Targin^® (Tablets) Instructions for Use

Marketing Authorization Holder

Mundipharma, Ges.m.b.H. (Austria)

Manufactured By

Bard Pharmaceuticals Ltd (United Kingdom)

Packaging and Quality Control Release

BARD PHARMACEUTICALS, Ltd. (United Kingdom)

Or

MUNDIPHARMA, GmbH (Germany)

Or

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

	Targin®	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 blue, oblong, biconvex, engraved with “5” on one side and “OXN” on the other side; white in cross-section.

Excipients: hypromellose – 5 mg, ethylcellulose (N45) – 20 mg, stearyl alcohol – 25 mg, lactose monohydrate – 71.75 mg, talc – 2.5 mg, magnesium stearate – 1.25 mg.

Shell composition Opadry II blue 85F30569 – 4 mg (partially hydrolyzed polyvinyl alcohol – 1.6 mg, titanium dioxide (E171) – 1 mg, macrogol 3350 – 0.81 mg, talc – 0.59 mg, brilliant blue (E133) – 0.004 mg), talc – 0.28 mg.

10 pcs. – blisters (2) – cardboard packs.

Prolonged-release film-coated tablets white, oblong, biconvex, engraved with “10” on one side and “OXN” on the other side; white in cross-section.

Excipients: povidone (K30) – 5 mg, ethylcellulose (N45) – 10 mg, stearyl alcohol – 25 mg, lactose monohydrate – 64.25 mg, talc – 2.5 mg, magnesium stearate – 1.25 mg.

Shell composition Opadry II white 85F18422 – 3.72 mg (partially hydrolyzed polyvinyl alcohol – 1.49 mg, titanium dioxide (E171) – 0.93 mg, macrogol 3350 – 0.75 mg, talc – 0.55 mg), talc – 0.12 mg.

10 pcs. – blisters (2) – cardboard packs.

Prolonged-release film-coated tablets pink, oblong, biconvex, engraved with “20” on one side and “OXN” on the other side; white in cross-section.

Excipients: povidone (K30) – 7.25 mg, ethylcellulose (N45) – 12 mg, stearyl alcohol – 29.5 mg, lactose monohydrate – 54.5 mg, talc – 2.5 mg, magnesium stearate – 1.25 mg.

Shell composition Opadry II pink 85F24151 – 4.17 mg (partially hydrolyzed polyvinyl alcohol – 1.67 mg, titanium dioxide (E171) – 0.61 mg, macrogol 3350 – 0.84 mg, talc – 0.61 mg, iron oxide red (E172) – 0.01 mg), talc – 0.14 mg.

10 pcs. – blisters (2) – cardboard packs.

Prolonged-release film-coated tablets pink, oblong, biconvex, engraved with “40” on one side and “OXN” on the other side; white in cross-section.

Excipients: povidone (K30) – 14.5 mg, ethylcellulose (N45) – 24 mg, stearyl alcohol – 59 mg, lactose monohydrate – 109 mg, talc – 5 mg, magnesium stearate – 2.5 mg.

Shell composition Opadry II yellow 85F32109 – 8.33 mg (partially hydrolyzed polyvinyl alcohol – 3.34 mg, titanium dioxide (E171) – 1.23 mg, macrogol 3350 – 1.68 mg, talc – 1.23 mg, iron oxide yellow (E172) – 0.28 mg), talc – 0.28 mg.

10 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Opioid receptor agonist-antagonist. Analgesic

Pharmacotherapeutic Group

Opioid analgesic agent: opioid receptor agonist-antagonist

Pharmacological Action

Naloxone and oxycodone have affinity for κ- (kappa-), µ- (mu-) and δ- (delta-) opioid receptors in the brain and spinal cord, and peripheral organs (e.g., the intestine). Oxycodone acts as an agonist at opioid receptors and produces analgesia 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 pronounced presystemic metabolism (first-pass effect), the bioavailability of naloxone after oral administration is less than 3%, so clinically significant systemic effects are unlikely. Due to local competitive antagonism of the effect of oxycodone on opioid receptors in the intestine, naloxone reduces the severity of bowel dysfunction typical during opioid treatment.

In a 12-week double-blind, parallel-group study involving 322 patients with opioid-induced constipation, patients receiving the Oxycodone hydrochloride/naloxone hydrochloride combination had on average one additional complete spontaneous (without laxatives) bowel movement during the last week of therapy compared to patients who continued to use similar doses of oxycodone hydrochloride in prolonged-release tablets (p<0.0001). The use of laxatives during the first four weeks of therapy was significantly lower in the oxycodone/naloxone group compared to the oxycodone monotherapy group (31% and 55%, respectively, p<0.0001). Similar results were obtained in a study of 265 non-oncological patients using Oxycodone hydrochloride/naloxone hydrochloride in doses from 60 mg/30 mg to 80 mg/40 mg compared to a similar range of oxycodone hydrochloride doses.

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 observed. Clinical symptoms may be explained by these hormonal changes.

Results from 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 not known 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.

Pharmacokinetics

Oxycodone hydrochloride

Absorption

After oral administration, oxycodone exhibits high absolute bioavailability, reaching 87%.

Distribution

After absorption, oxycodone is distributed throughout the body. About 45% is bound to plasma proteins. Oxycodone crosses the placental barrier and is found in breast milk.

Metabolism

Oxycodone is metabolized in the intestine and liver to form noroxycodone, oxymorphone, and various metabolites in the form of glucuronides. Cytochrome P450 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 negligible.

Elimination

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

Naloxone hydrochloride

Absorption

When taken orally, naloxone has very low systemic bioavailability – less than 3%.

Distribution

Naloxone crosses the placental barrier. It is not known whether naloxone passes into breast milk.

Metabolism and Elimination

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

Combination Oxycodone hydrochloride/naloxone hydrochloride (Targin^®)

The pharmacokinetic properties of oxycodone contained in Targin^® correspond to the properties of oxycodone in the prolonged-release tablet dosage form taken together with prolonged-release naloxone tablets.

All dosages of Targin^® are interchangeable.

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

Overall, when taken with a high-fat meal compared to fasting, the bioavailability and C_max of oxycodone in plasma increase by an average of 16% and 30%, respectively. Nevertheless, Targin^® tablets can be taken regardless of food intake.

Results from in vitro metabolism studies indicate that the development of clinically significant interactions with the components of the drug is unlikely.

Pharmacokinetics in special patient groups

Elderly patients

Oxycodone. In elderly patients compared to young volunteers, the AUC_t value of oxycodone increased on average to 118%. The C_max of oxycodone increased on average to 114%. The C_min of oxycodone increased on average to 128%.

Naloxone. In elderly patients compared to young volunteers, the AUC_t value of naloxone increased on average to 182%. The C_max of naloxone increased on average to 173%. The C_min of naloxone increased on average to 317%.

Naloxone-3-glucuronide. In elderly patients compared to young volunteers, the AUC_t value of naloxone-3-glucuronide increased on average to 128%. The C_max of naloxone-3-glucuronide increased on average to 127%. The C_min of oxycodone increased on average to 125%.

Patients with impaired liver function

Oxycodone. In patients with mild, moderate and severe liver failure compared to healthy volunteers, the AUC_∞ value of oxycodone increased on average to 143, 319 and 310%, respectively. The C_max of oxycodone increased on average to 120, 201 and 191%, and the T_1/2Z values increased on average to 108, 176 and 183%, respectively.

Naloxone. In patients with mild, moderate and severe liver failure compared to healthy volunteers, the AUC_t value of naloxone increased on average to 411, 11,518 and 10,666%, respectively. The C_max of naloxone increased on average to 193, 5292 and 5252%, respectively. Due to insufficient data, T_1/2Z values and corresponding AUC_∞ values for naloxone were not calculated. Therefore, comparison of naloxone bioavailability was based on AUC_t values.

Naloxone-3-glucuronide. In patients with mild, moderate and severe liver failure compared to healthy volunteers, the AUC_∞ value of naloxone-3-glucuronide increased on average to 157, 128 and 125%, respectively. The C_max of naloxone-3-glucuronide increased on average to 141, 118% and decreased to 98%, and the T_1/2Z values of naloxone-3-glucuronide increased on average to 117%, and decreased to 77 and to 94%, respectively.

Patients with impaired renal function

Oxycodone. In patients with mild, moderate and severe renal failure compared to healthy volunteers, the AUC_∞ value of oxycodone increased on average to 153, 166 and 224%, respectively. The C_max of oxycodone increased on average to 110, 135 and 167%, and the T_1/2Z values of oxycodone increased on average to 149, 123 and 142%, respectively.

Naloxone. In patients with mild, moderate and severe renal failure compared to healthy volunteers, the AUC_t value of naloxone increased on average to 2850, 3910 and 7612%, respectively. The C_max of naloxone increased on average to 1076, 858 and 1675%, respectively. Due to insufficient data, T_1/2Z values and corresponding AUC_∞ values for naloxone were not calculated. Therefore, comparison of naloxone bioavailability was based on AUC_t values. The calculated ratio values may have been influenced by the inability to fully characterize naloxone plasma profiles in healthy volunteers.

Naloxone-3-glucuronide. In patients with mild, moderate and severe renal failure compared to healthy volunteers, the AUC_∞ value of naloxone-3-glucuronide increased on average to 220, 370 and 525%, respectively. The C_max of naloxone-3-glucuronide increased on average to 148, 202 and 239%, respectively. No significant differences in the T_1/2Z value of naloxone-3-glucuronide were observed on average in patients with renal failure compared to healthy volunteers.

Misuse

To avoid compromising the prolonged-release properties, the tablets should be swallowed whole, not broken, chewed or crushed. If a prolonged-release tablet is broken, chewed or crushed, the active substances are released more quickly, which can lead to the absorption of a potentially fatal dose of oxycodone, as well as a marked increase in systemic exposure to naloxone. Furthermore, after intranasal administration, an effective (antagonistic) plasma concentration of naloxone will persist for several hours. Both properties act as protective against misuse of prolonged-release naloxone/oxycodone tablets. Intentional parenteral administration of drugs intended for oral use can lead to the development of serious adverse drug reactions, including fatal ones. In oxycodone-dependent rats, intravenous administration of oxycodone hydrochloride/naloxone hydrochloride in a 2:1 ratio led to the development of withdrawal syndrome.

Indications

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

The drug contains naloxone, which may reduce the manifestations of opioid-induced constipation by blocking the effect of oxycodone on intestinal opioid receptors.

ICD codes

Dosage Regimen

The drug is taken orally.

Targin^® should be taken 2 times a day, in an individually selected dose. The prolonged-release tablets can be taken with or without food with a sufficient amount of liquid. The tablet should be swallowed whole, not broken, chewed or crushed.

The dose of the drug is selected taking into account the intensity of the pain syndrome and the patient’s sensitivity. Unless otherwise prescribed, Targin^® is prescribed as follows

Adults

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

Targin^® in the 5 mg/2.5 mg dosage is intended for dose titration at the beginning of treatment, taking into account individual patient sensitivity.

The maximum daily dose of Targin^® is 160 mg of oxycodone hydrochloride and 80 mg of naloxone hydrochloride. The maximum daily dose should be prescribed only to those patients who are already receiving a stable daily dose of Targin^® and who required its increase. When deciding to increase the dose of the drug, special attention should be paid to patients with impaired renal function and mild hepatic impairment.

After completion of treatment with Targin^® and subsequent prescription of another opioid to the patient, gastrointestinal dysfunction may occur.

To relieve acute pain, some patients regularly taking Targin^® require an additional fast-acting analgesic. Since Targin^® is available in a prolonged-release dosage form, the drug is not intended for the treatment of acute pain syndrome. To relieve acute pain, fast-acting analgesics should be prescribed in a dose approximately equal to 1/6 of the daily dose of oxycodone hydrochloride. If more than two additional doses of a fast-acting analgesic are required, it is recommended to consider the possibility of increasing the dose of Targin^®. The increase in the dose of Targin^® should be gradual – every 1-2 days with twice-daily administration, the dose of the drug 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 reached. The goal of stepwise dose increase is to achieve the dose required for each patient when taken 2 times/day, which will provide sufficient pain relief with minimal need for additional fast-acting analgesic.

The drug Targin^® in an individually selected dose is intended for a fixed twice-daily administration. While for most patients a fixed morning and evening intake (every 12 hours) provides sufficient analgesic effect, some patients require an individual, uneven dosing schedule based on residual pain sensations. In general, the minimum effective dose of the drug should be selected.

When treating non-oncological patients, the therapeutic dose of Targin^® typically does not exceed 40 mg/20 mg oxycodone hydrochloride/naloxone hydrochloride, but a higher dose may be required.

Children and adolescents

The safety and efficacy of Targin^® in children under 18 years of age have not been studied.

Elderly patients

As in younger adult patients, the dose of the drug is selected based on pain intensity and individual sensitivity to the drug.

Patients with hepatic impairment

Results from a clinical study showed that the plasma concentration of oxycodone and naloxone is increased in patients with hepatic insufficiency, with this effect being more pronounced for naloxone. The clinical significance of the relatively higher naloxone exposure in patients with hepatic insufficiency is unknown. Targin^® should be used with caution in patients with mild hepatic insufficiency. Targin^® is contraindicated in moderate and severe hepatic insufficiency.

Patients with renal impairment

Results from a clinical study showed that the plasma concentration of oxycodone and naloxone is increased in patients with renal insufficiency, with this effect being more pronounced for naloxone. The clinical significance of the relatively higher naloxone exposure in patients with renal insufficiency is unknown. Targin^® should be used with caution in patients with renal insufficiency.

Duration of therapy

The use of Targin^® should not be longer than absolutely necessary. If a patient requires long-term analgesic therapy considering the type and severity of the disease, careful and regular monitoring should be organized to assess the need for, in general, and the intensity of the planned treatment. If opioid treatment is no longer indicated, the drug dose should be gradually reduced.

Adverse Reactions

The frequency of adverse reactions listed below was defined according to the following gradation: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000) and very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Immune system disorders uncommon – hypersensitivity reaction.

Metabolism and nutrition disorders common – decreased appetite up to loss of appetite.

Psychiatric disorders common – insomnia; uncommon – anxiety, unusual thoughts, anxiety, confusion, depression, nervousness, decreased libido; frequency not known – euphoria, hallucinations, nightmares.

Nervous system disorders common – dizziness, headache, somnolence; uncommon – convulsive seizures¹, decreased attention, speech disorder, loss of consciousness, tremor, somnolence, dysgeusia; frequency not known – paresthesia, lethargy.

Eye disorders uncommon – visual perception disturbance.

Ear and labyrinth disorders common – vertigo.

Cardiac disorders common – flushing; uncommon – angina pectoris², palpitations^3, decreased blood pressure, increased blood pressure; rare – yawning.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea, rhinorrhea, cough; rare – tachycardia; frequency not known – respiratory depression.

Gastrointestinal disorders common – abdominal pain, constipation, diarrhea, dry mouth, dyspepsia, vomiting, nausea, flatulence; uncommon – abdominal distension; rare – tooth disease; frequency not known – belching.

Hepatobiliary disorders uncommon – increased hepatic enzyme activity, biliary colic.

Reproductive system and breast disorders frequency not known – 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 – urinary urgency; frequency not known – urinary retention.

General disorders and administration site conditions common – asthenia, increased fatigue; uncommon – withdrawal syndrome, chest pain, chills, malaise, pain, peripheral edema, decreased body weight, thirst; rare – increased body weight.

Injury, poisoning and procedural complications uncommon – injury due to accidents.

¹ Characteristic for patients with epilepsy or increased seizure activity.

² Characteristic for patients with a history of coronary artery disease.

³ Characteristic for withdrawal syndrome.

For the active substance – oxycodone hydrochloride – the following additional adverse drug reactions are known

Due to its pharmacological action, oxycodone hydrochloride can cause respiratory depression, miosis, bronchospasm and spasm of smooth muscles, as well as suppress the cough reflex.

Infections and infestations rare – herpes simplex.

Immune system disorders frequency not known – anaphylactic reactions.

Metabolism and nutrition disorders uncommon – dehydration; rare – increased appetite.

Psychiatric disorders common – mood disorders and personality changes, decreased activity, increased psychomotor activity; uncommon – agitation, perception disturbance of the surrounding reality (e.g., loss of sense of reality of events), drug dependence; frequency not known – aggression.

Nervous system disorders uncommon – decreased attention, migraine, increased blood pressure, involuntary muscle contractions, hypoesthesia, coordination abnormal; frequency not known – hyperalgesia.

Eye disorders uncommon – miosis.

Ear and labyrinth disorders uncommon – hearing decreased.

Cardiac disorders common – vasodilation.

Respiratory, thoracic and mediastinal disorders uncommon – dysphonia.

Gastrointestinal disorders common – hiccups; uncommon – dysphagia, intestinal obstruction, mouth ulceration, stomatitis; rare – melena, gingival bleeding; frequency not known – dental caries.

Hepatobiliary disorders uncommon – cholestasis.

Skin and subcutaneous tissue disorders uncommon – dry skin; rare – skin eruptions.

Renal and urinary disorders common – dysuria.

Reproductive system and breast disorders uncommon – hypogonadism; frequency not known – amenorrhea.

General disorders and administration site conditions uncommon – edema, drug tolerance; frequency not known – neonatal withdrawal syndrome.

Injury, poisoning and procedural complications uncommon – injury due to accidents.

Contraindications

• Known hypersensitivity to naloxone and/or oxycodone or other components of the drug;
• Any clinical condition of the patient where the use of opioids is contraindicated;
• Respiratory depression with hypoxia and/or hypercapnia;
• Severe chronic obstructive pulmonary disease (COPD);
• Cor pulmonale;
• Severe bronchial asthma;
• Non-opioid paralytic ileus;
• Moderate and severe hepatic insufficiency;
• Children under 18 years of age;
• Lactase deficiency, galactose intolerance, glucose-galactose malabsorption (the drug contains lactose).

Use in Pregnancy and Lactation

Pregnancy

Data on the use of Targin^® during pregnancy and breastfeeding are lacking. 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, systemic exposure to naloxone in women after taking Targin^® is relatively low. Both oxycodone and naloxone cross the placental barrier. Studies of the combination of oxycodone and naloxone in animals have not been conducted. Separate studies of the toxicity of oxycodone and naloxone in animals did not reveal teratogenic or embryotoxic effects.

With long-term use of oxycodone during pregnancy, withdrawal syndrome may develop in the newborn. When oxycodone is used during labor, respiratory depression may be observed in the newborn. The use of Targin^® during pregnancy is possible if the benefit to the mother outweighs the potential risks to the fetus and newborn.

Breastfeeding 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 in the breastfed infant. Data on the passage of naloxone into breast milk are lacking. It has been noted that the systemic concentration of naloxone after taking Targin^® is very low. A risk to the breastfed infant cannot be excluded, especially with repeated use of Targin^® by the nursing mother. Breastfeeding should be discontinued during the use of Targin^®.

Fertility

Data on the effect of Targin^® on fertility are lacking.

Use in Hepatic Impairment

The drug should be prescribed with caution to patients with mild hepatic insufficiency.

The use of the drug is contraindicated in moderate and severe hepatic insufficiency.

Use in Renal Impairment

The drug should be prescribed with caution to patients with renal insufficiency.

Pediatric Use

Use in children under 18 years of age is contraindicated.

Geriatric Use

Caution should be exercised when prescribing Targin^® to elderly patients.

Special Precautions

The most serious consequence of opioid overdose is respiratory depression. Caution should be exercised when prescribing Targin^® 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.

The drug should be prescribed with caution to patients with renal insufficiency and mild hepatic insufficiency. Patients with severe renal insufficiency should be under careful medical supervision.

Diarrhea may be considered an expected adverse reaction to naloxone.

Transferring patients who have been taking opioids long-term to Targin^® may cause withdrawal syndrome or diarrhea at the beginning of treatment. Such patients require special attention.

Targin^® is not intended for the treatment of withdrawal symptoms.

During long-term use of the drug, the patient may develop tolerance, requiring higher doses of Targin^® to maintain the analgesic effect. Prolonged use of Targin^® may cause physical dependence. Sudden discontinuation of therapy may lead to withdrawal syndrome. If the need for therapy with Targin^® has ended, the dose should be gradually reduced to avoid withdrawal syndrome.

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

The profile of development of drug dependence to oxycodone is similar to other potent opioid receptor agonists. Patients who experience drowsiness and/or episodes of unexpected sleep attacks while taking the drug should refrain from driving vehicles and operating machinery. Furthermore, the possibility of reducing the dose or discontinuing therapy should be considered. Given the possibility of an additive effect, Targin^® should be used with caution in patients taking other sedative drugs.

Concurrent consumption of alcohol should be avoided, as it may enhance the adverse reactions of Targin^®.

There is no clinical experience with Targin^® in patients with complications of malignant tumors such as peritoneal carcinomatosis or with partial occlusion syndrome in advanced gastrointestinal or pelvic tumors, therefore it is not recommended to prescribe the drug to such patients.

Targin^® 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 benefit-risk assessment for each patient, taking into account the type and extent of the surgical intervention, the type of anesthesia, other concurrently taken drugs, and the general condition of the patient.

Any abuse of Targin^® by patients with drug dependence is highly undesirable.

In patients with opioid dependence (parenteral, intranasal and oral routes of administration), such as heroin, morphine or methadone, Targin^® will induce withdrawal syndrome due to the opioid receptor antagonist naloxone, or exacerbate existing withdrawal symptoms.

Targin^® is a dual-polymer matrix intended for oral use only. Parenteral administration of the drug components (especially talc) by patients with drug dependence may lead to local tissue necrosis and granulomatosis of the lungs or other serious, fatal adverse reactions.

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

While using Targin^®, doping control results may be positive. Taking Targin^® as a dope can be harmful to health.

Effect on ability to drive vehicles and operate machinery

Targin^® may affect the ability to drive vehicles and operate machinery. This is particularly likely at the start of therapy with Targin^®, after a dose increase, or after switching to other drugs, as well as when used concomitantly with other drugs that depress CNS activity. A mandatory preliminary consultation with the attending physician is required before driving vehicles or operating other machinery.

Overdose

Symptoms

Depending on the characteristics of the patient’s disease, an overdose of Targin^® may manifest with symptoms characteristic of an overdose of oxycodone (opioid receptor agonist) or naloxone (opioid receptor antagonist).

Symptoms of acute oxycodone overdose include miosis, respiratory depression, somnolence progressing to stupor, skeletal muscle flaccidity, bradycardia, and arterial hypotension. Severe cases of overdose may manifest as coma, non-cardiogenic pulmonary edema, and circulatory shock with a possibility of fatal outcome.

The development of symptoms of naloxone-only overdose is unlikely.

Treatment

Treatment of withdrawal syndrome as a consequence of naloxone overdose should be symptomatic under conditions of constant medical supervision.

Clinical symptoms suggesting oxycodone overdose can be reversed by the administration of opioid receptor antagonists (e.g., intravenous administration of 0.4-2 mg of naloxone hydrochloride). If necessary, administration can be repeated at 2-3 minute intervals. Administration of the drug as an intravenous infusion is possible: 2 mg of naloxone hydrochloride is added to 500 ml of 0.9% sodium chloride solution or 5% dextrose solution (naloxone concentration 0.004 mg/ml) and administered at a rate corresponding to the dosing of the drug during injection and the clinical response of the patient.

The possibility of gastric lavage should be considered.

Supportive therapy in the form of artificial ventilation, oxygen administration, vasoconstrictor drugs, and intravenous infusion of solutions is used as indicated, including circulatory shock as a consequence of overdose. Cardiac arrest or arrhythmia may require cardiac massage and defibrillation. Fluid and electrolyte balance should also be maintained.

Drug Interactions

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 Targin^® on the CNS.

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

Ethanol may enhance the pharmacodynamic effects of Targin^®, so the use of Targin^® concurrently with alcohol should be avoided.

Clinically significant changes in INR values in both directions have been observed in patients taking oxycodone and coumarin anticoagulants concomitantly.

The metabolism of oxycodone occurs primarily with the involvement of the cytochrome P450 system isoenzyme CYP3A4 and, partially, CYP2D6. The activity of these metabolic pathways may be decreased or increased due to the influence of other concurrently used drugs or food. Thus, the dose of Targin^® is subject to appropriate adjustment.

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 reduction in the dose of Targin^® and its re-titration 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, medicinal products that are 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 inhibitors of the CYP2D6 isoenzyme had a minor influence on the elimination of oxycodone and its pharmacodynamic effects.

The results of in vitro metabolism studies indicate that clinically significant interaction between oxycodone and naloxone is not expected. The likelihood of a clinically significant interaction between paracetamol, acetylsalicylic acid, or naltrexone and the combination of oxycodone and naloxone at therapeutic concentrations is minimal.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use the drug after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.