4.1. Therapeutic indications

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

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

Sofonac is indicated in adults.

4.2. Posology and method of administration

Posology

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

Analgesia

The analgesic efficacy of Sofonac 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.

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 oxycodone hydrochloride/naloxone hydrochloride depending on their previous opioid experience.

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

The maximum daily dose 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 of oxycodone hydrochloride/naloxone hydrochloride and who have become in need of an increased dose.

For patients requiring higher doses of oxycodone hydrochloride/naloxone hydrochloride, 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.

Some patients taking Sofonac according to a regular time schedule require immediate-release analgesics as “rescue” medication for breakthrough pain. Sofonac 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 Sofonac requires upward adjustment. This adjustment should be made every 1 to 2 days in steps of 5 mg/2.5 mg oxycodone hydrochloride/naloxone hydrochloride 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.

Sofonac 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.

Treatment goals and discontinuation

Before initiating treatment with Sofonac, 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).

Duration of use

Sofonac should not be administered for longer than absolutely necessary

Special populations

Elderly

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

Renal impairment

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 renally impaired patients is yet not known. Caution should be exercised when administering Sofonac to patients with renal impairment (see section 4.4) and particularly if a dose increase is considered.

Hepatic impairment

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 relatively high naloxone exposure in patients with hepatic impairment is not yet known.

Caution must be exercised when administering Sofonac to patients with mild hepatic impairment (see section 4.4). Similarly, special attention is required in patients with mild hepatic impairment if an increased dose is considered.

In patients with moderate and severe hepatic impairment Sofonac is contraindicated (see section 4.3).

Paediatric population

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

Method of administration

Oral use.

Sofonac is taken in the determined dose twice daily in a fixed time schedule.

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

The tablet can be divided into equal doses. Sofonac must be swallowed with sufficient liquid, and must not be broken, chewed or crushed.

4.3. Contraindications

• Hypersensitivity to the active substance(s) 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.

4.4. Special warnings and precautions for use

Caution must be exercised when administering these tablets to patients with:

• Severely impaired respiratory function

• Sleep apnoea

• CNS depressants co-administration (see below and section 4.5)

• Monoamine oxidase inhibitors (MAOIs, see below and section 4.5)

• Tolerance, physical dependence and withdrawal (see below)

• Psychological dependence [addiction], abuse profile and history of substance and/or alcohol abuse (see below)

• Elderly or infirm

• Head injury, intracranial lesions or increased intracranial pressure, reduced level of consciousness of uncertain origin

• Epileptic disorder or predisposition to convulsions

• Hypotension

• Hypertension

• Pancreatitis

• Mild hepatic impairment

• Renal impairment

• Opioid-induced paralytic ileus

• Myxoedema

• Hypothyroidism

• Addison's disease (adrenal cortical insufficiency)

• Prostate hypertrophy

• Toxic psychosis

• Alcoholism

• Delirium tremens

• Cholelithiasis

• Pre-existing cardiovascular diseases

Respiratory depression

The major risk of opioid excess is respiratory depression.

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 manner. In patients who present with CSA, consider decreasing the total opioid dosage.

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

Concomitant use of Sofonac 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 Sofonac 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).

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 Sofonac 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 Sofoanc 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 Sofonac 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.

Hepatic or renal impairment

Caution must also be exercised when administering Sofonac to patients with mild hepatic or renal impairment. A 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 increasing the risk of biliary tract symptoms and pancreatitis. Therefore, oxycodone / naloxone 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.

Tolerance, physical dependence and withdrawal.

During long-term administration, the patient may develop tolerance to the medicinal product and require higher doses to maintain the desired effect. Chronic administration of Sofonac may lead to physical dependence. Withdrawal symptoms may occur upon the abrupt cessation of therapy. If therapy with Sofonac is no longer required, it may be advisable to reduce the daily dose gradually in order to avoid the occurrence of withdrawal syndrome (see section 4.2).

Sofonac is not suitable for the treatment of withdrawal symptoms.

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 Sofonac (see sections 4.5 and 4.7).

Alcohol

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

Cancer

There is no clinical data available for cancer patients with peritoneal carcinomatosis or beginning intestinal obstruction in advanced stages of digestive and pelvic cancers. Therefore, the use of Sofonac in this population is not recommended.

Surgery

Sofonac is not recommended for pre-operative use or within the first 12 to 24 hours post-operatively. Do not use for acute post-operative pain owing to the increased risk of persistent post-operative opioid use (PPOU) and opioid-induced ventilatory impairment (OIVI). 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 Sofonac depends on a careful benefit-risk assessment for each individual patient.

Precautions for proper use

In order not to impair the prolonged-release characteristic of the tablets, they must not be 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).

Abuse

Any abuse of Sofonac by drug addicts is strongly discouraged.

If abused parenterally, intranasally or orally by individuals dependent on opioid agonists, such as heroin, morphine, or methadone, Sofonac 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).

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

In patients under long-term opioid treatment with higher doses of opioids, the switch to Sofonac can initially provoke withdrawal symptoms. Such patients may require specific attention.

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

Sofonac consists of a dual-polymer matrix, 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.

The empty prolonged-release tablet matrix may be visible in the stool.

<Doping

The use of Sofonac may produce positive results in doping controls. The use of Sofonac as a doping agent may become a health hazard.>

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per prolonged-release tablet, that is to say essentially 'sodium-free'.

Paediatric population

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

4.5. Interaction with other medicinal products and other forms of interaction

Substances having a CNS-depressant effect (e.g. other opioids, sedatives, hypnotics, antidepressants, phenothiazines, neuroleptics, antihistamines and antiemetics) may enhance the CNS-depressant effect (e.g. respiratory depression) of Sofonac.

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).

Concomitant administration of oxycodone with serotonin medicinal products, 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.

Concomitant administration of oxycodone with anticholinergics or medications with anticholinergic activity (e.g. tri-cyclic antidepressants, antihistamines, anti-psychotics, muscle relaxants, anti-Parkinson drugs) may result in increased anticholinergic adverse effects.

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

Clinically relevant changes in International Normalized 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. Sofonac doses may need to be adjusted accordingly.

CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin, telithromycin), azole-antifungals (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 Sofonac 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 hydrochloride/naloxone hydrochloride 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 Sofonac is relatively low (see section 5.2). Both oxycodone and naloxone pass 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.

Long-term administration of oxycodone during pregnancy may lead to withdrawal symptoms in the newborn. If administered during childbirth, oxycodone may evoke respiratory depression in the newborn.

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

Breastfeeding

Oxycodone passes into 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 breast milk. However, after use of Sofonac systemic naloxone levels are very low (see section 5.2).

A risk to the suckling child cannot be excluded in particular following intake of multiple doses of Sofonac by the breast-feeding mother.

Breast-feeding should be discontinued during treatment with Sofonac.

Fertility

There are no data with respect to fertility.

4.7. Effects on ability to drive and use machines

Sofonac has moderate influence on the ability to drive and use machines. This is particularly likely at the beginning of treatment with Sofonac, after dose increase or product rotation and if Sofonac is combined with other CNS depressant medicinal products. 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 machines is permitted.

Patients being treated with Sofonac 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

System organ class

(MedDRA)

Common

Uncommon

Rare

Not known

Immune system disorders

Hypersensitivity

Metabolism and nutrition disorders

Decreased appetite up to loss of appetite

Psychiatric disorders

Insomnia

Abnormal thinking

Anxiety

Confusion

Depression

Decreased libido

Nervousness

Restlessness

Euphoric mood

Hallucination

Nightmares

Aggression

Nervous system disorders

Dizziness

Headache

Somnolence

Convulsions1

Disturbance in attention

Dysgeusia

Speech disorder

Syncope

Tremor

Lethargy

Paraesthesia

Sedation

Sleep apnoea syndrome (see section 4.4)

Eye disorders

Visual impairment

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Angina pectoris2

Palpitations

Tachycardia

Vascular disorders

Hot flush

Blood pressure decreased

Blood pressure increased

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Rhinorrhoea

Cough

Yawning

Respiratory depression

Central sleep apnoea syndrome

Gastrointestinal disorders

Abdominal pain

Constipation

Diarrhoea

Dry mouth

Dyspepsia

Vomiting

Nausea

Flatulence

Abdominal distension

Tooth disorder

Eructation

Hepatobiliary disorders

Hepatic enzymes increased

Biliary colic

Skin and subcutaneous tissue disorders

Pruritus

Skin reactions

Hyperhidrosis

Musculoskeletal and connective tissue disorders

Muscle spasms

Muscle twitching

Myalgia

Renal and urinary disorders

Micturition urgency

Urinary retention

Reproductive system and breast disorders

Erectile dysfunction

General disorders and administration site conditions

Asthenic conditions

Fatigue

Chest pain

Chills

Drug withdrawal syndrome

Malaise

Pain

Oedema peripheral

Thirst

Investigations

Weight decreased

Weight increased

Injury, poisoning, and procedural complications

Injuries from accidents

1 particularly in patients 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.

System organ class

MedDRA

Common

Uncommon

Rare

Not known

Infections and infestations

Herpes simplex

Immune system disorders

Anaphylactic responses

Metabolism and nutrition disorders

Dehydration

Increased appetite

Psychiatric disorders

Altered mood and personality changes

Decreased activity

Psychomotor hyperactivity

Agitation

Perception disturbances (e.g. derealisation)

Nervous system disorders

Concentration impaired

Migraine

Hypertonia

Involuntary muscle contractions

Hypoaesthesia

Abnormal coordination

Hyperalgesia

Ear and labyrinth disorders

Hearing impaired

Vascular disorders

Vasodilation

Respiratory, thoracic and mediastinal disorders

Dysphonia

Gastrointestinal disorders

Hiccups

Dysphagia

Ileus

Mouth ulceration

Stomatitis

Melaena

Gingival bleeding

Dental caries

Hepatobiliary disorders

Cholestasis, Sphincter of Oddi dysfunction

Skin and subcutaneous tissue disorders

Dry skin

Urticaria

Renal and urinary disorders

Dysuria

Reproductive system and breast disorders

Hypogonadism

Amenorrhoea

General disorders and administration site conditions

Oedema

Drug tolerance

Drug withdrawal syndrome neonatal

Drug dependence

Repeated use of Sofonac 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 at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms of intoxication

Depending on the history of the patient, an overdose of Sofonac 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, skeletal muscle flaccidity, 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 to 2 mg intravenously). Administration should be repeated at 2 to 3 minute intervals, as clinically necessary. It is also possible to apply an infusion of 2 mg naloxone hydrochloride in 500 ml of sodium chloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%) (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 measure (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.