Document: spc-doc_PL 17907-0559 change

• spc-doc_PL 17907-0559
• spc-doc_PL 40800-0008

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Alivio 10 mg prolonged-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 10 mg oxycodone hydrochloride equivalent to 9 mg oxycodone.

Excipient with known effect:

Each prolonged-release tablet contains a maximum of 30 mg sucrose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet.

Pink, oblong, biconvex, film coated tablets with break scores on both sides. The height of the tablet is between 4 and 5 mm, the width is 4.8 mm and the length is 10.3 mm.

The tablet can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Severe pain, which can be adequately managed only with opioid analgesics. Alivio is indicated in adults and adolescents aged 12 years and older.

4.2 Posology and method of administration

Posology

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

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 adverse reactions.

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

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

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 Alivio prolonged-release tablets after conversion from other opioids, with 50-75% of the calculated oxycodone dose.

Dose adjustment

Some patients who take Alivio following a fixed schedule need rapid release analgesics as rescue medication in order to control breakthrough pain. Alivio 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 Alivio. Use of the rescue medication more than twice daily indicates that the dose of Alivio 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.

Elderly patients

A dose adjustment is not usually necessary in elderly patients.

Duration of administration

Alivio should not be used for 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.

Discontinuation of treatment

When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

Patients with renal or hepatic impairment

The dose initiation should follow a conservative approach in these patients. The recommended adult starting dose should be reduced by 50% (for example a total daily dose of 10 mg orally in opioid naive patients), and each patient should be titrated to adequate pain control according to their clinical situation.

Paediatric population Children under 12 years of age

Alivio should not be used in children under 12 years of age because of safety and efficacy concerns.

Method of administration For oral use.

Alivio 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 (‘A glass of water).

Alivio must not be taken broken, chewed or crushed.

Alivio should not be used with alcoholic beverages.

Contraindications

•    Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Oxycodone must not be used in any situation where opioids are contraindicated:

•    Severe chronic obstructive lung disease

•    Cor pulmonale

•    Severe bronchial asthma

•    Severe respiratory depression with    hypoxia

•    Elevated carbon dioxide levels    in the blood

•    Paralytic ileus

4.4 Special warnings and precautions for use

Caution must be exercised when administering oxycodone to the debilitated elderly, patients with severely impaired pulmonary function, impaired hepatic or renal function, patients with myxoedema, hypothyroidism, Addison’s disease , toxic psychosis (e.g. alcohol), prostate hypertrophy, alcoholism, known opioid dependence, delirium tremens, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, hypotension, hypovolaemia, head injury (due to risk of increased intracranial pressure), epilepsy or seizure tendency and in patients taking MAO inhibitors.

In suspicion or in case of paralytic ileus administration of Alivio has to be stopped immediately.

Surgical procedures

As with all opioid preparations, oxycodone products should be used with caution following abdominal surgery as opioids are known to impair intestinal motility and should not be used until the physician is assured of normal bowel function.

Alivio is not recommended for pre-operative use or within the first 12-24 hours postoperatively.

Respiratory- and cardiac depression

The major risk of opioid excess is respiratory depression. It 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.

Tolerance and Dependence

The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. There is a cross-tolerance to other opioids. Chronic use of oxycodone can cause 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. Withdrawal symptoms may include yawning, mydriasis, lacrimation, rhinorrhoea, tremor, hyperhidrosis, anxiety, agitation, convulsions and insomnia.

Hyperalgesia that will not respond to a further dose increase of oxycodone may very rarely occur, particularly in high doses. An oxycodone dose reduction or change to an alternative opioid may be required.

Abuse

Oxycodone has an abuse profile similar to other strong agonist opioids. Oxycodone may be sought and abused by people with latent or manifest addiction disorders. There is potential for development of psychological dependence (addiction) to opioid analgesics, including oxycodone. Alivio should be used with particular care in patients with a history of alcohol and drug abuse.

Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events. 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 prolonged release, tablets must not be swallowed broken, chewed or crushed. The administration of broken, chewed or crushed controlled release oxycodone tablets leads to a rapid release and absorption of a potentially fatal dose of oxycodone (see section 4.9).

Alcohol

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

Special patient groups Hepatic impairment

Patients with severe hepatic impairment should be closely monitored. Paediatric population

The safety and efficacy of oxycodone in children under 12 years of age have not been established. Alivio should not be used in children under 12 years of age because of safety and efficacy concerns.

'Anti-doping' warning

Athletes must be aware that this medicine may cause a positive reaction to 'anti-doping' tests. Use of Alivio as a doping agent may become a health hazard.

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

-    There can be an enhanced CNS depressant effect during concomitant therapy with medicinal products which affect the CNS, such as sedatives, hypnotics, phenothiazines, neuroleptics, anaesthetics, antidepressants, muscle relaxants) and other opioids or alcohol, in particular respiratory depression.

-    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).

-    Monoaminooxidase (MAO) inhibitors are known to interact with narcotic analgesics. MAO-inhibitors causes CNS excitation or depression associated with hypertensive or hypotensive crisis (see section 4.4). Oxycodone should be used with caution in patients administered MAO-inhibitors or who have received MAO-inhibitors during the last two weeks (see section 4.4).

Oxycodone is metabolised mainly by CYP3A4, with a contribution from

CYP2D6. The activities of these metabolic pathways may be inhibited or

induced by various co-administered medicinal products or dietary elements.

- CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin and telithromycin), azolantifungals (e.g. ketoconazole, voriconazole, itraconazole, and posaconazole), protease inhibitors (e.g. boceprevir, ritonavir, indinavir, nelfinavir and saquinavir), cimetidine and grapefruit juice may cause a reduced clearance of oxycodone that could cause an increase of the plasma concentrations of oxycodone. Therefore the oxycodone dose may need to be adjusted accordingly.

Some specific examples are provided below:

-    Itraconazole, a potent CYP3A4 inhibitor, administered 200 mg orally for five days, increased the AUC of oral oxycodone. On average, the AUC was approximately 2.4 times higher (range 1.5 - 3.4).

-    Voriconazole, a CYP3A4 inhibitor, administered 200 mg twice-daily for four days (400 mg given as first two doses), increased the AUC of oral oxycodone. On average, the AUC was approximately 3.6 times higher (range 2.7 - 5.6).

-    Telithromycin, a CYP3A4 inhibitor, administered 800 mg orally for four days, increased the AUC of oral oxycodone. On average, the AUC was approximately 1.8 times higher (range 1.3 - 2.3).

-    Grapefruit Juice, a CYP3A4 inhibitor, administered as 200 ml three times a day for five days, increased the AUC of oral oxycodone. On average, the AUC was approximately 1.7 times higher (range 1.1 - 2.1).

-    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. Medicinal products that inhibit CYP2D6 activity, such as paroxetine and quinidine, may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations.

-    Clinically relevant changes in International Normalised Ratio (INR) in both directions have been observed in individuals if coumarin anticoagulants are co-applied with oxycodone.

-    Alcohol may enhance the pharmacodynamic effects of Alivio; concomitant use should be avoided.

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

-    CYP3A4 inducers, such as rifampicin, carbamazepin, phenytoin and St John's Wort may induce the metabolism of oxycodone and cause an increased clearance of oxycodone that could cause a reduction of the plasma concentrations of oxycodone. The oxycodone dose may need to be adjusted accordingly.

Some specific examples are provided below:

-    St John’s Wort, a CYP3A4 inducer, administered as 300 mg three times a day for fifteen days, reduced the AUC of oral oxycodone. On average, the AUC was approximately 50% lower (range 37-57%).

-    Rifampicin, a CYP3A4 inducer, administered as 600 mg once-daily for seven days, reduced the AUC of oral oxycodone. On average, the AUC was approximately 86% lower.

4.6 Fertility, Pregnancy and lactation

Use of this medicinal product should be avoided to the extent possible in patients who are pregnant or lactating.

Pregnancy

There are limited data from the use of oxycodone in pregnant women.

Infants born to mothers who have received opioids during the last 3 to 4 weeks before giving birth should be monitored for respiratory depression.

Withdrawal symptoms may be observed in the newborn of mothers undergoing treatment with oxycodone.

Breastfeeding

Oxycodone may be secreted in breast milk and may cause respiratory depression in the newborn. Oxycodone should, therefore, not be used in breastfeeding mothers.

Fertility

Human data are not available. In animal studies, oxycodone had no adverse effects on fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Oxycodone may impair the ability to drive and use machines. In these circumstances Alivio has moderate to major influence on the ability to drive and use machines.

With stable therapy, a general ban on driving a vehicle is not necessary. In these circumstances Alivio has minor influence on the ability to drive and use machines. The treating physician must assess the individual situation.

4.8 Undesirable effects

Summary of the safety profile

Oxycodone can cause respiratory depression, miosis, bronchial spasms and spasms of the smooth muscles and can suppress the cough reflex. Tolerance and dependence may occur (see below).

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

Very common (> 1/10)

Common (> 1/100 to < 1/10)

Uncommon (> 1/1,000 to < 1/100)

Rare (> 1/10,000 to < 1/1,000)

Very rare (< 1/10,000)

Not known (cannot be estimated from the available data)

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

Immune system disorders:

Uncommon:    hypersensitivity

Very rare:    anaphylactic responses.

Metabolism and nutrition disorders Common:    decreased appetite

Uncommon:    dehydration

Psychiatric disorders

Common:    anxiety, confusional state, depression, insomnia, nervousness.

abnormal thinking

Uncommon:    agitation, affect lability, euphoric mood, hallucinations, decreased

libido, drug dependence (see section 4.4).

Frequency not known: aggression.

Nervous system disorders

Very common: somnolence, dizziness, headache

Common:    tremor

Uncommon:    amnesia, convulsion, hypertonia, hypoaesthesia, involuntary muscle

contractions, speech disorder, syncope, paraesthesia, dysgeusia Frequency unknown: hyperalgesia.

Eye disorders

Uncommon:    visual impairment,    miosis

Ear and labyrinth disorders:

Uncommon:    vertigo

Cardiac disorders

Uncommon:    palpitations (in the    context of withdrawal syndrome)

Vascular disorders Uncommon:    vasodilatation

Rare:    hypotension, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders Common:    dyspnea.

Uncommon:    respiratory    depression

Gastrointestinal disorders

Very common: constipation, nausea, vomiting

Common:    abdominal    pain, diarrhoea, dry mouth, dyspepsia

Uncommon:    dysphagia,    flatulence, eructation, ileus

Frequency not known: dental caries

Hepatobiliary disorders:

Uncommon: increased hepatic enzymes Frequency unknown: cholestasis, biliary colic Skin and subcutaneous tissue disorders Very common: pruritus Common:    rash, hyperhidrosis

Uncommon: dry skin Rare:    urticaria

Renal and urinary disorders Uncommon: urinary retention.

Reproductive system and breast disorders Uncommon:    erectile dysfunction

Frequency unknown: amenorrhoea

General disorders and administration site conditions Common:    asthenic conditions

Uncommon:    chills, drug withdrawal syndrome, malaise, oedema, peripheral

oedema, drug tolerance, thirst

Description of selected adverse reactions

Tolerance and dependence may develop with chronic use and a withdrawal syndrome

may occur upon abrupt cessation of therapy. The opioid abstinence or withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, hypertonia, miosis, bradycardia, hypotension, and death. In severe cases circulatory collapse and non-cardiogenic lung oedema may occur; abuse of high doses of strong opioids such as oxycodone can be fatal.

Management

A patent airway must be maintained.

The pure opioid antagonists such as naloxone are specific antidotes against symptoms from opioid overdose.

Other supportive measures should be employed as needed.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics; Opioids; Natural opium alkaloids ATC-Code: N02AA05

Mechanism of action

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.

Endocrine system

Opioids may influence the hypothalamic-pituitary-adrenal or - gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms may be manifest from these hormonal changes.

5.2 Pharmacokinetic properties

Absorption

The relative bioavailability of Alivio is comparable to that of rapid release oxycodone with maximum plasma concentrations being achieved after approximately 3-5 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.

Biotransformation

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.

Linearity/non-linearity

Across the 5-80 mg dose range of prolonged release oxycodone tablets linearity of plasma concentrations was demonstrated in terms of rate and extent of absorption.

5.3 Preclinical safety data

In rat studies, oxycodone had no effect on fertility and embryonic development. However, in rabbits, at dose levels which produced maternal toxicity, a dose related increase in developmental variations was observed (increased number of presacral vertebrae, extra pairs of ribs). In a rat study on pre- and post-natal development, there were neither effects on physical, reflexological, and sensory developmental parameters nor on behavioural and reproductive indices

Data from genotoxicity studies with oxycodone reveal no special hazard for humans. Long-term studies on carcinogenicity have not been performed.

Oxycodone showed a clastogenic potential in some in vitro investigations. However, under in vivo conditions such findings were not observed, even at toxic doses. The results indicate that the mutagenic risk of oxycodone to humans at therapeutic concentrations may be ruled out with adequate certainty.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Sugar spheres (sucrose, maize starch)

Hypromellose

Talc

Ethyl cellulose Hydroxypropylcellulose Propylene glycol Carmellose sodium Cellulose, microcrystalline Magnesium stearate (Ph. Eur.)

Silica, colloidal anhydrous

Tablet coating:

Polyvinyl alcohol Titanium dioxide (E171)

Macrogol 3350 Iron oxide red (E172)

Talc

6.2 Incompatibilities

Not applicable.

Shelf life

3 years

10 DATE OF REVISION OF THE TEXT

18/11/2015