4.1. Therapeutic indications

Oxycodone Hydrochloride G.L. Pharma is indicated in adults and adolescents (from 12 years and older) for the treatment of severe pain, which can be adequately managed only with opioid analgesics.

4.2. Posology and method of administration

Posology

The dosage depends on the pain intensity, the total condition of the patient, previous or concurrent medication, and the patient's individual susceptibility to the treatment.

For doses not realisable/practicable with this strength other pharmaceutical forms and strenghts of Oxycodone Hydrochloride G.L. Pharma are available.

The following general dosage recommendations apply:

Adults and adolescents (from 12 years and older)

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

Some patients receiving modified-release oxycodone medication according to a fixed time schedule may require immediate-release analgesics as rescue medication for the management of breakthrough pain. Oxycodone Hydrochloride G.L. Pharma is appropriate for the management of breakthrough pain. Single doses of the rescue medication should be adjusted based on the patients' individual requirements. In general, 1/8 to 1/6 of the daily modified-release oxycodone dose is appropriate.

The requirement of rescue medication more than twice daily may indicate that higher doses of modified-release oxycodone are necessary. The aim is to establish a patient-specific dosage which ensures adequate analgesia with tolerable undesirable effects and as low rescue medication as possible for as long as pain medication is necessary in patients receiving modified-release oxycodone treatment twice daily.

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

Conversion from oral morphine

Patients receiving oral morphine before oxycodone therapy should have their daily dose based on the following ratio: 10 mg oxycodone hydrochloride correspond to approximately 20 mg of oral morphine. Inter-patient variability requires that each patient is carefully titrated to the appropriate dose.

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

In general, patients should be titrated individually until pain relief is achieved, provided that undesirable adverse events can be adequately managed.

Use in non-malignant pain

Opioids are not first-line therapy for chronic non-malignant pain, nor are they recommended as the only treatment.

Special populations

Elderly

Elderly patients should be treated with caution. The lowest dose should be administered with careful titration to pain control.

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%, and each patient should be titrated to adequate pain control according to his/her clinical situation.

Other risk patients

In patients with low body weight or slow metabolism of drugs who are also opioid-naive, the recommended starting dose should be reduced to half the normally recommended starting dose for adults.

Paediatric population

Opioids must only be used for appropriate indications and prescribed by a specialist experienced in managing severe pain in children, with careful assessments of the benefits and risks.

Children below the age of 12 years

The safety and efficacy of oxycodone in children below 12 years of age has not yet been established. No data are available.

Method of administration

Oral use.

Oxycodone Hydrochloride G.L. Pharma oral solution should be taken every 4-6 hours based on a fixed schedule at the dosage determined.

The oral solution may be taken with or independent of meals with or without an amount of liquid.

Oxycodone Hydrochloride G.L. Pharma oral solution should not be used with alcoholic bevarages.

Oxycodone Hydrochloride G.L. Pharma liquid 5 mg/5 ml oral solution is provided with a graduated measuring cup. Each graduation mark (5 ml) of the measuring cup corresponds to 5 mg oxycodone hydrochloride.

Treatment goals and discontinuation

Before initiating treatment with Oxycodone Hydrochloride G.L. Pharma, 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 treatment

Oxycodone Hydrochloride G.L. Pharma should not be taken longer than necessary.

Instructions for use are provided in the package leaflet.

4.3. Contraindications

Hypersensitivity to the active substance 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

- elevated carbon dioxide levels in the blood

- severe chronic obstructive pulmonary disease

- cor pulmonale

- severe bronchial asthma

- paralytic ileus

- acute abdomen, delayed gastric emptying

4.4. Special warnings and precautions for use

Caution should be exercised in

- elderly or debilitated patients

- patients with severe impairment of lung, liver or kidney function

- central sleep apnoea

- myxoedema, hypothyroidism

- concomitant use of centrally depressant substances

- Addison's disease (adrenal insufficiency)

- intoxication psychosis (e.g. alcohol)

- prostatic hypertrophy

- alcoholism,

- known opioid dependence

- drug addiction, substance or alcohol abuse

- delirium tremens

- head injury, increased intracranial pressure,

- impaired consciousness of unknown cause,

- hypotension,

- hypovolaemia,

- epileptic disorder or predisposition to convulsions

- pancreatitis

- diseases of the biliary tract, biliary or ureteric colic

- inflammatory bowel disorders

- obstructive or inflammatory intestinal diseases,

- conditions with increased brain pressure (including head injuries)

- disturbances of circulatory regulation (including hypotension, hypovolaemia)

- in patients taking MAO inhibitors

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

Oxycodone should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, Oxycodone Hydrochloride G.L. Pharma oral solution should be discontinued immediately.

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

If opioid treatment is considered appropriate for the patient, then the main aim of treatment is not to minimise the dose of opioid but rather to achieve a dose which provides adequate pain relief with a minimum of side effects.

Respiratory depression

The major risk of opioid excess is respiratory depression. Caution must be exercised when administering oxycodone to the debilitated elderly; patients with severely impaired pulmonary function, impaired hepatic or renal function; patients with myxoedema, hypothyroidism, Addison's disease, toxic psychosis, prostate hypertrophy, adrenocortical insufficiency, alcoholism, delirium tremens, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, hypotension, hypovolaemia, head injury (due to risk of increased intracranial pressure) or patients taking MAO inhibitors.

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.

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

Concomitant use of Oxycodone Hydrochloride G.L. Pharma and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Oxycodone Hydrochloride G.L. Pharma 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).

Adrenal insufficiency

Opioids, such as oxycodone hydrochloride, may occasionally cause reversible adrenal insufficiency, with some hormonal changes including increases in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms may include e.g., severe abdominal pain, nausea and vomiting, low blood pressure, extreme fatigue, decreased appetite, and weight loss. Adrenal insufficiency may require monitoring and glucocorticoid replacement therapy.

MAO-inhibitors

Oxycodone should be used with caution in patients administered MAO-inhibitors or who have received MAO-inhibitors during the last two weeks (see section 4.5).

Tolerance, physical dependence and tapering off

The patient may develop tolerance to the medicinal product with chronic use and require progressively higher doses to maintain pain control.

Prolonged use of oxycodone may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent withdrawal symptoms. The opioid abstinence or withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, or increased blood pressure, respiratory rate or heart rate.

Hyperalgesia

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

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 Oxycodone Hydrochloride G.L. Pharma 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 Oxycodone Hydrochloride G.L. Pharma 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 Oxycodone Hydrochloride G.L. Pharma 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. As with other opioids, infants who are born to dependent mothers may exhibit withdrawal symptoms and may have respiratory depression at birth (please see section 4.6).

Parenteral abuse

Abuse of oral dosage forms by parenteral administration can result in serious adverse events, which may be fatal.

Alcohol

The intake of oxycodone hydrochloride with alcoholic beverages has to be avoided as alcohol may enhance the frequency of adverse reactions. Oxycodone hydrochloride should be used with particular care in patients with a history of alcohol and drug abuse.

Perioperative use, 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.

Oxycodone should be used with caution pre-operatively and 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 depends on a careful risk-benefit assessment for each individual patient.

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 has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.

Sodium

This medical product contains approx. 4.1 mg sodium per ml, equivalent to 0.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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

Alcohol

Alcohol may enhance the pharmacodynamic effects of Oxycodone hydrochloride G.L. Pharma, concomitant use should be avoided.

Central nervous system depressants (e.g. sedatives, hypnotics, phenothiazines, neuroleptics, anaesthetics, antidepressants, muscle relaxants, antihistamines, antiemetics) and other opioids or alcohol can enhance the CNS depressant effect of oxycodone, in particular respiratory depression.

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).

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

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

Monoaminoxidase (MAO) inhibitors are known to interact with narcotic analgesics, producing CNS excitation or depression with hyper- or hypotensive crisis. Oxycodone should be used with caution in patients administered MAO-inhibitors or who have received MAO-inhibitors during the last two weeks (see section 4.4).

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

Interactions via the CYP system

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

Some specific examples are provided below:

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

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

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

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

CYP3A4 inducers, such as rifampicin, carbamazepine, phenytoin and St. John's Wort may induce the metabolism of oxycodone and cause an increased clearance of oxycodone which could result in a reduction of oxycodone plasma concentrations. The oxycodone dose may need to be adjusted accordingly.

Some specific examples are provided below:

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

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

Drugs that inhibit CYP2D6 activity, such as paroxetine and quinidine, may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations.

4.6. Fertility, pregnancy and lactation

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

Pregnancy

There are limited data from the use of oxycodone in pregnant women. Infants born to mothers who have received opioids during the last 3 to 4 weeks before giving birth should be monitored for respiratory depression. Withdrawal symptoms may be observed in the newborns of mothers undergoing treatment with oxycodone.

Breast-feeding

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

4.7. Effects on ability to drive and use machines

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

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

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

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

The adverse reactions considered at least possibly related to treatment are listed below by system organ class and absolute frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very common

≥ 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

System organ class

Frequency

Adverse event

Blood and lymphatic system disorders

rare

Lymphadenopathy

Immune system disorders

uncommon

Hypersensitivity

not known

Anaphylactic responses

Endocrine disorders

uncommon

Syndrome of inappropriate antidiuretic hormone secretion

Metabolism and nutrition disorders

common

Decreased appetite

uncommon

Dehydration

Psychiatric disorders

common

Anxiety

Confusional state

Depression

Insomnia

Nervousness

Abnormal thinking

uncommon

Agitation

Affect lability

Euphoric mood

Hallucinations

Decreased libido

Drug dependence (see section 4.4)

not known

Aggression

Nervous system disorders

very common

Somnolence

Dizziness

Headache

common

Tremor

uncommon

Amnesia

Convulsion

Hypertonia

Hypoaesthesia

Involuntary muscle contractions

Speech disorder

Syncope

Paraesthesia

Dysgeusia

rare

Seizures, particularly in epileptic patients or patients with tendency to convulsions

Muscle spasm

not known

Hyperalgesia

Eye disorders

uncommon

Visual impairment

Miosis

Cardiac disorders

common

Lowering of blood pressure, rarely accompanied by secondary symptoms such as palpitations, syncope, bronchospasm

uncommon

Palpitation (in the context of withdrawal syndrome)

Supraventricular tachycardia

Vascular disorders

uncommon

Vasodilatation

rare

Hypotension

Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

common

Dyspnoea

uncommon

Respiratory depression

Increased coughing

Pharyngitis

Rhinitis

Voice changes

not known

Central sleep apnoea syndrome

Gastrointestinal disorders

very common

Constipation

Nausea

Vomiting

common

Dry mouth, rarely accompanied by thirst and difficulty swallowing

Abdominal pain

Diarrhoea

Dyspepsia

uncommon

Dysphagia

Oral ulcers

Gingivitis

Stomatitis

Flatulence

Eructation

Ileus

rare

Gingival bleeding

Increased appetite

Tarry stool

not known

Dental caries

Hepatobiliary disorders

uncommon

Increase hepatic enzymes

not known

Cholestasis

Biliary colic

Sphincter of Oddi dysfunction

Skin and subcutaneous tissue disorders

very common

Pruritus

common

Rash

Hyperhidrosis

uncommon

Dry skin

rare

Urticaria

Manifestations of herpes simplex

Increased photosensitivity

very rare

Exfoliative dermatitis

Renal and urinary disorders

uncommon

Micturition disturbances (urinary retention, but also increased urge to urinate)

rare

Haematuria

Reproductive system and breast disorders

uncommon

Reduced libido

Erectile dysfunction

not known

Amenorrhoea

General disorders and administration site conditions

common

Sweating

Asthenic conditions

uncommon

Chills

Malaise

Accidental injuries

Pain (e.g. chest pain)

Oedema, peripheral oedema

Migraine

Physical dependence with withdrawal symptoms

Drug tolerance

Thirst

rare

Weight changes (increase or decrease)

Cellulitis

not known

Drug withdrawal syndrome neonatal

Description of selected adverse reactions

Drug dependence

Repeated use of Oxycodone Hydrochloride G.L. Pharma 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).

Paediatric population

The frequency, type and severity of adverse reactions in adolescents (12 to 18 years of age) appear similar to those in adults (see section 5.1).

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,

Website: www.mhra.gov.uk/yellowcard,

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

4.9. Overdose

Symptoms

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

Management

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

In case of severe overdose, intravenous administration of an opioid antagonist (e.g. 0.4-2 mg intravenous naloxone) may be indicated. Administration of single doses must be repeated depending on the clinical situation at intervals of 2 to 3 minutes. Intravenous infusion of 2 mg of naloxone in 500 ml isotonic saline or 5% dextrose solution (corresponding to 0.004 mg naloxone/ml) is possible. The rate of infusion should be adjusted to the previous bolus injections and the response of the patient.

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

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.