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1. Dolocodon Pr 20 Mg Prolonged-Release Tablets
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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Dolocodon PR 20 mg Prolonged-release tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 20 mg oxycodone hydrochloride equivalent to 17.9 mg oxycodone.

Excipient:

Each prolonged-release tablet contains a maximum of 12 mg sucrose.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Prolonged-release tablet.

White to off-white, oblong, biconvex, film-coated tablets with break scores on both sides. The tablet can be divided into equal halves.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Severe pain which can be adequetely managed only with opioid analgesics.

4.2    Posology and method of administration

The dosage depends on the intensity of pain and the patient’s individual susceptibility to the treatment. The following general dosage recommendations apply:

Adults and adolescents (> 12 years)

Dose titration and adjustment

In general, the initial dose for opioid naive patients is 10 mg oxycodone hydrochloride given at intervals of 12 hours. Some patients may benefit from a starting dose of 5 mg to minimise the incidence of side effects.

Patients already receiving opioids may start treatment with higher dosages taking into account their experience with former opioid therapies.

According to well-controlled clinical studies 10-13 mg oxycodone hydrochloride correspond to approximately 20 mg morphine sulphate, both in the prolonged-release formulation.

Because of individual differences in sensitivity for different opioids, it is recommended that patients should start conservatively with Dolocodon prolonged-release tablets after conversion from other opioids, with 50-75% of the calculated oxycodone dose.

Some patients who take Dolocodon prolonged-release tablets following a fixed schedule need rapid release analgesics as rescue medication in order to control breakthrough pain. Dolocodon prolonged-release tablets are not indicated for the treatment of acute pain and/or breakthrough pain. The single dose of the rescue medication should amount to 1/6 of the equianalgesic daily dose of Dolocodon prolonged-release tablets. Use of the rescue medication more than twice daily indicates that the dose of Dolocodon prolonged-release tablets needs to be increased. The dose should not be adjusted more often than once every 1-2 days until a stable twice daily administration has been achieved.

Following a dose increase from 10 mg to 20 mg taken every 12 hours dose adjustments should be made in steps of approximately one third of the daily dose. The aim is a patient specific dosage which, with twice daily administration, allows for adequate analgesia with tolerable undesirable effects and as little rescue medication as possible as long as pain therapy is needed.

Even distribution (the same dose mornings and evenings) following a fixed schedule (every 12 hours) is appropriate for the majority of the patients. For some patients it may be advantageous to distribute the doses unevenly. In general, the lowest effective analgesic dose should be chosen. For the treatment of non malignant pain a daily dose of 40 mg is generally sufficient; but higher dosages may be necessary. Patients with cancer-related pain may require dosages of 80 to 120 mg, which in individual cases can be increased to up to 400 mg. If even higher doses are required, the dose should be decided individually balancing efficacy with the tolerance and risk of undesirable effects.

Use in non-malignant pain:

Opioids are not first line therapy for chronic non-malignant pain, nor are they recommended as the only treatment. Types of chronic pain which have been shown to be alleviated by strong opioids include chronic osteoarthritic pain and intervertebral disc disease. The need for continued treatment in non-malignant pain should be assessed at regular intervals.

Method of administration For oral use.

Dolocodon prolonged-release tablets should be taken twice daily based on a fixed schedule at the dosage determined.

The prolonged-release tablets may be taken with or independent of meals with a sufficient amount of liquid. Dolocodon prolonged release tablets must be swallowed whole, not chewed.

For doses not realisable/practicable with this medicinal product other strengths and medicinal products are available.

Dolocodon prolonged-release tablets should not be used with alcoholic beverages. Duration of administration

Dolocodon prolonged-release tablets should not be taken longer than necessary. If long-term treatment is necessary due to the type and severity of the illness careful and regular monitoring is required to determine whether and to what extent treatment should be continued. If opioid therapy is no longer indicated it may be advisable to reduce the daily dose gradually in order to prevent symptoms of a withdrawal syndrome.

Children under 12 years of age

Dolocodon prolonged-release tablets are not recommended for children under 12 years of age.

Elderly patients

Controlled pharmacokinetic studies in elderly patients (aged over 65 years) have shown that, compared with younger adults, the clearance of oxycodone is only slightly reduced. No untoward adverse drug reactions were seen based on age, therefore adult doses and dosage intervals are appropriate.

Adults with mild to moderate renal impairment and mild hepatic impairment:

The plasma concentration in this population may be increased. Therefore dose initiation should follow a conservative approach. Patients should be started on 5 mg of oxycodone 12-hourly or 2.5 mg of oxycodone 6-hourly and titrated to pain relief as described above.

Special population

Risk patients, for example patients with impaired renal or hepatic function, low body weight or slow metabolism of medicinal products, should initially receive half the recommended adult dose if they are opioid naive. Therefore the lowest recommended dosage, i.e. 10 mg, may not be suitable as a starting dose. Dose titration should be performed in accordance with the individual clinical situation.

4.3    Contraindications

•    Hypersensitivity to active substance or to any of the excipients

•    Severe respiratory depression with hypoxia and/or hypercapnia

•    Severe chronic obstructive pulmonary disease

•    Cor pulmonale

•    Severe bronchial asthma

•    Paralytic ileus, chronic constipation

•    Pregnancy (see section 4.6)

•    Lactation (see section 4.6)

•    Acute abdomen, delayed gastric emptying.

•    Concurrent administration of monoamine oxidase inhibitors or within 2 weeks of discontinuation of their use.

4.4    Special warnings and precautions for use

Dolocodon prolonged-release tablets have not been studied in children younger than 12 years of age. The safety and efficacy of the tablets have not been demonstrated and the use in children younger than 12 years of age is therefore not recommended.

Caution is required in elderly or debilitated patients, in patients with severe impairment of lungs, liver or kidney function, myxoedema, hypothyroidism,

Addison’s disease (adrenal insufficiency), intoxication psychosis (e.g. alcohol), prostatic hypertrophy, alcoholism, known opioid dependence, delirium tremens, pancreatitis, diseases of the biliary tract, biliary or ureteric colic, conditions with increased brain pressure, disturbances of circulatory regulation, epilepsy or seizure tendency and in patients taking MAO inhibitors.

Concomitant use of alcohol and Dolocodon may increase the undesirable effects of Dolocodon; concomitant use should be avoided.

80 mg and higher dose of oxycodone should not be used in patients not previously exposed to opioids. These doses may cause fatal respiratory depression when administered to opioid naive patients.

For appropriate patients who suffer with chronic non-malignant pain, opioids should be used as part of a comprehensive treatment programme involving other medications and treatment modalities. A crucial part of the assessment of a patient with chronic non-malignant pain is the patient’s addiction and substance abuse history.

Should paralytic ileus be suspected or occur during use, oxycodone should be discontinued immediately.

Patients with severe hepatic impairment should be closely monitored.

In case of abusive parenteral venous injection the tablet excipients may lead to necrosis of the local tissue, granulomas of the lung or other serious, potentially fatal events. To avoid damage to the controlled release properties of the tablets the prolonged release tablets must not be chewed or crushed. The administration of chewed or crushed tablets leads to rapid release and absorption of a potentially fatal dose of oxycodone (see section 4.9).

Respiratory depression

Respiratory depression is the most significant risk induced by opioids and is most likely to occur in elderly or debilitated patients. The respiratory depressant effect of oxycodone can lead to increased carbon dioxide concentrations in blood and hence in cerebrospinal fluid. In predisposed patients opioids can cause severe decrease in blood pressure.

Head injury, increased intracranial pressure

Respiratory depressant effects of opioids with carbon dioxide retention and secondary elevation of CSF pressure may be markedly exaggerated in the presence of head injury, intracranial lesions, or a pre-existing increase in intracranial pressure. Neurologic signs of further increases in pressure in patients with head injuries may be obscured.

Tolerance

Long-term use of Dolocodon prolonged-release tablets can cause the development of tolerance which leads to the use of higher doses in order to achieve the desired analgesic effect. There is a cross-tolerance to other opioids. Chronic use of Dolocodon prolonged-release tablets can cause physical dependence. Withdrawal symptoms may occur following abrupt discontinuation of therapy. If therapy with oxycodone is no longer required it may be advisable to reduce the daily dose gradually in order to avoid the occurrence of a withdrawal syndrome.

Dependence

Dolocodon prolonged-release tablets have a primary dependence potential. However, when used as directed in patients with chronic pain the risk of developing physical or psychological dependence is markedly reduced or needs to be assessed in a differentiated manner. There are no data available on the actual incidence of psychological dependence in chronic pain patients. In patients with a history of alcohol and drug abuse the medicinal product must be prescribed with special care.

Surgical procedures

The safety of Dolocodon prolonged release tablets used pre-operatively has not been established and cannot be recommended.

Special care should be taken when oxycodone is applied in patients undergoing bowel-surgery. Opioids should only be administered post-operatively when the bowel function has been restored.

As with all opioid preparations, patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive oxycodone for 12 hours prior to the intervention. If further treatment with oxycodone is indicated then the dosage should be adjusted to the new post-operative requirement.

‘Anti-doping’ tests

Athletes must be aware that this medicine may cause a positive reaction to ‘antidoping’ tests.

Excipients

This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

•    Central nervous system depressants (e.g. sedatives, hypnotics, phenothiazines, neuroleptics, anaesthetics, antidepressants, muscle relaxants, antihistamines, antiemetics) and other opioids or alcohol can enhance the adverse reactions of oxycodone, in particular respiratory depression.

•    Alcohol may enhance the pharmacodynamic effects of Dolocodon; concomitant use should be avoided.

•    Anticholinergics (e.g. neuroleptics, antihistamines, antiemetics, antiparkinson medicinal products) can enhance the anticholinergic undesirable effects of oxycodone (such as constipation, dry mouth or micturition disorders).

•    Cimetidine can inhibit the metabolism of oxycodone.

•    MAO inhibitors are known to interact with narcotic analgesics, producing CNS excitation or depression with hyper- or hypotensive crisis (see section 4.4).

•    The inhibition of cytochrome P450 2D6 and 3A4 has no clinical relevance, however, strong CYP2D6 inhibitors may have an effect on the elimination of oxycodone. The effect of other relevant isoenzyme inhibitors on the metabolism of oxycodone is not known. Potential interactions should be taken into account.

•    Clinically relevant changes in International Normalised Ratio (INR) in both directions have been observed in individuals if coumarin anticoagulants are coapplied with Dolocodon prolonged release tablets.

•    There are no studies investigating the effect of oxycodone on CYP catalysed metabolism of other active substances.

4.6    Pregnancy and lactation

Pregnancy

Dolocodon prolonged-release tablets must not be taken during pregnancy (see section

4.3) .

There are no adequate data from the use of oxycodone in pregnant women. Oxycodone crosses the placenta. Prolonged use of oxycodone during pregnancy can cause withdrawal symptoms in newborns. Use of oxycodone during labour can cause foetal respiratory depression.

Lactation

Dolocodon prolonged-release tablets must not be taken during lactation (see section

4.3) .

Oxycodone passes into breast milk. The milk/plasma concentration ratio was 3.4:1.

4.7    Effects on ability to drive and use machines

Oxycodone can impair alertness and reactivity to such an extent that the ability to drive and operate machinery is affected or ceases altogether. With stable therapy, a general ban on driving a vehicle is not necessary. The treating physician must assess the individual situation.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

•    The medicine is likely to affect your ability to drive

•    Do not drive until you know how the medicine affects you

•    It is an offence to drive while under the influence of this medicine

•    However, you would not be committing an offence (called ‘statutory defence’) if:

o The medicine has been prescribed to treat a medical or dental problem and o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely

4.8 Undesirable effects

Adverse drug reactions are typical of full opioid agonists. Tolerance and dependence may occur (see Tolerance and Dependence, below). Constipation may be prevented

with an appropriate laxative. If nausea and vomiting are troublesome, oxycodone may be combined with an anti-emetic.

Oxycodone can cause respiratory depression, miosis, bronchial spasms and spasms of the smooth muscles and can suppress the cough reflex.

The adverse reactions considered at least possibly related to treatment are listed below by system organ class and absolute frequency.

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

Frequencies are defined as

(>1/10)

(>1/100 and <1/10)

(>1/1,000 and <1/100)

(>1/10,000 and <1/1,000)

(<1/10,000), not known (cannot be estimated from the available data)

Blood and lymphatic system disorders Rare:    Lymphadenopathy

Endocrine disorders:

Uncommon:    Syndrome of inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders Common:    Anorexia.

Rare:    Dehydration.

Psychiatric disorders

Common:    Various psychological adverse reactions including changes in mood

(e.g. anxiety, depression, euphoria), changes in activity (mostly suppression sometimes associated with lethargy, occasionally increase with agitation, nervousness and insomnia) and changes in cognitive performance (abnormal thinking, confusion, amnesia, isolated cases of speech disorders).

Uncommon:    Change in perception such as depersonalisation, hallucinations,

change in taste, visual disturbances, hyperacousis.

Nervous system disorders

Very common: Somnolence; dizziness; headache Common:    Asthenia, paraesthesia.

Uncommon:	both increased and decreased muscle tone, tremor, involuntary muscle contractions; hypaesthesia; coordination disturbances; malaise; vertigo.
Rare:	seizures, in particular in epileptic patients or patients with tendency to convulsions; muscle spasm.

Cardiac and vascular disorders

Common:    Lowering of blood pressure, rarely accompanied by secondary

Uncommon:	symptoms such as palpitations; syncope. Supraventricular tachycardia; vasodilatation.
Eye disorders Uncommon:	Miosis, lacrimation disorder.

Respiratory, thoracic and mediastinal disorders Common:    Respiratory depression; bronchospasm.

Uncommon:    Increased coughing; pharyngitis; rhinitis; voice changes.

Gastrointestinal disorders

Very common: Constipation, nausea; vomiting.

Common:    Dry mouth, rarely accompanied by thirst and difficulty swallowing;

Skin and subcutaneous tissue disorders Very common: Itching.

Common:    Skin eruptions including rash, in rare cases increased

Rare:

photosensitivity, in isolated cases urticaria or exfoliative dermatitis. Dry skin; herpes simplex.

Renal and urinary disorders

Common:    Micturition disturbances (urinary retention, but also increased urge to

urinate).

Haematuria.

Reproductive system and breast disorders Uncommon:    Reduced libido; impotence.

Rare:    Amenorrhoea.

General disorders and administration site conditions Common:    Sweating and even chills.

Uncommon:    Accidental injuries; pain (e.g. chest pain); oedema; migraine;

physical dependence with withdrawal symptoms; allergic reactions.

Rare:    Weight changes (increase or decrease); cellulitis.

Very rare:    Anaphylactic reactions.

Tolerance and dependence may develop.

Tolerance and Dependence:

The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use of Dolocodon tablets may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. The opioid abstinence or withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, or increased blood pressure, respiratory rate or heart rate.

The development of psychological dependence (addiction) to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of psychological dependence (addiction) in chronic pain patients.

Overdose

Symptoms of overdose

Miosis, respiratory depression, somnolence, reduced skeletal muscle tone and drop in blood pressure. In severe cases circulatory collapse, stupor, coma, bradycardia and non-cardiogenic lung oedema may occur; abuse of high doses of strong opioids such as oxycodone can be fatal.

Therapy of overdose

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation

In the event of overdosing intravenous administration of an opiate antagonist (e.g. 0.4-2 mg intravenous naloxone) may be indicated. Administration of single doses must be repeated depending on the clinical situation at intervals of 2 to 3 minutes. Intravenous infusion of 2 mg of naloxone in 500 ml isotonic saline or 5% dextrose solution (corresponding to 0.004 mg naloxone/ml for an adult and 0.01 mg/kg body weight for children) is possible. The rate of infusion should be adjusted to the previous bolus injections and the response of the patient. Infusions are not a substitute for frequent review of the patient's clinical state. Intramuscular naloxone is an alternative in the event IV access is not possible. As the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdosage. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on oxycodone. In such cases, an abrupt or complete reversal of opioid effects may precipitate pain and an acute withdrawal syndrome.

Gastric lavage can be taken into consideration. Consider activated charcoal (50 g for adults, 10 -15 g for children), if a substantial amount has been ingested within 1 hour, provided the airway can be protected. It may be reasonable to assume that late administration of activated charcoal may be beneficial for prolonged release preparations; however there is no evidence to support this.

For speeding up the passage a suitable laxative (e.g. a PEG based solution) may be useful.

Supportive measures (artificial respiration, oxygen supply, administration of vasopressors and infusion therapy) should, if necessary, be applied in the treatment of accompanying circulatory shock. Upon cardiac arrest or cardiac arrhythmias cardiac massage or defibrillation may be indicated. If necessary, assisted ventilation as well as maintenance of water and electrolyte balance.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Natural opium alkaloids, ATC-Code: N02AA05

Oxycodone shows an affinity to kappa, mu and delta opioid receptors in the brain and spinal cord. It acts at these receptors as an opioid agonist without an antagonistic effect. The therapeutic effect is mainly analgesic and sedative. Compared to rapid-release oxycodone, given alone or in combination with other substances, the prolonged-release tablets provide pain relief for a markedly longer period without increased occurrence of undesirable effects.

The efficacy of oxycodone has been demonstrated in cancer pain, post-operative pain and severe non-malignant pain such as diabetic neuropathy, postherpetic neuralgia, low back pain and osteoarthritis. In the latter indication, treatment was continued for up to 18 months and proved effective in many patients for whom NSAIDs alone provided inadequate relief. The efficacy of oxycodone in neuropathic pain was confirmed by three placebo-controlled studies.

In patients with chronic non-malignant pain, maintenance of analgesia with stable dosing was demonstrated for up to three years.

5.2 Pharmacokinetic properties

Absorption

The relative bioavailability of Dolocodon prolonged-release tablets is comparable to that of rapid release oxycodone with maximum plasma concentrations being achieved after approximately 4-5 hours after intake of the prolonged-release tablets compared to 1 to 1.5 hours. Peak plasma concentrations and oscillations of the concentrations of oxycodone from the prolonged-release and rapid-release formulations are comparable when given at the same daily dose at intervals of 12 and 6 hours, respectively.

A fat-rich meal before the intake of the tablets does not affect the maximum concentration or the extent of absorption of oxycodone.

The tablets must not be crushed or chewed as this leads to rapid oxycodone release due to the damage of the prolonged release properties.

Distribution

The absolute bioavailability of oxycodone is approximately two thirds relative to parenteral administration. In steady state, the volume of distribution of oxycodone amounts to 2.6 l/kg; plasma protein binding to 38-45%; the elimination half-life to 4 to 6 hours and plasma clearance to 0.8 l/min. The elimination half-life of oxycodone from prolonged-release tablets is 4-5 hours with steady state values being achieved after a mean of 1 day.

Metabolism

Oxycodone is metabolised in the intestine and liver via the P450 cytochrome system to noroxycodone and oxymorphone as well as to several glucuronide conjugates. In vitro studies suggest that therapeutic doses of cimetidine probably have no relevant effect on the formation of noroxycodone. In man, quinidine reduces the production of oxymorphone while the pharmacodynamic properties of oxycodone remain largely unaffected. The contribution of the metabolites to the overall pharmacodynamic effect is irrelevant.

Elimination

Oxycodone and its metabolites are excreted via urine and faeces. Oxycodone crosses the placenta and is found in breast milk.

Elderly

The AUC in elderly subjects is 15% greater when compared with young subjects.

Gender

Female subjects have, on average, plasma oxycodone concentrations up to 25% higher than males on a body weight adjusted basis. The reason for this difference is unknown.

Patients with renal impairment

Preliminary data from a study of patients with mild to moderate renal dysfunction show peak plasma oxycodone and noroxycodone concentrations approximately 50% and 20% higher, respectively and AUC values for oxycodone, noroxycodone and oxymorphone approximately 60%, 60% and 40% higher than normal subjects, respectively. There was an increase in t./₂ of elimination for oxycodone of only 1 hour.

Patients with mild to moderate hepatic impairment

Patients with mild to moderate hepatic dysfunction showed peak plasma oxycodone and noroxycodone concentrations approximately 50% and 20% higher, respectively, than normal subjects. AUC values were approximately 95% and 75% higher, respectively. Oxymorphone peak plasma concentrations and AUC values were lower by 15% to 50%. The t_/ elimination for oxycodone increased by 2.3 hours.

5.3 Preclinical safety data

There is insufficient data on the reproduction toxicity properties of oxycodone and there is no data available on fertility and postnatal effects following intrauterine exposure. Oxycodone did not cause malformations in rats and rabbits at dosages, which were 1.5 to 2.5 times of the human dose of 160 mg/day, based on mg/kg basis.

Long-term studies on carcinogenicity have not been performed.

Oxycodone was not mutagenic in the following assays: Ames Salmonella and E. Coli test with and without metabolic activation at doses of up to 5000 pg, chromosomal aberration test in human lymphocytes (in the absence of metabolic activation and with activation after 48 hours of exposure) at doses of up to 1500 pg/ml, and in the in vivo bone marrow micronucleus assay in mice (at plasma levels of up to 48 pg/ml). Mutagenic results occurred in the presence of metabolic activation in the human chromosomal aberration test (at greater than or equal to 1250 pg/ml) at 24 but not 48 hours of exposure and in the mouse lymphoma assay at doses of 50 pg/ml or greater with metabolic activation and at 400 pg/ml or greater without metabolic activation. The data from these tests indicate that the genotoxic risk to humans may be considered low.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Active pellets:

Sugar spheres (Sucrose, Maize starch)

Hypromellose

Pellet coating:

Ethylcellulose Hydroxypropylcellulose Propylene glycol

Final blending:

Carmellose sodium Microcrystalline cellulose Magnesium stearate [plant-based]

Colloidal anhydrous silica

Tablet coating:

Titanium dioxide (E171)

Hypromellose Macrogol 6000 Talc

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 years

HDPE bottles: The product should be used within 4 weeks after first opening when stored in original tightly closed inner package.

6.4    Special precautions    for storage

Blisters: Store in the original package in order to protect from moisture.

HDPE bottles: Keep the container tightly closed in order to protect from moisture.

6.5    Nature and contents    of container

Child resistant PVC/PE/PVDC-aluminium blisters consisting of a white opaque PVC/PE/PVDC laminated foil and an aluminium foil.

HDPE bottles with child-resistant PE twist-off caps.

Pack sizes:

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

7.    MARKETING AUTHORISATION HOLDER

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS, UK

Or

Trading as: Zentiva, Onslow Street, Guildford, Surrey, GU1 4YS, UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 17780/0490

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/08/2010

10    DATE OF REVISION OF THE TEXT

28/03/2014