Nalbuphine-pharmex

INSTRUCTION for medical use of the medicinal product NALBUPHINE-PHARMEX (NALBUPHINE-PHARMEX)

Composition:

Active substance: nalbuphine hydrochloride;

1 ml of solution contains nalbuphine hydrochloride 10 mg;

Excipients: sodium chloride, sodium citrate, citric acid monohydrate, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless or almost colorless liquid.

Pharmacotherapeutic group.

Analgesics. Opioids. Morphinan derivatives. ATC code N02AF02.

Pharmacological properties.

Pharmacodynamics.

Nalbuphine is an opioid analgesic belonging to the group of opioid receptor agonist-antagonists. It acts as a kappa-receptor agonist and a mu-receptor antagonist, disrupting interneuronal transmission of pain impulses at various levels of the central nervous system (CNS) by affecting higher regions of the brain. Nalbuphine provides analgesic effect equivalent to that of morphine. It suppresses conditioned reflexes, produces sedative effects, causes dysphoria, miosis, and stimulates the vomiting center. Compared to morphine, promethazine, and fentanyl, nalbuphine has a lesser effect on respiratory depression and gastrointestinal motility. Administration of nalbuphine does not lead to significant changes in cardiovascular system parameters or gastrointestinal motility. Nalbuphine has not demonstrated spasmogenic effects on smooth muscle. When administered at therapeutic doses, respiratory depression is moderate and does not increase beyond a dose of 0.3 mg/kg (ceiling effect). It does not affect hemodynamics. The risk of developing tolerance and opioid dependence with controlled use is significantly lower than with pure opioid agonists.

Adults

After intravenous administration, the effect develops within 2–3 minutes; after intramuscular administration, within 10–15 minutes. Maximum effect is reached within 30–60 minutes. Duration of action is 3–6 hours.

Pharmacokinetics.

The drug produces rapid analgesic action. Time to reach maximum plasma concentration after intramuscular administration is 0.5–1 hour. Metabolized in the liver. Excreted as metabolites via bile; a small amount is excreted in urine. Crosses the placental barrier and, during labor, may cause respiratory depression in the newborn. Penetrates into breast milk. Elimination half-life is 2–3 hours.

Clinical characteristics.

Indications.

Pain of moderate to severe intensity; as an adjunctive agent during anesthesia; for pain reduction in pre- and postoperative periods; analgesia during labor.

Contraindications.

Hypersensitivity to nalbuphine hydrochloride or any component of the medicinal product.

Children under 18 years of age.

Should not be used in cases of respiratory depression or pronounced central nervous system (CNS) depression, increased intracranial pressure, head injury, acute alcohol intoxication, alcoholic psychosis, or evident impairment of liver or kidney function.

Concomitant use of the drug with pure morphine-mimetic agonists is not recommended.

The drug should not be administered without appropriate diagnosis in cases of acute abdominal syndrome, as nalbuphine may mask its clinical manifestations.

The medicinal product should not be used in breastfeeding women (except during labor).

Interaction with other medicinal products and other types of interactions.

The drug should be used with caution and in reduced doses when administered concomitantly with anesthetics, hypnotics, anxiolytics, antidepressants, and neuroleptics, to prevent excessive central nervous system (CNS) depression and suppression of respiratory center activity. Alcohol also enhances the CNS depressant effect of nalbuphine. The drug should not be taken together with other narcotic analgesics due to the risk of reduced analgesic effect and potential precipitation of withdrawal syndrome in opioid-dependent patients.

Combination with phenothiazine derivatives and penicillin preparations may intensify nausea and vomiting.

Concomitant use is contraindicated. Alfentanil, codeine, dextropropoxyphene, dihydrocodeine, fentanyl, methadone, morphine, oxycodone, pethidine, sufentanil, tramadol – reduced analgesic effect may occur due to receptor blockade, with risk of withdrawal syndrome.

Concomitant use is not recommended. Alcohol – increased sedative effect of morphine-type analgesics. Impaired attention may be dangerous when driving or operating machinery. Consumption of alcoholic beverages and use of medicinal products containing ethanol should be avoided.

Use with caution:

• with other morphine-type analgesics (antitussives or substitution therapy), benzodiazepines, barbiturates – increased risk of respiratory depression, which may lead to fatal outcome in case of overdose;
• with other central nervous system depressants: other morphine-type analgesics, barbiturates, benzodiazepines, anxiolytics (except benzodiazepines), sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), antihistamines (H1), hypnotics, centrally acting antihypertensives, neuroleptics, thalidomide, baclofen – enhanced central nervous system depression.

Impaired attention may be dangerous when driving or operating machinery.

Special precautions for use

In patients suffering from drug addiction, the medicinal product may cause an acute withdrawal episode.

The risk of drug abuse is low due to nalbuphine's significant antagonistic properties. Sudden discontinuation after prolonged use may lead to withdrawal syndrome.

Nalbuphine-Farmeks is not recommended for outpatient use due to the risk of daytime drowsiness.

During labor, the medicinal product should be administered under strict medical supervision to women with cervical dilation of no more than 4 cm. In such cases, intravenous administration should be avoided.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Nalbuphine-Farmeks has a moderate potential to cause respiratory depression; therefore, its use may provoke the development of respiratory insufficiency.

Since the drug is metabolized in the liver and excreted by the kidneys, dosage reduction is recommended in patients with hepatic or renal impairment.

In morphine-dependent individuals or patients who have undergone morphine therapy, withdrawal syndrome may occur due to the antagonistic properties of nalbuphine hydrochloride.

Use during pregnancy or breastfeeding

Due to lack of clinical data, the drug should not be administered during pregnancy or breastfeeding.

Pregnancy

Animal studies have not revealed any signs of teratogenic effects. Given the absence of teratogenic effects in animals, congenital malformations in humans are not expected. To date, substances causing developmental abnormalities in humans have shown teratogenic effects in two animal species in properly conducted animal studies.

In clinical practice, there is currently insufficient evidence to assess the potential malformative effect of nalbuphine when used during the first trimester of pregnancy.

Therefore, nalbuphine should preferably not be used during pregnancy.

As with any morphine-type drug, prolonged use of nalbuphine during pregnancy, especially toward the end of gestation, regardless of dose, may lead to neonatal withdrawal syndrome. Administration of high doses to the mother near term, even with short-term treatment, may result in respiratory depression in the newborn.

When nalbuphine is used during labor, respiratory depression (even delayed) has been observed in newborns. Therefore, the maximum dose should not exceed 20 mg for intramuscular administration. Monitoring of the newborn, particularly respiratory function, should be considered.

Nalbuphine use should be avoided during high-risk pregnancies, particularly in cases of preterm labor or twin delivery.

Breastfeeding

Nalbuphine passes into breast milk; several cases of hypotonia and apnea in infants have been reported following maternal use of morphine derivatives in doses exceeding therapeutic levels.

Therefore, breastfeeding is contraindicated during prolonged treatment with this medicinal product.

Breastfeeding may be possible when the drug is used in obstetric practice.

Ability to affect reaction speed when driving or operating machinery

During treatment, patients should refrain from driving vehicles or operating machinery.

Administration and Dosage.

The medicinal product is intended for intravenous and intramuscular administration.

Dosage should correspond to the intensity of pain, the patient's physical condition, and take into account interactions with other concurrently administered medicinal products.

Dosage depends on the patient's body weight. Exercise caution to avoid dosage errors due to confusion between milligrams (mg) and milliliters (mL), which may lead to accidental overdose (see Dosage Table 1).

For pain relief, the usual dose is 0.1 to 0.3 mg of the drug per 1 kg of the patient's body weight, administered intravenously or intramuscularly.

The single dose may be repeated every 3–6 hours as needed, with a maximum daily dose of 160 mg.

Maximum single dose for adults: 0.3 mg/kg body weight.

Table 1. Dosage for adult patients.

In myocardial infarction, 20 mg of the drug administered slowly intravenously is often sufficient; however, dose escalation up to 30 mg may be required. If there is no clear improvement in pain symptoms, repeat 20 mg after 30 minutes.

For premedication – 100–200 mcg/kg body weight. For intravenous anesthesia induction – 0.3–1 mg/kg over 10–15 minutes; for anesthesia maintenance – 250–500 mcg/kg every 30 minutes.

Use with caution in elderly patients, those with general debilitation, or impaired respiratory function.

Instructions for preparing the syringe with the medicinal product prior to use.

1. Remove the blister pack containing the syringe and needle from the carton.
2. Take the syringe out of the packaging by holding the glass cylinder. While holding the syringe cylinder with one hand (avoid holding the syringe by the plunger), unscrew the syringe cap by turning it along the thread.

1. Remove the needle protective cap (with label), while holding the needle container.

1. Attach the needle to the syringe by screwing it on until fully secured (fully tightened).

1. Press the syringe plunger until a drop of liquid appears at the tip of the needle inside the cap (clearly visible through the transparent cap).
2. Immediately before injection, remove the protective needle cap.

Children.

Do not use.

Overdose.

Symptoms of overdose may include: respiratory depression; arterial hypotension, circulatory failure; deepening of coma; seizures; rhabdomyolysis progressing to renal failure.

Treatment of overdose includes:

• In conscious patients, early administration of activated charcoal orally;
• Supportive therapy (oxygen, intravenous fluid replacement, vasopressor agents);
• Intravenous administration of naloxone (specific antidote).

Adverse Reactions

Somnolence is the most commonly observed adverse reaction in patients treated with nalbuphine.

Immune system disorders: Anaphylactic reactions.

Nervous system disorders: Dizziness, headache, muscle rigidity, increased intracranial pressure.

Psychiatric disorders: Drug dependence, psychomimetic reactions, neurotic reactions, somnolence, depression, confusion, dysphoria, speech disturbances, mood alterations, restlessness, nervousness (irritability), hallucinations, euphoria.

The potential for physical and psychological dependence, as well as tolerance during prolonged treatment, is similar to that of other morphine derivatives.

Hepatobiliary disorders: Abnormal liver function tests, spasm of the biliary tract.

Renal and urinary disorders: Antidiuretic effect, spasm of the urinary tract.

Reproductive system and breast disorders: Decreased libido or potency.

Gastrointestinal disorders: Nausea, vomiting, dry mouth, abdominal cramps, constipation.

Cardiovascular disorders: Increased or decreased blood pressure, bradycardia, tachycardia, orthostatic hypotension, palpitations.

Eye disorders: Blurred vision or visual disturbances, miosis.

Skin and subcutaneous tissue disorders: Urticaria, pruritus.

General disorders and administration site reactions: Hypothermia; local pain, swelling, redness, burning, sensation of warmth, flushing, and increased sweating may occur.

When used in obstetric practice – respiratory depression in newborns, which may be prolonged or delayed in onset.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the reporting system.

Shelf life

For ampoules: 4 years.

For vials: 3 years.

For pre-filled syringes: 3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities

Do not mix with other injectable solutions in the same syringe.

Nalbuphine-Farmeks is compatible with 0.9 % sodium chloride solution, 5 % glucose solution, and Hartmann's solution.

Packaging

1 ml or 2 ml in a pre-filled syringe; 1 or 5 pre-filled syringes with needles in a contour cell pack or blister, 1 contour cell pack or blister per carton.

1 ml or 2 ml in an ampoule; 5 ampoules in a blister, 1 or 2 blisters per carton; 10 ampoules in a blister, 1 blister per carton.

1 ml or 2 ml in a vial; 5 vials in a contour cell pack or blister, 1 or 2 contour cell packs or blisters per carton; 10 vials in a contour cell pack or blister, 1 contour cell pack or blister per carton.

Prescription category

By prescription only.

Manufacturer

LLC “FARMEKS GROUP”

LIMITED LIABILITY COMPANY “CORPORATION “ZDOROV’YA””

Manufacturer’s address and place of business

Ukraine, 08301, Boryspil, Kyiv region, Shevchenka St., 100.

(LLC “FARMEKS GROUP”)

Ukraine, 61013, Kharkiv, Kharkiv region, Shevchenka St., 22.

(LIMITED LIABILITY COMPANY “CORPORATION “ZDOROV’YA”)