Doneloxon 10 mg/5 mg prolonged-release tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Doneloxon 10 mg/5 mg prolonged-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet prolonged-release tablet contains 10 mg of oxycodone hydrochloride (equivalent to 9mg oxycodone) and 5 mg of naloxone hydrochloride (as 5.45 mg naloxone hydrochloride dihydrate, equivalent to 4.5 mg naloxone).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet

Pink, oblong, biconvex prolonged-release tablet with break scores on both sides, with a length of 10.2 mm, a width of 4.7 mm and a height of 3.0 - 4.0 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.

Second line symptomatic treatment of patients with severe to very severe idiopathic restless legs syndrome after failure of dopaminergic therapy.

The opioid antagonist naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut.

Doneloxon is indicated in adults.

4.2 Posology and method of administration

Posology

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

Analgesia

The analgesic efficacy of Doneloxon is equivalent to oxycodone hydrochloride prolonged-release formulations.

The dose should be adjusted to the intensity of pain and the sensitivity of the individual patient. Unless otherwise prescribed, Doneloxon should be administered as follows:

Adults

The usual starting dose for an opioid naive patient is 10 mg/5 mg of oxycodone hydrochloride/ naloxone hydrochloride at 12 hourly intervals.

Patients already receiving opioids may be started on higher doses of Doneloxon depending on their previous opioid experience.

Doneloxon 5 mg/2.5 mg is intended for dose titration when initiating opioid therapy and individual dose adjustment.

The maximum daily dose of Doneloxon is 160 mg oxycodone hydrochloride and 80 mg naloxone hydrochloride. The maximum daily dose is reserved for patients who have previously been maintained on a stable daily dose and who have become in need of an increased dose. Special attention should be given to patients with compromised renal function and patients with mild hepatic impairment if an increased dose is considered. For patients requiring higher doses, administration of supplemental prolonged-release oxycodone hydrochloride at the same time intervals should be considered, taking into account the maximum daily dose of 400 mg prolonged-release oxycodone hydrochloride. In the case of supplemental oxycodone hydrochloride dosing, the beneficial effect of naloxone hydrochloride on bowel function may be impaired.

After complete discontinuation of therapy with oxycodone/naloxone with a subsequent switch to another opioid a worsening of the bowel function can be expected.

Some patients taking these prolonged-release tablets according to a regular time schedule require immediate-release analgesics as “rescue” medication for breakthrough pain. Doneloxon is a prolonged-release formulation and therefore not intended for the treatment of breakthrough pain. For the treatment of breakthrough pain, a single dose of “rescue medication” should approximate one sixth of the equivalent daily dose of oxycodone hydrochloride. The need for more than two “rescues” per day is usually an indication that the dose of Doneloxon requires upward adjustment. This adjustment should be made every 1-2 days in steps of 5 mg/2.5 mg twice daily, or where necessary 10 mg/5 mg, oxycodone hydrochloride/naloxone hydrochloride until a stable dose is reached. The aim is to establish a patient-specific twice daily dose that will maintain adequate analgesia and make use of as little rescue medication as possible for as long as pain therapy is necessary.

Doneloxon is taken at the determined dose twice daily according to a fixed time schedule. While symmetric administration (the same dose mornings and evenings) subject to a fixed time schedule (every 12 hours) is appropriate for the majority of patients, some patients, depending on the individual pain situation, may benefit from asymmetric dosing tailored to their pain pattern. In general, the lowest effective analgesic dose should be selected.

In non-malignant pain therapy, daily doses of up to 40 mg/20 mg oxycodone hydrochloride/naloxone hydrochloride are usually sufficient, but higher doses may be needed.

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

Restless legs syndrome (RLS)

Doneloxon is indicated for patients suffering from RLS for at least 6 months. RLS symptoms should be present daily and during daytime (on at least 4 days per week). Doneloxon should be used after failure of previous dopaminergic treatment. Dopaminergic treatment failure is defined as inadequate initial response, a response that has become inadequate with time, occurrence of augmentation or unacceptable tolerability despite adequate doses. Previous treatment with at least one dopaminergic medicinal product should have lasted in general 4 weeks. A shorter period might be acceptable in case of unacceptable tolerability with dopaminergic therapy.

The dose should be adjusted to the sensitivity of the individual patient.

Treatment of patients with restless legs syndrome with oxycodone/naloxone should be under the supervision of a clinician with experience in the management of restless legs syndrome.

Unless otherwise prescribed, Doneloxon should be administered as follows:

Adults

The usual starting dose is 5 mg/2.5 mg of oxycodone hydrochloride/naloxone hydrochloride at 12 hourly intervals.

Titration on a weekly basis is recommended in case higher doses are required. The mean daily dose in the pivotal study was 20 mg/10 mg oxycodone hydrochloride/naloxone hydrochloride.

Some patients may benefit from higher daily doses up to a maximum of 60 mg/30 mg oxycodone hydrochloride/naloxone hydrochloride.

Doneloxon is taken at the determined dose twice daily according to a fixed time schedule. While symmetric administration (the same dose mornings and evenings) subject to a fixed time schedule (every 12 hours) is appropriate for the majority of patients, some patients, depending on the individual situation, may benefit from asymmetric dosing tailored to the individual patient. In general, the lowest effective dose should be selected.

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

Analgesia/restless legs syndrome

Elderly patients

As for younger adults the dose should be adjusted to the intensity of the pain or RLS symptoms and the sensitivity of the individual patient.

Patients with impaired hepatic function

A clinical trial has shown that plasma concentrations of both oxycodone and naloxone are elevated in patients with hepatic impairment. Naloxone concentrations were affected to a higher degree than oxycodone (see section 5.2). The clinical relevance of a relative high naloxone exposure in hepatic impaired patients is yet not known. Caution must be exercised when administering oxycodone/naloxone to patients with mild hepatic impairment (see section 4.4). In patients with moderate and severe hepatic impairment Doneloxon is contraindicated (see section 4.3).

Patients with impaired renal function

A clinical trial has shown that plasma concentrations of both oxycodone and naloxone are elevated in patients with renal impairment (see section 5.2). Naloxone concentrations were affected to a higher degree than oxycodone. The clinical relevance of a relative high naloxone exposure in renal impaired patients is yet not known. Caution should be exercised when administering oxycodone/naloxone to patients with renal impairment (see section 4.4).

Paediatric population

The safety and efficacy of Doneloxon in children aged below 18 years has not been established. No data are available.

Duration of treatment

Doneloxon should not be administered for longer than absolutely necessary.

Analgesia

When the patient no longer requires opioid therapy, it may be advisable to taper the dose gradually (see section 4.4).

Restless legs syndrome

At least every three months during therapy with Doneloxon patients should be clinically evaluated. During the initiation of treatment and dose adjustments, more frequent evaluation may be undertaken. Treatment should only be continued if Doneloxon is considered effective and the benefit is considered to outweigh adverse effects and potential harms in individual patients. Prior to continuation of RLS treatment beyond 1 year a discharge regimen by gradually tapering down of Doneloxon over a period of approximately one week should be considered to establish if continued treatment with oxycodone/naloxone is indicated.

When a patient no longer requires opioid therapy cessation of treatment by tapering down over a period of approximately one week is recommended in order to reduce the risk of a withdrawal reaction (see section 4.4).

Method of administration

Treatment goals and discontinuation

Before initiating treatment with Doneloxon, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4).

Oral use.

These prolonged-release tablets are taken in the determined dose twice daily in a fixed time schedule.

The prolonged-release tablets may be taken with or without food.

Doneloxon must be swallowed whole with sufficient liquid, and must not be divided, broken chewed or crushed (see section 4.4).

4.3 Contraindications

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1
• Severe respiratory depression with hypoxia and/or hypercapnia
• Severe chronic obstructive pulmonary disease
• Cor pulmonale
• Severe bronchial asthma
• Non-opioid induced paralytic ileus

• Moderate to severe hepatic impairment

  Additionally for restless legs syndrome:

• History of opioid abuse

4.4 Special warnings and precautions for use

Respiratory depression

The major risk of opioid excess is respiratory depression.

Caution must be exercised when administering oxycodone/naloxone to elderly or infirm patients, patients with opioid-induced paralytic ileus, patients presenting severely impaired pulmonary function, patients with sleep apnoea, myxoedema, hypothyroidism, Addison’s disease (adrenal cortical insufficiency), toxic psychosis, cholelithiasis, prostate hypertrophy, alcoholism, delirium tremens, pancreatitis, hypotension, hypertension, pre-existing cardiovascular diseases, head injury (due to the risk of increased intracranial pressure), epileptic disorder or predisposition to convulsions. Caution is advised in patients taking MAO inhibitors or CNS depressants.

Risk from concomitant use of sedative medicinal products such as benzodiazepines or related medicinal product

Concomitant use of oxycodone/naloxone and sedative medicinal products such as benzodiazepines or related medicinal products may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe oxycodone/naloxone concomitantly with sedative medicinal products, 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).

Caution is advised in treating restless legs syndrome patients with additional sleep apnoea syndrome with oxycodone/naloxone due to the additive risk of respiratory depression. No data about the risk exist because in the clinical trial patients with sleep apnoea syndrome were excluded.

Hepatic or renal impairment

Caution must also be exercised when administering oxycodone/naloxone to patients with mild hepatic or renal impairment. Careful medical monitoring is particularly necessary for patients with severe renal impairment.

Hepatobiliary disorders

Oxycodone may cause dysfunction and spasm of the sphincter of Oddi, thus raising

intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis.

Therefore, oxycodone has to be administered with caution in patients with pancreatitis and

diseases of the biliary tract.

Diarrhoea

Diarrhoea may be considered as a possible effect of naloxone.

Drug dependence, tolerance and potential for abuse

Opioid Use Disorder (abuse and dependence)

Tolerance and physical and/or psychological dependence may develop upon repeated

administration of opioids such as oxycodone.

Repeated use of Doneloxon may lead to Opioid Use Disorder (OUD). A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of Doneloxon may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Before initiating treatment with {product name} and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician.

Patients will require monitoring for signs of drug-seeking behavior (e.g. too early requests

for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD,

consultation with an addiction specialist should be considered.

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.

Tolerance

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 this medicine.

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.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

In order not to impair the prolonged-release characteristic of the prolonged-release tablets, the tablets must not be divided, broken, chewed or crushed. Breaking, chewing or crushing the prolonged-release tablets for ingestion leads to a faster release of the active substances and the absorption of a possibly fatal dose of oxycodone (see section 4.9).

Empty matrix (tablets) may be seen in the stool.

Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of the dose or termination of therapy may be considered. Because of possible additive effects, caution should be advised when patients are taking other sedating medicinal products in combination with oxycodone/naloxone (see sections 4.5 and 4.7).

Alcohol

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

Paediatric population

Studies have not been performed on the safety and efficacy of oxycodone/naloxone in children and adolescents below the age of 18 years. Therefore, their use in children and adolescents under 18 years of age is not recommended.

Cancer

There is no clinical experience in patients with cancer associated to peritoneal carcinomatosis or with sub-occlusive syndrome in advanced stages of digestive and pelvic cancers. Therefore, the use of oxycodone/naloxone in this population is not recommended.

Surgery

Oxycodone/naloxone is not recommended for pre-operative use or within the first 12-24 hours post-operatively. Depending on the type and extent of surgery, the anaesthetic procedure selected, other co-medication and the individual condition of the patient, the exact timing for initiating post-operative treatment with oxycodone/naloxone depends on a careful risk-benefit assessment for each individual patient.

Abuse

Any abuse of Doneloxon by drug addicts is strongly discouraged.

If abused parenterally, intranasally or orally by individuals dependent on opioid agonists, such as heroin, morphine, or methadone, oxycodone/naloxone is expected to produce marked withdrawal symptoms - because of the opioid receptor antagonist characteristics of naloxone - or to intensify withdrawal symptoms already present (see section 4.9).

These tablets are intended for oral use only. Abusive parenteral injections of the prolonged-release tablet constituents (especially talc) can be expected to result in local tissue necrosis and pulmonary granulomas or may lead to other serious, potentially fatal undesirable effects.

Endocrine system

Opioids such as oxycodone 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.

Athletes must be aware that this medicinal product may cause a positive reaction to sports doping control tests. The use of Doneloxon as a doping agent may become a health hazard.

Doneloxon contains less than 1 mmol sodium (23 mg) per prolonged-release tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Sedative medicinal products such as benzodiazepines or related medicinal products:

The concomitant use of opioids with sedative medicinal products such as benzodiazepines or related medicinal products 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).

Substances which depress the CNS include, but are not limited to: other opioids, anxiolytics, hypnotics, sedatives (including benzodiazepines), antidepressants, antipsychotics, antihistamines and antiemetics.

Alcohol may enhance the pharmacodynamic effects of Doneloxon ; 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 dose may need to be reduced in patients using these medicinal products.

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

Oxycodone is metabolised primarily via the CYP3A4 pathways and partly via the CYP2D6 pathway (see section 5.2). The activities of these metabolic pathways may be inhibited or induced by various co-administered medicinal products or dietary elements. Doneloxon doses may need to be adjusted accordingly.

CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin, telithromycin), azole-antifungal agents (e.g. ketoconazole, voriconazole, itraconazole, posaconazole), protease inhibitors (e.g. ritonavir, indinavir, nelfinavir, saquinavir), cimetidine and grapefruit juice may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations. A reduction in the dose of Doneloxon and subsequent re-titration may be necessary.

CYP3A4 inducers, such as rifampicin, carbamazepine, phenytoin and St. John's Wort, may induce the metabolism of oxycodone and cause increased clearance of the active substance, resulting in a decrease in oxycodone plasma concentrations. Caution is advised and further titration may be necessary to reach an adequate level of symptom control.

Theoretically, medicinal products 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. Concomitant administration with CYP2D6 inhibitors had an insignificant effect on the elimination of oxycodone and also had no influence on the pharmacodynamic effects of oxycodone.

In vitro metabolism studies indicate that no clinically relevant interactions are to be expected between oxycodone and naloxone. The likelihood of clinically relevant interactions between paracetamol, acetylsalicylic acid or naltrexone and the combination of oxycodone and naloxone in therapeutic concentrations is minimal.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of oxycodone/naloxone in pregnant women and during childbirth. Limited data on the use of oxycodone during pregnancy in humans reveal no evidence of an increased risk of congenital abnormalities. For naloxone, insufficient clinical data on exposed pregnancies are available. However, systemic exposure of the women to naloxone after use of Doneloxon is relatively low (see section 5.2).

Both oxycodone and naloxone pass into the placenta. Animal studies have not been performed with oxycodone and naloxone in combination (see section 5.3). Animal studies with oxycodone or naloxone administered as single active substances have not revealed any teratogenic or embryotoxic effects.

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

Doneloxon should only be used during pregnancy if the benefit outweighs the possible risks to the unborn child or neonate.

Breast-feeding

Oxycodone passes into the breast milk. A milk-plasma concentration ratio of 3.4:1 was measured and oxycodone effects in the suckling infant are therefore conceivable. It is not known whether naloxone also passes into the breast milk. However, after use of Doneloxon systemic naloxone levels are very low (see section 5.2).

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

Fertility

There are no data with respect to fertility.

4.7 Effects on ability to drive and use machines

Oxycodone/Naloxone has moderate influence on the ability to drive and use machines. This is particularly likely at the beginning of treatment with Doneloxon , after dose increase or product rotation and if Doneloxon is combined with other CNS depressant agents. Patients stabilised on a specific dose will not necessarily be restricted. Therefore, patients should consult with their physician as to whether driving or the use of machinery is permitted.

Patients being treated with Doneloxon and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved (see also sections 4.4 and 4.5).

4.8 Undesirable effects

The following frequencies are the basis for assessing 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

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Undesirable effects in the treatment of pain

¹ particularly in persons with epileptic disorder or predisposition to convulsions ² particularly in patients with history of coronary artery disease

For the active substance oxycodone hydrochloride, the following additional undesirable effects are known

Due to its pharmacological properties, oxycodone hydrochloride may cause respiratory depression, miosis, bronchial spasm and spasms of nonstriated muscles as well as suppress the cough reflex.

Undesirable effects in the treatment of restless legs syndrome

The list below reflects the adverse drug reactions seen with oxycodone/naloxone in a 12-week, randomised, placebo-controlled clinical trial comprising a total of 150 patients on oxycodone/naloxone and 154 patients on placebo with daily doses between 10 mg/5 mg and 80 mg/40 mg oxycodone hydrochloride/naloxone hydrochloride. Adverse drug reactions associated with oxycodone/naloxone in pain and not observed in RLS study population were added with the frequency of not known.

¹ particularly in persons with epileptic disorder or predisposition to convulsions ² particularly in patients with a history of coronary artery disease ³ alanine aminotransferase increased, gamma-glutamyltransferase increased

Description of selected adverse reaction

Drug dependence

Repeated use of {product name} can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 4.4).

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 Yellow Card Scheme: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google play or Apple App store.

4.9 Overdose

Symptoms of intoxication

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.

Depending on the history of the patient, an overdose of oxycodone/naloxone may be manifested by symptoms that are either triggered by oxycodone (opioid receptor agonist) or by naloxone (opioid receptor antagonist).

Symptoms of oxycodone overdose include miosis, respiratory depression, somnolence progressing to stupor, hypotonia, bradycardia as well as hypotension. Coma, non-cardiogenic pulmonary oedema and circulatory failure may occur in more severe cases and may lead to a fatal outcome.

Toxic leukoencephalopathy has been observed with oxycodone overdose.

Symptoms of a naloxone overdose alone are unlikely.

Therapy of intoxication

Withdrawal symptoms due to an overdose of naloxone should be treated symptomatically in a closely-supervised environment.

Clinical symptoms suggestive of an oxycodone overdose may be treated by the administration of opioid antagonists (e.g. naloxone hydrochloride 0.4-2 mg intravenously). Administration should be repeated at 2-3 minute intervals, as clinically necessary. It is also possible to apply an infusion of 2 mg naloxone hydrochloride in 500 ml of 0.9% sodium chloride or 5% dextrose (0.004 mg/ml naloxone). The infusion should be run at a rate aligned to the previously administered bolus doses and to the patient's response.

Consideration may be given to gastric lavage.

Supportive measures (artificial ventilation, oxygen, vasopressors and fluid infusions) should be employed as necessary, to manage the circulatory shock accompanying an overdose. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Artificial ventilation should be applied if necessary. Fluid and electrolyte metabolism should be maintained.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics; opioids; natural opium alkaloids, ATC code: N02AA55

Mechanism of action

Oxycodone and naloxone have an affinity for kappa, mu and delta opiate receptors in the brain, spinal cord and peripheral organs (e.g. intestine). Oxycodone acts as opioid-receptor agonist at these receptors and binds to the endogenous opioid receptors in the CNS. By contrast, naloxone is a pure antagonist acting on all types of opioid receptors.

Pharmacodynamic effects

Because of the pronounced first-pass metabolism, the bioavailability of naloxone upon oral administration is <3%, therefore a clinically relevant systemic effect is unlikely. Due to the local competitive antagonism of the opioid receptor mediated oxycodone effect by naloxone in the gut, naloxone reduces the bowel function disorders that are typical for opioid treatment.

Clinical efficacy and safety

For effects of opioids on the endocrine system, see section 4.4.

Preclinical studies show differing effects of natural opioids on components of the immune system. The clinical significance of these findings is not known. It is not known whether oxycodone, a semi-synthetic opioid, has similar effects on the immune system to natural opioids.

Analgesia

In a 12 weeks parallel group double-blinded study in 322 patients with opioid-induced constipation, patients who were treated with oxycodone hydrochloride/naloxone hydrochloride had on average one extra complete spontaneous (without laxatives) bowel movement in the last week of treatment, compared to patients who continued using similar doses of oxycodone hydrochloride prolonged release tablets (p<0.0001). The use of laxatives in the first four weeks was significantly lower in the oxycodone/naloxone group compared to the oxycodone monotherapy group (31% versus 55%, respectively, p<0.0001). Similar results were shown in a study with 265 non-cancer patients comparing daily doses of oxycodone hydrochloride/naloxone hydrochloride of 60 mg/30 mg to up to 80 mg/40 mg with oxycodone hydrochloride monotherapy in the same dose range.

Restless legs syndrome

In a 12-week double-blind efficacy study, 150 patients with severe to very severe idiopathic restless legs syndrome at randomisation were treated with oxycodone hydrochloride/naloxone hydrochloride. Severe syndrome is defined as IRLS score between 21 and 30, and very severe as score between 31 and 40. Patients showed a clinically relevant and a statistically significant improvement in mean IRLS score compared to placebo during the entire treatment period with a decrease in the mean IRLS score of 5.9 points compared to placebo at week 12 (assuming an effect similar to placebo completers for patients who discontinued the study representing a very conservative approach). The onset of efficacy was demonstrated from as early as week 1 of treatment. Similar results were shown for the RLS symptom severity improvement (as measured by the RLS-6-Rating scale), in quality of life as measured by a QoL-RLS questionnaire, in sleep quality (measured by MOS sleep scale), and for the proportion of IRLS score remitters. No subject had a confirmed case of augmentation during the study.

5.2 Pharmacokinetic properties

Oxycodone hydrochloride

Absorption

Oxycodone has a high absolute bioavailability of up to 87% following oral administration.

Distribution

Following absorption, oxycodone is distributed throughout the entire body. Approximately 45% is bound to plasma protein. Oxycodone crosses the placenta and may be detected in breast milk.

Biotransformation

Oxycodone is metabolised in the gut and the liver to noroxycodone and oxymorphone and to various glucuronide conjugates. Noroxycodone, oxymorphone and noroxymorphone are produced via the cytochrome P450 system. Quinidine reduces the production of oxymorphone in man without substantially influencing the pharmacodynamics of oxycodone. The contribution of the metabolites to overall pharmacodynamic effect is insignificant.

Elimination

Oxycodone and its metabolites are excreted in both urine and faeces.

Naloxone hydrochloride

Absorption

Following oral administration, naloxone has a very low systemic availability of <3%.

Distribution

Naloxone passes into the placenta. It is not known, whether naloxone also passes into breast milk.

Biotransformation and elimination

After parenteral administration, the plasma half-life is approximately one hour. The duration of action depends upon the dose and route of administration, intramuscular injection producing a more prolonged effect than intravenous doses. It is metabolised in the liver and excreted in the urine. The principal metabolites are naloxone glucuronide, 6β-naloxol and its glucuronide.

Oxycodone hydrochloride/naloxone hydrochloride combination (Doneloxon) Pharmacokinetic/pharmacodynamic relationships

The pharmacokinetic characteristics of oxycodone from Doneloxon is equivalent to those of prolonged-release oxycodone hydrochloride tablets administered together with prolonged-release naloxone hydrochloride tablets.

All dose strengths of Doneloxon are interchangeable.

After the oral administration of oxycodone hydrochloride/naloxone hydrochloride in maximum dose to healthy subjects, the plasma concentrations of naloxone are so low that it is not feasible to carry out a pharmacokinetic analysis. To conduct a pharmacokinetic analysis naloxone-3-glucuronide as surrogate marker is used, since its plasma concentration is high enough to measure.

Overall, following ingestion of a high-fat breakfast, the bioavailability and peak plasma concentration (C_max) of oxycodone were increased by an average of 16% and 30% respectively compared to administration in the fasting state. This was evaluated as clinically not relevant, therefore Doneloxon prolonged-release tablets may be taken with or without food (see section 4.2).

In vitro metabolism studies have indicated that the occurrence of clinically relevant interactions involving oxycodone hydrochloride/naloxone hydrochloride is unlikely.

Elderly patients

Oxycodone

For AUCτ of oxycodone, on average there was an increase to 118% (90% C.I.: 103, 135), for elderly compared with younger volunteers. For C_max of oxycodone, on average there was an increase to 114% (90% C.I.: 102, 127). For C_min of oxycodone, on average there was an increase to 128% (90% C.I.: 107, 152).

Naloxone

For AUCτ of naloxone, on average there was an increase to 182% (90% C.I.: 123, 270), for elderly compared with younger volunteers. For C_max of naloxone, on average there was an increase to 173% (90% C.I.: 107, 280). For C_min of naloxone, on average there was an increase to 317% (90% C.I.: 142, 708).

Naloxone-3-glucuronide

For AUCτ of naloxone-3-glucuronide, on average there was an increase to 128% (90% C.I.: 113, 147), for elderly compared with younger volunteers. For C_max of naloxone-3-glucuronide, on average there was an increase to 127% (90% C.I.: 112, 144). For C_min of naloxone-3-glucuronide, on average there was an increase to 125% (90% C.I.: 105, 148).

Patients with impaired hepatic function

Oxycodone

For AUC_INF of oxycodone, on average there was an increase to 143% (90% C.I : 111, 184), 319% (90% C.I.: 248, 411) and 310% (90% C.I.: 241, 398) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For C_max of oxycodone, on average there was an increase to 120% (90% C.I.: 99, 144), 201% (90% C.I.: 166, 242) and 191% (90% C.I.: 158, 231) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For t_1/2Z of oxycodone, on average there was an increase to 108% (90% C.I.: 70, 146), 176% (90% C.I.: 138, 215) and 183% (90% C.I.: 145, 221) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers.

Naloxone

For AUC_t of naloxone, on average there was an increase to 411% (90% C.I.: 152, 1112), 11518% (90% C.I.: 4259, 31149) and 10666% (90% C.I.: 3944, 28847) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For C_max of naloxone, on average there was an increase to 193% (90% C.I.: 115, 324), 5292% (90% C.I: 3148, 8896) and 5252% (90% C.I.: 3124, 8830) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. Due to insufficient amount of data available t_1/2Z and the corresponding AUC_INF of naloxone were not calculated. The bioavailability comparisons for naloxone were therefore based on AUC_t values.

Naloxone-3-glucuronide

For AUC_INF of naloxone-3-glucuronide, on average there was an increase to 157% (90% C.I.: 89, 279), 128% (90% C.I.: 72, 227) and 125% (90% C.I.: 71, 222) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For C_max of naloxone-3-glucuronide, on average there was an increase to 141% (90% C.I.: 100, 197), 118% (90% C.I.: 84, 166) and a decrease to 98% (90% C.I.: 70, 137) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For t_1/2Z of naloxone-3-glucuronide, on average there was an increase to 117% (90% C.I.: 72, 161), a decrease to 77% (90% C.I.: 32, 121) and a decrease to 94% (90% C.I.: 49, 139) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers.

Patients with impaired renal function

Oxycodone

For AUC_INF of oxycodone, on average there was an increase to 153% (90% C.I.: 130, 182), 166% (90% C.I.: 140, 196) and 224% (90% C.I.: 190, 266) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For C_max of oxycodone, on average there was an increase to 110% (90% C.I.: 94, 129), 135% (90% C.I.: 115, 159) and 167% (90% C.I.: 142, 196) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For t_1/2Z of oxycodone, on average there was an increase to 149%, 123% and 142% for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers.

Naloxone

For AUC_t of naloxone, on average there was an increase to 2850% (90% C.I.: 369, 22042), 3910% (90% C.I.: 506, 30243) and 7612% (90% C.I.: 984, 58871) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For C_max of naloxone, on average there was an increase to 1076% (90% C.l.: 154, 7502), 858% (90% C.I.: 123, 5981) and 1675% (90% C.I.: 240, 11676) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. Due to insufficient amount of data available t_1/2Z and the corresponding AUC_INF of naloxone were not calculated. The bioavailability comparisons for naloxone were therefore based on AUC_t values. The ratios may have been influenced by the inability to fully characterise the naloxone plasma profiles for the healthy subjects.

Naloxone-3-glucuronide

For AUC_INF of naloxone-3-glucuronide, on average there was an increase to 220% (90% C.I.: 148, 327), 370% (90% C.I.: 249, 550) and 525% (90% C.I.: 354, 781) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy subjects. For C_max of naloxone-3-glucuronide, on average there was an increase to 148% (90% C.I.: 110, 197), 202% (90% C.I.: 151, 271) and 239% (90% C.I.: 179, 320) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy subjects. For t_1/2Z of naloxone-3-glucuronide, on average there was no significant change between the renally impaired subjects and the healthy subjects.

Abuse

To avoid damage to the prolonged-release properties of the Doneloxon prolonged-release tablets, the tablets must not be broken, crushed or chewed, as this leads to a rapid release of the active substances.

In addition, naloxone has a slower elimination rate when administered intranasally. Both properties mean that abuse of Doneloxon will not have the effect intended. In oxycodone-dependent rats, the intravenous administration of oxycodone hydrochloride/naloxone hydrochloride at a ratio of 2:1 resulted in withdrawal symptoms.

5.3 Preclinical safety data

There are no data from studies on reproductive toxicity of the combination of oxycodone and naloxone. Studies with the single components 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 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. The standard oral reproduction toxicity studies with naloxone show that at high oral doses naloxone was not teratogenic and/or embryo/foetotoxic, and does not affect perinatal/postnatal development. At very high doses (800 mg/kg/day) naloxone produced increased pup deaths in the immediate post-partum period at doses that produced significant toxicity in maternal rats (e.g. body weight loss, convulsions). However, in surviving pups, no effects on development or behaviour were observed.

Long-term carcinogenicity studies with oxycodone/naloxone in combination or oxycodone as a single entity have not been performed. For naloxone, a 24-months oral carcinogenicity study was performed in rats with naloxone doses up to 100 mg/kg/day. The results indicate that naloxone is not carcinogenic under these conditions.

Oxycodone and naloxone as single entities show 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/naloxone to humans at therapeutic concentrations may be ruled out with adequate certainty.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Polyvinyl acetate

Povidone

Sodium laurilsulfate

Silica, colloidal anhydrous

Cellulose, microcrystalline

Magnesium stearate

Tablet coating

Polyvinyl alcohol,

Titanium dioxide (E171)

Macrogol 3350

Talc

Iron oxide red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blister: 3 years

Bottles: 3 years

Shelf life after first opening: 3 months

6.4 Special precautions for storage

Blister:

Do not store above 25°C.

Bottles:

Do not store above 30°C

6.5 Nature and contents of container

Blister

Child resistant aluminium/PVC/PE/PVDC perforated unit dose push-through blister.

Child resistant aluminium/PVC/PE/PVDC perforated unit dose peel-off blister.

Child resistant aluminium/PVC/PE/PVDC blister

Bottle

HDPE bottles with child-resistant, tamper-evident screw cap made of PP.

Pack sizes

Unit-dose blister: 10x1 (hospital pack), 14x1, 20x1, 28x1, 30x1, 50x1, 56x1, 60x1, 98x1, 100x1 prolonged-release tablets.

Blister: 28, 56 and 84 prolonged-release tablets.

Bottles: 50 and 100 prolonged-release tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

Sandoz Limited

Maxis 1, Western Road

Bracknell

RG12 1RF

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 04416/1654

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

20/08/2021

10 DATE OF REVISION OF THE TEXT

10/07/2026