Fentanyl calcex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FENTANYL KALCEKX (FENTANYLKALCEKS)

Composition:

Active substance: fentanyl;

2 ml of solution (1 ampoule) contains 0.1 mg of fentanyl (as fentanyl citrate 0.157 mg);

10 ml of solution (1 ampoule) contains 0.5 mg of fentanyl (as fentanyl citrate 0.785 mg);

Excipients: hydrochloric acid diluted, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: colorless clear liquid.

Pharmacotherapeutic group.
Opioid anesthetics. ATC code N01AH01.

Pharmacological properties.

Pharmacodynamics.

Fentanyl is a synthetic opioid analgesic similar to morphine. It produces rapid and short-acting analgesic effects. When administered parenterally, fentanyl causes pronounced analgesia, respiratory depression, bradycardia, and other effects typical of morphine (nausea and vomiting, constipation, physical dependence, certain vagal effects, and sedation of varying degrees). The maximum effect lasts approximately 30 minutes.

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.

Clinical characteristics.

Indications.

Fentanyl Kaltsex is used:

• in small doses for analgesia during minor surgical procedures;
• 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, such as 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 airway disease.
• Head injuries, increased intracranial pressure.
• Drug addiction.
• Hepatic insufficiency.
• Pregnancy or breastfeeding period.
• Age under 2 years.
• Use with monoamine oxidase inhibitors (MAOIs) concomitantly or within 2 weeks after discontinuation of MAOIs.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on fentanyl action

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

If a patient is taking CNS depressants, the dose of fentanyl should be lower than usual.

Fentanyl is rapidly and extensively metabolized by CYP3A4. Itraconazole (a potent CYP3A4 inhibitor), administered orally at a dose of 200 mg daily for 4 days, had no significant effect on the pharmacokinetics of intravenously administered fentanyl.

Ritonavir (one of the most potent CYP3A4 inhibitors), administered orally, reduced the clearance of intravenously administered fentanyl by two-thirds. However, a single intravenous dose did not affect the maximum concentration of fentanyl.

Careful monitoring of the patient is required when fentanyl is administered concomitantly with a strong CYP3A4 inhibitor such as ritonavir.

Concomitant use of fentanyl with fluconazole or voriconazole (moderate-strength CYP3A4 inhibitors) may enhance the effect of fentanyl.

With prolonged concomitant use of fentanyl and CYP3A4 inhibitors, dose reduction of fentanyl may be necessary to avoid accumulation, thereby reducing the risk of prolonged or delayed respiratory depression.

In patients who have not received adequate anticholinergic medication, or when fentanyl is used concomitantly with non-depolarizing muscle relaxants, bradycardia and cardiac arrest may occur. Bradycardia can be treated with atropine.

Concomitant use with droperidol may more frequently cause arterial hypotension.

Calcium channel blockers (e.g., diltiazem, verapamil) may increase plasma fentanyl concentrations, thereby enhancing opioid effects.

The use of magnesium sulfate during induction anesthesia in addition to fentanyl significantly improves conditions for intubation without the need for muscle relaxants.

Grapefruit juice slows the metabolism of fentanyl, thereby reducing its effect.

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.

Effect of fentanyl on the action of other medicinal products

After administration of fentanyl, doses of other CNS depressants should be reduced.

Concomitant use with fentanyl significantly increases (2- to 3-fold) plasma concentrations of etomidate. When used concomitantly with fentanyl, the total plasma clearance of etomidate and volume of distribution are reduced 2- to 3-fold, while the half-life remains unchanged.

Concomitant intravenous administration of fentanyl and midazolam results in an increased terminal 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

Physical dependence and addiction may develop (see section "Drug dependence and abuse potential" below).

Following intravenous administration of fentanyl, arterial blood pressure may suddenly decrease, particularly in patients with hypovolemia. This effect is transient. Appropriate measures should be taken to maintain stable arterial blood pressure.

When doses of fentanyl exceeding 200 mcg are administered, severe respiratory depression may occur. This and other pharmacological effects of fentanyl can be reversed by using specific opioid antagonists (e.g., naloxone). Additional doses of opioid antagonists may be required, as respiratory depression may persist longer than the duration of action of the opioid antagonist. Additional supportive care and monitoring may be necessary when administering the drug to patients at risk of opioid abuse.

A detailed patient history should be obtained to document concomitant medications, including over-the-counter drugs, and to consider the patient's past and current medical and psychiatric conditions.

Patients may find that treatment becomes less effective with prolonged use of the drug and may express a need to increase the dose to achieve the same level of pain control as initially observed. Patients may also supplement their treatment with additional analgesics. These may be signs of developing tolerance. Patients should be informed about the risks of developing tolerance.

Excessive or inappropriate use may lead to overdose and/or fatal outcome. It is important that patients use only the medications and doses prescribed by their physician and do not give these medications to anyone else.

Patients should be closely monitored to prevent misuse, abuse, or dependence on the drug.

The clinical need for analgesic treatment should be regularly reassessed.

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

Hyperalgesia may be diagnosed if a patient undergoing long-term opioid therapy experiences increased pain. This may differ anatomically from pain associated with disease progression or breakthrough pain due to opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse and less localized than the original pain. Symptoms of hyperalgesia may resolve with a reduction in opioid dose.

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

• Administer the drug slowly intravenously (usually small incremental doses are sufficient);
• Premedicate with benzodiazepines;
• Administer muscle relaxants.

(Myoclonic) movements not related to epilepsy may occur.

Special warnings

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

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

Elderly and debilitated patients require reduced doses of fentanyl.

Dose selection should be cautious in patients with hypothyroidism, pulmonary disease, reduced pulmonary reserve, hepatic or renal impairment, and in patients with alcohol dependence; prolonged postoperative monitoring may be required.

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

Patients should be informed about the specific effects of fentanyl and neuroleptic agents (e.g., droperidol) when used concomitantly, particularly regarding differences in duration of action. Hypotension occurs more frequently when these drugs are used together. Neuroleptic agents may cause extrapyramidal symptoms, which can be reversed with antiparkinsonian agents.

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.

Administration of fentanyl during labor may cause respiratory depression in the newborn.

As with all potent opioids, complete analgesia is associated with pronounced respiratory depression, which may persist or recur in the early postoperative period. After administration of high doses of fentanyl or fentanyl infusion, caution should be exercised to ensure adequate spontaneous respiration after emergence from anesthesia, before patient transfer.

Resuscitation equipment and opioid antagonists should be readily available. Hyperventilation during anesthesia may alter the patient's response to CO₂, thereby affecting postoperative respiration.

Rapid bolus administration of opioids should be avoided in patients with impaired cerebral function. In such patients, transient decreases in arterial blood pressure may occasionally lead to transient reductions in intracerebral arterial pressure.

Serotonin syndrome

Caution is advised when fentanyl is used concomitantly with drugs affecting serotonergic neurotransmission.

Concomitant use with serotonergic agents, such as SSRIs, SNRIs, and drugs that inhibit serotonin metabolism (including MAO inhibitors), may result in a life-threatening condition—serotonin syndrome. This may occur even with recommended doses of fentanyl.

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.

Tolerance and opioid use disorders (abuse and dependence)

Tolerance, physical and psychological dependence may develop with repeated opioid use.

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

Drug dependence and abuse potential

Regular use of opioids in all patients may lead to drug dependence (addiction), even when used at therapeutic doses. The risk is increased in patients with a history of substance abuse, including alcohol, or in patients with psychiatric disorders (e.g., severe depression).

Withdrawal syndrome

Prior to initiating opioid therapy, patients should be counseled on a tapering strategy for discontinuation of fentanyl.

Withdrawal syndrome may occur upon abrupt discontinuation or dose reduction. When discontinuing the drug, the dose should be gradually reduced to minimize withdrawal symptoms. Discontinuation after high-dose therapy may take several weeks to months.

Opioid withdrawal syndrome is characterized by some or all of the following signs: anxiety, lacrimation, rhinorrhea, yawning, sweating, chills, muscle pain, mydriasis, and tachycardia. Other symptoms may also develop, including irritability, restlessness, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhea, elevated blood pressure, tachypnea, and increased heart rate.

If women take these drugs during pregnancy, there is a risk that their newborns will experience neonatal withdrawal syndrome.

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

Concomitant use of fentanyl and CNS depressants, especially benzodiazepines or similar medicinal products, in patients with spontaneous respiration may increase the risk of profound sedation, respiratory depression, coma, and death. If a decision is made to use fentanyl concomitantly with a CNS depressant, particularly a benzodiazepine or similar medicinal product, the lowest effective dose of both drugs should be used, and the duration of treatment should be as short as possible. Patients must be closely monitored for signs and symptoms of respiratory depression and excessive 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").

Children

The type of analgesia used in spontaneously breathing children should only be applied as an anesthesia technique or part of a sedation/analgesia regimen under the supervision of experienced personnel capable of performing necessary intubation in case of sudden chest wall rigidity, and providing ventilation in case of respiratory arrest.

Use during pregnancy or breastfeeding.

Pregnancy.

There are insufficient data on the use of fentanyl in pregnant women. Fentanyl may cross the placenta in early pregnancy. Animal studies have shown reproductive toxicity. The potential risk to humans is unknown.

Since fentanyl crosses the placenta, it is not recommended for use during labor (including cesarean section), as the fetal respiratory center is particularly sensitive to opioids.

If fentanyl is used, resuscitation equipment for assisted ventilation must be immediately available for both mother and child. An opioid antagonist for the newborn must always be readily accessible.

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

If prolonged opioid use is required during pregnancy, the patient should be informed about the risk of neonatal opioid withdrawal syndrome, and appropriate treatment should be ensured.

Use during labor may cause respiratory depression in the newborn; therefore, an antidote for the newborn must be readily available.

Breastfeeding.

Fentanyl may pass into breast milk and cause respiratory depression in the infant; therefore, administration to breastfeeding women is not recommended. The risk/benefit of breastfeeding after fentanyl administration should be 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 maternally toxic doses.

Ability to influence reaction speed when driving or operating machinery.

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

This medicinal product may impair cognitive function and affect the patient's ability to safely drive a vehicle. When prescribing this medicinal product, patients should be informed:

• The drug may affect their ability to drive;
• They should not drive until they know how the drug affects them;
• Driving under the influence of this drug is a legal offense;
• However, no legal offense will be committed if:
  • The drug was prescribed to treat a medical or dental condition;
  • The patient uses the drug according to the instructions provided by the physician and the information accompanying the product;
  • The use of the drug has not impaired the ability to drive safely.

Method of Administration and Dosage

Before initiating opioid therapy, it is necessary to discuss with patients a strategy for discontinuation of fentanyl treatment in order to minimize the risk of dependence and opioid withdrawal syndrome (see section "Special Precautions").

Fentanyl may be administered only when respiratory monitoring by a qualified specialist is possible.

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

When opening the ampoule, it is recommended to wear gloves.

Fentanyl can be administered intravenously either as a bolus injection or as an infusion, as well as intramuscularly.

The intravenous route of administration is applicable for both adults and children. The dose should be individually adjusted depending on age, body weight, patient's physical condition, concomitant diseases, concomitant use of other medicinal products, type of surgical procedure, and type of anesthesia.

Adult Patients

Recommended doses

	Initial dose, mcg	Additional dose, mcg
Spontaneous breathing	50-200	50
Artificial ventilation	300-3500	100-200

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

For surgical procedures associated with low-intensity pain, intravenous administration of 2 mL of Fentanyl Kalceks solution to patients without premedication provides adequate analgesia lasting 10–20 minutes. A bolus injection of 10 mL 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 a fentanyl dose of 50 mcg/kg body weight, which is sufficient for intensive surgical interventions.

Fentanyl Kalceks may also be administered as infusions. In patients undergoing mechanical ventilation, the initial dose may be administered as a stepwise infusion: 1 mcg/kg/min for the first 10 minutes, followed by 0.1 mcg/kg/min. The initial dose may also be given as a bolus injection. The infusion rate should be adjusted according to the individual patient's response; reduction of the infusion rate may be necessary. If mechanical ventilation is not planned in the postoperative period, 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 during cardiac surgery.

Elderly and debilitated patients

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

Patients with excessive body weight

In patients with excessive body weight, there is a risk of overdose if the dose is calculated based on total body weight. Therefore, the dose in such patients should be calculated according to their predicted lean body mass.

Renal insufficiency

In patients with renal insufficiency, a reduced dose of Fentanyl Kalceks should be considered, and such patients should be closely monitored for signs of fentanyl toxicity.

Children

Children aged 12 to 17 years: The same doses as for adults are used.

Children aged 2 to 11 years:

	Age	Initial doses, mcg/kg	Additional doses, mcg/kg
Spontaneous breathing	2-11 years	1-3	1-1.25
Artificial ventilation of the lungs	2-11 years	1-3	1-1.25

The drug is used in children for analgesia during surgery and for enhancing anesthesia while preserving spontaneous respiration.

The type of analgesia used in spontaneously breathing children should be applied only 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 rigidity, and of ensuring ventilation in case of apnea (see section "Special precautions for use").

Overdose.

Symptoms. Symptoms of fentanyl overdose usually reflect its enhanced pharmacological effect. 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, artificial ventilation.

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

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

Muscle rigidity: a muscle relaxant should be administered intravenously to facilitate artificial ventilation.

The patient should be closely monitored, kept warm, and provided with an appropriate amount of fluid. If hypotension is severe or prolonged, hypovolemia should be considered. In cases of hypovolemia, parenteral solutions should be administered.

Adverse Reactions

The most commonly observed adverse effects are: nausea, vomiting, muscle rigidity, arterial hypotension/hypertension, bradycardia, and sedation.

The adverse reactions listed below were observed during clinical trials and in the post-marketing period with the use of fentanyl.

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

Immune system disorders: frequency not known – allergic reactions (anaphylactic shock, anaphylactic reaction, urticaria).

Psychiatric disorders: common – agitation; uncommon – euphoria; very rare – insomnia, sexual dysfunction (decreased libido); frequency not known – delirium (symptoms may include a combination of agitation, restlessness, disorientation, confusion, fear, visual and auditory hallucinations, sleep disturbances, nightmares).

Nervous system disorders: very common – muscle rigidity (may also affect chest wall muscles); common – dyskinesia, sedation, dizziness; uncommon – headache; frequency not known – seizures, loss of consciousness, myoclonus.

Eye disorders: common – visual disturbances.

Cardiac disorders: common – bradycardia, tachycardia, arrhythmia; rare – asystole.

Vascular disorders: common – arterial hypotension/hypertension, venous pain, vasodilation; uncommon – phlebitis, blood pressure fluctuations.

Respiratory, thoracic and mediastinal disorders: common – respiratory depression, laryngospasm, bronchospasm, apnea; uncommon – hyperventilation, hiccups; rare – recurrent respiratory depression.

Gastrointestinal disorders: very common – nausea, vomiting; uncommon – dysphagia.

Skin and subcutaneous tissue disorders: common – allergic dermatitis; frequency not known – pruritus.

General disorders and administration site conditions: uncommon – chills, hypothermia; frequency not known – drug withdrawal syndrome (see section "Special Warnings and Precautions for Use").

Injury, poisoning and procedural complications: common – postoperative confusion; uncommon – anesthesia-related respiratory complications.

With prolonged use of the drug, its effect may diminish (tolerance may develop) and dependence may occur (see section "Special Warnings and Precautions for Use").

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

Shelf life.

5 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep in the original packaging to protect from light. Do not refrigerate or freeze.

Keep out of reach of children.

Incompatibilities.

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

Packaging.

2 ml or 10 ml in a colorless glass ampoule of hydrolytic class I, with a break ring or score mark and color-coded rings.

5 ampoules (2 ml and 10 ml) in a blister pack (cavity tray) made of polyvinyl chloride film.

1, 2 or 20 blister packs (cavity trays) containing 2 ml ampoules, or 2 blister packs (cavity trays) containing 10 ml ampoules, in a cardboard carton with a first-opening control in the form of a self-adhesive sticker on each opening part of the carton.

Prescription status.

Prescription only.

Manufacturer.

Manufacturer responsible for batch release:

JSC "Kalceks".

Manufacturer's address and place of business.

71E Krustpils Street, Riga, LV-1057, Latvia.

Marketing Authorization Holder.

JSC "Kalceks".

Address of the Marketing Authorization Holder.

71E Krustpils Street, Riga, LV-1057, Latvia.