Document: Oxycodone Vitabalans film-coated tablet ENG SmPC change

• Oxycodone Vitabalans film-coated tablet SmPC
• Oxycodone Vitabalans film-coated tablet ENG SmPC

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Oxycodone Vitabalans 5 mg film-coated tablets

Oxycodone Vitabalans 10 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5 mg or 10 mg oxycodone hydrochloride.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Film-coated tablet.

5 mg: white, round, convex tablet, diameter 6 mm.

10 mg: white, round, convex tablet, with score on one side, diameter 8 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.

4.2 Posology and method of administration

Posology

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

Adults and adolescents (≥ 12 years of age)

Dose titration and adjustment

The usual starting dose for opioid naive patients is 5 mg every 6 hours. The dose may be increased in steps of 25% to 50% of the respective dose. The aim is a patient-specific dosage which allows for adequate analgesia with tolerable undesirable effects. Therefore, the dosing interval may be shortened to 4 hours if needed. However, Oxycodone Vitabalans should be taken no more often than 6 times a day.

Some patients receiving modified-release oxycodone medication according to a fixed time schedule may require immediate-release analgesics as rescue medication for the management of breakthrough pain. Oxycodone Vitabalans is appropriate for the management of breakthrough pain. Single doses of the rescue medication should be adjusted based on the patients’ individual requirements. In general, 1/8 to 1/6 of the daily modified-release oxycodone dose is appropriate.

The requirement of rescue medication more than twice daily may indicated that higher doses of modified-release oxycodone are necessary. The aim is to establish a patient-specific dosage which ensures adequate analgesia with tolerable undesirable effects and as low rescue medication as possible for as long as pain medication is necessary in patients receiving modified-release oxycodone treatment twice daily.

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

10-13 mg oxycodone hydrochloride corresponds to approximately 20 mg morphine sulphate, both in the film-coated formulation.

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

In generall, patients should be titrated individually until pain relief is achieved, provided that undesirable adverse events can be adequately managed.

If long-term pain treatment is required, the patients should be switched to oxycodone hydrochloride modified-release tablets.

Duration of treatment

Oxycodone 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.

Special populations

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 naïve. Therefore the lowest recommended dosage, i.e. 5 mg, may not be suitable as a starting dose.

Dose titration should be performed in accordance with the individual clinical situation.

Elderly patients

The lowest dose should be administered with careful titration to pain control.

Paediatric population

Oxycodone hydrochloride film-coated tablets are not recommended for children under 12 years of age.

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.

Method of administration

Oxycodone Vitabalans film-coated tablets should be taken every 4-6 hours based on a fixed schedule at the dosage determined.

The film-coated tablets may be taken with or independent of meals with a sufficient amount of liquid.

Oxycodone Vitabalans film-coated tablets should not be used with alcoholic bevarages.

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 respiratory depression with hypoxia and/or hypercapnia,

• severe chronic obstructive pulmonary disease,

• severe bronchial asthma,

• cor pulmonale,

• elevated carbon dioxide levels in the blood,

• paralytic ileus,

• acute abdomen, delayed gastric emptying.

4.4 Special warnings and precautions for use

The major risk of opioid excess is respiratory depression. The respiratory depressant effect of oxycodone can lead to increased carbon dioxide concentrations in blood and hence in cerebrospinal fluid. 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 (adrenal insufficiency), toxic psychosis, prostate hypertrophy, adrenocortical insufficiency, alcoholism, known opioid dependence, delirium tremens, pancreatitis, inflammatory bowel disorders, disease of the biliary tract, biliary or ureteric colic, hypotension, hypovolaemia, head injury (due to risk of increased intracranial pressure), disturbances of circulatory regulation, epilepsy or seizure tendency and patients taking MAO inhibitors.

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.

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. Prolonged use of Oxycodone Vitabalans may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. Withdrawal symptoms may include yawning, mydriasis, lacrimation, rhinorrhoea, tremor, hyperhidrosis, anxiety, agitation, convulsions and insomnia.

However, when used as intended the risk of developing physical or psychological dependence is markedly reduced. There are no data available on the actual incidence of psychological dependence in chronic pain patients.

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. Oxycodone Vitabalans should be used with particular care in patients with a history of alcohol and drug abuse.

In case of abusive parenteral injection the tablet excipients may lead to necrosis of the local tissue, granulomas of the lung or other serious, potentially fatal events. The parenteral administration of Oxycodone Vitabalans film-coated tablets may result in a potentially fatal dose of oxycodone (see section 4.9).

Surgical procedures

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

Oxycodone Vitabalans should be used with caution pre-operatively and within the first 12-24 hours post-operatively.

Paediatric population

Oxycodone hydrochloride have not been studied in children and adolescents below 12 years of age. The safety and efficacy of the tablets have not been demonstrated and the use in children and adolescents below 12 years of age is therefore not recommended.

Patients with severe hepatic impairment

Patients with severe hepatic impairment should be closely monitored.

Alcohol

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

4.5 Interaction with other medicinal products and other forms of interaction

There can be an enhanced Central nervous system depressants effect during concomitant therapy with drugs which affect the CNS such as other opioids, sedatives, hypnotics, anti-depressants, antipsychotics, anaesthetics, muscle relaxants, antihistamines and antiemetics.

MAO inhibitors are known to interact with opioid analgesics. MAO-inhibitors cause 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).

The effect of other relevant isoenzyme inhibitors on the metabolism of oxycodone is not known. Potential interactions should be taken into account. The potential effect of oxycodone on cytochrome P450-enzymes has not been studied in vitro or in vivo.

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

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

Alcohol can enhance the adverse reactions of oxycodone, in particular respiratory depression.

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 drugs or dietary elements.

CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin and telithromycin), azol-antifungals (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:

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:

Drugs 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 Normalized Ratio (INR) in both directions have been observed in individuals if coumarin anticoagulants are co-applied with Oxycodone Vitabalans tablets.

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 womenOxycodone crosses the placenta. 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. Animal studies with oxycodone have not revealed any teratogenic or embryotoxic effects. Oxycodone should only be used during pregnancy if the benefit outweighs the possible risks to the unborn child or neonate.

Breast-feeding

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 studies do not indicate that oxycodone hydrochloride may influence fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Oxycodone Vitabalans may impair the ability to drive and use machines.

Oxycodone can impair alertness and reactivity to such an extent that the ability to drive and operate machinery is affected or ceases altogether.

With stable therapy, a general ban on driving a vehicle is not necessary. The treating physician must assess the individual situation.

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

The adverse reactions considered at least possibly related to treatment are listed below by system organ class and absolute frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The following frequency categories form the basis for classification of the undesirable effects:

• 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: anaphylactic reactions, hypersensitivity, allergic reactions.

Endocrine disorders

uncommon: syndrome of inappropriate anti-diuretic hormone secretion.

Metabolism and nutrition disorders

common: anorexia, decreased appetite.

uncommon: dehydration.

Psychiatric disorders

common: anxiety, confusional state, depression, insomnia, nervousness, abnormal thinking, euphoric mood, lethargy.

uncommon: agitation, affect lability, decreased libido, depersonalisation, hallucinations, visual disturbances, hyperacousis, drug dependence (see section 4.4).

frequency unknown: aggression.

Nervous system disorders

very common: somnolence, dizziness, headache.

common: tremor.

uncommon: amnesia, convulsion, hypertonia, hypoaesthesia, involuntary muscle contractions, speech disorder, syncope, paraesthesia, dysgeusia, coordination disturbances.

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

frequency unknown: hyperalgesia.

Eye disorders

uncommon: lacrimation disorder, miosis, visual impairment.

Ear and labyrinth disorders

uncommon: vertigo.

Cardiac disorders

uncommon: supraventricular tachycardia, palpitations (in the context of withdrawal syndrome).

Vascular disorders

uncommon: vasodilatation.

rare: hypotension, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders

common: dyspnoea,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), abdominal pain, diarrhoea, eructation, dyspepsia.

uncommon: dysphagia, oral ulcers, gingivitis, stomatitis, flatulence.

rare: gum bleeding, increased appetite, tarry stool, tooth staining and damage, ileus.

frequency unknown: dental caries.

Hepatobiliary disorders

uncommon: increased hepatic enzymes.

frequency unknown: cholestasis, biliary colic.

Skin and subcutaneous tissue disorders

very common: pruritus.

common: rash, hyperhidrosis.

rare: dry skin, manifestations of herpes simplex, increased photosensitivity.

very rare: urticaria or exfoliative dermatitis.

Renal and urinary disorders

common: micturition disturbances.

uncommon: urinary retention.

rare: haematuria.

Reproductive system and breast disorders

uncommon: erectile dysfunction.

rare: amenorrhoea.

General disorders and administration site conditions

common: asthenic conditions.

uncommon: chills, accidental injuries, pain (e.g. chest pain), malaise,oedema, peripheral oedema, migraine, drug withdrawal syndrome, drug tolerance, thirst.

rare: weight changes (increase or decrease), cellulitis.

Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, hypotonia, miosis, bradycardia, hypotension, circulatory collapse, non-cardiogenic lung oedema, and death.

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.

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 balances.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Natural opium alkaloids

ATC-Code: N02A A05

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.

5.2 Pharmacokinetic properties

Correlation between dose and plasma concentrations of oxycodone, as well as correlation between concentration and certain expected opioid effects has been demonstrated.

Absorption

The bioavailability following oral administration of oxycodone is 60-87 %. Maximum plasma concentration is reached after approximately one hour and effect lasts approximately six hours.

Distribution

Following absorption, the active substance is distributed throughout the body. 38 % of the compound is bound to plasma proteins and the volume of distribution in steady state is 2.6 l/kg; the elimination half-life is 3.2 – 5.1 hours and plasma clearance is 0.8 l/min.

Biotransformation

Oxycodone is metabolised in the intestine and liver to noroxycodone and oxymorphone as well as to several glucuronide conjugates. CYP3A and CYP2D6 are probably involved in the formation of noroxycodone and oxymorphone respectively. Oxymorphone has some analgesic activity but is present in the plasma in low concentrations and is not considered to contribute to oxycodone's pharmacological effect.

Elimination

Oxycodone and its metabolites are excreted via urine. Faecal excretion has not been studied.

5.3 Preclinical safety data

Studies showed that 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 and in rabbits in doses of 125 mg/kg bodyweight. However, in rabbits, when individual fetuses 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 carcinogenicity studies with oxycodone have not been 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 Vitabalans to humans at therapeutic concentrations may be ruled out with adequate certainty.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Cellulose, microcrystalline

Starch, pregelatinised (maize)

Magnesium stearate

Tablet coating:

Polydextrose

Hypromellose

Titanium dioxide (E171)

Macrogol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

30 and 100 tablets in blister (PVC/Al).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Vitabalans Oy

Varastokatu 8

FI-13500 Hämeenlinna

FINLAND

Tel: +358 3 615 600

Fax: +358 3 618 3130

8. MARKETING AUTHORISATION NUMBER(S)

To be completed nationally.

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

2012-05-03

10. DATE OF REVISION OF THE TEXT

2015-06-02