SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Carenoxa 80 mg prolonged-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains to 80 mg oxycodone hydrochloride equivalent to 71.7 mg oxycodone.

Excipient with known effect:

Each prolonged-release tablet contains a maximum of 24 mg sucrose.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Prolonged-release tablet

Yellow, biconvex, oblong prolonged-release tablets, with dimensions of 17.0/8.0/4.7 mm (l/w/h) to 17.5/8.5/5.4 mm (l/w/h) and 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. Carenoxa is indicated in adults and adolescents aged 12 years and older.

4.2

Adults and adolescents of 12 years of age and older:

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 adverse reactions.

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 strength other strengths of this medicinal product 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 Carenoxa after conversion from other opioids, with 50-75% of the calculated oxycodone hydrochloride dose.

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

Duration of administration

Carenoxa 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.

Special populations

Elderly patients

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

Patients with renal or hepatic impairment

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

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

Method of administration

For oral use.

Carenoxa should be taken twice daily based on a fixed schedule at the dosage determined.

The prolonged-release tablets (either whole or divided) may be taken with or independent of meals with a sufficient amount of liquid. Carenoxa must not be 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

4.5 Interaction with other medicinal products and other forms of interaction

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 hydrochloride 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 Carenoxa 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 Carenoxa can cause physical dependence. Withdrawal symptoms may occur following abrupt discontinuation of therapy. If therapy with oxycodone hydrochloride is no longer required it may be advisable to reduce the daily dose gradually in order to avoid the occurrence of a withdrawal syndrome.

Carenoxa 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 (especially talc) 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 hydrochloride (see section 4.9).

Alcohol

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

Special patient groups

Caution is required in elderly or debilitated patients, in patients with head injury, 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, disease of the biliary tract, biliary or ureteric colic, inflammatory bowel disorders, conditions with increased brain pressure, disturbances of circulatory regulation, epilepsy or seizure tendency and in patients taking MAO inhibitors within the last two weeks. Patients with severe hepatic impairment should be closely monitored.

Surgical procedures

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

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

Paediatric population

The safety and efficacy of Carenoxa in children younger than 12 years of age have not been established. Carenoxa should not be used in children younger than 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 ‘antidoping’ tests.

Use of Carenoxa 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.

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 hydrochloride, in particular respiratory depression.

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

Cimetidine and inhibitors of cytochrome P450-3A such as ketoconazole, voriconazole and erythromycin may 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 has no clinical relevance, however, strong CYP2D6-inhibitors (e.g. quinidine) 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 co-applied with Carenoxa.

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

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

4.6 Fertility, pregnancy and lactation

Pregnancy

Limited data on the use of oxycodone during pregnancy in humans reveal no evidence of an increased risk of congenital abnormalities. Oxycodone crosses the placenta. Animal studies with oxycodone have not revealed any teratogenic or embryotoxic effects.

Prolonged use of oxycodone during pregnancy can cause withdrawal symptoms in newborns. Use of oxycodone hydrochloride during labour can cause foetal respiratory depression. Oxycodone hydrochloride should only be used during pregnancy if the benefit outweighs the possible risks to the unborn child or neonate.

Breast-feeding

Oxycodone is excreted into breast milk. The milk/plasma concentration ratio was 3.4:1 and oxycodone effects in the suckling infant are therefore conceivable. A risk to the suckling child cannot be excluded in particular following intake of multiple doses of oxycodone hydrochloride by the breast-feeding mother. Breast-feeding should be discontinued during treatment with oxycodone hydrochloride.

Fertility

Oxycodone showed no effect on fertility in male and female rats (see section 5.3).

4.7 Effects on ability to drive and use machines

At the beginning of therapy and after dose adjustment, oxycodone hydrochloride can have major influence on the ability to drive and use machines. Alertness and reactivity can be impaired 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. In these circumstances oxycodone hydrochloride 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 hydrochloride 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. Frequencies are defined as:

Tabulated list of adverse reactions

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.

Endocrine disorders:

Uncommon:    Syndrome of inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders 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.

Eye disorders

Uncommon:    Lacrimation disorder, miosis

Cardiac disorders

Uncommon:    Supraventricular tachycardia.

Vascular disorders

Common:    Lowering of blood pressure, rarely accompanied by secondary

symptoms such as palpitations; syncope.

Uncommon:    vasodilatation

Respiratory, thoracic and mediastinal disorders

Common:    Respiratory depression, bronchospasm, dyspnoea.

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; anorexia.

Uncommon:    Biliary colics; oral ulcers; gingivitis; stomatitis; flatulence.

Rare: Gingival bleeding; increased appetite; tarry stool; tooth staining and damage; ileus.

Skin and subcutaneous tissue disorders Very common: Itching.

Common:    Skin eruptions including rash, in rare cases increased

photosensitivity, in isolated cases urticaria or exfoliative dermatitis

Uncommon Facial flushing

Rare Dry skin; herpes simplex.

Renal and urinary disorders

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:    Sweating, 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.

Opioid withdrawal syndrome:

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.

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 hydrochloride can be fatal.

The effects of overdose will be potentiated by the simultaneous ingestion of alcohol or other psychotropic drugs.

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.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose. 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.

Carenoxa will continue to release and add to the oxycodone load for up to 12 hours after administration and management of oxycodone overdose should be modified accordingly. 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 should be implemented.

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.

5.2 Pharmacokinetic properties

Absorption:

The relative bioavailability of Carenoxa is comparable to that of rapid release oxycodone with maximum plasma concentrations being achieved after approximately 3-4.5 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 hydrochloride release due to the damage of the prolonged release properties.

Distribution:

The absolute bioavailability of oxycodone is 60-87%. In steady state, the volume of distribution of oxycodone amounts to 2.6 l/kg and plasma protein binding to 38-45%; the elimination half-life to 4 to 6 hours and plasma clearance to 0.8 l/min.

Biotransformation:

Oxycodone is metabolised in the intestine and liver via the P450 cytochrome system to noroxycodone (CYP3A4) and oxymorphone (CYP2D6) as well as to several glucuronide conjugates. 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.

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.

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.

Patients with renal impairment

Preliminary data from a study ofpatients 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% 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

Oxycodone had no effect on fertility and early embryonic development in male and 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 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.

Long-term carcinogenic studies were not performed.

Oxycodone shows a clastogenic potential in in vitro assays. No similar effects were observed, however, under in vivo conditions, 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 Macrogol 6000 Talc

Ethylcellulose Hydroxypropylcellulose Propylene glycol Cellulose microcrystalline Magnesium stearate Silica, colloidal anhydrous

Tablet coating:

Hypromellose

Talc

Macrogol 6000 Titanium dioxide (E 171)

Iron oxide yellow (E 172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.5 Nature and contents of container

PVC/PVdC-aluminium blister with child-resistant closure Pack sizes:

10, 14, 20, 25, 28, 30, 40, 50, 56, 60, 98 and 100 prolonged-release tablets

HDPE bottles with PP child resistant screw caps Pack sizes:

20, 25, 28, 30, 50, 56, 98 and 100 prolonged-release tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

ACINO AG Am Windfeld 35 83714 Miesbach, Germany

8    MARKETING AUTHORISATION NUMBER(S)

PL 21806/0043

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/04/2013

10    DATE OF REVISION OF THE TEXT

29/04/2013