OXYACT 20 MG FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Oxyact 20 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20 mg oxycodone hydrochloride equivalent to 17.93 mg oxycodone.

Excipients with known effect:

Each film-coated tablet contains 87 mg lactose (as monohydrate) and 0.35 mg soya lecithin.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Light blue, vaulted, oblong film-coated tablets with break score on both sides. The tablet can be divided into equal halves.

Length: 12.1 mm

Thickness: 3.5 mm

Width: 5.2 mm

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Severe pain, which requires opioid analgesics to be adequately managed.

4.2 Posology and method of administrationPosology

The dose depends on the pain intensity and the patient’s indi­vidual susceptibility to the treatment.

For doses not realisable/prac­ticable with this strength other strengths of this medicinal product are available.

The following general dose recommendations apply:

Adults and adolescents (> 12 years of age)

Dose titration and adjustment

The initial dose for opioid-naive patients is usually 5 mg oxycodone hydrochloride given at intervals of every 6 hours. The dose may be increased in steps of 25% to 50% of the respective dose. The aim is a patient-specific dose which allows for adequate analgesia with tolerable undesirable effects. Therefore, the dosing interval may be shortened to 4 hours if needed. However, Oxyact should not be taken more often than 6 times a day.

Some patients receiving prolonged-release oxycodone medicinal products according to a fixed time schedule may require immediate-release analgesics as rescue medication for the management of breakthrough pain. Oxyact 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 prolonged-release oxycodone dose is appropriate.

The requirement of rescue medication more than twice daily may indicate that higher doses of prolonged-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 prolonged-release oxycodone treatment twice daily.

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

10–13 mg oxycodone hydrochloride correspond 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 general, 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 prolonged-release tablets.

Oxycodone hydrochloride should not be taken longer than necessary. If longterm 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 without clinical manifestation of impaired liver and/or kidney function usually do not require dose adjustments.

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 his/her clinical situation.

Other patients at risk

Patients with low body weight or slow metabolisers who are also opioid naïve, should initially be treated with half the dose usually recommended for adults.

Paediatric population

The safety and efficacy of Oxyact in children under 12 years of age has not been established. Therefore use of Oxyact is not recommended in this age group.

Oral Use

Oxyact 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.

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

4.3 Contraindications

Hypersensitivity to the active substance, peanut or soya 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

cor pulmonale

severe bronchial asthma

paralytic ileus

acute abdomen, delayed gastric emptying

4.4 Special warnings and precautions for use

Caution should be exercised in

elderly or debilitated patients,

patients with severe impairment of lung,

patients with impaired liver or kidney 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 and

in patients taking MAO inhibitors.

Opioids, such as oxycodone hydrochloride, 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 manifest from these hormonal changes.

Respiratory depression

The major risk of opioid excess is respiratory depression.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

Concomitant use of Oxyact and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Oxyact concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation.

In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Paralytic ileus

In case of paralytic ileus or suspicion thereof Oxyact should be discontiuned straight away.

Tolerance and dependence

The patient may develop tolerance to the medicinal product with chronic

use and require progressively higher doses to maintain pain control.

Oxycodone hydrochloride has a primary dependence potential. 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.

Prolonged use of oxycodone hydrochloride 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 withdrawal symptoms. 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 opioid agonists. Oxycodone may be sought and abused by people with latent or manifest addictive disorders. There is potential for the development of psychological dependence [addiction] to opioid analgesics, including oxycodone. Oxyact 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, which may be fatal.

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.

Oxyact is not recommended for pre-operative use and within the first 1224 hours post-operatively.

Patients with severe hepatic impairment

Patients with severe hepatic impairment should be closely monitored.

Alcohol

The intake of oxycodone hydrochloride with alcoholic beverages has to be avoided as alcohol may enhace the frequency of adverse reactions.

Lactose

Oxyact contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Soya

Oxyact contains soya. If you are allergic to peanut or soya, do not use this medicinal product.

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 CNS depressant effect of oxycodone, in particular respiratory depression.

Concomitant administration of oxycodone with serotonin agents, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) may cause serotonin toxicity. The symptoms of serotoin toxicity may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). Oxycodone should be used with caution and the dosage may need to be reduced in patients using these medications.

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

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 can inhibit the metabolism of oxycodone.

Monoaminoxidase (MAO) inhibitors are known to interact with narcotic analgesics, producing CNS excitation or depression with hyper-or hypotensive crisis. 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).

Clinically relevant changes in International Normalized Ratio (INR) in both directions have been observed in individuals if coumarin

anticoagulants are co-applied with Oxyact.

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), azole-type antifungals (e.g. ketoconazole, voriconazole, itraconazole, and posaconazole), protease inhibitors (e.g. boceprevir, ritonavir, indinavir, nelfinavir and saquinavir), cimetidine and grapefruit juice may reduce the clearance of oxycodone which could result in an increase of oxycodone plasma concentrations. Therefore the oxycodone dose may need to be adjusted accordingly.

Some specific examples are provided below:

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

Telithromycin, a CYP3A4 inhibitor, administered as 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 timeshigher (range 1.1 – 2.1).

CYP3A4 inducers, such as rifampicin, carbamazepine, phenytoin and St John's Wort may induce the metabolism of oxycodone and cause an increased clearance of oxycodone which could result in a reduction of oxycodone plasma concentrations. 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 3757%).

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.

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.

4.6 Fertility, pregnancy and lactation

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

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 newborns of mothers undergoing treatment with oxycodone.

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

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

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

The medicine is likely to affect your ability to drive

Do not drive until you know how the medicine affects you

It is an offence to drive while under the influence of this medicine

However, you would not be committing an offence (called ‘statutory defence’) if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

4.8 Undesirable effects

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.

Very common

Common

Uncommon

Rare

Very rare

Frequency unknown

> 1/10

> 1/100 to < 1/10

> 1/1,000 to < 1/100

> 1/10,000 to < 1/1,000

< 1/10,000

cannot be estimated from the available data

Rare: Herpes simplex

Immune system disorders:

Uncommon:

hypersensitivity

Frequency unknown: anaphylactic responses

Blood and lymphatic system disorders

Rare: lymphadenopathy

Endocrine disorders

Uncommon: syndrome of inappropriate antidiuretic hormone secretion

Metabolism and nutrition disorders

Common: decreased appetite up to loss of

appetite Uncommon: dehydration

Rare: Increased appetite

Psychiatric disorders

Common: Altered mood and personality change (e.g. anxiety, depression), decreased activity, restlessness, psychomotor hyperactivity, nervousness, insomnia, abnormal thinking, confusional state

Uncommon: Agitation, affect lability, euphoric mood, perception disturbances (e.g. hallucinations, depersonalisation), decreased libido, drug dependence (see section 4.4) Frequency unknown: aggression

Nervous system disorders

Very common: somnolence, dizziness, headache Common: tremor

Uncommon: amnesia, concentration impaired, convulsions (especially in persons with epileptic disorder or predisposition to convulsions), migraine, hypertonia, hypoaesthesia, involuntary muscle contractions, abnormal coordination, speech disorder, syncope, paraesthesia, dysgeusia

Frequency unknown: hyperalgesia

Eye disorders

Uncommon: visual impairment, miosis

Uncommon: Hearing impaired, vertigo.

Cardiac disorders

Uncommon: palpitation (in the context of withdrawal syndrome), tachycardia

Vascular disorders

Uncommon:

vasodilatation

Rare: hypotension, orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Common: dyspnoea

Uncommon: Dysphonia, cough, respiratory depression

Gastrointestinal disorders

Very common: constipation, nausea, vomiting

Common: dry mouth, rarely accompanied by thirst and difficulty swallowing; hiccups, abdominal pain, diarrhoea, dyspepsia Uncommon: dysphagia, oral ulcers, gingivitis, stomatitis, flatulence, eructation, ileus

Rare: gingival bleeding, melaena, tooth disorders Frequency unknown: dental caries

Hepatobiliary disorders

Uncommon: increase hepatic enzymes

Frequency unknown: cholestasis, biliary colic

Skin and subcutaneous tissue disorders

Very common: pruritus

Common: skin reactions/rash, hyperhidrosis Uncommon: dry skin Rare: urticaria

Renal and urinary disorders

Common: Dysuria, micturition urgency

Uncommon: Urinary retention

Reproductive system and breast disorders

Uncommon: reduced libido, erectile dysfunction, hypogonadism Frequency unknown: amenorrhoea

General disorders and administration site conditions

Common: asthenic conditions

Uncommon: chills, malaise, pain (e.g. chest pain), oedema, peripheral oedema, physical dependence with withdrawal symptoms, drug tolerance, thirst

Rare: weight changes (increase or decrease)

Frequency unknown: drug withdrawal syndrome neonatal

Uncommon: Accidental injury

For infants born to mothers receiving oxycodone see section

4.6. 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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard,

or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 OverdoseSymptoms

Acute overdose with oxycodone can be manifested by miosis, respiratory depression, somnolence progressing to stupor or coma, reduced skeletal muscle tone and drop in blood pressure. In severe cases circulatory collapse, bradycardia and non-cardiogenic lung oedema may occur; abuse of high doses of strong opioids such as oxycodone can be fatal.

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.

In case of overdose, intravenous administration of an opioid 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 sodium chloride 9 mg/ml (0.9%)or glucose 50 mg/ml (5%) 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. The adminsitration of activated charcoal (50 g for adults, 10 –15 g for children) should be considered within 1 hour, 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 film-coated 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

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 propertiesAbsorption

Maximum oxycodone plasma concentrations are achieved after approximately 1 to 1.5 hours after the intake. Plasma concentrations are linear within a dose range of 5 to 20 mg.

The absolute oral bioavailability of oxycodone is up to 87% with an elimination half-life of about 3 hours.

Oxycodone is metabolised in the intestine and liver via the cytochrome P450 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.

Oxycodone and its metabolites are excreted via urine and faeces. Oxycodone crosses the placenta and is found in breast milk.

The 5, 10 and 20 mg film-coated tablets are dose-proportional with regard to the amount of active substance absorbed as well as comparable with regard to the rate of absorption.

5.3 Preclinical safety data

Non-clinical data based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity reveal no special hazards for humans beyond those already outlined in other sections of the SmPC.

Oxycodone showed 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 peri- 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Sodium starch glycolate type A

Lactose monohydrate

Cellulose, microcrystalline Colloidal anhydrous silica Magnesium stearate

Tablet coating

Polyvinyl alcohol

Talc

Titanium dioxide (E 171)

Macrogol 3350

Lecithin, soya (E 322)

Indigo carmine, aluminium lake (E 132)

Iron oxide yellow (E 172) (20 mg film-coated tablets only)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 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 PVC/PVdC//aluminium blisters containing 10, 20, 30, 56 and 60, film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

G.L. Pharma GmbH, Schlossplatz 1, 8502 Lannach, Austria

8 MARKETING AUTHORISATION NUMBER(S)

PL 21597/0043