1. Name Of The Medicinal Product
Morcap SR 20 mg, 50mg, 100mg
2. Qualitative And Quantitative Composition
Morphine Sulphate BP 20 mg, 50 mg, 100 mg per capsule
3. Pharmaceutical Form
Modified release capsule
4. Clinical Particulars
4.1 Therapeutic Indications
Morcap SR is indicated for the prolonged relief of chronic, moderate to severe pain. Morcap SR is intended for use in patients who require repeated dosing with potent opioid analgesics over a period of more than a few days.
4.2 Posology And Method Of Administration
(see: Pharmacology, Warnings and Precautions sections)
Morcap SR capsules are to be administered either twice daily (every 12 hours) or once daily (every 24 hours).
Selection of the initial dose of Morcap SR should take into account the following:
i) the total daily dose, potency and characteristics of previous opioid analgesics (e.g. pure agonists or mixed agonist/antagonist.)
ii) the reliability of the relative potency estimate used to calculate the dose of morphine required (Potency estimates vary with the route of administration.)
iii) the degree of opioid tolerance
iv) the patient's general medical condition
v) concurrent medication
vi) type and severity of pain
The initial dose of Morcap SR in opioid naive patients should be 20 mg every 12 hours or 40 mg every 24 hours.
The first dose of Morcap SR may be taken with the last dose of any immediate-release opioid medication.
For patients who have difficulty swallowing, Morcap SR pellets may be sprinkled onto a small amount of soft foods (such as yoghurt, apple sauce or jam). This should be taken within 30 minutes of sprinkling. The pellets must not be chewed or crushed and the mouth should be rinsed to ensure that all pellets have been swallowed.
MORCAP SR CAPSULES SHOULD BE SWALLOWED WHOLE. THE CAPSULES AND PELLETS SHOULD NOT BE CHEWED OR CRUSHED.
The use of opioid analgesics for the relief of chronic pain, including cancer pain, should be only part of a complete approach to pain control which should include other types of treatment or drug therapy, non-drug measures and psychosocial support.
If signs of excessive opioid effects are observed early in the dosing interval, the next dose should be reduced. If this adjustment leads to inadequate analgesia, that is, 'breakthrough pain occurs, a supplemental dose of a short acting analgesic may be given. The dosing interval of Morcap SR should not be reduced below every 12 hours. As experience is gained, adjustments can be made to obtain an appropriate balance between pain relief and opioid side effects.
Because of the sustained release properties of Morcap SR, dosage increases should generally be separated by 24 hours.
The peak morphine plasma levels following administration of Morcap SR once daily (every 24 hours) are significantly higher than the peak morphine plasma levels that follow administration of Morcap SR twice daily (every 12 hours). While clinical studies have not shown any difference in morphine related side effects between the dosage regimens, the possibility of increased side effects with the 24 hourly regimen cannot be discounted. Accordingly, close observation is recommended when converting patients from 12 hourly to 24 hourly administration.
For patients currently receiving opioids, the following dosing recommendations should be considered.
Conversion from Other Oral Morphine Formulations to Morcap SR
Patients on other oral morphine formulations may be converted to Morcap SR by administering one half of the patient's total daily morphine dose as Morcap SR capsules on an every 12 hours dosing regimen, or by administering the total daily morphine dose as Morcap SR capsules on an every 24 hours dosing regimen. Dose is then adjusted as needed.
Conversion from Parenteral Morphine or other Parenteral or Oral Opioids to Morcap SR
Morcap SR can be administered as the initial oral morphine drug product. However, in this case, particular care must be exercised in the conversion process. Because of uncertainty about and inter-subject variation in relative estimates of opioid potency and cross tolerance, initial dosing regimens should be conservative, that is, an underestimation of the 24 hour oral morphine requirement is preferred to an overestimate. To this end, initial individual doses of Morcap SR should be estimated conservatively.
Estimates of the relative potency of opioids are only approximate and are influenced by route of administration, individual patient differences, and possibly, by an individual's medical condition.
Consequently, it is difficult to recommend any fixed rule for converting a patient to Morcap SR directly. The following general points should be considered:
Parenteral to oral morphine ratio: Estimates of the oral to parenteral potency of morphine vary. Some authorities suggest that a dose of oral morphine only three times the daily parenteral morphine requirement may be sufficient in chronic use settings.
Other parenteral or oral opioids to oral morphine: Because there are no data on these types of analgesic substitutions, specific recommendations are not possible. Physicians are advised to refer to published relative potency data, keeping in mind that such ratios are only approximate (see Table 1). In general, it is safer to underestimate the daily dose of Morcap SR required and rely upon ad hoc supplementation to deal with inadequate analgesia.
Table 1: APPROXIMATE ORAL OPIOID POTENCY RATIOS RELATIVE TO ORAL MORPHINE*
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1 Dextromoramide: a single 5 mg dose is equivalent to morphine 15 mg in terms of peak effect but is shorter acting. The overall potency ratio has been adjusted accordingly.
2 Methadone: a single 5 mg dose is equivalent to morphine 7.5 mg. It has a prolonged plasma half-life, which leads to cumulation when given repeatedly. This means that when given regularly it is several times more potent.
* Adapted from Twycross and Lack, (1989). Oral morphine in advanced cancer. 2nd ed. Beaconsfield.
Conversion from Morcap SR to other Controlled-Release Oral Morphine Formulations
Morcap SR is not bioequivalent to other controlled-release morphine preparations. Although for a given dose the same amount of morphine is available from Morcap SR as from morphine solution or controlled-release morphine tablets (i.e. AUC is the same), Morcap SR results in reduced maximum and increased minimum plasma morphine concentrations. Conversion from Morcap SR to the same daily dose of other morphine preparations may lead to an initial change in the clinical status of the patient and close observation is recommended.
Conversion from Morcap SR to Parenteral Opioids
When converting a patient from Morcap SR to parenteral opioids, it is best to assume that the parenteral to oral potency is high. NOTE THAT THIS IS THE CONVERSE OF THE STRATEGY USED WHEN THE DIRECTION OF CONVERSION IS FROM THE PARENTERAL TO ORAL FORMULATIONS. IN BOTH CASES, HOWEVER, THE AIM IS TO ESTIMATE THE NEW DOSE CONSERVATIVELY.
For example, to estimate the required 24 hour dose of morphine for i.m. use, one could employ a conversion of 1 mg of morphine i.m. for every 6 mg of morphine as Morcap SR. Of course, the i.m. 24-hour dose would have to be divided by six and administered every 4 hours. This approach is recommended because it is least likely to cause overdose.
Opioid analgesic agents do not effectively relieve dysesthetic pain, post-herpetic neuralgia, stabbing pains, activity-related pain, and some forms of headache. This does not mean that patients with advanced cancer suffering these types of pain should not be given an adequate trial of opioid analgesics. However, such patients may need to be referred early on for other types of pain therapy. Pain without nociception is usually not opioid-responsive.
Use in children
The use of Morcap SR in children has not been evaluated.
Use in the elderly
Morcap SR should be administered with caution and in reduced dosages in elderly patients
4.3 Contraindications
Morcap SR should not be given to patients with: known hypersensitivity to morphine, morphine salts or any of the capsule components; head Injury or increased intracranial pressure; acute or severe bronchial asthma; acute alcoholism; respiratory depression; biliary colic; acute abdomen; gastrointestinal obstruction, particularly paralytic ileus; concurrent MAO inhibitors or within 14 days of such therapy (see Interactions).
4.4 Special Warnings And Precautions For Use
- Warnings:
Impaired Respiration: Respiratory depression is the chief hazard of all morphine preparations. Respiratory depression occurs more frequently in elderly and debilitated patients, and in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may significantly decrease pulmonary ventilation.
Morphine should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia or pre-existing respiratory depression. In such patients, even usual therapeutic doses of morphine may increase airway resistance and decrease respiratory drive to the point of apnoea. Severe pain antagonises the respiratory depressant effects of morphine.
Hypotensive Effect: Morcap SR, like all opioid analgesics may cause severe hypotension in an individual whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or a concurrent administration of drugs such as phenothiazines or general anaesthetics (see Interactions).
Morcap SR may produce orthostatic hypotension in ambulatory patients. Morcap SR, like all opioid analgesics should be administered with caution to patients in circulatory shock, as vasodilation produced by the drug may further reduce cardiac output and blood pressure.
Gastrointestinal Motility: Morcap SR should not be given to patients with gastrointestinal obstruction particularly paralytic ileus as there is a risk of the product remaining in the stomach for an extended period and the subsequent release of a bolus of morphine when normal gut motility is restored.
As with any other solid dose morphine formulation, diarrhoea may reduce morphine absorption.
Drug Dependence: Morphine has a potential for physical and psychological dependence. However, this is not a prime concern in the management of terminally ill patients or patients in severe pain. Abrupt cessation or a sudden reduction in dose after prolonged use may result in withdrawal symptoms. If withdrawal is necessary it must be undertaken gradually.
Infants born to mothers who are physically dependent on opioid analgesics may also be physically dependent and may exhibit withdrawal symptoms. These infants may have respiratory depression at birth (see Precautions).
Tolerance: Tolerance may develop upon repeated administration of morphine. The dose of Morcap SR may need to be increased to maintain adequate pain relief (see Dosage and Administration).
- Precautions:
General: Morcap SR is intended for use in patients who require more than several days continuous treatment with a potent opioid analgesic.
As with any potent opioid, it is critical to adjust the dosing regimen of Morcap SR for each patient individually, taking into account the patient's prior analgesic treatment experience. Although it is clearly impossible to enumerate every consideration that is important to the selection of the initial dose of Morcap SR, attention should be given to the points listed under Dosage and Administration.
Cordotomy: Patients who are scheduled for cordotomy or other interruption of pain transmission pathways should not receive Morcap SR within 24 hours of the procedure.
Post Operative Use: Sustained release morphine sulphate should not be used in the first 24 hours following surgery and should be administered with caution thereafter, especially following abdominal surgery.
Special risk groups: Morcap SR should be administered with caution, and in reduced dosages in elderly or debilitated patients; patients with severe renal or hepatic insufficiency; patients with Addison's disease; myxoedema; hypothyroidism; prostatic hypertrophy or urethral stricture.
Caution should also be exercised in the administration of Morcap SR to patients with CNS depression; toxic psychosis; delerium tremens; severe kyphoscoliosis; convulsive disorders; about to undergo biliary surgery and patients with acute pancreatitis secondary to biliary tract disease.
Driving and operating dangerous machinery: Morphine may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Patients must be cautioned accordingly. Patients should also be warned about the potential combined effects of morphine with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics and alcohol (see Interactions).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
CNS Depressants: Morphine should be used with great caution and in reduced dosage in patients concurrently receiving other central nervous system depressants including sedatives, hypnotics, general anaesthetics, phenothiazines, other tranquillisers and alcohol because of the risk of respiratory depression, hypotension and profound sedation or coma. When such combined therapy is contemplated, the dose of one or both agents should be reduced.
Muscle Relaxants: Morphine may enhance the neuromuscular blocking action of skeletal relaxants and produce an increased degree of respiratory depression.
Mixed Agonist/Antagonist Opioid Analgesics: From a theoretical perspective, mixed agonist/antagonist opioid analgesics (e.g. pentazocine, and buprenorphine) should NOT be administered to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect or may precipitate withdrawal symptoms.
Monoamine Oxidase Inhibitors (MAOIs): MAOIs intensify the effects of morphine and other opioid drugs which can cause anxiety, confusion and significant depression of respiration, sometimes leading to coma. Morphine should not be given to patients taking MAOIs or within 14 days of stopping such treatment.
Anti-Arrhythmics: Morphine may delay absorption of mexilitine.
Antibacterials: Morphine may reduce plasma concentration of ciprofloxacin.
Antivirals: Plasma concentration of Morphine may be increased by ritonavir.
Cisapride: Possible antagonism of gastrointestinal effect.
Metaclopramide and Domperidone: Antagonism of gastrointestinal effect.
Cimetidine: There is a report of confusion and severe respiratory depression when a haemodialysis patient was administered morphine and cimetidine.
Diuretics: Morphine reduces the efficacy of diuretics by inducing the release of antidiuretic hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with prostatism.
Food: The bioavailability of Morcap SR is not significantly affected by food.
4.6 Pregnancy And Lactation
Use in pregnancy: Animal reproduction studies have not been performed using morphine. It is not known whether morphine can cause foetal damage when administered throughout pregnancy or if it can effect reproductive capacity in humans. Pregnant patients should only be given Morcap SR when the benefits clearly outweigh potential risks to the foetus.
Use in labour/delivery and in nursing mothers: Morcap SR is not recommended for use in women during and immediately before labour. The effects of opioid analgesics are unpredictable. They may prolong labour by temporarily reducing the strength, duration and frequency of uterine contractions, or conversely they may tend to shorten labour by increasing the rate of cervical dilatation. Infants born to mothers receiving opioid analgesics during labour should be observed closely for signs of respiratory depression. In such infants a specific opioid antagonist, naloxone hydrochloride, should be available for reversal of narcotic-induced respiratory depression. Morphine is excreted in human milk and breast-feeding is not recommended while a patient is receiving Morcap SR. Withdrawal symptoms have been observed in breast-fed infants when maternal administration of morphine sulphate is stopped.
4.7 Effects On Ability To Drive And Use Machines
Morphine may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g. driving, operating machinery).
4.8 Undesirable Effects
- Adverse Reactions:
The adverse reactions caused by morphine are essentially the same as those observed with other oral and parenteral opioid analgesics. They include the following major hazards: respiratory depression, apnoea and to a lesser degree circulatory depression, respiratory arrest, shock and cardiac arrest.
Most common adverse effects: Constipation, lightheadedness, dizziness, sedation, nausea, vomiting, sweating, headache; dysphoria and euphoria.
Sedation: Most patients receiving morphine will experience initial drowsiness. This usually disappears in three to five days and is not a cause for concern unless it is excessive, or accompanied with unsteadiness or confusion. Excessive or persistent sedation should be investigated. Factors to be considered should include: concurrent sedative medications, the presence of hepatic or renal insufficiency, exacerbated respiratory failure, tolerance to the dose used especially in older patients, disease severity and the patient's general condition. If the dose of Morcap SR has been reduced and pain is not adequately controlled, the dose may be carefully increased again after a few days.
Dizziness and unsteadiness may be associated with morphine-induced postural hypotension, particularly in elderly or debilitated patients. The dosage should be adjusted according to individual needs but, because of reduced clearance, dosage may be lower in patients over 50 years of age.
Nausea and Vomiting: Nausea and vomiting is common after single doses of morphine or as an early undesirable effect of regular opioid therapy. The prescription of a suitable antiemetic should be considered. The frequency of nausea and vomiting usually decreases within a week or so but may persist due to opioid-induced gastric stasis. Metoclopramide is often useful in such patients.
Constipation: Virtually all patients suffer from constipation while taking opioids on a chronic basis. Some patients, particularly elderly, debilitated or bedridden patients may become impacted. Patients must be cautioned accordingly and laxatives, softeners and other appropriate treatments should be initiated at the beginning of opioid therapy.
- Other adverse reactions include:
Cardiovascular: Flushing of the face, chills, tachycardia, bradycardia, palpitations, faintness, syncope, hypotension and hypertension.
Central Nervous System (CNS): Euphoria, dysphoria, weakness, insomnia, dizziness, confusional symptoms and occasionally hallucinations.
Gastrointestinal: Dry mouth, anorexia, constipation, laryngospasm, colic, taste alterations and biliary colic.
Genitourinary: Urinary retention or hesitancy, reduced libido or potency.
Endocrine: A syndrome of inappropriate antidiuretic hormone secretion characterised by hyponatraemia secondary to decreased free-water excretion may occur (monitoring of electrolytes may be necessary).
Visual Disturbances: Blurred vision, nystagmus, diplopia and miosis.
Allergic: Pruritus, urticaria, other skin rashes and oedema.
Withdrawal (Abstinence) Syndrome: Chronic use of opioid analgesics may be associated with the development of physical dependence. An abstinence syndrome may be precipitated when opioid administration is suddenly discontinued or opioid antagonists administered.
Withdrawal symptoms that may be observed after discontinuation of opioid use include: body aches, diarrhoea, piloerection, anorexia, nervousness or restlessness, rhinorrhoea, sneezing, tremors or shivering, abdominal colic, nausea, sleep disturbance, unusual increase in sweating and yawning, weakness, tachycardia and unexplained fever. With appropriate dose adjustments and gradual withdrawal these symptoms are usually mild.
4.9 Overdose
Symptoms: Acute overdosage with morphine is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia and hypotension.
Treatment: Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation. The pure opioid antagonist, naloxone hydrochloride, is a specific antidote against respiratory depression which results from opioid overdose. Naloxone (usually 0.4 to 2.0 mg) should be administered intravenously. However, because its duration of action is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. Morcap SR will continue to release and add to the morphine load for up to 12 hours after administration and the management of morphine overdosage should be modified accordingly. If the response to naloxone is suboptimal or not sustained, additional naloxone may be administered as needed, or given by continuous intravenous infusion to maintain alertness and respiratory function. There is no information available about the cumulative dose of naloxone that may be safely administered.
Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdosage. Naloxone should be administered cautiously to persons who are known or suspected to be physically dependent on Morcap SR. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. If it is necessary to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.
Supportive measures (including oxygen, vasopressors) should be employed in the management of circulatory shock and pulmonary oedema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
Gastric contents may need to be emptied as this can be useful in removing unabsorbed drug, particularly when a sustained-release formulation has been taken.
Morphine toxicity may be a result of overdosage but because of the large inter-individual variation in sensitivity to opioids it is difficult to assess the exact dose of any opioid that is toxic or lethal. The toxic effects of morphine tend to be overshadowed by the presence of pain or tolerance. Patients having chronic morphine therapy have been known to take in excess of 3,000 mg/day with no apparent toxic effects being present.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Morphine is an opioid analgesic which exerts an agonist effect at specific, saturable opioid receptors in the CNS and other tissues. Morphine produces diverse pharmacological effects in man including analgesia, suppression of the cough reflex, respiratory depression due to a reduction in the responsiveness of the respiratory centre to carbon dioxide, nausea and emesis through direct stimulation of the chemoreceptor trigger-zone (CTZ), mood changes including euphoria and dysphoria, sedation, mental clouding, alterations in both the endocrine and autonomic nervous systems, and a decrease in gastrointestinal motility leading to constipation.
5.2 Pharmacokinetic Properties
Morphine is rapidly absorbed from the gastrointestinal tract, nasal mucosa, lung and after subcutaneous (s.c.) and intramuscular (i.m.) injection. When administered orally it is subject to extensive but variable 'first-pass' metabolism and only about 40% of the administered dose reaches the central compartment.
Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. It crosses the placental membranes and has been found in breast milk. About 30 to 35% of morphine is reversibly protein bound.
Although a small fraction of morphine (less than 5%) is demethylated, for all practical purposes, virtually all morphine is converted to glucuronide metabolites including morphine-3-glucuronide and morphine-6-glucuronide. The glucuronide system has very high capacity and is not easily saturated even in disease. Studies in healthy subjects and cancer patients have shown that the glucuronide metabolite to morphine mean molar ratio (based on AUC) are similar following single doses of Morcap SR and morphine sulphate solution, and at steady state for Morcap SR, controlled-release morphine sulphate tablets and morphine sulphate solution. The morphine to morphine-3-glucuronide to morphine-6-glucuronide mean molar ratios (based on AUC) are approximately 1:24:4, similar to those occurring with both morphine sulphate solution and controlled-release morphine tablets following single doses and at steady state.
There has been no evaluation of Morcap SR in patients with impaired hepatic and renal function.
Pharmacokinetic parameters of morphine show considerable inter-subject variation. The average volume of distribution (Vd) is approximately 4 L/kg and the terminal half life is 2 to 4 hours.
Following oral administration the dose normalised extent of absorption (AUC) of morphine from Morcap SR is similar to that obtained from morphine solution or controlled-release tablets. However, the rate of absorption of morphine from Morcap SR is significantly slower.
A single 50 mg oral dose of Morcap SR in 30 healthy male subjects resulted in a mean peak plasma morphine concentration of 8.1 ng/mL (Cmax) at 8.5 hours (Tmax). The extent of absorption was unaffected by food but the Tmax was slightly delayed to 10 hours. However, this is not clinically significant. Morcap SR can be administered with or without food.
When Morcap SR is given on a fixed dosing regimen, steady state is achieved within about two days.
On a 12 hourly dosing schedule Morcap SR at steady state will exhibit a lower mean peak plasma morphine concentration (Cmax) and higher mean trough plasma morphine concentration (Cmin) than the same total daily dose of morphine solution administered on a 4 hourly dosing regimen or controlled-release morphine tablets administered on a 12 hourly dosing regimen. Although there is no clear relationship between analgesic effect or the incidence of adverse reactions and plasma morphine concentrations, the reduced fluctuation in blood morphine concentrations following administration of Morcap SR may reduce adverse reactions and the incidence of breakthrough pain.
Morphine is excreted primarily in the urine as morphine-3-glucuronide and morphine-6-glucuronide. A small amount of the glucuronide metabolites is excreted in the bile and there is some minor enterohepatic cycling. Seven to 10% of administered morphine is excreted in the faeces. Morphine-6-glucuronide has been shown to be pharmacologically active. Because accumulation of this metabolite has been observed in patients with renal disease, caution should be exercised in patients with clinically significant impairment of renal function.
5.3 Preclinical Safety Data
Not applicable.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sugar spheres (sucrose, maize starch), hypromellose, ethylcellulose, methacrylic acid copolymer, polyethylene glycol, diethyl phthalate, purified talc, gelatin, shellac, black iron oxide (E172), propylene glycol, ammonium hydroxide, potassium hydroxide.
6.2 Incompatibilities
None known.
6.3 Shelf Life
PVC/PVDC blister strips: 36 months from date of manufacture of product cores.
Other blister strips: 30 months from date of manufacture of product cores.
HDPE containers: 24 months from date of manufacture of product cores.
6.4 Special Precautions For Storage
Store capsules below 25°C. Protect from light and moisture.
6.5 Nature And Contents Of Container
Blister packs of 30or 60 capsules
HDPE containers of 60 capsules
The capsules are transparent, contain creamy-white to light-tan sustained release pellets and are identified as follows:
20 mg capsule - coded K 20 with 2 discontinuous black bands
50 mg capsule - coded K 50 with 3 discontinuous black bands
100 mg capsule - coded K 100 with 4 discontinuous black bands
6.6 Special Precautions For Disposal And Other Handling
Take orally with water. No special instructions required.
7. Marketing Authorisation Holder
Faulding Pharmaceuticals Plc
Queensway
Royal Leamington Spa
Warwickshire, CV31 3RW
UK
8. Marketing Authorisation Number(S)
Morcap SR 20 mg: PL 04515/0080
Morcap SR 50 mg: PL 04515/0081
Morcap SR 100 mg: PL 04515/0082
9. Date Of First Authorisation/Renewal Of The Authorisation
7 July 1995/10 August 2000
10. Date Of Revision Of The Text
5 October 2000
11. Legal Category
POM
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