Reltebon 80 mg prolonged-release tablets

1. Name of the medicinal product

Reltebon 80 mg prolonged-release tablets

 

2. Qualitative and quantitative composition

Each prolonged-release tablet contains 80 mg oxycodone hydrochloride corresponding to 72 mg of oxycodone.

Excipient with known effect:

The prolonged-release tablets contain lactose monohydrate.

Each prolonged-release tablet contains 63.2 mg lactose monohydrate

For the full list of excipients, see section 6.1.

 

3. Pharmaceutical form

Prolonged-release tablet.

Green, round, biconvex tablets, 9 mm in diameter, with 'OX 80' debossed on one side.

 

4. Clinical particulars

4.1 Therapeutic indications

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

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

 

4.2 Posology and method of administration

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with oxycodone hydrochloride in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

Posology

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

Adults and adolescents 12 years 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 to minimize the incidence of side effects.

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 these strengths, other strengths 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 Reltebon prolonged-release tablets after conversion from other opioids, with 50-75% of the calculated oxycodone dose.

Some patients who take Reltebon prolonged-release tablets following a fixed schedule need rapid release analgesics as rescue medication in order to control breakthrough pain. Reltebon prolonged-release tablets 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 Reltebon prolonged-release tablets. Use of the rescue medication more than twice daily indicates that the dose of Reltebon prolonged-release tablets 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 individual balancing efficacy with the tolerance and risk of undesirable effects.

Use in non-malignant pain

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.

Duration of administration

Reltebon prolonged-release tablets 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.

Paediatric population

There have been no studies in patients under 12 years of age, therefore oxycodone hydrochloride should not be used in patients under 12 years.

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.

Elderly patients

A dose adjustment is not usually necessary in elderly patients.

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.

Risk patients

Risk patients, for example patients with low body weight or slow metabolism of medicinal products, should initially receive half the recommended adult dose if they are opioid naïve. Dose titration should be performed in accordance with the individual clinical situation.

For instructions how to open the child resistant blisters, see section 6.6.

Method of administration

For oral use.

Reltebon prolonged-release tablets 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. Reltebon prolonged release tablets must be swallowed whole and not broken, chewed or crushed.

 

4.3 Contraindications

- Hypersensitivity to oxycodone 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.

- Elevated carbon dioxide levels in the blood.

- Paralytic ileus.

- Acute abdomen, delayed gastric emptying.

- Moderate to severe hepatic impairment

- Chronic constipation

 

4.4 Special warnings and precautions for use

Paediatric population

Reltebon prolonged-release tablets have not been studied in children younger than 12 years of age. The safety and efficacy of the tablets have not been demonstrated and the use in children younger than 12 years of age is therefore not recommended.

Elderly or debilitated patients

The major risk of opioid excess is respiratory depression. Caution is required in elderly or debilitated patients, in patients with severe impairment of lung, liver or kidney function, myxoedema, hypothyroidism, Addison's disease (adrenal insufficiency), intoxication psychosis (e.g. alcohol), prostatic hypertrophy, adrenocortical insufficiency, alcoholism, known opioid dependence, delirium tremens, pancreatitis, diseases of the biliary tract, inflammatory bowel disorders, biliary or ureteric colic, hypotension, hypovolaemia, conditions with increased brain pressure such as head injury, disturbances of circulatory regulation, epilepsy or seizure tendency and in patients taking benzodiazepines, other CNS depressants (including alcohol) or MAO inhibitors.

Patients undergoing abdominal surgery

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.

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

Concomitant use of Reltebon prolonged-release tablets 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 Reltebon prolonged-release tablets 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).

Reltebon prolonged-release tablets should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, Reltebon prolonged-release tablets should be discontinued immediately.

Respiratory depression

Respiratory depression is the most significant risk induced by opioids and is most likely to occur in elderly or debilitated patients. The respiratory depressant effect of oxycodone can lead to increased carbon dioxide concentrations in blood and hence in cerebrospinal fluid. In predisposed patients opioids can cause severe decrease in blood pressure.

Reltebon 80mg may cause fatal respiratory depression when administered to opioid naïve patients.

Long-term use

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.

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with oxycodone hydrochloride.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Dependence potential

Reltebon prolonged-release tablets have a primary dependence potential. 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. 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.

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

Pre-operative use

Reltebon prolonged release tablets are not recommended for pre-operative use or within the first 12-24 hours post operatively.

Abusive parenteral venous injection

In case of abusive parenteral venous injection the tablet excipients may lead to necrosis of the local tissue, infection, increased risk of endocarditis, and valvular heart injury which may be fatal, granulomas of the lung or other serious, potentially fatal events.

Tablets must not be chewed or crushed

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

Alcohol

Concomitant use of alcohol and oxycodone hydrochloride prolonged-release tablets may increase the undesirable effects of oxycodone hydrochloride; concomitant use should be avoided.

Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, such as local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, which may be fatal.

Reltebon contains lactose

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

 

4.5 Interaction with other medicinal products and other forms of interaction

Drugs which affect the CNS include, but are not limited to: as alcohol, tranquillisers, other opioids, non-benzodiazepine sedatives, phenothiazines, neuroleptic drugs, antihypertensives, hypnotics, anti-depressants, antipsychotics, anaesthetics, muscle relaxants, antihistamines and antiemetics. MAO-inhibitors are known to interact with opioid analgesics. MAO-inhibitors causes 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).

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.

Concomitant administration of oxycodone with anticholinergics or medicines with anticholinergic activity (e.g. tricyclic anti-depressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson drugs) may result in increased anticholinergic adverse effects. Oxycodone should be used with caution and the dosage may need to be reduced in patients using these medications.

Sedative medicines such as benzodiazepines or related drugs:

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).

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

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

Cimetidine can inhibit the metabolism of 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 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:

• 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, 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:

• St Johns 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, fluoxetine and quinidine, may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations. Concurrent administration of quinidine resulted in an increase in oxycodone Cmax by 11%, AUC by 13%, and t½ elim. by 14%. Also, an increase in noroxycodone level was observed, (Cmax by 50%; AUC by 85%, and t½ elim. by 42%). The pharmacodynamic effects of oxycodone were not altered.

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 Normalized Ratio (INR) in both directions have been observed in individuals if coumarin anticoagulants are co-applied with oxycodone hydrochloride.

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

 

4.6 Fertility, pregnancy and lactation

Pregnancy

Reltebon prolonged release tablets tablets are 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.

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Breastfeeding

Administration to nursing women is not recommended as oxycodone hydrochloride may be secreted in breast milk and may cause respiratory depression in the infant.

 

4.7 Effects on ability to drive and use machines

Oxycodone may impair the ability to drive and use machines.

Oxycodone may modify patients' reactions to a varying extent depending on the dosage and individual susceptibility. Therefore, patients should not drive or operate machinery if affected.

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:

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

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

- It was not affecting your ability to drive safely

 

4.8 Undesirable effects

Adverse drug reactions are typical of full opioid agonists. Tolerance and dependence may occur (see Section 4.4). Constipation may be prevented with an appropriate laxative. If nausea and vomiting are troublesome, oxycodone may be combined with an anti-emetic.

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

The adverse events considered at least possibly related to treatment are tabulated below by system organ class and absolute frequency.

Tolerance and dependence may develop.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system 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 Overdose

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Symptoms and intoxication:

Miosis, respiratory depression, somnolence, reduced skeletal muscle tone and drop in blood pressure. In severe cases circulatory collapse, stupor, coma, bradycardia, pulmonaryoedema, hypotension, hallucinations, and death may occur; abuse of high doses of strong opioids such as oxycodone can be fatal.

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

Therapy of intoxications:

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

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 case of massive overdosage, administer naloxone intravenously (0.4 to 2 mg for an adult and 0.01 mg/kg body weight for children) if the patient is in a coma or respiratory depression is present.

Repeat the dose at 2 minute intervals if there is no response. If repeated doses are required an infusion of 60% of the initial dose per hour is a useful starting point. A solution of 10 mg made up in 50 ml dextrose will produce 200 micrograms/ml for infusion using an IV pump (dose adjusted to the clinical response). Infusions are not a substitute for frequent review of the patient's clinical state. Intramuscular naloxone is an alternative in the event that IV access is not possible. As the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. Naloxone is a competitive antagonist and large doses (4 mg) may be required in seriously poisoned patients.

For less severe overdosage, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.

The patient should be observed for at least 6 hours after the last dose of naloxone.

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

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.

Reltebon prolonged-release tablets will continue to release and add to the oxycodone load for up to 12 hours after administration and the management of oxycodone overdosage should be modified accordingly. Gastric contents may therefore need to be emptied as this can be useful in removing unabsorbed drug, particularly when a prolonged release formulation has been taken.

 

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. 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.

Gastrointestinal System

Opioids may induce spasm of the sphincter of Oddi.

Endocrine system

Opioids may influence the hypothalamic-pituitary-adrenal or – gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms may be manifest from these hormonal changes.

Other pharmacological effects

In- vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown. Whether oxycodone, a semisynthetic opioid, has immunological effects similar to morphine is unknown.

Clinical studies

The efficacy of Oxycodone prolonged-release tablets has been demonstrated in cancer pain, post-operative pain and severe non-malignant pain such as diabetic neuropathy, postherpetic neuralgia, low back pain and osteoarthritis. In the latter indication, treatment was continued for up to 18 months and proved effective in many patients for whom NSAIDs alone provided inadequate relief. The efficacy of Oxycodone prolonged-release tablets in neuropathic pain was confirmed by three placebo-controlled studies.

In patients with chronic non-malignant pain, maintenance of analgesia with stable dosing was demonstrated for up to three years.

 

5.2 Pharmacokinetic properties

Absorption:

The relative bioavailability of Reltebon prolonged-release tablets is comparable to that of rapid release oxycodone with maximum plasma concentrations being achieved approximately 3 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, divided or chewed as this leads to rapid oxycodone release and absorption of a potentially fatal dose of oxycodone due to the damage of the prolonged release properties.

Distribution:

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

Metabolism:

Oxycodone is metabolised in the intestine and liver to noroxycodone and oxymorphone as well as to several glucuronide conjugates. CYP3A4 and CYP2D6 are probably involved in the formation of noroxycodone and oxymorphone respectively. Oxymorphone has 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 and faeces. Oxycodone crosses the placenta and is found in breast milk.

Linearity/non-linearity:

The prolonged-release tablets are bioequivalent in a dose proportional manner with regard to the amount of active substance absorbed as well as comparable with regard to the rate of absorption.

Elderly

The plasma concentration of oxycodone in elderly subjects is 15% greater when compared with young subjects.

Gender

Female subjects have, on average, plasma oxycodone concentrations up to 25% higher than males on a body weight adjusted basis. The reason for this difference is unknown.

Patients with renal impairment

Patients with mild, moderate and severe renal impairment showed 1.1-, 1.4- and 1.7- fold increased plasma concentrations respectively compared to patients with normal renal function. AUC increased on average 1.5-, 1.7- and 2.3-fold respectively compared to patients with normal renal function. The elimination half-life for oxycodone increased 1.5-, 1.2- and 1.4- fold respectively compared to patients with normal renal function.

Patients with hepatic impairment

Patients with mild, moderate and severe hepatic impairment showed 1.2-, 2.0- and 1.9- fold increased plasma concentrations respectively compared to patient with normal hepatic function. AUC increased on average 1.4-, 3.2- and 3.2- fold respectively compared to patients with normal hepatic function. The elimination half-life of oxycodone increased 1.1-, 1.8- and 1.8- fold respectively compared to patients with normal hepatic function.

Oxycodone was not genotoxic in a bacterial mutagenicity assay or in an in-vivo micronucleus assay in the mouse. Oxycodone produced a positive response in the in-vitro mouse lymphoma assay in the presence of rat liver S9 metabolic activation at dose levels greater than 25 μg/mL. Two in-vitro chromosomal aberrations assays with human lymphocytes were conducted. In the first assay, oxycodone was negative without metabolic activation but was positive with S9 metabolic activation at the 24 hour time point but not at other time points or at 48 hour after exposure. In the second assay, oxycodone did not show any clastogenicity either with or without metabolic activation at any concentration or time point.

 

5.3 Preclinical safety data

Teratogenicity

Oyxcodone 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.

In a study of peri- and postnatal development in rats, maternal body weight and food intake parameters were reduced for doses ≥ 2 mg/kg/d compared to the control group. Body weights were lower in the F1 generation from maternal rats in the 6 mg/kg/d dosing group. There were no effects on physical, reflexological, or sensory developmental parameters or on behavioural and reproductive indices in the F1 pups (the NOEL for F1 pups was 2 mg/kg/d based on body weight effects seen at 6 mg/kg/d). There were no effects on the F2 generation at any dose in the study.

Carcinogenicity

Long-term carcinogenicity studies were not performed.

Mutagenicity

The results of in-vitro and in-vivo studies indicate that the genotoxic risk of oxycodone to humans is minimal or absent at the systemic oxycodone concentrations that are achieved therapeutically.

 

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core:

Lactose monohydrate

Hypromellose

Povidone K30

Stearic acid

Magnesium stearate

Colloidal anhydrous silica

Tablet coating

Polyvinyl alcohol

Macrogol 3350

Talc

Titanium dioxide (E171)

Blue Indigo Carmine Aluminium Lake (E132)

Iron oxide, yellow (E172)

 

6.2 Incompatibilities

Not applicable.

 

6.3 Shelf life

3 years.

 

6.4 Special precautions for storage

Blister packs:

Do not store above 25°C.

HDPE container:

This medicinal product does not require any special storage conditions.

 

6.5 Nature and contents of container

Child resistant blister packs (PVC/PVdC/Al/PET/paper).

Pack sizes: 1, 20, 28, 30, 50, 56, 60, 98 and 100 prolonged-release tablets

Blister packs (PVC/Al) in cartons.

Pack sizes: 80 mg: 1, 20, 28, 30, 50, 56, 60, 98 and 100 prolonged-release tablets

White, round, HDPE tablet containers with LDPE caps.

Pack size: 98 and 100 prolonged-release tablets

White, round, child-resistant, HDPE tablet containers with LDPE caps.

Pack size: 98 and 100 prolonged-release tablets

Not all pack sizes may be marketed.

 

6.6 Special precautions for disposal and other handling

No special requirements.

Instructions for use of child resistant blisters:

1. Do not push the tablet directly out of the pocket

2. Separate one blister cell from the strip at the perforations

3. Carefully peel off the backing to open the pocket

 

7. Marketing authorisation holder

Accord Healthcare Limited

Sage House

319 Pinner Road

North Harrow

Middlesex

HA1 4HF

United Kingdom

 

8. Marketing authorisation number(s)

PL 20075/1000

 

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 15.04.2014

Date of latest renewal: 03/07/2018

 

10. Date of revision of the text

02/04/2020