Nalbuphine

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NALBUPHINE (NALBUPHINE)

Composition:

Active substance: nalbuphine;

1 ml of solution contains 10 mg of nalbuphine hydrochloride, calculated as 100 % dry substance;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear solution ranging from colorless to pale yellow.

Pharmacotherapeutic group. Analgesics. Opioids. Morphine derivatives. ATC code N02AF02.

Pharmacological Properties

Pharmacodynamics

Nalbuphine is an opioid analgesic belonging to the group of opioid receptor agonist-antagonists of the phenanthrene series. 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 action equivalent to that of morphine. It suppresses conditioned reflexes, exerts a sedative effect, causes dysphoria, miosis, and stimulates the vomiting center.

Compared to morphine, promethazine, and fentanyl, nalbuphine has a lesser depressant effect on the respiratory center and gastrointestinal motility. Administration of nalbuphine does not lead to significant changes in cardiovascular parameters or gastrointestinal motility. Nalbuphine does not exert spasmogenic effects on smooth muscle. When administered at therapeutic doses, respiratory depression is moderate and does not increase with doses exceeding 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 provides rapid analgesic effect. Time to reach maximum plasma concentration after intramuscular administration is 0.5–1 hour. It is metabolized in the liver. Excreted as metabolites in bile and, to a minor extent, in urine. It crosses the placental barrier and may cause respiratory depression in the newborn during labor. It is excreted into breast milk. The elimination half-life from plasma is 2–3 hours.

Clinical Characteristics.

Indications.

Pain of moderate to severe intensity. Used as an adjunct in anesthesia to reduce pain in the pre- and postoperative periods, and for analgesia during labor.

Contraindications.

Hypersensitivity to nalbuphine hydrochloride or to any of the excipients. Pediatric use under 18 years of age.

Nalbuphine should not be used in cases of respiratory depression or pronounced CNS depression, increased intracranial pressure, head injury, acute alcohol intoxication, alcoholic psychosis, or hepatic and renal insufficiency.

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

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

Nalbuphine should not be used in breastfeeding women (except during labor).

Interaction with other medicinal products and other forms of interaction.

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

Combination with phenothiazine derivatives and penicillin preparations may increase 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 hazardous 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 be fatal in case of overdose;
• With other CNS 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 CNS depression.

Special precautions for use

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

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

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

During labor, nalbuphine 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.

Nalbuphine has a moderate potential to cause respiratory depression; therefore, its use may provoke 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 nalbuphine's antagonistic properties.

This medicinal product contains 1.39 mg (0.06 mmol) of sodium per 1 ml, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Due to lack of clinical data, the drug must not be used during pregnancy and breastfeeding.

Pregnancy

Animal studies have not revealed any evidence of teratogenic effects. Since no teratogenic effects were observed in animals, congenital malformations in humans are not expected. Currently, substances responsible for developmental abnormalities in humans have shown teratogenic effects in two animal species in adequately performed studies.

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

Therefore, as a precautionary measure, nalbuphine should preferably not be used during pregnancy.

As with any morphine-type opioid, prolonged use of the drug during pregnancy, particularly towards the end of gestation, regardless of dose, may lead to neonatal withdrawal syndrome. Administration of high doses to a pregnant woman 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's condition, particularly respiratory function, should be considered.

Nalbuphine 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 respiratory arrest in nursing 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 influence reaction speed while driving or operating machinery

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

Administration and Dosage

Nalbuphine is administered intravenously or intramuscularly.

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 (Adults) below*).

Adults

The recommended dose for adults is 10–20 mg of nalbuphine hydrochloride for patients with a body weight of 70 kg, equivalent to 0.1–0.3 mg/kg body weight. The maximum single dose for adults should not exceed 20 mg.

The dose may be repeated every 3–6 hours, if necessary, with a maximum daily dose of 160 mg. Dosage must be individualized according to the intensity of pain, the patient's physical condition, and potential interactions with other concurrently administered medicinal products.

Table 1.

Dosage Table for Adult Patients

The information provided refers to the dosage form – injection solution 10 mg/mL

In myocardial infarction, 20 mg of the drug administered slowly intravenously is often sufficient; however, dosage may need to be increased up to 30 mg. If there is no clear positive dynamics in pain syndrome, repeat 20 mg after 30 minutes.

For premedication: 100–200 mcg/kg body weight.

For intravenous anesthesia: for induction – 0.3–1 mg/kg over 10–15 minutes; for maintenance – 250–500 mcg/kg every 30 minutes.

The drug should be prescribed with caution in elderly patients, those with general debilitation, or impaired respiratory function.

Children.

Do not use.

Overdose.

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

Treatment of overdose includes:

• in early stages, activated charcoal administered orally to conscious patients;
• supportive therapy (oxygen, intravenous fluid replacement, vasopressors to raise blood pressure);
• intravenous administration of naloxone (specific antidote).

Adverse Reactions

In patients treated with Nalbuphine, somnolence was the most commonly observed adverse reaction.

Cardiovascular system: increased or decreased arterial pressure, orthostatic hypotension, bradycardia, tachycardia, palpitations.

Eye disorders: blurred or impaired vision, miosis.

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

General disorders and administration site conditions: hypothermia, local pain, swelling, redness, burning, warmth, hot flushes, increased sweating.

Hepatobiliary disorders: impaired liver function tests, biliary tract spasm.

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 changes, 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.

Renal and urinary disorders: antidiuretic effect, urinary tract spasm.

Reproductive system and breast disorders: decreased libido or potency.

Skin and subcutaneous tissue disorders: urticaria, pruritus.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life: 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions: Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibilities: Should not be mixed in the same syringe with other injectable solutions.

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

Packaging:

1 mL or 2 mL in an ampoule; 5 ampoules per pack.

1 mL or 2 mL in an ampoule; 5 ampoules per blister; 1 or 2 blisters per pack.

1 mL in a pre-filled syringe with needle; 1 pre-filled syringe with needle per blister; 1 or 2 blisters per pack.

1 mL in a pre-filled syringe with needle; 1 pre-filled syringe with needle per tube; 1 or 10 tubes per pack.

1 mL in a pre-filled syringe without needle; 1 pre-filled syringe without needle and 1 needle separately blister-packed as a set; 1 or 2 sets per pack.

Prescription status: Prescription only.

Manufacturer: JSC "Farmak".

Manufacturer's address and place of business:

74, Kyrylivska Street, Kyiv, 04080, Ukraine.