Fentadol (Transdermal system) Instructions for Use

ATC Code

N02AB03 (Fentanyl)

Active Substance

Fentanyl (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Pure opioid receptor agonist. Analgesic

Pharmacotherapeutic Group

Narcotic analgesic agent

Pharmacological Action

Fentanyl is an opioid analgesic, an agonist of opioid receptors (primarily μ-receptors) of the CNS, spinal cord, and peripheral tissues. It increases the activity of the antinociceptive system and raises the pain sensitivity threshold.

The main therapeutic effects of the drug are analgesic and sedative.

The duration of action of the drug is 72 hours.

It has a depressant effect on the respiratory center, slows the heart rate, excites the centers of the vagus nerve and the vomiting center. It increases the tone of the smooth muscles of the biliary tract, sphincters (including the urethra, bladder, sphincter of Oddi), reduces intestinal peristalsis, and improves the absorption of water from the gastrointestinal tract.

It has almost no effect on blood pressure and reduces renal blood flow.

In the blood, it increases the concentration of amylase and lipase; reduces the concentration of somatotropic hormone (STH), catecholamines, cortisol, prolactin. It promotes the onset of sleep (primarily due to the relief of pain syndrome). It causes euphoria. The rate of development of drug dependence and tolerance to the analgesic effect has significant individual differences.

The minimum effective analgesic concentration of fentanyl in plasma in patients who have not previously used narcotic analgesics is 0.3-1.5 ng/ml; with fentanyl concentrations in serum above 2 ng/ml, the likelihood of adverse effects increases.

Unlike other narcotic analgesics, it causes histamine reactions much less frequently.

The transdermal therapeutic system (TTS) is a dosage form for maintaining the constant release of fentanyl over 72 hours.

Pharmacokinetics

Plasma protein binding is 80-89% (primarily with albumin and lipoproteins, depends on plasma pH). Volume of distribution is 60-80 L (3.1-7.8 L/kg). The fraction of fentanyl not bound to plasma proteins in plasma is 13-21%.

After application of the Fentanyl TTS, it accumulates in adipose tissue and muscles and is then slowly released into the blood. The release of fentanyl occurs at a constant rate over 72 hours, with the therapeutic concentration in serum gradually increasing during the first 12-24 hours and remaining relatively constant for the remaining period.

The concentration of fentanyl in blood plasma is proportional to the TTS area.

After repeated applications, an equilibrium plasma concentration is achieved, which is maintained by subsequent applications of the same size TTS. After removal of the TTS, the concentration of fentanyl in blood plasma gradually decreases, with a T_1/2 of approximately 17 hours (13-22 hours). The ongoing absorption of fentanyl from the skin (more characteristic after the 4th application) explains the slow disappearance of the drug from the blood plasma. In elderly, debilitated, or weakened patients, the clearance of fentanyl may be reduced, leading to a prolongation of the T_1/2 of fentanyl.

Fentanyl is metabolized primarily in the liver (via N-dealkylation and hydroxylation) with the participation of cytochrome P450 (isoenzyme CYP3A4), as well as in the kidneys, intestines, and adrenal glands. The main metabolite, norfentanyl, is inactive.

It is excreted by the kidneys (75% as metabolites and 10% unchanged) and with bile (9% as metabolites).

It penetrates the blood-brain barrier (BBB), placenta, and into breast milk.

Indications

Chronic pain syndrome of severe and moderate intensity

• Pain caused by an oncological disease;
• Pain syndrome of non-oncological origin requiring repeated pain relief with narcotic analgesics (e.g., neuropathy, arthritis and arthrosis, phantom pains after limb amputation).

ICD codes

Dosage Regimen

Transdermal system

The dose of the drug Fentadol Reservuar is selected individually depending on the patient’s condition; the effectiveness of the dose should be regularly evaluated after each TTS application.

The TTS is applied to intact and non-irradiated skin surface with minimal hair: chest, back, shoulders. If hair removal is necessary, it should be cut (not shaved!). If the application site needs to be washed before applying the TTS, this should be done with clean water. Do not use soap, lotions, oils, alcohol, or other agents, as they may cause skin irritation or change its properties.

Before application, the skin must be absolutely dry. Since the TTS is protected by a waterproof outer protective film, it does not need to be removed during short-term showers.

Before use, the TTS must be carefully checked for damage: cut or otherwise damaged TTS should not be used!

The drug Fentadol Reservuar should be used immediately after removal from the sealed original packaging.

1. Separate part of the protective film from the back side of the TTS.

2. Apply the film-free part of the TTS to the selected area of skin and press it firmly.

3. Remove the remaining part of the protective film without touching the adhesive layer with your fingers.

4. After removing all the protective film, firmly press the TTS with the palm of your hand at the application site for about 30 seconds. Ensure that the TTS adheres tightly to the skin, especially at the edges. If necessary, additional fixation of the TTS may be used.

5. After applying the TTS Fentadol Reservuar, wash your hands with clean water (without soap).

The TTS should be worn for 72 hours, after which it must be replaced with a new one (in exceptional cases, replacement is done after 48 hours, but not earlier!). A new TTS should always be applied to a different area of skin, avoiding the site of the previous application. The same application site can be reused no earlier than 7 days later.

The analgesic effect may persist for some time after removal of the TTS.

The TTS Fentadol Reservuar should not be divided or cut!

If there are residues of the TTS on the skin after removal, they must be removed using plenty of water and soap.

Do not use alcohol or other solvents for this purpose, as organic solvents (due to the TTS effect) can penetrate the skin.

Selection of the initial dose

The initial dose of the drug Fentadol Reservuar is selected individually, based on previous use of narcotic analgesics, as well as taking into account the possible development of tolerance and its degree, concomitant drug therapy, and the general condition of the patient (including body surface area, age, degree of exhaustion).

Patients who have not previously taken narcotic analgesics

In the absence of prior treatment with narcotic analgesics, it is recommended to start treatment with small doses – 25 mcg/h of the drug Fentadol Reservuar.

The dose can subsequently be decreased or increased if necessary by 12.5-25 mcg/h to achieve the lowest effective dose of Fentadol Reservuar depending on the effect and the need for additional analgesia (see Table No. 1 “Conversion to equivalent analgesic dose” and Table No. 2 “Recommended dose of Fentadol Reservuar”).

Patients who have previously taken narcotic analgesics

When switching from oral or parenteral administration of narcotic analgesics to Fentadol Reservuar in patients tolerant to narcotic analgesics, the initial dose is calculated as follows:

• Determine the total daily dose of previously used narcotic analgesics;
• Convert the obtained total dose into the corresponding oral dose of morphine using Table No. 1 “Conversion to equivalent analgesic dose”;
• Determine the corresponding dose of fentanyl using Table No. 2 “Recommended dose of Fentadol Reservuar” (depending on the daily oral dose of morphine).

The dose can subsequently be decreased or increased if necessary by 12.5-25 mcg/h to achieve the minimum effective dose of Fentadol Reservuar depending on the response and the need for additional analgesia. All intramuscular (IM) and oral doses of narcotic analgesics listed in Table No. 1 are equivalent in analgesic effect to 10 mg of morphine IM.

Table 1. Conversion to equivalent analgesic dose

Table 2. Recommended dose of Fentadol Reservuar (depending on daily oral morphine dose)

The initial assessment of the maximum analgesic effect of Fentadol Reservuar can be carried out no earlier than 24 hours after application. This limitation is due to the fact that the increase in fentanyl concentration in serum during the first 24 hours after application occurs gradually. Therefore, for a successful transition from one drug to another, the previous analgesic therapy should be gradually discontinued after application of the initial dose of Fentadol Reservuar until its analgesic effect stabilizes.

During the first 12 hours after prescribing the fentanyl TTS, patients should continue to receive narcotic analgesics at the previous dose; if application exceeds 12 hours, this analgesic is prescribed as needed. Dose selection and maintenance therapy

The TTS should be replaced with a new one every 72 hours. The dose is selected individually until the required analgesic effect is achieved.

If a significant decrease in analgesic effect occurs 48-72 hours after application of the initial dose, then replacement of the TTS may be required after 48 hours.

A dose of 25 mcg/h is usually sufficient for dose selection in the lower dose range. If analgesia is insufficient by the end of the first application period, the dose can be increased every 3 days until the desired effect is achieved.

Usually, the dose is increased by 12.5-25 mcg/h at a time, however, the patient’s condition and the need for additional analgesia must be taken into account.

To achieve a dose greater than 100 mcg/h, several TTS can be used simultaneously.

In case of breakthrough pain, patients may periodically require additional doses of short-acting narcotic analgesics. If the required dose of Fentadol^® Reservuar exceeds 300 mcg/h, the possibility of using additional or alternative methods of analgesia or alternative routes of administration of narcotic analgesics should be considered. Use of Fentadol^® Reservuar in special patient groups In elderly, debilitated, and weakened patients, as well as in patients with renal or hepatic insufficiency, the dose should be reduced if necessary. Discontinuation of treatment with Fentadol^® Reservuar

If it is necessary to discontinue the use of the TTS, switching to any other narcotic analgesics should be done gradually, starting with a low dose and slowly increasing it. This is because the fentanyl content in the blood serum after removal of the TTS decreases gradually; it takes at least 17 hours for the fentanyl concentration in the blood serum to decrease by 50%. Discontinuation of narcotic analgesics should be gradual to avoid withdrawal syndrome (nausea, vomiting, diarrhea, anxiety, and muscle tremor).

Adverse Reactions

According to the World Health Organization (WHO), adverse effects are classified according to their frequency of occurrence as follows: very common (> 1/10), common (> 1/100, <1/10), uncommon (> 1/1000, <1/100), rare (> 1/10000, < 1/1000), very rare (<1/10000, including isolated cases).

Nervous system and sensory organs

Very common: headache, dizziness, drowsiness (including in newborns);

Common: sedation, anorexia, confusion, anxiety, nervousness, involuntary muscle contractions, hypesthesia;

Uncommon: euphoria, amnesia, insomnia, hallucinations, agitation, tremor, paresthesia, speech disorder;

Rare: amblyopia;

Very rare: impaired coordination of movements, convulsions (including clonic convulsions and grand mal epileptic seizure), depression, anxiety, delirium, states of excitation, asthenia, sexual dysfunction, withdrawal syndrome.

Respiratory system

Common: yawning, rhinitis;

Uncommon: dyspnea, hypoventilation;

Very rare: respiratory depression (including respiratory failure, apnea and bradypnea), dyspnea.

Cardiovascular system

Common: palpitations;

Uncommon: tachycardia, bradycardia, increase or decrease in blood pressure;

Rare: arrhythmia, vasodilation.

Digestive system

Very common: nausea, vomiting, constipation;

Common: dry mouth, dyspepsia, abdominal pain;

Uncommon: diarrhea;

Rare: hiccups;

Very rare: intestinal obstruction, painful flatulence.

Urinary system

Uncommon: urinary retention, urinary tract infections, ureteral spasm;

Very rare: oliguria, cystalgia;

Allergic reactions

Uncommon: itching;

Very rare: anaphylaxis.

Dermatological reactions

Very common: increased sweating;

Common: skin reaction at the application site;

Uncommon: rash, erythema. Rash, erythema, and itching at the application site in most cases disappear within one day after removal of the TTS.

Other

Uncommon: conjunctivitis, fatigue, malaise, flu-like symptoms;

Rare: chills, peripheral edema.

With long-term use of fentanyl, as with the use of other narcotic analgesics, tolerance, physical and mental dependence, and short-term muscle rigidity (including chest muscles) may develop. When switching from previously taken narcotic analgesics to the use of Fentadol Matrix or in case of sudden discontinuation of therapy, a withdrawal syndrome may occur, characterized by nausea, vomiting, diarrhea, anxiety, and chills.

Contraindications

• Depression of the respiratory center, including acute depression;
• TTS should not be used for the treatment of acute or postoperative pain due to the inability to select an adequate dose in a short period of time and the likelihood of developing life-threatening respiratory depression;
• Concomitant use with monoamine oxidase inhibitors (MAOIs), both during the entire period of MAOI use and for 14 days after their discontinuation;
• Irritation and violation of the integrity of the skin, radiation dermatitis at the intended application site;
• Diarrhea against the background of pseudomembranous colitis caused by taking cephalosporins, lincosamides, penicillins;
• Toxic dyspepsia;
• Severe CNS lesions;
• Intestinal obstruction;
• Severe bronchial asthma or acute attack of bronchial asthma;
• Period of labor contractions and childbirth (including cesarean section), due to the likelihood of respiratory depression in the fetus/newborn;
• Age under 18 years;
• Hypersensitivity to the active substance or excipients of the TTS.

With caution: respiratory failure (pneumonia, atelectasis and pulmonary infarction, bronchial asthma, chronic obstructive bronchitis, tendency to bronchospasm), intracranial hypertension, brain tumors, traumatic brain injury, bradyarrhythmia, arterial hypotension, renal and hepatic failure, renal or hepatic colic (including in history), cholelithiasis, hypothyroidism, elderly, debilitated and weakened patients, acute surgical diseases of the abdominal organs before diagnosis, general severe condition of the patient, benign prostatic hyperplasia, urethral strictures, drug dependence (including narcotic), alcoholism, suicidal tendency, hyperthermia, simultaneous use of insulin, glucocorticosteroids (GCS), antihypertensive drugs.

Use in Pregnancy and Lactation

Data regarding the use of TTS containing Fentanyl in pregnant women are insufficient.

Fentanyl during pregnancy should be used only in case of urgent need, when the expected benefit to the mother outweighs the potential risk to the fetus.

Long-term use of fentanyl TTS during pregnancy may cause withdrawal syndrome in newborns.

Fentanyl should not be taken during labor contractions and childbirth (including cesarean section), as Fentanyl crosses the placenta and can cause respiratory depression in the fetus or newborn.

Fentanyl is excreted in breast milk and can cause sedative effects and respiratory depression in the breastfed infant. Therefore, if it is necessary to prescribe the drug during lactation, breastfeeding should be discontinued (for the entire duration of use and for 72 hours after removal of the TTS).

Use in Hepatic Impairment

Use with caution in hepatic insufficiency, hepatic colic (including in medical history).

Use in Renal Impairment

Use with caution in renal insufficiency, in renal colic (including in medical history).

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Fentadol Matrix may only be used by highly qualified personnel in a specialized hospital setting, as part of comprehensive treatment of pain syndrome in patients, provided there is an adequate medical, social, and psychological assessment of their condition.

Fentadol Matrix should not be prescribed for the relief of acute or postoperative pain, because there is no possibility to select an adequate dose for short-term use. There is a possibility of occurrence and development of serious and life-threatening pulmonary hypoventilation (or respiratory depression) as a result of TTS use.

Patients who have experienced severe adverse effects while using the TTS require careful monitoring of their condition for another 24 hours after TTS removal, because the plasma concentration of fentanyl decreases gradually and its 50% reduction is achieved in approximately 17 hours (13-22 hours).

Fentadol Matrix should be stored out of the reach of children, both before and after use!

The Fentadol Matrix TTS should not be divided or cut into pieces! Use in patients not previously treated with narcotic analgesics: When using Fentadol Matrix TTS in patients not previously treated with narcotic analgesics, very rare cases of significant respiratory depression and/or death have been noted when used as initial analgesic therapy. The risk of developing serious or life-threatening hypoventilation exists even when using the minimum dose of Fentadol Matrix TTS as initial analgesic therapy in patients not previously treated with narcotic analgesics.

It is recommended to use Fentadol Matrix in patients demonstrating tolerance to narcotic analgesics.

Respiratory Depression

As with the use of other potent narcotic analgesics, the use of Fentadol Matrix may cause significant respiratory depression in some patients. Patients should be carefully monitored for such effects. Respiratory depression may persist even after removal of the Fentadol Matrix TTS. The degree of respiratory depression increases with increasing dose of Fentadol Matrix.

Chronic Lung Diseases

The Fentadol Matrix TTS can cause a number of serious adverse effects in patients with chronic obstructive and other lung diseases (by reducing the excitability of the respiratory center and weakening respiration).

Increased Intracranial Pressure

The Fentadol Matrix TTS should be used with caution in patients who may be particularly sensitive to increased CO₂ levels (patients with increased intracranial pressure, impaired consciousness, and coma). The Fentadol Matrix TTS should be used with caution in patients with intracranial tumors.

Cardiovascular Diseases

Fentanyl can cause bradycardia and therefore should be used with caution in patients with bradyarrhythmia. In patients with arterial hypotension, the Fentadol Matrix TTS should be used with caution.

Liver Diseases

Since fentanyl is metabolized to inactive metabolites in the liver, liver diseases can lead to slowed elimination of the drug from the body. In patients with liver cirrhosis, no changes in pharmacokinetics were noted with a single use of Fentadol Matrix, although the serum fentanyl concentration tended to increase.

Patients with hepatic insufficiency require careful observation for symptoms of fentanyl overdose. In this case, a dose reduction of Fentadol Matrix is necessary.

Narcotic analgesics can increase the tone of the smooth muscles of the gastrointestinal tract and biliary tract. Fentadol Matrix should be used with caution in patients with a history of hepatic colic.

Kidney Diseases

Less than 10% of fentanyl is excreted unchanged by the kidneys; there are no known active metabolites that would be excreted by the kidneys.

Data obtained from intravenous fentanyl administration in patients with renal failure suggest that the volume of distribution of fentanyl may change during hemodialysis, which may affect the serum fentanyl concentration. Patients with renal failure require careful monitoring. If symptoms of overdose appear, the dose of the Fentadol Matrix TTS should be reduced.

When switching from long-term morphine treatment to transdermal fentanyl administration, a “withdrawal” syndrome may occur, despite adequate analgesic effect of the drug. If a “withdrawal” syndrome appears, it is recommended to administer low doses of short-acting morphine to patients.

Interaction with CYP3A4 Isoenzyme Inhibitors

Concomitant use with CYP3A4 isoenzyme inhibitors (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, verapamil, diltiazem, and amiodarone) may increase the plasma concentration of fentanyl, which may intensify or prolong both the therapeutic effect and adverse reactions, in particular cause severe respiratory depression. In such situations, the patient should be carefully observed. Based on this, concomitant use of the fentanyl TTS with CYP3A4 isoenzyme inhibitors is not recommended in the absence of careful patient monitoring. Patients prescribed the Fentadol Matrix TTS concomitantly with CYP3A4 isoenzyme inhibitors should be monitored for signs of respiratory depression; dose adjustment may be required.

Use in Elderly Patients

Data from studies of intravenous fentanyl administration suggest that in elderly patients, the clearance of fentanyl may decrease and the T_1/2 may be prolonged. Elderly patients may be more sensitive to fentanyl than young patients. In studies of the Fentadol Matrix TTS, the pharmacokinetics of fentanyl in elderly patients did not differ significantly from that in young patients, although the serum concentration was somewhat higher. Elderly patients require careful observation for symptoms of possible fentanyl overdose, which will require a reduction in the dose of the Fentadol Matrix TTS.

Use in Debilitated and Weakened Patients

Since debilitated and weakened patients may have reduced clearance and prolonged T_1/2 of fentanyl, they require careful observation for symptoms of possible fentanyl overdose, which will require a reduction in the dose of the Fentadol Matrix TTS.

Drug Dependence and Abuse Potential

With repeated administration of narcotic analgesics, tolerance, as well as physical and mental dependence, may develop. Iatrogenic dependence with the use of narcotic analgesics is rare. As with the use of other narcotic analgesics, cases of fentanyl abuse are possible. Abuse or intentional misuse of Fentadol Matrix may lead to overdose and/or death. Patients at increased risk of abuse of narcotic analgesics should be under careful supervision.

Hyperthermia/External Heat Sources

A pharmacokinetic model suggests that the serum fentanyl concentration may increase by approximately one-third when body temperature rises to 40°C (104°F). Therefore, patients with hyperthermia should be under careful observation for characteristic adverse effects of fentanyl and, if necessary, subsequent dose adjustment. All patients during treatment should avoid direct exposure of the Fentadol Matrix TTS application site to external heat sources, such as heating lamps, sunlamps, intense sunbathing, heating pads, saunas, hot tubs.

The TTS should always be removed before visiting a sauna. Sauna use is only possible when replacing the TTS (at 72-hour intervals). A new TTS should be applied to cold and absolutely dry skin.

Discontinuation of Fentadol Matrix

If it is necessary to discontinue the Fentadol Matrix TTS, replacement of this drug with other narcotic analgesics should be carried out gradually, starting with low doses, due to the gradual decrease in fentanyl concentration after removal of the Fentadol Matrix TTS, in which a 50% reduction in serum fentanyl concentration takes about 17 hours. Discontinuation of the drug should always be gradual to avoid the development of a “withdrawal” syndrome.

Effect on ability to drive vehicles and operate machinery.

The Fentadol Matrix TTS may affect mental and/or physical functions necessary for performing potentially hazardous work, such as driving a vehicle or operating machinery. During treatment, refrain from driving vehicles and engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Disposal Instructions

Used TTS should be folded in half tightly with the adhesive side inward and returned to the attending physician for disposal in accordance with established procedures. Unused TTS must also be returned to the attending physician for disposal. Before use, the Fentadol Matrix TTS should be stored in the original packaging.

Overdose

Symptoms dizziness, drowsiness, lethargy, nervousness, general weakness, depression of cardiovascular system activity, decreased BP, bradycardia, “clammy” sweat, miosis, muscle rigidity, depression of the respiratory center with Cheyne-Stokes respiration and/or cyanosis, comatose state, bradypnea, apnea.

Treatment removal of the TTS, physical and verbal stimulation of the patient to restore breathing (“slapping the cheeks”, calling by name), administration of the specific antidote – naloxone. Respiratory depression in overdose may last longer than the period of action of the opioid receptor antagonist, so there may be a need for repeated intravenous (IV) administration of naloxone (or continuous infusion). The use of an opioid receptor antagonist may lead to the development of an acute pain syndrome and catecholamine release.

The recommended initial dose for adults is 0.4-2 mg of naloxone IV. If necessary, the same dose can be administered every 2-3 minutes or administered as an infusion of 2 mg of naloxone dissolved in 500 ml of 0.9% sodium chloride solution or 5% dextrose solution (0.004 mg/ml). The infusion rate should be adjusted based on previous bolus administrations and the individual patient response. If IV administration is not possible, then naloxone may be prescribed intramuscularly (IM) or subcutaneously (SC). After IM or SC administration of naloxone, the onset of action will be slower compared to IV administration. IM administration provides a more prolonged effect than IV administration.

Symptomatic and supportive therapy to maintain vital functions is carried out (including administration of muscle relaxants, artificial lung ventilation, for bradycardia – administration of atropine, for a pronounced decrease in BP – replenishment of circulating blood volume).

Drug Interactions

With simultaneous use of other medicinal products that have a depressant effect on the CNS, including other narcotic analgesics, sedatives and hypnotics, general anesthetics, phenothiazines, tranquilizers, central muscle relaxants, antihistamines with sedative effect, alcohol, the risk of developing and intensifying hypoventilation, decreased BP, excessive sedative effect, coma, or fatal outcome may increase (taking any of the specified drugs simultaneously with the use of Fentadol Matrix requires special monitoring of the patient).

If it becomes necessary to use Fentadol Matrix concomitantly with one of the above-mentioned medicinal products, dose adjustment of one or both drugs is necessary.

Fentanyl has a high clearance; it is rapidly and extensively metabolized, mainly by the CYP3A4 isoenzyme. Concurrent use of potent CYP3A4 inhibitors (e.g., erythromycin, ritonavir, ketoconazole, itraconazole, diltiazem, cimetidine, antibiotics from the macrolide group) with transdermally administered fentanyl may lead to increased plasma concentrations of fentanyl. This may intensify or prolong both the therapeutic effect and adverse reactions, which can cause pronounced respiratory depression. Careful monitoring of the patient is necessary. Combined use of ritonavir or another potent CYP3A4 isoenzyme inhibitor with transdermal fentanyl is not recommended unless careful patient monitoring is conducted. Fentanyl enhances the effect of hypotensive medicinal products.

Buprenorphine, nalbuphine, pentazocine, naloxone, naltrexone reduce the analgesic effect of fentanyl and eliminate its depressant effect on the respiratory center.

Muscle relaxants prevent or eliminate muscle rigidity; muscle relaxants with m-cholinolytic activity (including pancuronium bromide) reduce the risk of bradycardia and decreased BP (especially against the background of beta-blockers and other vasodilators) and may increase the risk of tachycardia and increased BP; muscle relaxants without m-cholinolytic activity (including suxamethonium) do not reduce the risk of bradycardia and decreased BP (especially against the background of a significant cardiac history) and increase the risk of severe cardiovascular adverse effects.

Nitrous oxide enhances muscle rigidity.

The dose of fentanyl should be reduced when used concomitantly with insulin, corticosteroids, and hypotensive medicinal products.

Concomitant use of fentanyl with MAO inhibitors is not recommended, both during the entire period of MAO inhibitor use and for 14 days after their discontinuation, because they increase the risk of severe complications when using fentanyl (enhancement of the effects of narcotic analgesics or enhancement of serotonergic effects).

Storage Conditions

Belongs to List II of narcotic drugs, psychotropic substances and their precursors, approved by Decree of the Government of the Russian Federation No. 681 dated June 30, 1998. Store at a temperature not exceeding 25°C (77°F). Store out of the reach of children!

Shelf Life

Shelf life – 2 years.

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.