OXYCODONE HYDROCHLORIDE GL PHARMA CONCENTRATED 10 MG / ML ORAL SOLUTION - Summary of medicine characteristics

Oxycodone Hydrochloride G.L. Pharma concentrated 10 mg/ml oral solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 10 mg oxycodone hydrochloride, corresponding to 9 mg oxycodone.

Excipients with known effect:

Each ml contains approx. 4.5 mg sodium and 0.15 mg Sunset yellow FCF (E 110)

For the full list of excipients, see section 6.1.

Oral solution

Oxycodone Hydrochloride G.L. Pharma concentrated 10 mg/ml oral solution is a clear orange-red-coloured solution.

4.1 Therapeutic indications

Severe pain, which requires opioid analgesics to be adequately managed.

For adults only.

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 (> 18 years of age)

The initial dose for opioid-naive 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. The need for continued treatment in non-malignant pain should be assessed at regular intervals.

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.

Paediatric population

Oxycodone Hydrochloride G.L. Pharma oral solution is not recommended for children and adolescents under 18 years of age.

Duration of treatment

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

If long-term treatment is necessary due to the type and severity of the illness, careful and regular monitoring is required to determine whether and to what extent treatment should be continued.

If long-term pain treatment is required, the patients should be switched to an alternative dosage form of oxycodone.

Discontinuation of treatment

When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

Method of administration

Oral use.

Oxycodone Hydrochloride G.L. Pharma oral solution should be taken every 46 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 concentrated 10 mg/ml oral solution is provided with a graduated oral syringe for conventional withdrawal or together with an adapter for over-head withdrawal. Each 1 ml graduation mark of the oral syringe corresponds to 10 mg oxycodone hydrochloride (see section 6.5).

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

– myxoedema, hypothyroidism

– Addison’s disease (adrenal insufficiency)

– intoxication psychosis (e.g. alcohol)

– prostatic hypertrophy

– alcoholism, known opioid dependence

– delirium tremens

– pancreatitis

– diseases of the biliary tract, biliary or ureteric colic

– conditions with increased brain pressure (including head injuries)

– disturbances of circulatory regulation (including hypotension, hypovolaemia)

– epilepsy or seizure tendency and

– in patients taking MAO inhibitors

– inflammatory bowel disorders

Opioids, such as oxycodone hydrochloride, may influence the hypothalamic-pituitaryadrenal 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.

Oxycodone Hydrochloride G.L. Pharma oral solution should be used with caution pre-or intra-operatively and within the first 12–24 hours post-operatively.

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.

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

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

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.

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).

Tolerance and dependence

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 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.

Abuse

Oxycodone has an abuse profile similar to other strong opioid agonists. Oxycodone Hydrochloride G.L. Pharma oral solution may be sought and abused by people with latent or manifest addictive disorders. There is potential for the development of psychological dependence [addiction] to opioid analgesics, including oxycodone. Oxycodone Hydrochloride G.L. Pharma oral solution should be used with particular care in patients with a history of alcohol and drug abuse.

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).

Abuse of oral dosage forms by parenteral administration can be expected to 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 enhace the frequency of adverse reactions.

Surgical procedures

Special care should be taken when oxycodone is used in patients undergoing bowelsurgery. Opioids should only be administered post-operatively when the bowel function has been restored.

Patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive Oxycodone Hydrochloride G.L. Pharma 1 mg/ml oral solution for 6 hours prior to the intervention. If further treatment with oxycodone is indicated the dosage should be adjusted to the new post-operative requirement.

Oxycodone Hydrochloride G.L. Pharma oral solution should be used with caution pre-operatively and within the first 12–24 hours post-operatively.

Sunset yellow (FCF)

This medical product contains the coloring agent sunset yellow (FCF) which may cause allergic reactions.

Sodium

This medical product contains approx. 4.5 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 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.

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.

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.

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

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

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.

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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics; Opioids; Natural opium alkaloids ATC code: N02AA05

Oxycodone shows an affinity to kappa, mu and delta opioid receptors in the brain and spinal cord. It acts at these receptors as an opioid agonist without an antagonistic effect. The therapeutic effect is mainly analgesic, anxiolytic and sedative.

5.2 Pharmacokinetic properties

Absorption

The mean absolute bioavailability of oxycodone is approximately 50%. A pharmacokinetic study in healthy volunteers has demonstrated that, following administration of a single 10 mg dose, oxycodone liquid 1 mg/ml and oxycodone concentrate 10 mg/ml provided an equivalent rate and extent of absorption of oxycodone. Mean peak plasma concentrations of approximately 20 ng/ml were achieved within 1.5 hours of administration, median tmax values from both strengths of liquid being less than 1 hour. Plasma concentrations are linear within a dose range of 5 to 20 mg.

Distribution

Approximately 45% is bound to plasma protein.

The volume of distribution at steady-state is 2.6 l/kg.

Biotransformation

Oxycodone is metabolised in the liver via CYP3A4 and CYP2D6 to noroxycodone, oxymorphone and noroxymorphone as well as to several glucuronide conjugates. The analgesic effect of the metabolites is considered clinically insignificant.

Elimination

Oxycodone and its metabolites are excreted via urine and faeces. Oxycodone has an elimination half-life of about 3 hours.

Special populations

The plasma concentrations of oxycodone are only minimally affected by age, being 15% greater in elderly as compared to young subjects.

Female subjects have, on average, plasma oxycodone concentrations up to 25% higher than males on a body weight adjusted basis.

When compared to normal subjects, patients with mild to severe hepatic dysfunction may have higher plasma concentrations of oxycodone and noroxycodone and lower plasma concentrations of oxymorphone. There may be an increase in the elimination half-life of oxycodone and this may be accompanied by an increase in drug effects.

When compared to normal subjects, patients with mild to severe renal dysfunction may have higher plasma concentrations of oxycodone and its metabolites. There may be an increase in the elimination half-life of oxycodone and this may be accompanied by an increase in drug effects.

5.3 Preclinical safety data

Studies 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.

Long-term carcinogenicity studies with oxycodone have not been conducted owing to the length of clinical experience with the drug substance.

Oxycodone shows 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 hydrochloride to humans at therapeutic concentrations may be ruled out with adequate certainty.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium benzoate

Saccharin sodium

Citric acid monohydrate

Sodium hydroxide (for pH-adjustment)

Sunset yellow FCF (E 110)

Water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years

After first opening: 3 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Amber glass bottle with child-resistant white polypropylene screw cap and a graduate oral syringe made of polyethylene together with an adapter. The syringes are graduated with marks of 0.5 ml and 1.0 ml. Each 1 ml graduation mark of the oral syringe corresponds to 10 mg oxycodone hydrochloride.

30 ml bottle with a 3 ml oral syringe and an adapter.

100 ml bottle with a 5 ml oral syringe and an adapter.

120 ml bottle with a 5 ml oral syringe and an adapter.

Not all pack sizes may be marketed.