Palexia (Tablets) Instructions for Use

ATC Code

N02AX06 (Tapentadol)

Active Substance

Tapentadol (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Opioid analgesic with a mixed mechanism of action

Pharmacotherapeutic Group

Analgesics; opioids; other opioids

Pharmacological Action

Tapentadol is a potent analgesic that is an agonist of mu-opioid receptors and an inhibitor of norepinephrine reuptake. Tapentadol exerts its analgesic effect directly without the involvement of pharmacologically active metabolites.

Tapentadol has demonstrated efficacy in nociceptive, neuropathic, visceral pain, and pain caused by an inflammatory process. Clinical studies have confirmed the analgesic efficacy of tapentadol in nociceptive pain (including postoperative orthopedic and abdominal pain, as well as chronic pain in osteoarthritis of the hip or knee).

Effect on the cardiovascular system: upon thorough investigation of the QT interval, no effects of therapeutic and supratherapeutic doses of tapentadol on the QT interval were established. Tapentadol did not have significant effects on other ECG parameters (heart rate, PR interval, QRS complex, T and U wave morphology).

Pharmacokinetics

Absorption

After oral administration of Palexia film-coated tablets, tapentadol is rapidly and completely absorbed. The mean absolute bioavailability after a single oral dose of film-coated tablets on an empty stomach is approximately 32% due to intensive first-pass metabolism. Maximum plasma concentrations of tapentadol are observed 1.25 hours after oral administration of film-coated tablets. A dose-proportional increase in C_max (maximum concentration) and AUC (area under the concentration-time curve) was noted after oral administration of film-coated tablets within the therapeutic dose range.

Long-term oral administration of tapentadol (every 6 hours) in doses from 75 mg to 175 mg in film-coated tablets showed that the accumulation factor of tapentadol ranges from 1.4 to 1.7 and from 1.7 to 2.0 for its main metabolite, tapentadol-O-glucuronide, which was mainly determined by the dosing interval and the half-life of tapentadol. The equilibrium concentration of tapentadol in plasma is reached on the second day after starting oral administration of film-coated tablets.

Effect of food

AUC and C_max increase by 25% and 16%, respectively, when film-coated tablets are taken orally after a high-fat, high-calorie meal. The time to reach C_max is delayed by 1.5 hours when taken with a high-calorie meal. This was considered clinically insignificant. Palexia can be taken orally either before or after meals.

Distribution

Tapentadol has a large volume of distribution. After intravenous administration of tapentadol, the volume of distribution during the terminal elimination phase (V_d) is 540 ± 98 liters. Binding to plasma proteins is low and does not exceed 20%.

Metabolism

Tapentadol undergoes extensive metabolism. About 97% of the compound is metabolized. The main pathway of tapentadol metabolism is conjugation with glucuronic acid. After oral administration, approximately 70% of the dose is excreted in the urine as conjugated forms (55% glucuronide and 15% sulfate of tapentadol). Uridine diphosphate glucuronosyltransferase (UGT) is the main enzyme involved in the glucuronidation process (mainly isoenzymes UGT1A6, UGT1A9 and UGT2B7). A total of 3% of tapentadol is excreted unchanged in the urine. Tapentadol is also metabolized to N-desmethyltapentadol (13%) by CYP2C9 and CYP2C19 isoenzymes and to hydroxytapentadol (2%) by the CYP2D6 isoenzyme, which are then conjugated. For this reason, the metabolism of tapentadol mediated by the cytochrome P450 isoenzyme system is less significant compared to glucuronidation.

None of the metabolites of tapentadol have analgesic activity.

Excretion

Tapentadol and its metabolites are excreted almost completely (99%) by the kidneys. The total clearance after intravenous administration is 1530 ± 177 ml/min. The terminal half-life after oral administration of tapentadol in film-coated tablets averages 4 hours.

Special patient categories

Elderly patients

The AUC of tapentadol is similar in elderly (65-78 years) and middle-aged (19-43 years) patients, while in elderly patients the mean C_max is 16% lower than in middle-aged patients.

Renal impairment

The AUC and C_max of tapentadol are comparable in patients with varying degrees of renal function (from normal to severe impairment). Conversely, with increasing severity of renal failure, an increase in the area under the concentration-time curve (AUC) of tapentadol-O-glucuronide was noted. In patients with mild, moderate and severe renal impairment, the AUC of tapentadol-O-glucuronide increased by 1.5, 2.5 and 5.5 times, respectively, compared with patients with normal renal function.

Hepatic impairment

In patients with impaired liver function, oral administration of tapentadol was characterized by higher AUC and serum concentrations compared to patients with normal liver function. The ratios of tapentadol pharmacokinetic parameters for groups of patients with mild and moderate hepatic insufficiency compared to the group of patients with normal liver function were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for C_max; and 1.2 and 1.4, respectively, for half-life. The rate of formation of tapentadol-O-glucuronide is lower in patients with more severe liver dysfunction.

Pharmacokinetic interactions

Tapentadol is mainly metabolized via phase 2 (glucuronidation), and only a small amount is metabolized via phase 1 oxidative processes.

Since glucuronidation is a high-capacity, low-affinity system, any clinically significant interaction associated with glucuronidation is unlikely. This is confirmed by the experience of simultaneous use of tapentadol with naproxen and probenecid, which resulted in an increase in the AUC of tapentadol by 17% and 57%, respectively. No changes in the pharmacokinetic parameters of tapentadol were observed when used concomitantly with paracetamol and acetylsalicylic acid.

Tapentadol is not an inducer or inhibitor of cytochrome P450 isoenzymes. Therefore, clinically significant interactions mediated by the cytochrome P450 isoenzyme system are unlikely.

The pharmacokinetics of tapentadol did not change under the influence of increased pH or gastrointestinal motility caused by omeprazole and metoclopramide, respectively.

The binding of tapentadol to plasma proteins is low (approximately 20%). For this reason, the likelihood of pharmacokinetic interactions due to displacement from plasma protein binding is low.

Indications

• Acute pain syndrome of moderate to severe intensity.

The drug is used only for pain syndrome of moderate to severe intensity requiring opioid analgesics.

ICD codes

Dosage Regimen

Tablets

As with treatment with other centrally acting analgesics, the dose of the drug should be selected individually according to the severity of the pain syndrome, previous therapy and the possibility of monitoring the patient. Palexia prolonged-release film-coated tablets should be taken twice a day, approximately every 12 hours, regardless of meals. The tablet should be taken orally with a sufficient amount of liquid, without chewing, breaking or dissolving.

Initiation of treatment

Patients not taking narcotic analgesics therapy should be started with a dose of 50 mg 2 times/day.

Patients taking narcotic analgesics when switching from other narcotic analgesics to Palexia and choosing the initial dose, the characteristics of the previously prescribed drug, its frequency of administration and the average daily dose should be taken into account.

Dose titration and maintenance therapy

After initiation of treatment, under close medical supervision, the dose should be titrated individually to achieve adequate pain relief with minimal side effects. Available experience shows that a tapentadol dose titration regimen with an increase of 50 mg twice daily every 3 days is sufficient for most patients to achieve adequate pain control.

A daily dose of tapentadol exceeding 500 mg in prolonged-release film-coated tablets has not been prescribed, so the use of the drug in such doses is not recommended.

Discontinuation of treatment

Abrupt discontinuation of tapentadol may lead to withdrawal syndrome. It is recommended to gradually reduce the dose of the drug before complete discontinuation to prevent the development of withdrawal syndrome.

Adults with chronic diseases

Dose adjustment is not required in patients with mild to moderate renal impairment. There is no experience of use in patients with severe renal impairment, so the use of the drug in this group of patients is contraindicated.

Dose adjustment is not required in patients with mild hepatic impairment. Caution should be exercised when prescribing Palexia to patients with moderate hepatic impairment. Treatment of such patients with tapentadol in the form of prolonged-release film-coated tablets should be started with a dose of 50 mg no more than once a day. Further therapy should be aimed at maintaining the analgesic effect with an acceptable level of tolerability. There is no experience of use in patients with severe hepatic impairment, so use in this group of patients is contraindicated.

In general, the recommended doses for elderly patients (65 years and older) with normal liver and kidney function are the same as for middle-aged patients with normal kidney and liver function. Since elderly patients are more likely to have reduced renal and hepatic function, caution should be exercised when selecting the dose and not exceeding the recommended doses.

Palexia is contraindicated for use in children under 18 years of age due to insufficient data on efficacy and safety.

Adverse Reactions

Approximately 65% of patients taking Palexia film-coated tablets experienced adverse reactions, mostly of mild or moderate intensity. The most common of these were disorders of the gastrointestinal tract and central nervous system (nausea, dizziness, vomiting, drowsiness and headache).

The table below shows the adverse reactions of Palexia identified during its use. They are presented by class and frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000).

When taking Palexia orally in film-coated tablets for up to 90 days, cases of mild withdrawal syndrome upon abrupt discontinuation of therapy were noted, classified as mild in severity. Nevertheless, physicians should be aware of the possibility of withdrawal syndrome and provide necessary treatment if it occurs.

During post-marketing use of tapentadol, reports of suicidal thoughts in patients have been received. A causal relationship between the occurrence of suicidal thoughts and the use of tapentadol has not been established.

If the side effects listed in the instructions occur, or other side effects not listed in the instructions are noticed, inform your doctor.

Contraindications

• Hypersensitivity to tapentadol or any of the excipients included in the drug;
• In situations where μ-opioid receptor agonist drugs are contraindicated, i.e., in patients with significant respiratory depression (if monitoring is impossible or resuscitation equipment is unavailable), as well as in patients with exacerbation or severe bronchial asthma or hypercapnia;
• Presence or suspicion of paralytic ileus;
• Acute intoxication with alcohol, hypnotics, centrally acting analgesics and psychotropic drugs;
• In patients receiving monoamine oxidase inhibitors (MAOIs) or having taken them within the last 14 days;
• Severe renal failure;
• Severe hepatic failure;
• Age under 18 years;
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution

Palexia should be used with caution

• In case of increased risk of misuse or abuse of the drug;
• In case of respiratory dysfunction;
• In patients with traumatic brain injury and depressed consciousness;
• In patients with a history of seizure disorder or any conditions that increase the risk of seizures;
• In patients with moderate hepatic impairment;
• In patients with biliary tract pathology and acute pancreatitis;
• In patients with low blood pressure.

It is recommended to gradually reduce the dose of Palexia before complete discontinuation. Caution is required when using Palexia concomitantly with serotonergic drugs.

Use in Pregnancy and Lactation

Data on the use of tapentadol during pregnancy are limited. In animal studies, no teratogenic effects associated with tapentadol were found. However, at doses exceeding the upper limit of the therapeutic range, delayed embryonic development and embryotoxicity (effects on the central nervous system associated with mu-opioid receptor agonism) were identified. Effects on postnatal development of offspring were identified when tapentadol was administered at doses that did not cause adverse events in pregnant females.

The use of Palexia during pregnancy is acceptable only if the potential benefit to the mother outweighs the potential risk to the fetus.

Labor

The effect of tapentadol when used during labor is not known. The use of Tapentadol during labor and immediately before labor is not recommended. Due to the affinity of tapentadol for mu-opioid receptors, newborns whose mothers have taken Tapentadol should be closely monitored for possible development of respiratory depression.

Breastfeeding

Information on the excretion of tapentadol into breast milk is limited. Physicochemical and pharmacodynamic/toxicological data on tapentadol indicate excretion into breast milk, so the risk of exposure to the breastfed infant cannot be excluded. Palexia should not be prescribed during breastfeeding.

Use in Hepatic Impairment

Dose adjustment is not required in patients with mild hepatic impairment. Caution should be exercised when prescribing to patients with moderate hepatic impairment. Treatment in such patients should be started with 50 mg of tapentadol in film-coated tablets no more than once every 8 hours (maximum three doses per day). Further therapy should be aimed at maintaining the analgesic effect with an acceptable level of tolerability, which is achieved by increasing or decreasing the interval between doses of the drug.

There is no experience of use in patients with severe hepatic impairment, and therefore use in this group of patients is contraindicated.

Use in Renal Impairment

Dose adjustment is not required in patients with mild or moderate renal impairment.

There is no experience with use in patients with severe renal impairment, therefore the use of the drug in this patient group is contraindicated.

Pediatric Use

Palexia is contraindicated for use in patients under 18 years of age due to insufficient data on efficacy and safety.

Geriatric Use

In general, the recommended doses for elderly patients with normal liver and kidney function are the same as for middle-aged patients with normal kidney and liver function. Since elderly patients are more likely to have reduced renal and hepatic function, caution should be exercised when selecting the dose and the recommended doses should not be exceeded.

Special Precautions

Potential for drug abuse

There is a potential risk of abuse of Palexia. This should be taken into account when prescribing the drug in situations where there is a risk of misuse, abuse of the drug, or diversion of the drug to others.

All patients treated with mu-opioid receptor agonist drugs should be closely monitored for signs of drug abuse and dependence.

Respiratory depression

In high doses and in patients with increased sensitivity to mu-opioid receptor agonists, Tapentadol may cause dose-dependent respiratory depression. For this reason, Palexia should be prescribed with caution to patients with impaired respiratory function. The use of analgesics that are not mu-opioid receptor agonists should be considered, and Palexia in such patients should be used only under close medical supervision and at the lowest effective doses. In case of respiratory depression, treatment should be carried out as in the case of respiratory depression associated with the use of any other mu-opioid receptor agonist.

Head injury and increased intracranial pressure

As with the use of other mu-opioid receptor agonist drugs, Tapentadol should not be prescribed to patients who may be particularly sensitive to the pathophysiological reactions that develop with an increase in the partial pressure of carbon dioxide in the intracranial vessels and brain tissue, for example, with increased intracranial pressure, depression of consciousness, or coma. Analgesics characterized by affinity for mu-opioid receptors may mask the clinical manifestations of head injury. Palexia should be used with caution in patients with head trauma and brain tumors.

Seizures

Tapentadol has not been systematically studied in patients with a seizure disorder. Nevertheless, like other analgesics with affinity for mu-opioid receptors, Palexia should be prescribed with caution to patients with a history of seizure disorder or any conditions that put the patient at risk of developing seizures.

Hepatic impairment

In patients with impaired liver function, increased serum concentrations of tapentadol have been identified compared to patients with normal liver function. Palexia should be used with caution in patients with moderate hepatic impairment. Palexia has not been studied in patients with severe hepatic impairment and is therefore contraindicated for use in this patient group.

Use in pancreatic and biliary tract pathology

Drugs with affinity for mu-opioid receptors may cause spasm of the sphincter of Oddi. Palexia should be used with caution in patients with biliary tract disease and acute pancreatitis.

Withdrawal syndrome

Abrupt discontinuation of tapentadol may lead to the development of a withdrawal syndrome. The following symptoms may occur: anxiety, increased sweating, insomnia, chills, pain, nausea, tremor, diarrhea, upper respiratory symptoms, piloerection and, rarely, hallucinations. To prevent withdrawal syndrome, it is recommended to gradually reduce the dose of the drug before complete discontinuation.

Central nervous system depression

Concomitant use of tapentadol with other analgesic mu-opioid receptor agonists, anesthetics, phenothiazine derivatives, tranquilizers, sedatives, hypnotics and other drugs that depress the central nervous system, including alcohol and drugs, may enhance CNS depression. Drug interactions leading to profound sedation and coma may develop in case of simultaneous use of these drugs with tapentadol. If such a combination is necessary, the issue of reducing the dose of one of the drugs should be considered.

Reduction in blood pressure

Palexia may cause a significant decrease in blood pressure, especially in patients with hypovolemia or those taking drugs that reduce peripheral vascular tone (e.g., phenothiazine derivatives, anesthetics) concomitantly with tapentadol.

Serotonin syndrome

There are reports of the development of life-threatening serotonin syndrome with the concomitant use of tapentadol, even in therapeutic doses, with serotonergic drugs: selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, triptans, drugs that affect serotonergic neurotransmission in the central nervous system (e.g., mirtazapine, trazodone and tramadol), and drugs that impair serotonin metabolism (e.g., MAO inhibitors). Possible symptoms of serotonin syndrome may include, for example: confusion, agitation, coma, tachycardia, increased body temperature, impaired coordination, nausea, vomiting and diarrhea.

Tapentadol should be used with caution in patients with adrenocortical insufficiency (e.g., Addison’s disease), in patients with alcoholic delirium, toxic psychosis, with myxedema and hypothyroidism, as well as in cases of prostatic hypertrophy and urethral strictures.

Effect on ability to drive vehicles and operate machinery

Like other mu-opioid receptor agonist drugs, Palexia may adversely affect the ability to drive vehicles and operate complex machinery because it affects the central nervous system. This effect is particularly possible at the start of treatment, with any changes in the drug dose, or with concomitant use of tranquilizers or alcohol. Patients should refrain from driving and engaging in potentially hazardous activities.

Overdose

Data on overdose are very limited.

Symptoms characteristic of all drugs with central analgesic action and characterized by affinity for mu-opioid receptors should be expected – miosis, vomiting, collapse, impaired consciousness up to coma, convulsions and respiratory depression with possible respiratory arrest.

Emergency care treatment of overdose should focus on eliminating the symptoms of mu-opioid receptor stimulation. If a tapentadol overdose is suspected, primary attention should be given to restoring airway patency and applying assisted or controlled ventilation. Full opioid receptor antagonists, such as naloxone, are specific antidotes for respiratory depression associated with overdose of narcotic analgesics. Respiratory depression after overdose may exceed the duration of action of the opioid receptor antagonist. Administration of an opioid receptor antagonist does not replace continuous monitoring of the airway, breathing, and circulation disorders that have developed as a result of the narcotic analgesic overdose. If the response to the administration of opioid receptor antagonists is insufficient or short-lived, additional doses of the antagonist may be administered. Gastrointestinal decontamination may be performed to remove unabsorbed tapentadol. Administration of activated charcoal or gastric lavage may be performed within 2 hours of oral ingestion. The airway must be secured prior to gastrointestinal decontamination.

Drug Interactions

Concomitant use of tapentadol with benzodiazepines, barbiturates and opioids (analgesics, antitussives and drugs for the treatment of withdrawal syndrome) may increase the risk of respiratory depression. Drugs that depress the central nervous system (benzodiazepines, antipsychotics, H₁-histamine receptor blockers, opioids, alcohol) may enhance the sedative effect of tapentadol and CNS depression. If a combination of tapentadol and drugs that cause respiratory or CNS depression is necessary, the issue of reducing the dose of the drugs should be considered.

Opioid receptor agonist-antagonists. Caution should be exercised when using tapentadol concomitantly with mu-opioid receptor agonist-antagonists (e.g., pentazocine, nalbuphine) or partial mu-opioid receptor agonists (e.g., buprenorphine). When used concomitantly with buprenorphine, an increased dose of mu-opioid receptor agonists was noted, and under these circumstances, careful monitoring for such adverse effects as respiratory depression is necessary.

There are isolated reports of the development of serotonin syndrome, temporally associated with the concomitant use of tapentadol and serotonergic drugs, for example, selective serotonin reuptake inhibitors (SSRIs). Possible symptoms of serotonin syndrome may include, for example: confusion, agitation, increased body temperature, increased sweating, ataxia, hyperreflexia, myoclonus and diarrhea. Discontinuation of serotonergic drugs usually led to rapid resolution of symptoms. Therapy is determined by the nature and severity of the symptoms.

Since the main pathway of tapentadol metabolism is conjugation with glucuronic acid involving the UGT1A6, UGT1A9 and UGT2B7 isoenzymes, concomitant use with potent inhibitors of these isoenzymes (such as ketoconazole, fluconazole, meclofenamic acid) may increase the systemic exposure of tapentadol.

Patients being treated with tapentadol should exercise caution at the start and end of concomitant use of potent inducers of hepatic microsomal enzymes (e.g., rifampicin, phenobarbital, St. John’s wort preparations), as this may lead to a decrease in efficacy or a risk of adverse effects, respectively.

Tapentadol is contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs) or who have taken them in the last 14 days, as it may increase norepinephrine levels, which can cause cardiovascular side effects such as hypertensive crisis.

Concomitant use of tapentadol with naproxen and probenecid resulted in an increase in the AUC of tapentadol by 17% and 57%, respectively. No changes in the pharmacokinetic parameters of tapentadol were observed with concomitant use with paracetamol and acetylsalicylic acid.

Storage Conditions

At a temperature not exceeding 30°C (86°F). Keep out of reach of children.

Shelf Life

Shelf life – 3 years.

Dispensing Status

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.