Naloxone + Oxycodone (Tablets) Instructions for Use

Marketing Authorization Holder

Moscow Endocrine Plant FSUE (Russia)

ATC Code

N02AA55 (Oxycodone and naloxone)

Active Substances

Naloxone (Rec.INN registered by WHO)

Oxycodone (Rec.INN registered by WHO)

Dosage Forms

	Naloxone + Oxycodone	Prolonged-release film-coated tablets, 2.5 mg+5 mg: 20 pcs.
		Prolonged-release film-coated tablets, 5 mg+10 mg: 20 pcs.
		Prolonged-release film-coated tablets, 10 mg+20 mg: 20 pcs.
		Prolonged-release film-coated tablets, 20 mg+40 mg: 20 pcs.

Dosage Form, Packaging, and Composition

Prolonged-release film-coated tablets

10 pcs. – contour cell packs (2) – cardboard packs.

Prolonged-release film-coated tablets

10 pcs. – contour cell packs (2) – cardboard packs.

Prolonged-release film-coated tablets

10 pcs. – contour cell packs (2) – cardboard packs.

Prolonged-release film-coated tablets

10 pcs. – contour cell packs (2) – cardboard packs.

Clinical-Pharmacological Group

Opioid receptor agonist-antagonist. Analgesic

Pharmacotherapeutic Group

Analgesics; opioids; natural opium alkaloids

Pharmacological Action

A combined opioid analgesic. Naloxone and oxycodone have affinity for opioid κ-, μ- and δ-receptors in the brain and spinal cord, and peripheral organs (e.g., the intestine). Oxycodone acts as an agonist of opioid receptors and functions as an analgesic by binding to endogenous opioid receptors in the CNS. Naloxone, in contrast, is a full antagonist acting on all types of opioid receptors.

Due to a pronounced first-pass effect, the bioavailability of naloxone when taken orally is less than 3%, so a clinically significant systemic effect is unlikely. Due to local competitive antagonism of the effect of oxycodone on opioid receptors in the intestine, naloxone reduces the severity of intestinal dysfunction typical of opioid treatment.

Opioids can affect the hypothalamic-pituitary-adrenal system or the gonads. An increase in serum prolactin concentration and a decrease in plasma cortisol and testosterone concentrations are noted. Clinical symptoms may be explained by these hormonal changes.

Results of preclinical studies have shown multidirectional effects of natural opioids on components of the immune system. The clinical significance of these observations has not been established. It is unknown whether oxycodone, a semi-synthetic opioid, has an effect on the immune system similar to natural opioids.

Opioids can cause spasm of the sphincter of Oddi.

Naloxone, which can reduce the manifestations of opioid-induced constipation by blocking the action of oxycodone on intestinal opioid receptors.

Pharmacokinetics

Oxycodone hydrochloride

After oral administration, oxycodone exhibits high absolute bioavailability, reaching 87%. After absorption, oxycodone is distributed throughout the body. About 45% binds to plasma proteins. Oxycodone crosses the placental barrier and is found in breast milk.

Oxycodone is metabolized in the intestine and liver to form noroxycodone, oxymorphone, and various metabolites in the form of glucuronides. Cytochrome P450 system isoenzymes are involved in the formation of noroxycodone, oxymorphone, and noroxymorphone. Quinidine reduces the formation of oxymorphone in humans without significantly affecting the pharmacodynamic effects of oxycodone. The contribution of metabolites to the overall pharmacodynamic effect is insignificant.

Oxycodone and its metabolites are excreted by the kidneys and through the intestine.

Naloxone hydrochloride

When taken orally, naloxone has very low systemic bioavailability – less than 3%. Naloxone crosses the placental barrier. It is not known whether naloxone passes into breast milk.

It is metabolized in the liver and excreted by the kidneys. The main metabolites are naloxone glucuronide, 6β-naloxol and its glucuronide.

Oxycodone hydrochloride+Naloxone hydrochloride

After oral administration of the drug at the maximum dose to healthy volunteers, the plasma concentration of naloxone is so low that pharmacokinetic analysis is not possible. Therefore, naloxone-3-glucuronide was used as a surrogate marker, since its plasma concentration is sufficient for measurement.

In general, when taking a high-fat meal compared to taking on an empty stomach, the bioavailability and C_max of oxycodone in plasma increase by an average of 16% and 30%, respectively. Nevertheless, the drug can be taken regardless of food intake.

Results of in vitro metabolism studies have shown that the development of clinically significant interaction with the components of the drug is unlikely.

Indications

Severe pain syndrome in adults requiring the use of opioid analgesics.

ICD codes

Dosage Regimen

Orally, 2 times/day.

This product in the form of prolonged-release tablets is not intended for the treatment of acute pain syndrome.

The initial dose for adult patients who have not previously taken opioids is 10 mg/5 mg of oxycodone hydrochloride/naloxone hydrochloride, respectively, every 12 hours. Patients who have previously taken opioids may require higher doses depending on the duration of previous therapy.

The maximum daily dose of the drug is 160 mg of oxycodone hydrochloride and 80 mg of naloxone hydrochloride. The maximum daily dose should be used only in those patients who are already receiving a stable daily dose of this combination and who require its increase.

The dose should be increased gradually: every 1-2 days with twice-daily administration, the dose of this product can be increased by 5 mg/2.5 mg, and if necessary, by 10 mg/5 mg of oxycodone hydrochloride/naloxone hydrochloride, respectively, until a stable therapeutic dose is achieved.

The use of this product should not be longer than absolutely necessary. If the patient requires a long course of pain therapy, taking into account the type and severity of the disease, careful and regular monitoring should be organized to decide on the need and intensity of the planned treatment. If opioid therapy is no longer indicated, the dose should be reduced gradually.

Adverse Reactions

From the immune system uncommon – hypersensitivity reactions.

Psychiatric disorders common – insomnia; uncommon – anxiety, unusual thoughts, anxiety, confusion, depression, nervousness, decreased libido; frequency unknown – euphoria, hallucinations, nightmares.

From the nervous system common – dizziness, headache, drowsiness; uncommon – seizures (typical for patients with epilepsy or increased seizure activity), decreased attention, speech impairment, loss of consciousness, tremor, drowsiness, dysgeusia; frequency unknown – paresthesia, lethargy.

From the organ of vision uncommon – visual perception disorder.

From the organ of hearing and balance common – vertigo.

From the cardiovascular system common – flushing; uncommon – angina pectoris (typical for patients with a history of coronary artery disease), palpitations (typical for withdrawal syndrome), decreased blood pressure, increased blood pressure; rare – tachycardia.

From the respiratory system uncommon – dyspnea, runny nose, cough; frequency unknown – respiratory depression.

From the digestive system common – decreased appetite up to its loss, abdominal pain, constipation, diarrhea, dry mouth, dyspepsia, vomiting, nausea, flatulence; uncommon – abdominal distension, increased activity of liver enzymes, biliary colic; rare – dental diseases; frequency unknown – belching.

From the urinary system uncommon – imperative urge to urinate; frequency unknown – urinary retention.

From the reproductive system and mammary gland frequency unknown – erectile dysfunction.

From the skin and subcutaneous tissues common – itching, rash, hyperhidrosis.

From the musculoskeletal system uncommon – muscle spasms, muscle twitching, myalgia.

Other common – asthenia, increased fatigue; uncommon – withdrawal syndrome, chest pain, chills, malaise, pain, peripheral edema, weight loss, thirst, injury due to accidents; rare – weight gain.

Oxycodone hydrochloride

Due to the pharmacological action, Oxycodone hydrochloride can cause respiratory depression, miosis, bronchospasm and spasm of smooth muscles, and also suppress the cough reflex.

Allergic reactions frequency unknown – anaphylactic reactions.

From metabolism uncommon – dehydration.

Psychiatric disorders common – mood disorders and personality changes, decreased activity, increased psychomotor activity; uncommon – agitation, impaired perception of reality (e.g., loss of sense of reality of what is happening), drug dependence; frequency unknown – aggression.

From the nervous system uncommon – decreased attention, migraine, involuntary muscle twitching, hypoesthesia, impaired coordination; frequency unknown – hyperalgesia.

From the organ of vision uncommon – miosis.

From the organ of hearing uncommon – hearing loss.

From the cardiovascular system common – vasodilation; uncommon – increased blood pressure.

From the respiratory system uncommon – dysphonia.

From the digestive system common – hiccups; uncommon – dysphagia, intestinal obstruction, ulcer of the oral mucosa, stomatitis, cholestasis; rare – increased appetite, melena, gum bleeding; frequency unknown – dental caries.

From the skin and subcutaneous tissue uncommon – dry skin; rare – rashes.

From the urinary system common – dysuria.

From the reproductive system and mammary gland uncommon – hypogonadism; frequency unknown – amenorrhea.

Other uncommon – edema, drug tolerance, injury due to accidents; rare – herpes simplex; frequency unknown – neonatal withdrawal syndrome.

Contraindications

Any clinical condition of the patient in which the use of opioids is contraindicated; respiratory depression with hypoxia and/or hypercapnia; severe COPD; cor pulmonale; severe bronchial asthma; non-opioid paralytic intestinal obstruction; moderate and severe hepatic insufficiency; age under 18 years; hypersensitivity to naloxone and/or oxycodone.

With caution

Renal insufficiency, mild hepatic insufficiency, elderly patients over 65 years of age.

Use in Pregnancy and Lactation

Pregnancy

Limited use of oxycodone in pregnant women has not revealed an increased risk of congenital anomalies. Data on the use of naloxone during pregnancy are insufficient. However, the systemic exposure of naloxone in women after taking the drug is relatively low. Both oxycodone and naloxone cross the placental barrier. Separate studies of the toxicity of oxycodone and naloxone in animals did not reveal a teratogenic or embryotoxic effect.

With long-term use of oxycodone during pregnancy, the newborn may develop withdrawal syndrome. When oxycodone is used during childbirth, the newborn may experience respiratory depression. The use of the drug during pregnancy is possible if the benefit to the mother outweighs the potential risk to the fetus and newborn.

Lactation period

Oxycodone passes into breast milk. The milk-to-plasma concentration ratio is 3.4:1, so it is very likely that oxycodone will exert its effect on the breastfed infant. There are no data on the passage of naloxone into breast milk. It has been noted that the systemic concentration of naloxone after taking the drug is very low. The risk to the breastfed infant cannot be ruled out, especially with repeated use of the drug by the nursing mother. Breastfeeding should be discontinued during the use of the drug.

Pediatric Use

Children and adolescents under 18 years of age.

Geriatric Use

In elderly patients, the dose is selected taking into account the intensity of pain and individual sensitivity to the components of the combination.

Special Precautions

The most serious consequence of opioid overdose is respiratory depression. Caution should be exercised when prescribing the drug to elderly or debilitated patients, patients with opioid-induced paralytic ileus, severe respiratory disorders, sleep apnea syndrome, myxedema, hypothyroidism, Addison’s disease (adrenal insufficiency), toxic psychosis, alcoholism and alcoholic delirium, cholelithiasis, prostatic hyperplasia, pancreatitis, increased or decreased blood pressure, history of coronary artery disease, head injury (risk of increased intracranial pressure), epilepsy or predisposition to convulsions, or patients simultaneously taking MAO inhibitors.

Diarrhea may be considered an expected adverse reaction to naloxone.

Transferring patients who have been taking opioids for a long time to the combined drug may cause withdrawal syndrome or diarrhea at the beginning of treatment. Such patients should be given special attention.

This product is not intended for the treatment of withdrawal symptoms.

During long-term use of this product, the patient may develop resistance, so higher doses of the drug will be required to maintain the analgesic effect. Prolonged use of the drug can cause physical dependence. With sudden discontinuation of therapy, withdrawal syndrome may develop. If the need for therapy with the drug has ended, the dose should be gradually reduced to avoid the development of withdrawal syndrome.

There is a risk of developing psychological dependence (addiction) to opioid analgesics. Therefore, this product should be used with extreme caution in patients with a history of alcohol or drug dependence.

Given the possibility of an additive effect, this product should be used with caution in patients taking other sedative drugs.

Simultaneous consumption of alcohol should be avoided, as adverse reactions of the drug may be enhanced.

There is no clinical experience with the use of this product in patients with complications of malignant tumors in the form of peritoneal carcinomatosis or with partial occlusion syndrome in common tumors of the gastrointestinal tract or pelvic area, so the use of this product in such patients is not recommended.

The drug is not recommended for use before surgery or within the first 12-24 hours after surgery. Subsequent use of the drug is possible after a thorough assessment of the benefit-risk ratio for each patient, taking into account the type and volume of surgery performed, the type of anesthesia, other simultaneously taken drugs and the general condition of the patient.

Any abuse of the drug by patients with drug dependence is highly undesirable. In patients with opioid dependence (parenteral, intranasal and oral administration), such as heroin, morphine or methadone, the drug will cause withdrawal syndrome due to the opioid receptor antagonist – naloxone, or enhance existing withdrawal symptoms.

The drug is a dual polymer matrix intended exclusively for oral administration. Parenteral administration of the drug components (especially talc) by patients with drug dependence can lead to the development of local tissue necrosis and granulomatosis of the lungs or other serious, fatal adverse reactions.

The empty matrix that provides prolonged release of the active substance from the tablet may be found in the patient’s stool.

While using the drug, the results of doping control may be positive. Taking the drug as a dope can be harmful to health.

Effect on the ability to drive vehicles and mechanisms

The drug may affect the ability to drive vehicles and operate machinery. This is especially likely at the beginning of therapy with the drug, after increasing the dose or after switching to other drugs, as well as when used simultaneously with other drugs that depress the activity of the central nervous system. A mandatory preliminary consultation with the attending physician is required before driving vehicles or working with other mechanisms.

Drug Interactions

Results of in vitro metabolism studies indicate that clinically significant interaction between oxycodone and naloxone is not expected.

Concomitantly used drugs that depress the central nervous system (e.g., ethanol, other opioids, sedatives and hypnotics, antidepressants, phenothiazines, neuroleptics, antihistamines and antiemetics), may enhance the depressive effect of the combined drug on the central nervous system.

Concomitant use of oxycodone with anticholinergic drugs or drugs with anticholinergic activity (e.g., tricyclic antidepressants, antihistamines, antipsychotics, muscle relaxants, antiparkinsonian drugs), may be accompanied by an increase in anticholinergic adverse reactions.

Ethanol may enhance the pharmacodynamic effects of the drug, so concomitant use with alcohol should be avoided.

In patients concomitantly taking oxycodone and coumarin derivative anticoagulants, clinically significant changes in INR values in both directions have been observed.

Inhibitors of the CYP3A4 isoenzyme, such as macrolide antibiotics (clarithromycin, erythromycin, telithromycin), azole antifungals (ketoconazole, voriconazole, itraconazole, posaconazole), HIV protease inhibitors (ritonavir, indinavir, nelfinavir, saquinavir), cimetidine, and grapefruit juice may reduce the clearance of oxycodone and lead to an increase in its plasma concentration. In this case, a dose reduction and subsequent retitration may be required.

Inducers of the CYP3A4 isoenzyme, such as rifampicin, carbamazepine, phenytoin, and St. John’s wort, may activate metabolism and increase the clearance of the drug, resulting in a decrease in the plasma concentration of oxycodone. Caution should be exercised, and furthermore, additional dose titration may be required for adequate pain control.

Theoretically, inhibitors of the CYP2D6 isoenzyme, such as paroxetine, fluoxetine, and quinidine, may reduce the clearance of oxycodone and accordingly increase the plasma concentration of oxycodone. Concomitant use with CYP2D6 isoenzyme inhibitors had a minor effect on the elimination of oxycodone and its pharmacodynamic effects.

The likelihood of clinically significant interaction between paracetamol, acetylsalicylic acid, or naltrexone and the combination of oxycodone and naloxone at therapeutic concentrations is minimal.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.