SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Onexila XL 80 mg prolonged-release tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 80 mg oxycodone hydrochloride equivalent to 71.75 mg oxycodone.

Excipient with known effect:

Each prolonged-release tablet contains a maximum of 40 mg sucrose.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Prolonged-release tablet.

White, oblonged, biconvex prolonged-release tablets with a diameter of 16.3 mm x 7.8 mm and with a breakline on both sides.

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. Onexila XL 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 once daily. Some patients may benefit from a starting dose of 5 mg to minimise the incidence of adverse reactions. For the lower starting dose other medicinal products with more appropriate strengths are available.

Patients already receiving opioids may start treatment with higher dosages 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 Onexila XL after conversion from other opioids, with 50-75% of the calculated oxycodone dose.

Dose adjustment

Some patients who take Onexila XL need rapid release analgesics as rescue medication in order to control breakthrough pain. Onexila XL is 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 Onexila XL. Use of the rescue medication more than twice daily indicates that the dose of Onexila XL needs to be increased. The dose should not be adjusted more often than once every 12 days until a stable once daily administration has been achieved.

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

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.

Duration of administration

Onexila XL 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.

Elderly patients

Elderly patients without clinical manifestation of impaired liver and/or kidney function usually do not require dose adjustments.

Risk patients

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.

Paediatric population

Children under 12 years of age

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

Method of administration For oral use.

Onexila XL should be taken once daily at the dosage determined.

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

4.3 Contraindications

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

Severe respiratory depression with hypoxia and/or hypercapnia.

Severe chronic obstructive pulmonary disease. Cor pulmonale.

Severe bronchial asthma.

Paralytic ileus.

Acute abdomen, delayed gastric emptying.

4.4 Special warnings and precautions for use

Caution is required in

-    elderly or debilitated patients,

-    patients with severe impairment of lung, hepatic or renal 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,

-    patients taking MAO inhibitors.

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

Surgical procedures

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.

The safety of Onexila XL used pre-operatively has not been established and cannot be recommended.

Respiratory and cardiac 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.

Tolerance and dependence

Long-term use of oxycodone 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 oxycodone 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.

Oxycodone has 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.

Abuse

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).

Alcohol

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

Special patient groups

Patients with severe hepatic impairment should be closely monitored.

Paediatric population

The safety and efficacy of Onexila XL in children aged 12 years and younger have not been established. Onexila XL should not be used in children aged 12 years and younger because of safety and efficacy concerns.

Anti-doping warning

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

Use of Onexila XL 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

•    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.

•    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 and inhibitors of cytochrome P450-3A such as ketoconazole, variconazole and erythromycin may inhibit the metabolism of oxycodone.

•    Monoaminooxidase (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 oxycodone.

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

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

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

Animal toxicology studies have not shown any effects on fertility (see section 5.3).

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. In these circumstances Onexila XL 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 Onexila XL 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 most serious adverse reaction, as with other opioids, is respiratory depression (see section 4.9). This is most likely to occur in elderly, debilitated or opioid-intolerant patients. In predisposed patients opioids can cause severe drop in blood pressure.

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)

Blood and lymphatic system disorders Rare: lymphadenopathy

Immune system disorders Uncommon:    hypersensitivity

Very rare:    anaphylactic reactions

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

Nervous system disorders

Very common: somnolence, dizziness, headache

Common:    paraesthesia

Uncommon:    both increased and decreased muscle tone, tremor, involuntary

muscle contractions, hypaesthesia, coordination disturbances, vertigo

Rare: seizures, in particular in epileptic patients or patients with tendency to convulsions, muscle spasm

Eye disorders

Uncommon:    lacrimation disorder, miosis, visual disturbances

Ear and labyrinth disorders Uncommon:    hyperacousis

Cardiac disorders

Common:    lowering of blood pressure, rarely accompanied by secondary

symptoms such as palpitations, syncope

Uncommon:    supraventricular tachycardia, vasodilatation

Vascular disorders

Common:    lowering of blood pressure, rarely accompanied by    secondary

symptoms such as palpitations, syncope

Uncommon:    supraventricular tachycardia, vasodilatation

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;

gastrointestinal disorders such as abdominal pain, diarrhoea, eructation, dyspepsia,

Uncommon:    oral ulcers, gingivitis, stomatitis, flatulence

Rare: gingival bleeding, increased appetite, melaena, tooth staining and damage, ileus

Hepatobiliary disorders

Uncommon:    biliary colics, hepatic enzyme increased

Skin and subcutaneous tissue disorders Very common: pruritus

Common:    skin eruptions including rash, in rare cases increased photosensitivity,

in isolated cases urticaria or exfoliative dermatitis

Rare: dry skin, herpes simplex

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

urinate)

Rare: haematuria

Reproductive system and breast disorders Uncommon:    reduced libido, impotence

Rare: amenorrhoea

General disorders and administration site conditions Common:    asthenia, hyperhydrosis, chills

Uncommon:    accidental injuries, pain (e.g. chest pain), malaise, oedema, migraine,

physical dependence with withdrawal symptoms

Rare: weight changes (increase or decrease), cellulitis

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

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.

Management

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) is possible. The rate of infusion should be adjusted to the previous bolus injections and the response of the patient.

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: 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 approved CR formulation of oxycodone for twice daily administration shows an apparent biphasic in vitro dissolution profile (dual-release formulation), with an initial release at 40 min accounting for 38% of the dose and a prolonged release fraction accounting for 62% of the dose. This biphasic delivery is not apparent with the newly developed once daily oxycodone PR formulation.

The plasma concentration-time curves of Onexila XL showed the typical pattern of a PR preparation for once daily dosing, which was characterised by an increase over 4 h, a plateau for approximately 10 h, followed by a gradual decline until 24 h after dosing. Thus, the intended more continuous plasma levels accompanied by lower peak-to-trough fluctuation in comparison to oxycodone CR bid were achieved with the new product.

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

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.

Linearitv/non-linearitv

Across the 10-80 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

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.

Oyxcodone showed no effect on fertility in male and female rats and early embryonic development in female rats in doses of up to 8 mg/kg body weight and induced no malformations in rats in doses of up to 8 mg/kg and in rabbits in doses of up to 125 mg/kg bodyweight. However, in rabbits, when individual foetuses were used in statistical evaluation, a dose related increase in developmental variations was observed (increased incidences of 27 presacral vertebrae, extra pairs of ribs). When these parameters were statistically evaluated using litters, only the incidence of 27 presacral vertebrae was increased and only in the 125 mg/kg group, a dose level that produced severe pharmacotoxic effects in the pregnant animals.

In a study on pre- and postnatal development in rats, F1 body weights were lower at 6 mg/kg/d when compared to body weights of the control group at doses which reduced maternal weight and food intake (NOAEL 2 mg/kg body weight). There were neither effects on physical, reflexological, and sensory developmental parameters nor on behavioural and reproductive indices. There were no effects on the F2 generation.

Long-term studies on the carcinogenic potential of oxycodone 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

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

Silica, colloidal anhydrous

Tablet coating:

Opadry® II White (consisting of polyvinyl alcohol, talc, titanium dioxide (E171), macrogol 3350)

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 perforated unit dose PVC/PE/PVDC-aluminium blisters consisting of a white opaque PVC/PE/PVDC laminated foil and an aluminium foil.

Pack sizes: 10, 14, 20, 28, 30, 50, 56, 60, 98 and 100 prolonged-release tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

Rivopharm UK Ltd.

30^th Floor 40 Bank Street Canary Wharf London E14 5NR United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 33155/0046

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/08/2016

10    DATE OF REVISION OF THE TEXT

25/08/2016