RENOCONTIN 30 MG PROLONGED-RELEASE TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Renocontin 30 mg prolonged-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 30 mg oxycodone hydrochloride corresponding to 26.9 mg oxycodone.

Excipients with known effect:

Each prolonged-release tablet contains 36 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet

Brown, round, biconvex, prolonged-release tablets with a diameter of 6.9 – 7.3 mm and a height of 3.2 – 3.9 mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Severe pain, which can be adequately managed only with opioid analgesics.

Renocontin is indicated in adults and adolescents aged 12 years and older.

4.2 Posology and method of administration

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 of age and older

Dose titration and adjustment

In general, the initial dose for opioid naïve patients is 10 mg oxycodone hydrochloride given at intervals of 12 hours. Some patients may benefit from a starting dose of 5 mg oxycodone hydrochloride to minimize 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.

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

Some patients who take Renocontin following a fixed schedule need rapid release analgesics as rescue medication in order to control breakthrough pain. Renocontin 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 Renocontin. Use of the rescue medication more than twice daily indicates that the dose of Renocontin 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. Doses in excess of 1000mg have been recorded.

Conversion from oral morphine

According to well-controlled clinical studies 10–13 mg oxycodone hydrochloride correspond to approximately 20 mg morphine sulphate, both in the prolonged-release formulation.

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

Controlled pharmacokinetic studies in elderly patients (aged over 65 years) have shown that, compared with younger adults, the clearance of oxycodone is only slightly reduced. No untoward adverse drug reactions were seen based on age, therefore adult doses and dosage intervals are appropriate.

Risk patients, for example patients with low body weight or slow metabolism of medicinal products, should initially half the recommended adult dose if they are opioid naïve.

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.

The dose initiation should follow a conservative approach as the plasma concentration may be increased 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.

Opioids are not first line therapy for chronic non-malignant pain, nor are they recommended as the only treatment. Types of chronic pain which have been shown to be alleviated by strong opioids include chronic osteoarthritic pain and intervertebral disc disease. The need for continued treatment in non-malignant pain should be assessed at regular intervals.

Oxycodone has not been studied in children younger than 12 years of age. The safety and efficacy of Renocontin have not been demonstrated and the use in children younger than 12 years of age is therefore not recommended.

For oral use.

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

The prolonged-release tablets may be taken with or independent of meals with a sufficient amount of liquid. Renocontin must be swallowed whole, not chewed, divided or crushed. Taking chewed, divided or crushed Renocontin tablets may lead to a rapid release and absorption of a potentially fatal dose of oxycodone.

Renocontin should not be taken with alcoholic beverages.

Duration of treatment

Renocontin 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.

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.

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 elevated carbon dioxide levels in the blood (hypercapnia).

Severe chronic obstructive pulmonary disease.

Cor pulmonale.

Severe bronchial asthma.

Paralytic ileus.

Acute abdomen, delayed gastric emptying.

Head injury.

Moderate to severe hepatic impairment.

Severe renal impairment (creatinine clearance <10 ml/min).

Chronic constipation.

Concurrent administration of monoamine oxidase inhibitors or within 2 weeks of discontinuation of their use.

4.4 Special warnings and special precautions for use

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.

Oxycodone 60mg, 80mg and 120mg tablets should not be used in patients not previously exposed to opioids. These tablet strengths may cause fatal respiratory depression when administered to opioid naïve patients.

For appropriate patients who suffer with chronic non-malignant pain, opioids should be used as part of a comprehensive treatment programme involving other medications and treatment modalities. A crucial part of the assessment of a patient with chronic non-malignant pain is the patient's addiction and substance abuse history.

If opioid treatment is considered appropriate for the patient, then the main aim of treatment is not to minimise the dose of opioid but rather to achieve a dose which provides adequate pain relief with a minimum of side effects. There must be frequent contact between physician and patient so that dosage adjustments can be made. It is strongly recommended that the physician defines treatment outcomes in accordance with pain management guidelines. The physician and patient can then agree to discontinue treatment if these objectives are not met.

Long-term use of Renocontin 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 Renocontin 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.

Withdrawal symptoms may include restlessness, perspiration, chills, myalgia, palpitations, yawning, mydriasis, lacrimation, rhinorrhoea, tremor, hyperhidrosis, anxiety, agitation, convulsions and insomnia. Other symptoms also may develop, including: irritability, backache, joint pain, weakness, abdominal cramps, nausea, anorexia, vomiting, diarrhoea, or increased blood pressure, respiratory rate or heart rate.

Hyperalgesia that will not respond to a further dose increase of oxycodone may occur, particularly in high doses. An oxycodone dose reduction or change to an alternative opioid may be required.

Renocontin 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.

Oxycodone has an abuse profile similar to other strong 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 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 other serious adverse events, such as local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, which may be fatal.

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

Caution is required in elderly or debilitated patients, in patients with severe impairment of lung, hepatic or renal function, myxoedema, hypothyroidism, Addison’s disease (adrenal insufficiency), intoxic psychosis (e.g. alcohol), prostatic hypertrophy, adrenocortical insufficiency, alcoholism, known opioid dependence, delirium tremens, pancreatitis, disease of the biliary tract, biliary or renalcolic, inflammatory bowel disorders, raised intracranial pressure, hypotension, hypovolemia, epilepsy or seizure tendency and in patients taking MAO inhibitors within the last two weeks. Patients with severe hepatic impairment should be closely monitored.

Oxycodone should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, oxycodone should be discontinued immediately.

Special care should be taken when oxycodone is applied to patients undergoing bowel-surgery as opioids are known to impair intestinal motility. Opioids should only be administered post-operatively when the bowel function has been restored.

The safety of Renocontin used pre-operatively has not been established.

Renocontin is not recommended for pre-operative use or within the first 12 – 24 hours post operatively.

Patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive oxycodone tablets for 12 hours prior to the intervention. If further treatment with oxycodone tablets is indicated then the dosage should be adjusted to the new post-operative requirement.

The safety and efficacy of Renocontin in children younger than 12 years of age have not been established. Renocontin should not be used in children younger than 12 years of age because of safety and efficacy concerns.

As with other opioids, infants who are born to dependent mothers may exhibit withdrawal symptoms and may have respiratory depression at birth.

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

Use of Renocontin as a doping agent may become a health hazard.

To avoid damage to the controlled release properties of the tablets the prolonged release tablets must be swallowed whole, not chewed, divided or crushed. The administration of chewed, divided or crushed prolonged-release tablets leads to rapid release and absorption of a potentially fatal dose of oxycodone (see section 4.9).

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

Concomitant use of oxycodone 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 Oxycodone 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).

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.

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

4.5 Interaction with other medicinal products and other forms of interaction

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

Medicinal products affecting the central nervous system (CNS) include non-benzodiazepine-containing sedatives, hypnotics, antipsychotics, antidepressants, antihistamines, antiemetics and other opioids.

Alcohol may enhancejhe pharmacodynamics effects of Renocontin; concomitant use should be avoided.

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 serotonin 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.

Anticholinergic drugs (e.g. psychotropic drugs, tricyclic antidepressants, antihistamines, antiemetics, muscle relaxants, Parkinson's disease drugs) may increase anticholinergic side effects of Oxycodone, such as constipation, dry mouth, or difficulty urinating.

Renocontin should be used with caution in patients who have used or received MAO inhibitors in the last two weeks.

Clinically relevant changes in International Normalised Ratio (INR) in both directions have been observed in individuals if coumarin anticoagulants are co-applied with oxycodone.

Oxycodone is metabolised mainly by CYP3A4, with a contribution from CYP2D6. The activities of these metabolic pathways may be inhibited or induced by various coadministered drugs or dietary elements.

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

Itraconazole, a potent CYP3A4 inhibitor, administered 200 mg orally for five days, increased the AUC of oral oxycodone. On average, the AUC was approximately 2.4 times higher (range 1.5 – 3.4).

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

Telithromycin, a CYP3A4 inhibitor, administered 800 mg orally for four days, increased the AUC of oral oxycodone. On average, the AUC was approximately 1.8 times higher (range 1.3 – 2.3).

Grapefruit Juice, a CYP3A4 inhibitor, administered as 200 ml three times a day for five days, increased the AUC of oral oxycodone. On average, the AUC was approximately 1.7 times higher (range 1.1 – 2.1).

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 that could cause a reduction of the plasma concentrations of oxycodone. The oxycodone dose may need to be adjusted accordingly. Some specific examples are provided below:

St John’s Wort, a CYP3A4 inducer, administered as 300 mg three times a day for fifteen days, reduced the AUC of oral oxycodone. On average, the AUC was approximately 50% lower (range 37–57%).

Rifampicin, a CYP3A4 inducer, administered as 600 mg once-daily for seven days, reduced the AUC of oral oxycodone. On average, the AUC was approximately 86% lower

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.

4.6 Pregnancy and lactation

Pregnancy

Oxycodone is not recommended for use in pregnancy nor during labour. 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.

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.

4.7 Effects on ability to drive and use machines

Oxycodone may impair the ability to drive and use machines. This is particularly likely at the initiation of treatment with Renocontin, after dose increase or product rotation and if Renocontin is combined with other CNS depressant agents.

Patients stabilised on a specific dose will not necessarily be restricted. Therefore, the physician should decide whether the patient is allowed to drive or use machinery.

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

Summary of the safety profile

Due to its pharmacological properties oxycodone may cause respiratory depression, miosis, bronchial spasm and spasm of unstriated muscles and may suppress the cough reflex.

The most frequently reported undesirable effects are nausea (especially at the beginning of treatment) and constipation.

Respiratory depression is the chief hazard of an opioid overdose and occurs most commonly in elderly or debilitated patients.

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)

Rare:                                H­erpes simplex

Uncommon:

Hypersensitivity

Anaphylactic responses, anaphylactoid

Not known:

reaction

Metabolism and nutrition disorders

Cardiac disorders

Vascular disorders

Respiratory, thoracic and mediastinal disorders

Gastrointestinal disorders

Skin and subcutaneous tissue disorders

Reproductive system and breast disorders

General disorders and administration site conditions

5   PHARMACOLOGICAL PROPERTIES

7   MARKETING AUTHORISATION HOLDER

8 MARKETING AUTHORISATION NUMBER(S)

PL 25258/0221

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

26/09/2018