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ALIVIO 10 MG PROLONGED-RELEASE TABLETS

Active substance(s): OXYCODONE HYDROCHLORIDE / OXYCODONE HYDROCHLORIDE

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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 naïve 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 naïve 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 (½ glass of water).
Alivio must not be taken broken, chewed or crushed.
Alivio should not be used with alcoholic beverages.

4.3

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






4.4

Severe bronchial asthma
Severe respiratory depression with hypoxia
Elevated carbon dioxide levels in the blood
Paralytic ileus

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 sucraseisomaltase 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 MAOinhibitors 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








4.6

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.

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 rapidrelease 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.

6.3

Shelf life
3 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
Child resistant white opaque PVC/PE/PVDC-aluminium perforated unit dose blisters.
HDPE bottles with PP child-resistant closure.
Pack sizes:
10x1, 14x1, 20x1, 28x1, 30x1, 50x1, 56x1, 98x1, 100x1 prolonged-release tablets in
blister.
10, 20, 30, 50, 100 prolonged-release tablets in HDPE bottles.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Bristol Laboratories Ltd,
Unit 3, Canalside,
Northbridge Road, Berkhamsted,
Hertfordshire, HP4 1EG,
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 17907/0559

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
15/09/2015

10

DATE OF REVISION OF THE TEXT
18/11/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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