Oxycodone Hydrochloride/ Naloxone Hydrochloride

Registered South African indications:

• Pain requiring the use of an opioid analgesic - moderate to severe
• Idiopathic restless legs syndrome (RLS) - severe to very severe
  - As second line symptomatic treatment after failure of dopaminergic therapy

Registered South African contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Moderate to severe renal impairment
• Moderate to severe hepatic impairment
• Non-opioid induced paralytic ileus
• Severe respiratory depression with hypoxia and/or hypercapnia
• Severe chronic obstructive pulmonary disease
• Cor pulmonale
• Severe bronchial asthma
• Central sleep apnoea
• Any situation where opioids are contraindicated
• History of opioid abuse (for patients with Restless Leg Syndrome)

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Mild renal impairment
• Mild hepatic impairment
• Elderly
• Infirm patients
• Opioid-induced paralytic ileus
• Severely impaired pulmonary function
• Sleep apnoea
• Hypothyroidism
• Alcoholism
• Predisposition to convulsions

Opioid excess

• The major risk of all opioid excess is respiratory depression

Sleep-related breathing disorders

• Opioids, such as oxycodone/naloxone, may cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxaemia, and is therefore not recommended for patients who present with CSA

Concomitant sedative medicines

• Concomitant use with sedative medicines such as benzodiazepines or related medicines 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/naloxone concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible
• Patients and their caregivers should be followed closely for signs and symptoms of respiratory depression and sedation

Monoamine oxidase inhibitors (MAOIs)

• Oxycodone/naloxone must be administered with caution in patients taking MAOIs or who have received MAOIs within the previous two weeks

Tolerance, physical dependence and withdrawal

• In patients under long-term opioid treatment with higher doses, the switch to oxycodone/naloxone can initially provoke withdrawal symptoms. Oxycodone/naloxone is not suitable for the treatment of withdrawal symptoms
• During long-term administration, the patient may develop tolerance and require higher doses to maintain the desired analgesic effect
• Hyperalgesia that will not respond to a further dose increase may occur, and a dose reduction or change in opioid may be required
• Chronic administration of oxycodone/naloxone may lead to physical dependence. If therapy is no longer required, it may be advisable to gradually reduce the daily dose to avoid withdrawal syndrome
• There is potential for psychological dependence (addiction) to opioid analgesics. oxycodone/naloxone should be used with particular care in patients with a history of alcohol and drug abuse
• Abusive parenteral, intranasal, or oral use is expected to produce marked withdrawal symptoms
• The prolonged-release tablets must be taken whole and not be broken, chewed, or crushed, as this can lead to the absorption of a possibly fatal dose of oxycodone

Effect on hormonal changes

• Opioids such as oxycodone may influence the hypothalamic-pituitary-adrenal or -gonadal axes, which can lead to hormonal changes

Considerations in cancer

• The use of oxycodone/naloxone is not recommended in patients with cancer associated with peritoneal carcinomatosis or with subocclusive syndrome in advanced stages of digestive and pelvic cancers

Additional precautions

• The empty prolonged-release tablet matrix may be visible in the stool
• The use of oxycodone/naloxone may produce positive results in doping controls
• It is not recommended for pre-operative use or within the first 12-24 hours postoperatively
• There is no experience with the use of oxycodone/naloxone in the paediatric population

Effects on ability to drive and use machines

• Oxycodone/naloxone may impair the ability to drive and use machines. This is particularly likely at the beginning of treatment, after dose increase or product rotation and if combined with alcohol or other CNS depressant agents
• Patients stabilised on a specific dosage will not necessarily be restricted. Advise patients on whether driving or the use of machinery is permitted

Forms avail. in SA and covered in this monograph: srt

South African registered indications and dosages

Pain requiring the use of an opioid analgesic - moderate to severe
- Initiation and dose titration in opioid naïve patient

Oxycodone/ Naloxone
5/2.5 (mg)
10/5 (mg)
20/10 (mg)
40/20 (mg)

• Oral (srt): 10/5 (mg), 12hrly; Titrate by 5/2.5 (mg) OR 10/5 (mg), 12hrly at 1-2 day intervals, until a stable dose is reached; Max: 80/40 (mg)/24hrs

- In those already receiving opioids

• Oral (srt): 20/10 (mg)-40/20 (mg), 12hrly; Titrate by 5/2.5 (mg) OR 10/5 (mg), 12hrly at 1-2 day intervals, based on patient's previous opioid dose, until a stable dose is reached; Max: 80/40 (mg)/24hrs

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The dosage should be adjusted to the intensity of pain and the sensitivity of the individual patient

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Those taking oxycodone/ naloxone prolonged release tablets according to a regular time schedule may require immediate-release analgesics as "rescue" medication for breakthrough pain (for which prolonged-release tablets are not intended). 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 oxycodone/ naloxone prolonged release tablets requires upward adjustment
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

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Idiopathic restless legs syndrome (RLS) for at least 6 months - severe to very severe
- As second line symptomatic treatment after failure of dopaminergic therapy and symptoms are present daily and during daytime ≥4 days/week

Oxycodone/ Naloxone
5/2.5 (mg)
10/5 (mg)
20/10 (mg)
40/20 (mg)

• Oral (srt): Initial: 5/2.5 (mg), 12hrly; Titrate on a weekly basis in case higher doses are required; Maintenance: 10/5 (mg), 12hrly; Max: 60/30 (mg)/24hrs

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The mean daily dose in the pivotal study was 20mg/10mg oxycodone hydrochloride/naloxone hydrochloride. Some patients may benefit from higher daily doses up to a maximum of 60mg/30mg oxycodone hydrochloride/naloxone hydrochloride

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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

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For all indications, while symmetric administration (the same dose mornings and evenings) subject to a fixed time schedule (12hrly) 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

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Method of administration
Oxycodone/ naloxone is for oral administration and must be swallowed whole and not broken or chewed. It may be taken with or without food with sufficient liquid

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Treatment of patients with RLS with oxycodone/ naloxone should be under the supervision of a clinician with experience in the management of RLS

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Duration of use
Oxycodone/ naloxone should not be administered for longer than absolutely necessary. If long-term pain treatment is necessary in view the nature and severity of the illness, careful and regular monitoring is required to establish whether and to what extent further treatment is necessary. When the patient no longer requires opioid therapy, it may be advisable to taper the dose gradually

There is no clinical experience with oxycodone/ naloxone in the long-term treatment of RLS beyond 1 year

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Caution; not recommended
• Oxycodone/naloxone prolonged-release tablets are not recommended for use in pregnancy or during labour. Both oxycodone and naloxone pass into the placenta
• 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

Breastfeeding

South African recommendations

• Caution; not recommended 
• Oxycodone/naloxone prolonged-release tablets should not be used in mothers breastfeeding their infants as oxycodone passes into the breast milk

Fertility

South African recommendations

• No human data on the effect of oxycodone and naloxone on fertility are available. In rats, there was no effect on mating or fertility during treatment

South African recommendations

• Mild: Caution; no dose adjustment recommended 
• Moderate to severe: Contraindicated 

South African recommendations

• Mild: Caution; no dose adjustment recommended 
• Moderate to severe: Contraindicated 

South African recommendations

• Caution; no dose adjustment recommended

Immune System Disorders

Uncommon

• Hypersensitivity

Metabolism and Nutrition Disorders

Common

• Decreased appetite up to loss of appetite

Psychiatric Disorders

Common

• Restlessness
• Insomnia

Uncommon

• Abnormal thinking
• Anxiety
• Confusional state
• Depression
• Libido decreased
• Euphoric mood
• Hallucination
• Nervousness

Rare

• Nightmares

Very rare

• Aggression

Not known

• Drug dependence

Nervous System Disorders

Common

• Dizziness
• Headache
• Somnolence

Uncommon

• Convulsions (particularly in persons with epileptic disorder or predisposition to convulsions)
• Disturbance in attention
• Paraesthesia
• Dysgeusia
• Speech disorder
• Syncope tremor
• Lethargy

Rare

• Sedation

Eye Disorders

Uncommon

• Visual impairment

Ear and Labyrinth Disorders

Common

• Vertigo

Cardiac Disorders

Uncommon

• Angina pectoris in particular in patients with a history of coronary artery disease
• Palpitations (in the context of withdrawal syndrome)

Rare

• Tachycardia

Vascular Disorders

Common

• Hot flush
• Decrease in blood pressure

Uncommon

• Blood pressure increased

Respiratory, Thoracic and Mediastinal Disorders

Uncommon

• Dyspnoea
• Rhinorrhoea
• Cough

Rare

• Yawning

Very rare

• Respiratory depression
• Central sleep apnoea syndrome

Gastrointestinal Disorders

Common

• Abdominal pain
• Constipation
• Diarrhoea
• Dry mouth
• Dyspepsia
• Flatulence
• Vomiting
• Nausea

Uncommon

• Abdominal distension
• Eructation

Rare

• Tooth disorder

Hepatobiliary Disorders

Common

• Increased hepatic enzymes

Uncommon

• Biliary colic

Reproductive System and Breast Disorders

Uncommon

• Erectile dysfunction

Skin and Subcutaneous Tissue Disorders

Common

• Pruritus
• Rash
• Hyperhidrosis

Musculoskeletal and Connective Tissue Disorders

Uncommon

• Muscle spasms
• Muscle twitching
• Myalgia

Renal and Urinary Disorders

Uncommon

• Micturition urgency

Rare

• Urinary retention

General Disorders and Administration Site Conditions

Common

• Feeling hot and cold
• Chills
• Asthenia
• Fatigue

Uncommon

• Chest pain
• Malaise
• Pain
• Oedema peripheral
• Weight decrease
• Thirst

Rare

• Weight increase

Not known

• Drug withdrawal syndrome

Injury and Poisoning

Uncommon

• Injuries from accidents

Oxycodone Hydrochloride

Infections and Infestations

Rare

• Herpes simplex

Immune System Disorders

Very rare

• Anaphylactic responses

Metabolism and Nutrition Disorders

Uncommon

• Dehydration

Rare

• Increased appetite

Psychiatric Disorders

Common

• Altered mood and personality change
• Decreased activity
• Psychomotor hyperactivity
• Agitation

Uncommon

• Perception disturbances (e.g. derealisation)
• Reduced libido

Nervous System Disorders

Uncommon

• Concentration impaired
• Migraine
• Dysgeusia
• Hypertonia
• Involuntary muscle contractions
• Hypoaesthesia
• Abnormal coordination

Not known

• Hyperalgesia

Eye Disorders

Uncommon

• Miosis

Ear and Labyrinth Disorders

Uncommon

• Impaired hearing

Vascular Disorders

Uncommon

• Vasodilatation

Respiratory, Thoracic and Mediastinal Disorders

Uncommon

• Dysphonia

Gastrointestinal Disorders

Common

• Hiccups

Uncommon

• Mouth ulceration
• Stomatitis
• Dysphagia
• Ileus

Rare

• Melaena
• Gingival bleeding

Not known

• Dental caries

Hepatobiliary Disorders

Not known

• Cholestasis
• Sphincter of Oddi dysfunction

Skin and Subcutaneous Tissue Disorders

Uncommon

• Dry skin

Rare

• Urticaria

Renal and Urinary Disorders

Common

• Dysuria

Reproductive System and Breast Disorders

Uncommon

• Hypogonadism

Rare

• Amenorrhoea

General Disorders and Administration Site Conditions

Uncommon

• Oedema

Rare

• Thirst

Not known

• Drug withdrawal syndrome neonatal
• Drug tolerance

Adverse events identified through post marketing experience

Rare

• Increased risk of abdominal pain, including pancreatitis has been reported

• Central nervous system depressant agents
• Benzodiazepines
• Other opioids
• Gabapentinoids
• Pregabalin
• Anxiolytics
• Hypnotics
• Sedatives
• Antipsychotics
• Antidepressants
• Phenothiazines
• Monoamine oxidase inhibitors (MAOIs)
• Warfarin
• Serotonin agents
• Serotonin Re-uptake Inhibitor (SSRI)
• Serotonin Norepinephrine Re-uptake Inhibitor (SNRI)
• Anticholinergics
• Tricyclic antidepressants
• Antihistamines
• Antipsychotics
• Muscle relaxants
• Anti-Parkinson medicines
• CYP3A4 inhibitors
• Macrolide antibiotics
• Clarithromycin
• Azole antifungal agents
• Ketoconazole
• Protease inhibitors
• Ritonavir
• CYP3A4 inducers
• Rifampin
• Carbamazepine
• Phenytoin
• CYP2D6 inhibitors
• Paroxetine
• Quinidine

Other interactions

• Alcohol
• Grapefruit juice
• St. John’s Wort

Observations

• Signs of Opioid Use Disorder (OUD)
• Clinical symptoms that may arise from hormonal changes such as increase in serum prolactin and a decrease in plasma cortisol and testosterone
• Signs and symptoms of respiratory depression

 

Oxycodone and naloxone have an affinity for kappa, mu and delta opiate receptors in the brain, spinal cord and peripheral organs (e.g. intestine). Opioids may induce spasm of the sphincter of Oddi.

Oxycodone Hydrochloride

Oxycodone acts as opioid-receptor agonist at these receptors and affects pain relief by binding to the endogenous opioid receptors in the CNS. Opioids can influence the hypothalamic-pituitary-adrenal or gonadal axes. Among the changes observed are an increase of prolactin in the serum and a reduced level of cortisol and testosterone in the plasma. Clinical symptoms may occur because of these hormone changes.

Naloxone Hydrochloride

Naloxone is a pure antagonist acting on all types of opioid receptors. The absolute bioavailability of naloxone upon oral administration is < 3%. Naloxone antagonises the opioid receptor mediated oxycodone effect. The opioid antagonist naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut. The benefit of naloxone is achieved locally in the GI tract.

COMBINATION PREPARATIONS

Naloxone/ Oxycodone

Tablet SRT 2.5/5mg 

• Targinact (Mundipharma) originator

Tablet SRT 5/10mg 

• Targinact (Mundipharma) originator

Tablet SRT 10/20mg 

• Targinact (Mundipharma) originator

Tablet SRT 20/40mg

• Targinact (Mundipharma) originator