BUPRENORPHINE
DESCRIPTION
TIDIGESIC (buprenorphine hydrochloride) is a narcotic under the Controlled
Substances Act due to its chemical derivation from thebaine. Chemically, it is
17-(cyclopropylmethyl)-alpha- (1,1-dimethylethyl)-4, 5-epoxy-18, 19-dihydro- 3-
hydroxy-6-methoxy-alpha-methyl-6, 14-ethenomorphinan-7-methanol, hydrochloride
(5alpha, 7alpha(S)). Buprenorphine hydrochloride is a white powder, weakly
acidic and with limited solubility in water. TIDIGESIC is a clear, sterile,
injectable agonist-antagonist analgesic intended for intravenous or
intramuscular administration. Each ml of TIDIGESIC contains 0.324 mg
buprenorphine hydrochloride (equivalent to 0.3 mg buprenorphine), 50 mg
anhydrous dextrose, water for injection and HCl to adjust pH. Buprenorphine
hydrochloride has the molecular formula, C29H41NO4-HCl.
Molecular weight: 504.09
ACTIONS/CLINICAL PHARMACOLOGY:
TIDIGESIC is a parenteral opioid analgesic with 0.3 mg TIDIGESIC being
approximately equivalent to 10 mg morphine sulfate in analgesic and respiratory
depressant effects in adults. Pharmacological effects occur as soon as 15
minutes after intramuscular injection and persist for 6 hours or longer. Peak
pharmacologic effects usually are observed at 1 hour. When used intravenously,
the times to onset and peak effect are shortened.
The limits of sensitivity of available analytical methodology precluded
demonstration of bioequivalence between intramuscular and intravenous routes of
administration. In postoperative adults, pharmacokinetic studies have shown
elimination half-lives ranging from 1.2-7.2 hours (mean 2.2 hours) after
intravenous administration of 0.3 mg of buprenorphine. A single, ten-patient,
pharmacokinetic study of doses of 3 mcgm/kg in children (age 5-7 years) showed a
high inter-patient variability, but suggests that the clearance of the drug may
be higher in children than in adults. This is supported by at least one repeat-
dose study in postoperative pain that showed an optimal inter- dose interval of
4-5 hours in pediatric patients as opposed to the recommended 6-8 hours in
adults.
Buprenorphine, in common with morphine and other phenolic opioid analgesics, is
metabolized by the liver and its clearance is related to hepatic blood flow.
Studies in patients anesthetized with 0.5% halothane have shown that this
anesthetic decreases hepatic blood flow by about 30%.
MECHANISM OF ANALGESIC ACTION: TIDIGESIC exerts its analgesic effect via high
affinity binding to mu subclass opiate receptors in the central nervous system.
Although TIDIGESIC may be classified as a partial agonist, under the conditions
of recommended use it behaves very much like classical mu agonists such as
morphine. One unusual property of TIDIGESIC observed in In Vitro studies is its
very slow rate of dissociation from its receptor. This could account for its
longer duration of action than morphine, the unpredictability of its reversal by
opioid antagonists, and its low level of manifest physical dependence.
NARCOTIC ANTAGONIST ACTIVITY: Buprenorphine demonstrates narcotic antagonist
activity and has been shown to be equipotent with naloxone as an antagonist of
morphine in the mouse tail flick test.
CARDIOVASCULAR EFFECTS: TIDIGESIC may cause a decrease or, rarely, an increase in
pulse rate and blood pressure in some patients.
EFFECTS ON RESPIRATION: Under usual conditions of use in adults, both TIDIGESIC
and morphine show similar dose-related respiratory depressant effects. At adult
therapeutic doses, TIDIGESIC (0.3 mg buprenorphine) can decrease respiratory rate
in an equivalent manner to an equianalgesic dose of morphine (10 mg). (See
WARNINGS.)
INDICATIONS AND USAGE:
TIDIGESIC is indicated for the relief of moderate to severe pain.
CONTRAINDICATIONS:
TIDIGESIC should not be administered to patients who have been shown to be
hypersensitive to the drug.
WARNINGS:
IMPAIRED RESPIRATION: As with other potent opioids, clinically significant
respiratory depression may occur within the recommended dose range in patients
receiving therapeutic doses of buprenorphine. TIDIGESIC should be used with
caution in patients with compromised respiratory function (e.g., chronic
obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve,
hypoxia, hypercapnia, or preexisting respiratory depression). Particular caution
is advised if TIDIGESIC is administered to patients taking or recently receiving
drugs with CNS/respiratory depressant effects. In patients with the physical
and/or pharmacological risk factors above, the dose should be reduced by
approximately one-half.
NALOXONE MAY NOT BE EFFECTIVE IN REVERSING THE RESPIRATORY DEPRESSION PRODUCED
BY TIDIGESIC. THEREFORE, AS WITH OTHER POTENT OPIOIDS, THE PRIMARY MANAGEMENT OF
OVERDOSE SHOULD BE THE REESTABLISHMENT OF ADEQUATE VENTILATION WITH MECHANICAL
ASSISTANCE OF RESPIRATION, IF REQUIRED.
INTERACTION WITH OTHER CENTRAL NERVOUS SYSTEM DEPRESSANTS: Patients receiving
TIDIGESIC in the presence of other narcotic analgesics, general anesthetics,
antihistamines, benzodiazepines, phenothiazines, other tranquilizers,
sedative/hypnotics or other CNS depressants (including alcohol) may exhibit
increased CNS depression. When such combined therapy is contemplated, it is
particularly important that the dose of one or both agents be reduced.
HEAD INJURY AND INCREASED INTRACRANIAL PRESSURE: TIDIGESIC, like other potent
analgesics, may itself elevate cerebrospinal fluid pressure and should be used
with caution in head injury, intracranial lesions and other circumstances where
cerebrospinal pressure may be increased. TIDIGESIC can produce miosis and changes
in the level of consciousness which may interfere with patient evaluation.
USE IN AMBULATORY PATIENTS: TIDIGESIC may impair the mental or physical abilities
required for the performance of potentially dangerous tasks such as driving a
car or operating machinery. Therefore, TIDIGESIC should be administered with
caution to ambulatory patients who should be warned to avoid such hazards.
USE IN NARCOTIC-DEPENDENT PATIENTS: Because of the narcotic antagonist activity
of TIDIGESIC, use in the physically dependent individual may result in withdrawal
effects.
PRECAUTIONS:
GENERAL: TIDIGESIC should be administered with caution in the elderly,
debilitated patients, in children and those with severe impairment of hepatic,
pulmonary, or renal function; myxedema or hypothyroidism; adrenal cortical
insufficiency (e.g., Addison's disease); CNS depression or coma; toxic
psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism,
delirium tremens; or kyphoscoliosis.
Because TIDIGESIC is metabolized by the liver, the activity of TIDIGESIC may be
increased and/or extended in those individuals with impaired hepatic function or
those receiving other agents known to decrease hepatic clearance.
TIDIGESIC has been shown to increase intracholedochal pressure to a similar
degree as other opioid analgesics, and thus should be administered with caution
to patients with dysfunction of the biliary tract.
INFORMATION FOR PATIENTS: The effects of TIDIGESIC, particularly drowsiness, may
be potentiated by other centrally acting agents such as alcohol or
benzodiazepines. It is particularly important that in these circumstances
patients must not drive or operate machinery. TIDIGESIC has some pharmacologic
effects similar to morphine which in susceptible patients may lead to self-
administration of the drug when pain no longer exists. Patients must not exceed
the dosage of TIDIGESIC prescribed by their physician. Patients should be urged
to consult their physician if other prescription medications are currently being
used or are prescribed for future use.
DRUG INTERACTIONS: Drug interactions common to other potent opioid analgesics
also may occur with TIDIGESIC. Particular care should be taken when TIDIGESIC is
used in combination with central nervous system depressant drugs (see WARNINGS).
Although specific information is not presently available, caution should be
exercised when TIDIGESIC is used in combination with MAO inhibitors. There have
been reports of respiratory and cardiovascular collapse in patients who received
therapeutic doses of diazepam and TIDIGESIC. A suspected interaction between
TIDIGESIC and phenprocoumon resulting in purpura has been reported.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: The effects of TIDIGESIC on
fertility and gestation indices were investigated in rats by the subcutaneous
and intramuscular routes at doses 10 to 1,000 times the proposed human doses.
Dystocia was noted in dams treated with 1,000 times the human dose. No effects
on fertility or gestation were noted in these Segment 1 studies.
PREGNANCY: PREGNANCY CATEGORY C. Reproduction studies have been performed in the
rat at doses which ranged from 10 to 1,000 times the proposed human dose by the
subcutaneous and intramuscular routes and 160 times the proposed human dose by
the intravenous route. By the intramuscular route, TIDIGESIC produced mild but
statistically significant (p < 0.05) post-implantation losses and early fetal
deaths at 10 and 100 but not 1,000 times the proposed human dose. No fetal
malformations were noted in rats at any dose when TIDIGESIC was administered by
subcutaneous, intramuscular, or intravenous routes. In rabbits, intramuscularly
administered TIDIGESIC produced a dose-related trend for extra rib formation
which attained statistical significance (p < 0.01) at 1,000 times the proposed
human dose. By the intravenous route, doses in rats of 40 and 160 times the
proposed human dose of TIDIGESIC caused a slight increase in post-implantation
losses that may have been treatment-related. No major fetal malformations were
noted in drug treated groups when administered by intramuscular or intravenous
routes.
There are no adequate and well-controlled studies in pregnant women. TIDIGESIC
should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
LABOR AND DELIVERY: The safety of TIDIGESIC given during labor and delivery has
not been established.
NURSING MOTHERS: An apparent lack of milk production during general reproduction
studies with TIDIGESIC in rats caused decreased viability and lactation indices.
It is unknown at this time whether or not TIDIGESIC is excreted in human milk.
Despite the lack of specific knowledge on this issue, it is reasonable to assume
that TIDIGESIC will enter human milk and caution should be exercised in the use
of TIDIGESIC when it is administered to nursing mothers.
PEDIATRIC USE: The safety and effectiveness of TIDIGESIC have been established
for children between 2 and 12 years of age. Use of TIDIGESIC in children is
supported by evidence from adequate and well controlled trials of TIDIGESIC in
adults, with additional data from studies of 960 children ranging in age from 9
months to 18 years of age. Data is available from a pharmacokinetic study,
several controlled clinical trials, and several large post-marketing studies and
case series. The available information provides reasonable evidence that
TIDIGESIC may be used safely in children ranging from 2-12 years of age, and that
it is of similar effectiveness in children as in adults.
DRUG INTERACTIONS:
Drug interactions common to other potent opioid analgesics also may occur with
TIDIGESIC. Particular care should be taken when TIDIGESIC is used in combination
with central nervous system depressant drugs (see WARNINGS). Although specific
information is not presently available, caution should be exercised when
TIDIGESIC is used in combination with MAO inhibitors. There have been reports of
respiratory and cardiovascular collapse in patients who received therapeutic
doses of diazepam and TIDIGESIC. A suspected interaction between TIDIGESIC and
phenprocoumon resulting in purpura has been reported.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The most frequent side effect in clinical studies involving 1,133 patients was
sedation which occurred in approximately two-thirds of the patients. Although
sedated, these patients could easily be aroused to an alert state.
OTHER LESS FREQUENT ADVERSE REACTIONS OCCURRING IN 5-10% OF THE PATIENTS WERE:
Nausea Dizziness/Vertigo
OCCURRING IN 1-5% OF THE PATIENTS:
Sweating Headache
Hypotension Nausea/Vomiting
Vomiting Hypoventilation
Miosis
THE FOLLOWING ADVERSE REACTIONS WERE REPORTED TO HAVE OCCURRED IN LESS THAN 1%
OF THE PATIENTS:
CNS EFFECT: confusion, blurred vision, euphoria, weakness/fatigue, dry mouth,
nervousness, depression, slurred speech, paresthesia.
CARDIOVASCULAR: hypertension, tachycardia, bradycardia.
GASTROINTESTINAL: constipation.
RESPIRATORY: dyspnea, cyanosis.
DERMATOLOGICAL: pruritus.
OPHTHALMOLOGICAL: diplopia, visual abnormalities.
MISCELLANEOUS: injection site reaction, urinary retention, dreaming,
flushing/warmth, chills/cold, tinnitus, conjunctivitis, Wenckebach block, and
psychosis.
Other effects observed infrequently include malaise, hallucinations,
depersonalization, coma, dyspepsia, flatulence, apnea, rash, amblyopia, tremor,
and pallor.
The following reactions have been reported to occur rarely: loss of appetite,
dysphoria/agitation, diarrhea, urticaria, and convulsions/lack of muscle
coordination.
In the United Kingdom, buprenorphine hydrochloride was made available under
monitored release regulation during the first year of sale, and yielded data
from 1,736 physicians on 9,123 patients (17,120 administrations). Data on 240
children under the age of 18 years were included in this monitored release
program. No important new adverse effects attributable to buprenorphine
hydrochloride were observed.
DRUG ABUSE AND DEPENDENCE:
Buprenorphine hydrochloride is a partial agonist of the morphine type: i.e., it
has certain opioid properties which may lead to psychic dependence of the
morphine type due to an opiate-like euphoric component of the drug. Direct
dependence studies have shown little physical dependence upon withdrawal of the
drug. However, caution should be used in prescribing to individuals who are
known to be drug abusers or ex-narcotic addicts. The drug may not substitute in
acutely dependent narcotic addicts due to its antagonist component and may
induce withdrawal symptoms.
OVERDOSAGE:
MANIFESTATIONS: Clinical experience with TIDIGESIC overdosage has been
insufficient to define the signs of this condition at this time. Although the
antagonist activity of buprenorphine may become manifest at doses somewhat above
the recommended therapeutic range, doses in the recommended therapeutic range
may produce clinically significant respiratory depression in certain
circumstances. (See WARNINGS.)
TREATMENT: The respiratory and cardiac status of the patients should be
monitored carefully. Primary attention should be given to the reestablishment of
adequate respiratory exchange through provision of a patent airway and
institution of assisted or controlled ventilation. Oxygen, intravenous fluids,
vasopressors, and other supportive measures should be employed as indicated.
Doxapram, a respiratory stimulant, may be used. NALOXONE MAY NOT BE EFFECTIVE IN
REVERSING THE RESPIRATORY DEPRESSION PRODUCED BY TIDIGESIC. THEREFORE, AS WITH
OTHER POTENT OPIOIDS, THE PRIMARY MANAGEMENT OF OVERDOSE SHOULD BE THE
REESTABLISHMENT OF ADEQUATE VENTILATION WITH MECHANICAL ASSISTANCE OF
RESPIRATION, IF REQUIRED.
DOSAGE AND ADMINISTRATION:
ADULTS: The usual dosage for persons 13 years of age and over is 1 ml TIDIGESIC
(0.3 mg buprenorphine) given by deep intramuscular or slow (over at least 2
minutes) intravenous injection at up to 6-hour intervals, as needed. Repeat once
(up to 0.3 mg) if required, 30 to 60 minutes after initial dosage, giving
consideration to previous dose pharmacokinetics, and thereafter only as needed.
In high-risk patients (e.g., elderly, debilitated, presence of respiratory
disease, etc.) and/or in patients where other CNS depressants are present, such
as in the immediate postoperative period, the dose should be reduced by
approximately one-half. Extra caution should be exercised with the intravenous
route of administration, particularly with the initial dose.
Occasionally, it may be necessary to administer single doses of up to 0.6 mg to
adults depending on the severity of the pain and the response of the patient.
This dose should only be given I.M. and only to adult patients who are not in a
high risk category (see WARNINGS and PRECAUTIONS). At this time, there are
insufficient data to recommend single doses greater than 0.6 mg for long-term
use.
CHILDREN: TIDIGESIC has been used in children 2-12 years of age at doses between
2-6 micrograms/kg of body weight given every 4-6 hours. There is insufficient
experience to recommend a dose in infants below the age of two years, single
doses greater than 6 micrograms/kg of body weight, or the use of a repeat or
second dose at 30-60 minutes (such as is used in adults). Since there is some
evidence that not all children clear buprenorphine faster than adults, fixed
interval or "round-the-clock" dosing should not be undertaken until the proper
inter-dose interval has been established by clinical observation of the child.
Physicians should recognize that, as with adults, some pediatric patients may
not need to be remedicated for 6-8 hours.
SAFETY AND HANDLING: TIDIGESIC is supplied in sealed ampuls and poses no known
environmental risk to health care providers. Accidental dermal exposure should
be treated by removal of any contaminated clothing and rinsing the affected area
with water.
TIDIGESIC is a potent narcotic, and like all drugs of this class has been
associated with abuse and dependence among health care providers. To control the
risk of diversion, it is recommended that measures appropriate to the health
care setting be taken to provide rigid accounting, control of wastage, and
restriction of access.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.