Butolar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BUTOLAR® (BUTOLAR®)

Composition:

Active substance: butorphanol tartrate;

1 ml of the preparation contains 2 mg of butorphanol tartrate, calculated as 100% anhydrous substance;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Opioid analgesics. Morphine derivatives. Butorphanol.

ATC code: N02A F01.

Pharmacological properties.

Pharmacodynamics.

Butorphanol is an opioid analgesic that acts as a kappa-opioid receptor agonist and as a mixed agonist/antagonist at mu-opioid receptors, altering the perception of pain at the level of the central nervous system (CNS).

Butorphanol tartrate has opioid antagonist activity approximately equivalent to that of nalorphine, 30 times greater than that of pentazocine, and equal to 1/40 of the activity of naloxone. Regarding respiratory depression, intravenous administration of 2 mg butorphanol is comparable to the effect of 10 mg morphine; however, no further enhancement of this effect is observed with a 4 mg dose, although the duration of effect depends on the administered dose.

Respiratory depression caused by butorphanol is reversed by naloxone.

Butorphanol, like other mixed agonist/antagonists with high affinity for kappa receptors, may occasionally cause unpleasant psychomimetic effects.

The onset of analgesic effect of butorphanol depends on the route of administration: within a few minutes after intravenous injection and within 10–15 minutes after intramuscular injection. Maximum analgesic effect is achieved within 1–2 hours.

The duration of analgesia depends on the nature of the pain and the route of administration, but typically lasts 3–4 hours following intramuscular or intravenous administration.

Pharmacokinetics.

Butorphanol is rapidly absorbed after intramuscular injection. After administration of 1 mg of the drug, maximum plasma concentration of butorphanol is reached within 20–40 minutes.

Average pharmacokinetic parameters of the 2 mg/mL injection solution in different age groups a)

Butorphanol binding to plasma proteins does not depend on its concentration and is approximately 80%, when the drug is administered within the same dosage range as used in clinical practice: up to 7 mg/mL. The drug penetrates the blood-brain and placental barriers and enters breast milk.

Butorphanol undergoes extensive hepatic metabolism and is excreted from the body as oxidized and conjugated metabolites. Less than 5% of the intravenously administered dose is excreted unchanged in the urine.

Butorphanol is eliminated from the body via urine and feces. The main metabolite of butorphanol found in urine is hydroxybutorphanol (49% of the administered dose). A small amount of norbutorphanol is also excreted in the urine (less than 5%).

Clinical characteristics.

Indications.

Symptomatic treatment of moderate to severe pain, including postoperative pain, for analgesia in maxillofacial surgery, in migraine, for premedication before surgical procedures or anesthesia as an adjunct to balanced anesthesia, and also for labor analgesia.

Contraindications.

Hypersensitivity to butorphanol or to any other component of the medicinal product. Severe impairment of liver and/or kidney function.

Interaction with other medicinal products and other forms of interaction.

Benzodiazepines and other CNS depressants. Due to additive pharmacological effects, concomitant use of benzodiazepines or other CNS depressants such as alcohol, other sedatives/hypnotics, barbiturates, anxiolytics, tranquilizers, muscle relaxants, histamine H1-receptor blockers, general anesthetics, antipsychotics, and other opioids may increase the risk of arterial hypotension, respiratory depression, profound sedation, coma, and death. Pharmaceutically, butorphanol is incompatible with diazepam and barbiturates.

When butorphanol is used concomitantly with pure opioid agonists (e.g., morphine), a reduction in the degree of analgesia or the onset of withdrawal symptoms may occur.

Buprenorphine (including prior therapy) reduces the effect of other opioid analgesics.

Reduces the effect of metoclopramide.

Serotonergic agents. Caution should be exercised when using opioids concomitantly with medicinal products affecting the serotonergic neurotransmitter system, including 5-HT3 receptor antagonists, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, triptans, certain muscle relaxants (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase inhibitors (MAOIs) (used to treat psychiatric disorders), as potentially life-threatening serotonin syndrome may occur. If concomitant use is justified, close monitoring of the patient is required, especially at the beginning of treatment and during dose adjustments. Butorphanol injections should be discontinued if serotonin syndrome is suspected.

The medicinal product should also be used with caution concomitantly with MAO inhibitors due to possible CNS overstimulation or depression leading to hypertensive or hypotensive crises, and a high incidence of hyperpyrexic coma (initially, to assess interaction effects, the dose should be reduced to 1/4 of the recommended dose).

Medicinal products with anticholinergic activity and antidiarrheal agents (including loperamide) increase the risk of constipation up to intestinal obstruction, urinary retention, and CNS depression.

Enhances the hypotensive effect of medicinal products that lower blood pressure (including ganglion blockers, diuretics).

Naloxone reduces the effects of opioid analgesics and also reverses opioid-induced respiratory depression and CNS depression.

Naltrexone accelerates the onset of withdrawal symptoms in opioid dependence (symptoms may appear as early as 5 minutes after administration, last up to 48 hours, and are characterized by persistence and difficulty in management); reduces the effects of opioid analgesics (analgesic, antidiarrheal, antitussive); does not affect symptoms caused by histamine reactions.

Butorphanol does not prevent or alleviate withdrawal symptoms in opioid dependence (including fentanyl-induced dependence).

Use in balanced anesthesia. The cumulative effect of respiratory depression caused by all drugs used in general anesthesia and administered intravenously may lead to reduced lung ventilation or dyspnea. Therefore, in balanced anesthesia, butorphanol should be used only in exceptional cases as an adjunctive agent and only under conditions ensuring adequate respiratory support.

Special precautions for use.

Drug dependence. The drug is not recommended for use in patients with narcotic dependence. As an opioid antagonist, the drug may precipitate withdrawal syndrome. Prior to initiating treatment with this drug, such patients should undergo a special course of therapy.

Caution should be exercised when prescribing the drug to patients who have recently used narcotic analgesics repeatedly, as it is difficult to assess the patient's tolerance to opioids.

Abuse and dependence. Isolated cases of abuse and dependence on butorphanol tartrate have been reported during treatment of chronic painful conditions in outpatients. Generally, patients receiving long-term opioid therapy are at increased risk of developing dependence on the drug.

Patients should be informed that use of butorphanol tartrate injections, even when taken as recommended, may lead to dependence, abuse, and misuse, which may result in overdose and death.

Risks associated with concomitant use of benzodiazepines or other CNS depressants. Concomitant use of opioids with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, alcohol) may result in profound sedation, respiratory depression, coma, and fatal outcomes. For patients for whom alternative treatment options are inadequate, concomitant use of butorphanol with benzodiazepines or other CNS depressants should be limited to the lowest effective dosages and shortest duration possible. Patients should be closely monitored for signs and symptoms of respiratory depression and sedation.

Adrenal insufficiency. Cases of adrenal insufficiency have been reported with opioid use, typically after use exceeding one month. Symptoms of adrenal insufficiency may include non-specific manifestations such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension. Available data do not identify any specific opioids most commonly associated with adrenal insufficiency.

Androgen deficiency. Cases of androgen deficiency have been observed with chronic opioid use.

Head injuries and intracranial pressure. Use with extreme caution and under close medical supervision. In patients with head trauma, butorphanol, like other opioids, may increase carbon dioxide levels in the body, elevate cerebrospinal fluid pressure, cause pupillary constriction, and induce psychiatric disturbances, thereby masking the clinical progression of head injury. Administration of butorphanol tartrate injections should be avoided in patients with impaired consciousness or coma.

Respiratory depression. Use with extreme caution and under close medical supervision. Serious, life-threatening, or fatal respiratory depression has been reported with opioid use, even when administered at recommended doses. Mixed opioid receptor agonist/antagonist drugs may depress respiratory function, particularly in patients receiving CNS-affecting drugs or those with CNS disorders or impaired respiratory function. Respiratory depression, if not promptly recognized and treated, may lead to respiratory arrest and death. Carbon dioxide (CO₂) retention due to opioid-induced respiratory depression may exacerbate the sedative effects of opioids.

Although serious, life-threatening, or fatal respiratory depression may occur at any time during butorphanol tartrate injection therapy, the greatest risk occurs at the beginning of treatment or after a dose increase. Patients should be closely monitored for signs of respiratory depression, especially during the first 24–72 hours after initiation of therapy and following any dose increase. Appropriate dosing and dose titration of butorphanol tartrate are essential to minimize the risk of respiratory depression. Overdosing when switching patients from another opioid to butorphanol may result in fatal overdose with the first dose. Opioids may cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent manner. Patients with CSA should have their opioid dose reduced.

Patients with severe chronic obstructive pulmonary disease, or those with significantly reduced respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression, even when receiving butorphanol tartrate injections at recommended doses, are at increased risk of respiratory center depression, including apnea. Life-threatening respiratory depression occurs more frequently in elderly, cachectic, or debilitated patients.

Such patients should be closely monitored, especially at the beginning of butorphanol therapy, during dose escalation, and when used concomitantly with other respiratory depressants. As an alternative, non-opioid analgesics should be considered for these patients.

Hepatic or renal disease. The drug is contraindicated in severe hepatic or renal impairment. Butorphanol should be used with caution in mild to moderate hepatic or renal disease, although laboratory tests have not revealed any abnormalities with drug use. If hepatic or renal impairment occurs, the dosing regimen should be adjusted accordingly.

Risks of use in patients with gastrointestinal disorders. Butorphanol injections should not be administered to patients with gastrointestinal obstruction, including paralytic ileus. Butorphanol may cause spasm of the sphincter of Oddi. Opioids may also increase serum amylase levels. Patients with biliary tract disorders, including acute pancreatitis, should be monitored for worsening of symptoms.

Effects on the cardiovascular system. Butorphanol increases cardiac activity, particularly in the pulmonary circulation; therefore, the drug should be prescribed to patients with acute myocardial infarction, ventricular dysfunction, or coronary insufficiency only when the expected benefit clearly outweighs the potential risk.

Severe arterial hypertension has been observed only rarely after drug administration. If arterial hypertension develops, the drug should be discontinued and antihypertensive therapy initiated. There have also been reports of naloxone being effective in patients without opioid dependence.

Serotonin syndrome. Opioids may cause a rare but potentially life-threatening condition resulting from concomitant use of serotonergic drugs. Patients should be warned about symptoms of serotonin syndrome and advised to seek immediate medical attention if symptoms develop.

Balanced anesthesia. The combined respiratory depressant effects of all drugs used in general anesthesia and administered intravenously may lead to reduced lung ventilation or respiratory distress. Therefore, during balanced anesthesia, butorphanol tartrate should be used only in exceptional cases as an adjunctive agent and only with adequate respiratory support.

Preoperative or pre-anesthetic administration. Caution should be exercised when administering the drug to patients with arterial hypertension.

Labour and delivery. Cases of respiratory distress syndrome/asphyxia in newborns have been reported following administration of the drug less than 2 hours before delivery, with repeated administration in combination with other analgesics or sedatives, or in preterm labour.

Neonatal opioid withdrawal syndrome. Prolonged use of opioid analgesics during pregnancy may lead to physical dependence in newborns and neonatal opioid withdrawal syndrome shortly after birth. Withdrawal syndrome in newborns manifests as irritability, hyperactivity, abnormal sleep patterns, high-pitched crying, tremors, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary depending on the specific opioid used, duration of use, timing and dose of the last maternal administration, and the rate of drug elimination by the newborn. Neonatal opioid withdrawal syndrome, unlike adult opioid withdrawal syndrome, may be life-threatening if not recognized and treated. Newborns should be monitored for symptoms of opioid withdrawal syndrome, and appropriate measures should be taken. Use of Butolar during pregnancy (except for labor preparation) is contraindicated.

Elderly patients. In addition to somewhat reduced drug elimination, elderly patients may be more susceptible to adverse effects, particularly dizziness.

This medicinal product contains 7.29 mg of sodium citrate and 6.4 mg of sodium chloride per 1 mL. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy (except for labor preparation) and during breastfeeding. Well-controlled studies on the effects of the drug in women with gestational age under 37 weeks have not been conducted.

During labor preparation, the drug should be used with caution and under strict medical supervision.

After administration, the drug passes into breast milk in low concentrations. However, the clinical significance of this has not been fully evaluated.

Ability to influence reaction speed when driving or operating machinery.

Drowsiness and dizziness associated with the use of the drug may affect the ability to drive vehicles, operate machines, or handle other mechanisms.

Administration and Dosage

The effect of the drug, like that of other potent analgesics, occurs rapidly; therefore, the dosage should be individually adjusted according to the clinical response.

Analgesia

For intramuscular administration, the recommended dose is a single dose of 2 mg, provided the patient is able to remain lying down in case drowsiness or dizziness occurs. If necessary, this dose may be repeated every 3 or 4 hours. Depending on the severity of pain, treatment is effective within a dosage range of 1 to 4 mg administered every 3–4 hours.

For intravenous administration, the recommended dose is a single dose of 1 mg, repeated every 3 or 4 hours if needed. Depending on the severity of pain syndrome, treatment is effective within a dosage range of 0.5 to 2 mg administered every 3–4 hours.

Anesthesia

Preoperative/pre-anesthetic administration. The dose should be individually adjusted. The usual dose is 2 mg administered intramuscularly 30–60 minutes before the start of surgical intervention. In patients with hepatic or renal dysfunction experiencing pain syndrome, the dosage should be halved. The drug should be avoided after myocardial infarction.

When balanced anesthesia is used, the usual dose is 2 mg administered intravenously shortly before induction of anesthesia, and/or 0.5 mg intravenously during surgery. With such fractionated administration, the total dose may be increased up to 0.06 mg/kg (4 mg/70 kg), depending on the doses of previously administered sedatives, analgesics, or hypnotics. The total dose may vary; however, patients rarely require administration of less than 4 mg or more than 12.5 mg of the drug (usually from 0.06 to 0.18 mg/kg).

Labor and Delivery

Pregnant women with normal gestational term may be administered 1–2 mg of the drug intravenously or intramuscularly at the onset of labor, with repeat administration of the same dose after 4 hours. During labor or if delivery is expected within 4 hours, alternative analgesic methods should be used. The drug should be used with caution in cases of premature labor.

Dose Adjustment. Patients with impaired liver or kidney function (creatinine clearance less than 30 mL/min) may require dose adjustment. The initial dose in elderly patients should be half the usual dose.

Children

Do not use in children under 18 years of age.

Overdose

Clinical manifestations of overdose are similar to those observed with overdose of other opioid drugs. The most serious symptoms include pulmonary hypoventilation, cardiovascular failure, and/or coma.

Symptoms: respiratory depression, cardiovascular failure (especially in patients previously predisposed), central nervous system (CNS) depression.

Fatal overdose cases following administration of the drug have been reported very rarely. The contribution of the drug, usually used in combination with other medicinal products, to the outcome of overdose has not been established.

Treatment: in suspected overdose, specific management includes immediate provision of adequate airway ventilation, followed by administration of an opioid antagonist such as naloxone (intravenously), if necessary.

Adverse Reactions

In almost all cases, the adverse reactions observed after administration of the drug were consistent with those commonly seen with opioid analgesics. There have been no reports of unexpected or unusual toxic effects.

The most commonly observed adverse reactions were drowsiness, nausea and/or vomiting, and increased sweating/skin moisture.

Listed below are symptoms observed during administration of the drug and considered to be related/possibly related to the use of butorphanol tartrate.

General disorders. Asthenia, lethargy, headache, hot flushes, increased sweating, discomfort, hyperemia, edema, burning sensation at the injection site, drug dependence, withdrawal syndrome.

Gastrointestinal system. Dry mouth, anorexia, nausea, vomiting, paralytic ileus and toxic megacolon in inflammatory bowel disease, liver function disorders.

Nervous system. Confusion, drowsiness, light-headedness/euphoria, dizziness, unusual dreams/nightmares, delirium, anxiety, depression, agitation, transient dysarthria, dysphoria, hallucinations, tremor, seizures, paresthesia, paresis, cold sensation, euphoria, restlessness, hostility, disorientation, catatonia, decreased concentration.

Cardiovascular system. Increased/decreased blood pressure, tachycardia, bradycardia, arrhythmia, palpitations, syncope.

Sensory organs. Blurred vision, diplopia, eye pain, tinnitus.

Skin and subcutaneous tissue. Allergic reactions including rash, pruritus, urticaria, facial hyperemia.

Urinary system. Decreased diuresis, ureteral spasm.

Musculoskeletal system. Myalgia.

Respiratory system. Slowed breathing, airway obstruction, shallow respiration, apnea.

Other: Serotonin syndrome when opioids are used concomitantly with serotonergic drugs, adrenal insufficiency, androgen deficiency.

Abuse and dependence. Although analgesics belonging to the class of mixed opioid agonist/antagonists have a much lower potential for dependence compared to morphine, cases of drug abuse have been reported. Physical dependence may lead to withdrawal symptoms if the opioid is abruptly discontinued or if the patient receives an opioid antagonist. Symptoms include anxiety, lacrimation, rhinorrhea, sneezing, yawning, increased sweating, insomnia, tremor, myalgia (especially in the back and legs), nausea, vomiting, diarrhea, abdominal pain, elevated body temperature, hypertension, tachycardia, and increased respiratory rate.

Particular caution should be exercised when prescribing the drug to emotionally unstable patients and in patients with a history of drug abuse.

Shelf life.

2 years.

Storage conditions.

In the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Incompatibility.

Pharmaceutically incompatible with diazepam and barbiturates.

Packaging.

1 ml of solution in an ampoule, 5 ampoules in a blister, 1 blister per carton.

Prescription category. Prescription only.

Manufacturer. Public joint-stock company "Scientific and Production Center "Borshchahivskiy Chemical and Pharmaceutical Plant".

Manufacturer's address and location of business activity.

17 Miru Street, Kyiv, 03134, Ukraine.