Nalbuphine injection 20 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NALBUPHINE INJECTION 10 mg NALBUPHINE INJECTION 20 mg (NALBUPHINE INJECTION 10 mg) (NALBUPHINE INJECTION 20 mg)

Composition:

Active substance: nalbuphine hydrochloride;

1 ml of solution contains 10 mg or 20 mg of nalbuphine hydrochloride dihydrate, calculated as anhydrous nalbuphine hydrochloride;

Excipients: sodium metabisulfite (E 223), sodium citrate, sodium chloride, anhydrous citric acid, diluted hydrochloric acid, water for injections (10 mg/ml); sodium metabisulfite (E 223), sodium citrate, anhydrous citric acid, diluted hydrochloric acid, water for injections (20 mg/ml).

Pharmaceutical form. Injection solution.

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

Pharmacotherapeutic group.

Analgesics. Opioids. Morphine derivatives. ATC code N02A F02.

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). It interferes with interneuronal transmission of pain impulses at various levels of the central nervous system by affecting higher regions of the brain. It suppresses conditioned reflexes, produces sedative effects, causes dysphoria, miosis, and stimulates the vomiting center. To a lesser extent than morphine, promedol (meperidine), or fentanyl, it affects the respiratory center and gastrointestinal motility. It does not influence hemodynamics. The risk of developing tolerance and opioid dependence with controlled use is significantly lower compared to pure opioid agonists. When administered intravenously, the effect develops within a few minutes; after intramuscular administration, within 10–15 minutes. Maximum effect is reached within 30–60 minutes; duration of action lasts 3–6 hours.

Pharmacokinetics.

The drug provides rapid analgesic action. Time to reach maximum plasma concentration after intramuscular administration is 0.5–1 hour. It is metabolized in the liver. Excreted in the form of metabolites via bile; a small amount is excreted in urine. It crosses the placental barrier and during labor may cause respiratory depression in the newborn. It passes into breast milk. Elimination half-life is 2.5–3 hours.

Clinical characteristics.

Indications.

Moderate to severe pain; as an adjunct in anesthesia to reduce pain in pre- and postoperative periods, and for analgesia during labor.

Contraindications.

Hypersensitivity to nalbuphine hydrochloride or any component of the drug. Pediatric use (under 18 years of age). Respiratory depression or marked central nervous system (CNS) depression, increased intracranial pressure, head injury, acute alcohol intoxication, alcohol psychosis. Epileptic syndrome; acute surgical abdominal conditions (prior to diagnosis); surgical interventions on the hepatobiliary system (risk of Oddi's sphincter spasm); drug dependence on morphine-like agents (morphine, promedol, fentanyl) – risk of withdrawal syndrome; diarrhea associated with pseudomembranous colitis induced by cephalosporins, lincosamides, penicillins; toxic dyspepsia.

The drug should be used with caution in: elderly patients, cachexia, hepatic and renal insufficiency, respiratory insufficiency (including chronic obstructive pulmonary disease, uremia), in cases of preterm labor and probable fetal immaturity; in cholelithiasis, severe inflammatory bowel diseases, bronchial asthma, arrhythmia, arterial hypertension, hypothyroidism, prostate hyperplasia, urethral stricture; in patients with suicidal tendencies or emotional lability; and in debilitated patients. Combined use of the drug with pure morphine agonists is not recommended. Nalbuphine should not be administered to breastfeeding women (except during labor).

The drug should not be used without appropriate diagnosis in surgical abdominal conditions, as nalbuphine may mask clinical signs.

Special safety precautions.

The drug should be administered as an adjunct to general anesthesia only by a specially trained specialist. Safety measures must be readily available in case of respiratory depression, including naloxone, intubation equipment, and artificial ventilation apparatus.

Interaction with other medicinal products and other forms of interaction.

The drug should be used with caution and in reduced doses when administered concomitantly with anesthetics, hypnotics, anxiolytics, antidepressants, and neuroleptics, to prevent excessive CNS depression and respiratory center suppression. Alcohol 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 effect and potential induction of withdrawal syndrome in opioid-dependent patients.

Concomitant use of nalbuphine with phenothiazine derivatives and penicillin preparations may enhance nausea and vomiting.

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

Combination use is not recommended. Alcohol increases the sedative effect of morphine-type analgesics. Impaired attention may be hazardous when driving or operating machinery. Concurrent consumption of alcoholic beverages and medicinal products containing ethanol should be avoided.

Use with caution:

• With other morphine-type analgesics (antitussives or substitution therapy), as well as with benzodiazepines and barbiturates, due to 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 – due to enhanced CNS depression.

Medicinal products with anticholinergic activity and antidiarrheal agents, including loperamide, increase the risk of constipation up to intestinal obstruction, urinary retention, and CNS depression. Nalbuphine enhances the hypotensive effect of antihypertensive agents, including ganglion blockers and diuretics. It reduces the efficacy of metoclopramide. Use with caution in combination with MAO inhibitors due to possible excitation or inhibition leading to hypertensive or hypotensive crises (initially, to assess interaction effects, the dose should be reduced to ¼ of the recommended dose).

Special precautions for use.

The drug should be used with caution in emotionally unstable patients. In patients with drug dependence, the drug may cause an acute withdrawal episode. When used concomitantly with other morphine derivatives, physical and psychological dependence may occur during prolonged use. Sudden discontinuation of nalbuphine after prolonged administration may lead to withdrawal syndrome. This medicinal product is not recommended for use in outpatient settings due to the risk of daytime drowsiness.

Nalbuphine Injection 10 mg, solution for injection 10 mg/mL, contains 2.84 mg of sodium per mL in each ampoule. Nalbuphine Injection 20 mg, solution for injection 20 mg/mL, contains 2.447 mg of sodium per mL in each ampoule – this should be taken into account when administering to patients on a strict low-sodium diet.

Nalbuphine 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, careful consideration should be given to the necessity of using nalbuphine in patients with hepatic and/or renal impairment. If use is necessary, the dosage should be reduced and the patient’s condition should be closely monitored.

When administering nalbuphine to patients scheduled for surgical intervention due to hepatobiliary pathology, the high risk of developing Oddi sphincter spasm should be considered.

In morphine-dependent individuals or patients who have undergone morphine therapy, withdrawal syndrome may occur due to the antagonistic properties of nalbuphine hydrochloride. Nalbuphine may interfere with enzymatic laboratory tests used to detect drug dependence.

The drug is not recommended for use without appropriate diagnosis in surgical abdominal syndromes, as nalbuphine hydrochloride may mask its clinical manifestations.

This medicinal product contains sodium metabisulfite (E 223), which may rarely cause hypersensitivity reactions and bronchospasm.

Use during pregnancy or breastfeeding.

Pregnancy

Animal studies have not revealed any signs of teratogenic effects. Since no teratogenic effect has been observed in animals, congenital malformations in humans are not expected. To date, substances responsible for developmental abnormalities in humans have shown teratogenic effects in two animal species in properly conducted animal studies.

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

Therefore, nalbuphine is best avoided during pregnancy. As with any morphine-type drug, prolonged use of nalbuphine during pregnancy, especially towards the end of pregnancy, regardless of dose, may lead to neonatal withdrawal syndrome. Administration of high doses of the drug to the mother towards the end of pregnancy, 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 of the drug should not exceed 20 mg when administered intramuscularly. Monitoring of the newborn, particularly respiratory function, should be considered.

Nalbuphine should be avoided during high-risk pregnancies, especially in cases of preterm labor or multiple births.

Breastfeeding period

Nalbuphine passes into breast milk; several cases of hypotonia and respiratory arrest in infants have been reported after 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 with nalbuphine, patients should refrain from driving vehicles and operating machinery.

Method of administration and dosage.

The medicinal product should be administered intravenously and intramuscularly.

Dosage depends on the patient's body weight. Care must be taken to avoid dosing errors and confusion between milligrams (mg) and milliliters (mL), as this may lead to accidental overdose (adult dosing, see Table 1 below).

Dosage should correspond to the intensity of pain, the patient's physical condition, and possible interactions with other concurrently administered medicinal products. The dose and frequency of administration should be carefully determined to avoid drug dependence. For analgesia, the usual recommended dose is 0.1–0.3 mg of the drug per 1 kg of body weight; if necessary, administrations may be repeated every 3–6 hours, with a maximum daily dose of 160 mg.

Table 1. Dosage for adult patients

In patients with opioid dependence, withdrawal symptoms (abstinence syndrome) may develop following administration of nalbuphine. In such cases, morphine should be administered intravenously slowly, with gradual dose escalation until pain relief is achieved. If the patient has previously received morphine, meperidine, codeine, or another opioid analgesic with similar duration of action prior to nalbuphine administration, nalbuphine should initially be given at a dose of 25% of the required amount, and the patient should be closely observed for possible onset of withdrawal symptoms (abdominal cramps, nausea, vomiting, lacrimation, rhinorrhea, anxiety, restlessness, hyperthermia, or piloerection). If no withdrawal symptoms occur, the nalbuphine dose should be gradually increased at recommended intervals until the desired level of analgesia is achieved.

The maximum single dose for adults is 0.3 mg per 1 kg of body weight (20 mg); the maximum daily dose is 160 mg. The duration of nalbuphine treatment depends on the patient's condition and should be as short as possible to avoid psychological or physical dependence.

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 positive change in pain symptoms, a repeat dose of 20 mg may be given after 30 minutes.

When nalbuphine is used as an adjunct to anesthesia, higher doses than those used for analgesia are required. For premedication: 100–200 mcg/kg body weight.

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

For analgesia during labor, the drug should be administered at a dose of 20 mg intramuscularly.

The drug should be prescribed with caution in elderly patients, in patients with general exhaustion, or impaired respiratory function. In such cases, treatment should be initiated with the lowest effective doses due to the higher likelihood of adverse reactions.

Children.

The medicinal product should not be used in children.

Overdose.

Symptoms of overdose include respiratory depression, periodic Cheyne-Stokes respiration; drowsiness, dysphoria, altered consciousness up to coma; pallor, hypothermia, miosis; decreased arterial blood pressure, cardiovascular insufficiency, seizures, rhabdomyolysis progressing to renal failure.

Treatment of overdose includes:

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

Adverse Reactions

Sedative-type reactions are most commonly observed in patients receiving nalbuphine.

Nervous system disorders: dizziness, general weakness, headache, sedation, diplopia, nervousness, depression, agitation, excitement, tearfulness, euphoria, hostility, drowsiness, night terrors, hallucinations, tinnitus, confusion, dysphoria, paresthesia, feelings of unreality, speech disturbances, mood changes; seizures, muscle rigidity, tremor, involuntary muscle contractions, increased intracranial pressure.

Psychiatric disorders: drug dependence, psychomimetic reactions, neurotic reactions, restlessness, nervousness (irritability), euphoria.

The potential for developing physical and psychological dependence, as well as tolerance during prolonged treatment, is the same as with other morphine derivatives.

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

Eye disorders: blurred vision or visual disturbances, miosis.

Gastrointestinal disorders: dry mouth, colic, abdominal cramps, constipation, dyspepsia, bitter taste, anorexia; gastrointestinal irritation symptoms, impaired liver function tests; biliary tract spasm, paralytic ileus and toxic megacolon (constipation, flatulence, nausea, gastralgia, vomiting) in inflammatory bowel diseases.

Respiratory system disorders: respiratory depression, reduced minute volume, dyspnea, asthmatic attacks.

Skin disorders: increased skin moisture, pruritus, urticaria, sensation of heat; scleral icterus and skin jaundice; injection site reactions including pain, hypothermia, swelling, redness, burning.

Reproductive system and mammary gland disorders: decreased libido or potency.

Allergic reactions: anaphylactic reactions, shock, respiratory distress syndrome, angioedema, facial swelling, sneezing, bronchospasm, pulmonary edema, skin rashes, increased sweating.

Other: hot flushes, blurred vision; reduced diuresis, frequent urge to urinate, urinary tract spasm; hepatotoxicity (dark urine, pale stools); drug dependence, withdrawal syndrome (spasmodic abdominal pain, nausea, vomiting, rhinorrhea, lacrimation, weakness, anxiety, elevated body temperature).

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

Shelf life.

3 years.

Storage conditions.

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

Incompatibility.

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

Nalbuphine is compatible with 0.9% sodium chloride solution and Hartmann's solution 5%.

Packaging.

1 ml of solution (10 mg/ml) in ampoules, pack of 10, in a cardboard box.

1 ml of solution (20 mg/ml) in ampoules, pack of 5, in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Rusan Pharma Ltd.

Manufacturer's address and place of business.

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