical 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

Lactose, anhydrous

Cellulose, microcrystalline (E460)

Sodium starch glycolate

Magnesium stearate

Silica, colloidal anhydrous (E551)

Methyl parahydroxybenzoate (E218)

6.2 Incompatibilities

None known.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

Protect from light.

6.5 Nature And Contents Of Container

Securitainer or HDPE bottle containing 500 tablets.

PVDC coated UPVC aluminium foil blister containing 84 tablets.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS, UK

8. Marketing Authorisation Number(S)

PL 17780/0458

9. Date Of First Authorisation/Renewal Of The Authorisation

17 July 2009

10. Date Of Revision Of The Text

6 April 2010

Legal status

POM