Fenstud

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FENSTUD (FENSTUD)

Composition:

Active substance: fentanyl;

1 ml of solution contains fentanyl citrate equivalent to fentanyl 50 mcg;

Excipients: citric acid anhydrous, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.
Opioid anesthetics. ATC code N01AH01.

Pharmacological properties.

Pharmacodynamics.

Fentanyl is a synthetic opioid analgesic with a clinical potency 50–100 times greater than morphine. It is characterized by rapid and short-duration analgesic action. In humans, a single intravenous dose of 0.5–1 mg/70 kg body weight produces pronounced surgical analgesia, respiratory depression, bradycardia, and other effects typical of morphine. The maximum effect lasts approximately 30 minutes. All potent morphine-like agents relieve pain, depress respiration, induce vomiting, cause constipation, physical dependence, certain vagal effects, and sedative effects of varying degrees. However, fentanyl differs from morphine not only by its shorter duration of action but also by the absence of emetic effects and minimal hypotensive action in animals.

Pharmacokinetics.

Pharmacokinetic parameters of fentanyl:

• plasma protein binding – 80%;
• volume of distribution – 4.0 ± 0.4 L/kg;
• clearance – 13 ± 2 mL/min/kg;
• urinary excretion – 8%;
• terminal half-life – 141–853 minutes.

Renal impairment

Data obtained during studies of intravenous fentanyl administration in patients who underwent kidney transplantation indicate that fentanyl clearance may be reduced in this patient population. If patients with impaired renal function receive fentanyl, they should be closely monitored for signs of fentanyl toxicity and, if necessary, the dose should be reduced (see section "Administration and dosage").

Obese patients

Increased fentanyl clearance is observed with increased body weight. In patients with BMI > 30, fentanyl clearance increases by approximately 10% per 10 kg increase in lean body mass (non-fat body mass).

Clinical characteristics.

Indications.

Fenstud is used:

• in small doses – for analgesia during minor surgeries;
• in large doses – for analgesia and reduction of spontaneous respiratory rate during artificial ventilation of the lungs;
• in combination with neuroleptic agents – for neuroleptanalgesia;
• for relief of severe pain, e.g. pain associated with myocardial infarction.

Contraindications.

Hypersensitivity to the active substance, to other morphine-like agents, or to any excipient of the medicinal product. Respiratory depression, obstructive respiratory tract diseases. Use with monoamine oxidase inhibitors (MAOIs), either concomitantly or within 2 weeks after discontinuation of MAOIs.

Interaction with other medicinal products and other types of interactions.

Effect of other medicinal products on fentanyl action

Central nervous system (CNS) depressants.

The respiratory depressant effect of fentanyl may be enhanced or prolonged by concomitant use of opioids (for premedication), barbiturates, benzodiazepines, neuroleptic agents, general anesthetics, gabapentinoids (gabapentin and pregabalin), and other non-selective CNS depressants (e.g. alcohol).

If a patient has received CNS depressants, the dose of fentanyl should be lower than usual. Concomitant use of the medicinal product in patients with spontaneous respiration may increase the risk of respiratory depression, profound sedation, coma, and death (see section "Special precautions for use").

Cytochrome P450 3A4 (CYP3A4) inhibitors

Fentanyl is rapidly and extensively metabolized by CYP3A4. When using Fenstud, concomitant administration of a CYP3A4 inhibitor may lead to reduced fentanyl clearance. After a single dose of Fenstud, the period of risk for respiratory depression may be prolonged, which may require special patient monitoring and longer observation. With repeated doses of Fenstud, the risk of acute and/or delayed respiratory depression may be increased, and a dose reduction of Fenstud may be necessary to avoid fentanyl accumulation. Oral ritonavir (a potent CYP3A4 inhibitor) reduced the clearance of a single intravenous dose of Fenstud by two-thirds, although the maximum plasma concentration of fentanyl was unchanged. However, itraconazole (a potent CYP3A4 inhibitor) administered orally at a dose of 200 mg/day for 4 days had no significant effect on the pharmacokinetics of intravenously administered fentanyl. Concomitant use of other potent or less potent CYP3A4 inhibitors, such as voriconazole or fluconazole, with Fenstud may lead to increased and/or prolonged fentanyl effects.

Combining fentanyl with non-depolarizing muscle relaxants may result in bradycardia and possibly cardiac arrest.

Serotonergic agents

Concomitant use of fentanyl and serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and MAOIs, increases the risk of serotonin syndrome – a potentially life-threatening condition (see section "Contraindications").

Effect of fentanyl on the action of other medicinal products

After administration of fentanyl, doses of other CNS depressants should be reduced. This is particularly important in the postoperative period, as complete analgesia is associated with pronounced respiratory depression, which may persist or recur postoperatively. Administration of other CNS depressants, such as benzodiazepines, or related drugs during this period may disproportionately increase the risk of respiratory depression (see section "Special precautions for use").

Concomitant administration of fentanyl significantly increases (2–3 times) the plasma concentration of etomidate. When used concomitantly with fentanyl, the total plasma clearance and volume of distribution of etomidate decrease by 2–3 times, while the elimination half-life remains unchanged.

Concomitant intravenous administration of fentanyl and midazolam results in an increased terminal elimination half-life of midazolam and reduced plasma clearance. When these medicinal products are used concomitantly with fentanyl, dose reduction may be necessary.

Special precautions for use.

Warnings

Opioid tolerance and opioid use disorder

Tolerance, physical and psychological dependence may develop with repeated administration of opioids.

Repeated administration of opioids may lead to opioid use disorder (OUD). Misuse or intentional inappropriate use of opioids may result in overdose and/or death. The risk of developing OUD is increased in patients with personal or family history (parents, siblings) of substance use disorders (including alcohol use disorders), in current tobacco users, or in patients with other pre-existing mental health disorders (e.g., major depression, anxiety, and personality disorders).

Long-term use of this medicinal product in all patients may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance abuse (including alcohol abuse) or mental health disorders (e.g., major depression).

Additional support and monitoring may be required when prescribing this medicinal product to patients at risk of opioid misuse.

A complete patient history should be obtained to document concomitant medications, including over-the-counter medications and online-prescribed drugs, as well as past and current medical and psychiatric conditions.

Patients may find that treatment becomes less effective with prolonged use and may express a need to increase the dose to achieve a similar level of pain control as initially observed. Patients may also add other analgesics to their treatment regimen. This may be a sign that the patient is developing tolerance. Patients should be informed about the risks of developing tolerance.

Excessive or inappropriate use may lead to overdose and/or fatal outcomes. It is important that patients use only the medications prescribed to them at the prescribed dose and do not share them with others.

Patients should be closely monitored for signs of inappropriate use, misuse, or dependence.

The clinical need for analgesic treatment should be regularly reassessed.

Withdrawal syndrome

Prior to initiating therapy with any opioid, a discontinuation strategy should be discussed with the patient when treatment with fentanyl is to be stopped.

Withdrawal syndrome may occur upon abrupt discontinuation of therapy or dose reduction. When a patient no longer requires treatment, gradual dose reduction is recommended to minimize withdrawal symptoms. Tapering high doses may take from several weeks to months.

Opioid withdrawal syndrome is characterized by some or all of the following adverse reactions: anxiety, lacrimation, rhinorrhea, yawning, sweating, chills, myalgia, miosis, and palpitations. Other symptoms may also develop, including irritability, restlessness, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhea, elevated blood pressure, increased respiratory rate, or palpitations.

If women take this medicinal product during pregnancy, there is a risk of neonatal opioid withdrawal syndrome in their newborns.

Hyperalgesia

Hyperalgesia may be diagnosed when a patient receiving long-term opioid therapy experiences increased pain. This pain may qualitatively and anatomically differ from pain due to disease progression or breakthrough pain resulting from opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse and less well-localized in quality than prior pain. Symptoms of hyperalgesia may resolve with opioid dose reduction.

Following intravenous administration of fentanyl, transient hypotension may occur, particularly in patients with hypovolemia. Appropriate measures should be taken to maintain stable blood pressure.

Respiratory depression

As with all potent opioids, profound analgesia is accompanied by significant respiratory depression, which may persist or recur in the early postoperative period. Caution should be exercised after administration of high doses or infusions of fentanyl to ensure that adequate spontaneous respiration has been established and maintained before discharge from the recovery area.

Following administration of fentanyl in doses exceeding 200 mcg, significant respiratory depression may occur. This and other pharmacological effects of fentanyl may be reversed by specific opioid antagonists; however, additional doses may be required, as respiratory depression may outlast the duration of action of opioid antagonists.

Resuscitation equipment and opioid antagonists should be readily available. Hyperventilation during anesthesia may alter the patient’s responsiveness to carbon dioxide (CO2), thereby affecting postoperative respiration.

Administration during labor may cause respiratory depression in the newborn.

Cardiac disorders

In patients who have not received adequate anticholinergic agents, and when fentanyl is administered concomitantly with muscle relaxants lacking vagolytic effects, bradycardia and cardiac arrest may occur. Bradycardia can be treated with atropine.

Muscle rigidity

Muscle rigidity (morphine-like effect) may occur. To prevent rigidity affecting the muscles of the chest wall, the following should be considered:

• administer the drug slowly intravenously (usually with small doses);
• premedicate with benzodiazepines;
• administer muscle relaxants.

(Myo)clonic movements, unrelated to epilepsy, may occur.

Special warnings

Fentanyl should only be administered when respiratory control by a qualified specialist is possible.

Special dosage conditions

Rapid bolus administration of opioids should be avoided in patients with impaired cerebral function. In such patients, transient hypotension may occasionally cause transient reduction in intracerebral blood pressure.

Elderly and debilitated patients should receive reduced doses of fentanyl.

Dosage should be carefully adjusted in patients with hypothyroidism, pulmonary disease, reduced pulmonary reserve, hepatic or renal impairment, and in alcohol-dependent patients; prolonged postoperative monitoring may be required.

Patients on long-term opioid therapy and those with a history of opioid dependence may require higher doses.

Myasthenia gravis

For patients with myasthenia gravis, the appropriateness of recommended anticholinergic agents and neuromuscular blocking agents should be evaluated prior to and during general anesthesia involving intravenous fentanyl administration.

Interaction with neuroleptics

Patients should be informed about the specific effects of fentanyl and neuroleptic agents when used concomitantly, particularly regarding differences in duration of action. Hypotension occurs more frequently when these medicinal products are used together. Neuroleptic agents may induce extrapyramidal symptoms, which can be managed with antiparkinsonian agents.

Biliary tract

Like other opioids, due to its anticholinergic effect, fentanyl may increase pressure in the biliary tract and, in some cases, cause spasm of the sphincter of Oddi.

Serotonin syndrome

Caution should be exercised when fentanyl is used concomitantly with medicinal products that affect serotonergic neurotransmission.

When used concomitantly with serotonergic agents, such as SSRIs, SNRIs, and agents that inhibit serotonin metabolism (including MAOIs), a potentially life-threatening condition—serotonin syndrome—may develop. This may occur even when fentanyl is used at recommended doses.

Serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular disturbances (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

If serotonin syndrome is suspected, rapid discontinuation of fentanyl may be necessary.

Risk of concomitant use of CNS depressants, particularly benzodiazepines or similar medicinal products

When fentanyl is used concomitantly with CNS depressants, particularly benzodiazepines or similar medicinal products, the risk of profound sedation, respiratory depression, coma, and death may increase in patients with spontaneous respiration. If a decision is made to co-prescribe fentanyl with CNS depressants, particularly benzodiazepines or similar agents, the lowest effective dose of both medicinal products should be used for the shortest duration possible. Patients should be closely monitored for signs and symptoms of respiratory depression and profound sedation. Therefore, patients and caregivers should be strongly advised to be aware of these symptoms (see section "Interaction with other medicinal products and other forms of interaction").

Pediatric use

The medicinal product is used in children for analgesia during surgery and for enhancing anesthesia while maintaining spontaneous respiration.

The type of analgesia used in spontaneously breathing children should only be employed as an anesthetic method or as part of sedative/analgesic techniques under the supervision of an experienced specialist capable of performing necessary intubation in case of sudden chest wall rigidity and ensuring ventilation in case of apnea.

Use during pregnancy or breastfeeding.

Pregnancy. Fentanyl can cross the placenta in early pregnancy. Animal studies have demonstrated reproductive toxicity.

Use during labor (including cesarean section) is not recommended, as fentanyl crosses the placenta and may depress spontaneous respiration in the fetus. When fentanyl is administered, equipment for artificial ventilation should be readily available for both mother and child, if needed. An opioid antagonist should always be accessible for the newborn.

Chronic use during pregnancy may lead to drug dependence in the fetus, resulting in withdrawal symptoms in the newborn.

If a pregnant woman requires prolonged opioid use, she should be informed about the risk of neonatal opioid withdrawal syndrome, and appropriate treatment should be ensured.

Administration of fentanyl during labor may depress respiration in the newborn; therefore, an antidote for the infant should be readily available.

Breastfeeding. Fentanyl passes into breast milk and may cause respiratory depression in the infant; therefore, administration of the medicinal product is not recommended during breastfeeding. The benefit-risk balance of fentanyl use during breastfeeding should be carefully considered.

Fertility. There are no clinical data on the effect of fentanyl on male or female fertility. Animal studies in rats showed reduced fertility in females at toxic doses of fentanyl.

Ability to drive and use machines.

If a patient is discharged quickly from hospital, they should be warned not to drive or operate machinery for 24 hours after administration of the medicinal product.

This medicinal product may impair cognitive function and affect the patient’s ability to drive a vehicle safely.

Method of administration and dosage.

Before initiating opioid therapy, discuss with patients a strategy for discontinuing fentanyl treatment to minimize the risk of dependence and withdrawal syndrome (see section "Special precautions").

Route of administration

Fentanyl is administered intravenously either as a bolus injection or by infusion, as well as intramuscularly.

Fentanyl should only be administered when respiratory monitoring by a qualified specialist is possible (see section "Special precautions").

To prevent bradycardia, it is recommended to administer a small intravenous dose of an anticholinergic agent immediately before induction of anesthesia.

It is recommended to wear gloves when opening the ampoule.

Dosage

The drug can be administered intravenously to both adults and children. The dose should be individually adjusted depending on age, body weight, physical condition of the patient, concomitant diseases, concomitant medications, type of surgical procedure, and type of anesthesia.

Adult patients

Recommended doses

Doses exceeding 200 mcg are administered only during anesthesia. For premedication, Fenstud solution may be administered intramuscularly at 1–2 mL, 45 minutes prior to anesthesia.

For surgical procedures with low pain intensity, intravenous administration of 2 mL of Fenstud solution to patients without premedication provides adequate analgesia lasting 10–20 minutes. A bolus injection of 10 mL of the solution provides analgesia lasting approximately 1 hour. The resulting analgesia is sufficient for surgical procedures involving moderate pain intensity. Strong analgesia lasting 4 to 6 hours is achieved with fentanyl administration at a dose of 50 mcg/kg body weight, which is sufficient for intensive surgical interventions.

Fenstud may also be administered as an infusion. In patients undergoing mechanical ventilation, the initial dose may be given as a stepwise infusion: 1 mcg/kg/min for the first 10 minutes, followed by 0.1 mcg/kg/min. The initial dose may alternatively be administered as a bolus injection. The infusion rate should be adjusted according to the individual patient's response; reduction of the infusion rate is possible. If postoperative mechanical ventilation is not planned, the infusion should be discontinued approximately 40 minutes before the end of surgery.

A lower infusion rate, e.g., 0.05–0.08 mcg/kg/min, is required when spontaneous respiration is preserved. A higher infusion rate (up to 3 mcg/kg/min) is used in cardiac surgery.

The medicinal product Fenstud is chemically incompatible with induction agents thiopental and methohexital due to significant differences in pH.

Children.

Children aged 12 to 17 years: the same doses as for adults should be used.

Children aged 2 to 11 years:

The drug is used in children for analgesia during surgery and to enhance anesthesia while maintaining spontaneous respiration.

The type of analgesia used in spontaneously breathing children should only be employed as an anesthetic method or as part of sedative/analgesic techniques, provided that analgesia is administered by an experienced specialist capable of performing necessary intubation in case of sudden chest wall rigidity, and of ensuring ventilation in case of apnea (see section "Special precautions for use").

Elderly and debilitated patients

As with other opioids, the initial dose should be reduced in elderly patients (>65 years of age) and debilitated patients. Additional doses should be determined based on the effect of the initial dose.

Patients with obesity

In obese patients, there is a risk of overdose if the dose is calculated based on total body weight. In obese patients, the dose should be calculated according to their estimated lean body weight.

Patients with renal impairment

In patients with impaired renal function, consider reducing the dose of Fenstud and closely monitor for signs of fentanyl toxicity (see section "Pharmacokinetics").

Children

The drug is not recommended for use in children under 2 years of age.

Overdose

Patients should be informed about the symptoms of overdose, and it should be ensured that family members and friends are also aware of these symptoms. In the event of such symptoms, immediate medical assistance must be sought.

Symptoms. Symptoms of fentanyl overdose typically reflect its enhanced pharmacological effects. Depending on individual sensitivity, respiratory depression of varying degrees may occur, ranging from bradypnea to apnea. Toxic leukoencephalopathy has been observed in cases of fentanyl overdose.

Treatment. Hypoventilation or apnea: administer oxygen, initiate artificial ventilation.

Respiratory depression: a specific opioid antagonist (e.g., naloxone) should be administered. However, this does not preclude the immediate implementation of other measures required to treat overdose.

Respiratory depression may persist longer than the duration of action of the antagonist; therefore, additional doses of the opioid antagonist may be necessary.

Muscle rigidity: intravenous administration of a muscle relaxant should be given to facilitate artificial ventilation.

Careful monitoring of the patient is required, along with warming and administration of appropriate fluid volumes. If hypotension is severe or prolonged, hypovolemia should be considered. In cases of hypovolemia, parenteral fluids should be administered.

Adverse Reactions

The safety of intravenous fentanyl was evaluated in 376 subjects who participated in 20 clinical studies assessing intravenous fentanyl as an anesthetic. These subjects received at least one dose of fentanyl intravenously. Based on the pooled safety data from these clinical studies, the most commonly reported adverse reactions (≥5% incidence) were: nausea (26.1%); vomiting (18.6%); muscle rigidity (10.4%); arterial hypotension (8.8%); arterial hypertension (8.8%); bradycardia (6.1%); sedation (5.3%).

The adverse reactions listed below were observed during clinical studies and in the post-marketing period.

Adverse reactions are listed by system organ class and frequency of occurrence (MedDRA): very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from the available data):

When fentanyl is used concomitantly with neuroleptic agents, the following adverse effects may occur: chills and/or shivering, anxiety, postoperative hallucinations, and extrapyramidal symptoms (see section "Special precautions for use").

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging, protected from light.

Do not freeze. Keep out of reach of children.

Incompatibility.

Fentanyl is chemically incompatible with the intravenous anesthetic thiopental and muscle relaxants due to a significant difference in the pH of the solutions.

Packaging.

2 ml in a vial. 10 vials in a blister pack. 1 blister pack in a cardboard box.

10 ml in a vial. 5 vials in a blister pack. 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Rusan Pharma Ltd.

Manufacturer's address and address of the place of business.

Khasra No. 122, MI, Central Haughtown, Selakui, Dehradun – 248197, Uttarakhand, India.