Butorphanol Tartrate

Butorphanol Tartrate

2mg/ml Solution for Injection (I.M. / I.V.)

Drug Category: Opioid Analgesic

Brand Name: Ziphanol

Description:

Brown clean ampule containing colorless solution.

Indications:

Butorphanol is used to relief of moderate to severe pain, for preoperative or pre-anesthetic medication as a supplement to balanced anesthesia, for relief of pain during labor.

Dosage and Administration:

Butorphanol has a factors to be considered in determining the dose are age, body-weight, physical status, underlying pathological conditions, use of other drugs, type of anesthesia to be used, and surgical procedure involved. Use in the elderly, in patients with hepatic or renal disease, or in labor requires extra caution. The following doses are for patients who do not have impaired hepatic or renal function and who are not on CNS active agents

1. Pain

• Intravenous: The usual recommended single dose for IV administration is 1mg repeated every 3 to 4 hours as necessary. The effective dosage range, depending on the severity of pain, is 0.5 to 2 mg repeated every 3 to 4 hours.
• Intramuscular: The usual recommended single dose for IM administration is 2mg in patients who will be able to remain recumbent, in the event drowsiness or dizziness occurs. This may be repeated every 3 to 4 hours, as necessary. The effective dosage range depending on the severity of pain is 1 to 4mg repeated every 3 to 4 hours. There are insufficient clinical data to recommend single doses above 4mg.
• Both expected efficacy and adverse reaction should be considered in dosage adjustment. The dose of this drug recommended for elderly patients, patients with hepatic or renal impairment should generally be half the recommended adult dose (0.5mg IV and 1.0mg IM). Repeat doses should be determined by the patient's response rather than at fixed intervals, but will generally be no less than 6 hours apart.

2. Use as Preoperative/Pre-anesthetic Medications
   The preoperative medication dosage should be individualized. The usual adult dose is 2mg IM, administered 60 – 90 minutes before surgery. This is approximately equivalent in sedative effect to 10mg morphine or 80mg meperidine.
3. Use in Balance Anesthesia
   The usual dose is 2mg IV shortly before induction and/or 0.5 to 1.0mg IV in increments during anesthesia. The increment may be higher, up to 0.06mg/kg (4mg/70kg), depending on previous sedative, analgesic, and hypnotic drugs administered. The total dose of this drug will vary; however, patients seldom requires less than 4mg or more than 12.5mg (approximately 0.06 to 0.18mg/kg).
   Opioid, including this drug, may not produce appropriate analgesic effect for every patients or every state during surgery. Analgesic fail during increased, intensive inhalation anesthetic or another IV should be considered.
4. Labor
   In patients at full term or without fetal distress in early labor a 1-2mg dose IV or IM may be administered and repeated after 4 hours. Alternative analgesic should be used for pain associated with delivery is expected to occur within 4hours. Other analgesics should be used when delivery is expected within 4 hours. Dosage titration should be based on concurrent analgesics, sedatives, expected time of delivery and response of the first administration. If concomitant use of this drug with drugs that may potentiate its effects effect is deemed necessary, the lowest effective dose should be employed.

Adverse Reactions:

1. The most frequently reported adverse experiences across all clinical trials with this drug were somnolence (43%), dizziness (19%0), nausea and/or vomiting (13%).
2. The following adverse experiences were reported at a frequency of 1% or greater in clinical trials.

• Body as a Whole: asthenia/lethargy, headache, sensation of heat.
• Digestive: dry mouth, nausea and or vomiting, stomach pain.
• Nervous: anxiety, confusion, dizziness, euphoria, floating feeling nervousness, paresthesia, somnolence.
• Skin and Appendages: sweating/clammy, pruritus.
• Special Senses: blurred vision

3. The following adverse experiences were reported with a frequency of less than 1% in clinical trials

• Cardiovascular: hypotension, syncope.
• Nervous: abnormal dreams, agitation, dysphoria, hallucination, hostility
• Skin and Appendages: rash/hives.
• Urogenital: impaired urination.

Contraindications:

Butorphanol is not recommended for use in patients dependent on narcotics. Such patients should have an adequate period of withdrawal from opioid drugs prior to beginning butorphanol therapy. In patients taking opioid analgesics chronically, butorphanol has precipitated withdrawal symptoms such as anxiety, agitation, mood changes, hallucination, dysphoria, weakness, and diarrhea, because of its opioid antagonist properties.

This drug should be carefully administered to the following patients.

1. Because of the difficulty in assessing opioid tolerance in patients who have recently received repeated doses of narcotic analgesic medication, caution should be used in the administration of butorphanol to such patients.
2. Head Injury and Increased Intracranial Pressure
   As with opioids, the use of butorphanol in patients with head injury may be associated with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, drug-induced miosis, and alterations in mental state that would obscure the interpretation of the clinical course of patients with head injuries. In such patients, butorphanol should be used only if the benefits of use outweigh the potential risks.
3. Disorders of Respiratory Function or Control
   Butorphanol may produce respiratory depression, especially in patients receiving other CNS active agents, or patients suffering from CNS disease or respiratory impairment.
4. Cardiovascular Effects
   Because butorphanol may increase the work of the heart, especially the pulmonary circuit, the use of butorphanol in patients with acute myocardial infarction, ventricular dysfunction, or coronary insufficiency should be limited to those situations where the benefits clearly outweigh the risk. Severe hypertension has been reported rarely during butorphanol therapy. In such cases, butorphanol should be discontinued and the hypertension treated with anti-hypertensive drugs. In patients who are not opioid dependent, naloxone has also been reported to be effective.

Precautions:

Warning

When ampules are cut, glass particles can mixed with drug solution. Therefore caution should be taken to prevent from mixing. In particular, caution should be taken when its is used by elderly or children.

General caution

1. Effects such as drowsiness or dizziness impair the mental and physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery.
2. Alcohol should not be consumed while using butorphanol.
3. Drugs having antagonistic action and effect of opioid, less frequent than morphine but can be abused. Due to prolonged use of this drug, light withdrawal symptoms, excessive use and addition have been reported. Special care should be exercised in administering butorphanol to patients with a history of drug abuse or to patients receiving the drug on a continuous bases for an extended period.
4. Use for outpatients
   Drowsiness and dizziness may occur. Caution should be taken until individual characteristic response to this drug is obtained.

Drug Interaction:

Concurrent use of butorphanol with central nervous system depressants (eg. Alcohol, barbiturates, tranquilizers, and antihistamines) may result in increased central nervous system depressant effects. When use concurrently with such drugs, the dose of butorphanol should be the smallest effective dose and the frequency of dosing reduced as much as possible when administered concomitantly with drugs that potentiate the action of opioids.

It is known if the effects of butorphanol are altered by other concomitant medications that affect hepatic metabolism of drugs (cimetidine, erythromycin, theophylline, etc), but physicians should be alert to the possibility that a smaller initial dose and longer intervals between doses may be needed.

NO information is available about the use of butorphanol concurrently with MAO inhibitors.

Pregnancy, Nursing mothers and Geriatric Use

1. Pregnancy
   Reproduction studies in mice, rats and rabbits during organogenesis did not reveal any teratogenic potential to butorphanol. However, pregnant rats treated subcutaneously with butorphanol at 1mg/kg (5.9mg/m2) had a higher frequency of stillbirths than controls. Butorphanol at 30mg/kg/oral (360mg/m2) and 60mg/kg/oral (720mg/m2) also showed higher incidences of post- implantation loss in rabbits. There are no adequate and well-controlled studies of this drug in pregnant women before 37 weeks of gestation. This drug should be use during pregnancy only if potential benefit justifies the potential risk to the infant.
2. Labor and Delivery
   There have been rare reports of infant respiratory distress/apnea following the administration of this drug during labor. The reports of respiratory distress/apnea have been associated with administration of a dose within 2 hours of delivery, use of multiple doses, use with additional analgesic or sedative drugs, or use in preterm pregnancies.
   In a study of 119 patients, the IV administration of 1mg of this drug during labor was associated with transient sinusoidal fetal heart rate patterns, but was not associated with adverse neonatal outcomes. In the presence of an abnormal fetal heart rate pattern, this drug should be used with caution.

3. Nursing mothers
   Butorphanol has been detected in milk following administration of this drug to nursing mothers. The amount an infant would receive is probably clinically insignificant (estimated 4mcg/L of milk in a mother receiving 2mg IM four times a day).
4. Geriatrics use
   Due to changes in clearance, the mean half-life of butorphanol is increased by 25% (to over 6hours) in patients over the age of 65 years. Elderly patients may be more sensitive to the side effects of butorphanol.
5. Others
   Butorphanol is not recommended for use in patients below 18 years of age because safety and efficacy have not been established in this population.

Overdosage:

The clinical manifestations of butorphanol overdose are those of opioid drugs in general. The most serious symptoms are hypoventilation, cardiovascular insufficiency, coma, and death.

The management of suspected butorphanol overdosage includes maintenance of adequate ventilation, peripheral perfusion, normal body temperature, and protection of the airway. Patients should be under continuous observation with adequate serial measure of mental state, responsiveness, and vital signs. Oxygen and ventilatory assistance should be available with continual monitoring by pulse oximety if indicated. In the presence of coma, placement of an artificial airway may be required. An adequately intravenous portal should be maintained to facilitate treatment of hypotension associated with vasodilation.

The use of specific opioid antagonist such as naloxone should be considered. As the duration of butorphanol action usually exceeds the duration of action of naloxone, repeated dosing with naloxone may be required.

In managing cases of suspected butorphanol overdosage, the possibility of multiple drug ingestion should always be considered.

Others (Carcinogenesis, Mutagenesis, Impairment of Fertility)

There was no evidence of carcinogenicity for this drug.

Butorphanol was not genotoxic in S. typhimurium or E. coli assays or in unschedules DNA synthesis and repair assays conducted in cultured human fibroblast cells.

Rats treated orally with 160mg/kg/day (955mg/m2) had reduced pregnancy rate. However, a similar effect was not observed with 2.5mg/kg/day (14.75mg/m2) subcutaneous dose.

Storage Condition:

Store at temperatures not exceeding 30^oC.

Keep medicine out of children's reach.