PENTAZOCINE
DESCRIPTION:
Pentazocine is a member of the benzazocine series (also known as the
benzomorphan series). Chemically, pentazocine is 1,2,3,4,5,6-hexahydro- 6,11-
dimethyl-3-(3-methyl-2-butenyl)-2,6-methano- 3-benzazocin-8-ol, a white,
crystalline substance soluble in acidic aqueous solutions.
ACTIONS/CLINICAL PHARMACOLOGY:
FORTWIN is an analgesic possessing antipyretic actions.
Pentazocine is an analgesic with agonist/antagonist action which when
administered orally is approximately equivalent on a mg for mg basis in
analgesic effect to codeine.
Onset of significant analgesia with pentazocine usually occurs between 15 and 30
minutes after oral administration, and duration of action is usually three hours
or longer. Onset and duration of action and the degree of pain relief are
related both to dose and the severity of pretreatment pain. Pentazocine weakly
antagonizes the analgesic effects of morphine, meperidine, and phenazocine; in
addition, it produces incomplete reversal of cardiovascular, respiratory, and
behavioral depression induced by morphine and meperidine. Pentazocine has about
1/50 the antagonistic activity of nalorphine. It also has sedative activity.
Pentazocine is well absorbed from the gastrointestinal tract. Plasma levels
closely correspond to the onset, duration, and intensity of analgesia. The mean
time to peak concentration in 24 normal volunteers was 1.7 hours (range 0.5 to 4
hours) after oral administration and the mean plasma elimination half-life was
3.6 hours (range 1.5 to 10 hours).
The action of pentazocine is terminated for the most part by biotransformation
in the liver with some free pentazocine excreted in the urine. The products of
the oxidation of the terminal methyl groups and glucuronide conjugates are
excreted by the kidney. Elimination of approximately 60% of the total dose
occurs within 24 hours. Pentazocine passes the placental barrier.
Onset of significant analgesic and antipyretic activity of acetaminophen when
administered orally occurs within 30 minutes and is maximal at approximately 2
1/2 hours. The pharmacological mode of action of acetaminophen is unknown at
this time.
INDICATIONS AND USAGE:
FORTWIN is indicated for the relief of mild to moderate pain.
CONTRAINDICATIONS:
FORTWIN should not be administered to patients who are hypersensitive to either
Pentazocine.
WARNINGS:
Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions
including anaphylactic symptoms and life-threatening or less severe asthmatic
episodes in certain susceptible people. The overall prevalence of sulfite
sensitivity in the general population is unknown and probably low. Sulfite
sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
Head Injury And Increased Intracranial Pressure. As in the case of other potent
analgesics, the potential of pentazocine for elevating cerebrospinal fluid
pressure may be attributed to CO2 retention due to the respiratory depressant
effects of the drug. These effects may be markedly exaggerated in the presence
of head injury, other intracranial lesions, or a preexisting increase in
intracranial pressure. Furthermore, pentazocine can produce effects which may
obscure the clinical course of patients with head injuries. In such patients,
FORTWIN must be used with extreme caution and only if its use is deemed
essential.
Acute CNS Manifestations. Patients receiving therapeutic doses of pentazocine
have experienced hallucinations (usually visual), disorientation, and confusion
which have cleared spontaneously within a period of hours. The mechanism of this
reaction is not known. Such patients should be closely observed and vital signs
checked. If the drug is reinstituted, it should be done with caution since these
acute CNS manifestations may recur.
There have been instances of psychological and physical dependence on parenteral
pentazocine in patients with a history of drug abuse, and rarely, in patients
without such a history. (See DRUG ABUSE AND DEPENDENCE.)
Due to the potential for increased CNS depressant effects, alcohol should be
used with caution in patients who are currently receiving pentazocine.
Pentazocine may precipitate opioid abstinence symptoms in patients receiving
courses of opiates for pain relief.
PRECAUTIONS:
In Prescribing FORTWIN For Chronic Use, The Physician Should Take Precautions To
Avoid Increases In Dose By The Patient.
Myocardial Infarction. As with all drugs, FORTWIN should be used with caution in
patients with myocardial infarction who have nausea or vomiting.
Certain Respiratory Conditions. Although respiratory depression has rarely been
reported after oral administration of pentazocine, the drug should be
administered with caution to patients with respiratory depression from any
cause, severely limited respiratory reserve, severe bronchial asthma and other
obstructive respiratory conditions, or cyanosis.
Impaired Renal Or Hepatic Function. Decreased metabolism of the drug by the
liver in extensive liver disease may predispose to accentuation of side effects.
Although laboratory tests have not indicated that pentazocine causes or
increases renal or hepatic impairment, the drug should be administered with
caution to patients with such impairment.
Since acetaminophen is metabolized by the liver, the question of the safety of
its use in the presence of liver disease should be considered.
Biliary Surgery. Narcotic drug products are generally considered to elevate
biliary tract pressure for varying periods following their administration. Some
evidence suggests that pentazocine may differ from other marketed narcotics in
this respect (i.e., it causes little or no elevation in biliary tract
pressures). The clinical significance of these findings, however, is not yet
known.
CNS Effect. Caution should be used when FORTWIN is administered to patients
prone to seizures; seizures have occurred in a few such patients in association
with the use of pentazocine although no cause and effect relationship has been
established.
Information For Patients. Since sedation, dizziness, and occasional euphoria
have been noted, ambulatory patients should be warned not to operate machinery,
drive cars, or unnecessarily expose themselves to hazards. Pentazocine may cause
physical and psychological dependence when taken alone and may have additive CNS
depressant properties when taken in combination with alcohol or other CNS
depressants.
Drug Interactions. Pentazocine is a mild narcotic antagonist. Some patients
previously given narcotics, including methadone for the daily treatment of
narcotic dependence, have experienced withdrawal symptoms after receiving
pentazocine.
Carcinogenesis, Mutagenesis, Impairment Of Fertility. Carcinogenesis,
mutagenesis, and impairment of fertility studies have not been done with this
combination product.
Pentazocine, when administered orally or parenterally, had no adverse effect on
either the reproductive capabilities or the course of pregnancy in rabbits and
rats. Embryotoxic effects on the fetuses were not shown.
The daily administration of 4 mg/kg to 20 mg/kg pentazocine subcutaneously to
female rats during a 14 day pre-mating period and until the 13th day of
pregnancy did not have any adverse effects on the fertility rate.
There is no evidence in long-term animal studies to demonstrate that pentazocine
is carcinogenic.
Pregnancy Category C. Animal reproduction studies have not been conducted with
FORTWIN. It is also not known whether FORTWIN can cause fetal harm when
administered to pregnant women or can affect reproduction capacity. FORTWIN
should be given to pregnant women only if clearly needed. However, animal
reproduction studies with pentazocine have not demonstrated teratogenic or
embryotoxic effects.
Nonteratogenic Effects. There has been no experience in this regard with the
combination pentazocine and acetaminophen. However, there have been rare reports
of possible abstinence syndromes in newborns after prolonged use of pentazocine
during pregnancy.
Labor And Delivery. Patients receiving pentazocine during labor have experienced
no adverse effects other than those that occur with commonly used analgesics.
FORTWIN should be used with caution in women delivering premature infants. The
effect of FORTWIN on the mother and fetus, the duration of labor or delivery,
the possibility that forceps delivery or other intervention or resuscitation of
the newborn may be necessary, or the effect of FORTWIN, on the later growth,
development, and functional maturation of the child are unknown at the present
time.
Nursing Mothers. It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when
FORTWIN is administered to a nursing woman.
Pediatric Use. Safety and effectiveness in pediatric patients below the age of
12 have not been established.
DRUG INTERACTIONS:
Pentazocine is a mild narcotic antagonist. Some patients previously given
narcotics, including methadone for the daily treatment of narcotic dependence,
have experienced withdrawal symptoms after receiving pentazocine.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
Clinical experience with FORTWIN has been insufficient to define all possible
adverse reactions with this combination. However, reactions reported after oral
administration of pentazocine hydrochloride in 50 mg dosage include
Gastrointestinal: nausea, vomiting, infrequently constipation; and rarely
abdominal distress, anorexia, diarrhea. CNS Effects: dizziness, lightheadedness,
hallucinations, sedation, euphoria, headache, confusion, disorientation;
infrequently weakness, disturbed dreams, insomnia, syncope, visual blurring and
focusing difficulty, depression; and rarely tremor, irritability, excitement,
tinnitus. Autonomic: sweating; infrequently flushing; and rarely chills.
Allergic: infrequently rash; and rarely urticaria, edema of the face.
Cardiovascular: infrequently decrease in blood pressure, tachycardia.
Hematologic: rarely depression of white blood cells (especially granulocytes),
which is usually reversible, moderate transient eosinophilia. Other: rarely
respiratory depression, urinary retention, paresthesia, toxic epidermal
necrolysis, and in one instance, an apparent anaphylactic reaction has been
reported.
Numerous clinical studies have shown that acetaminophen, when taken in
recommended doses, is relatively free of adverse effects in most age groups,
even in the presence of a variety of disease states.
A few cases of hypersensitivity to acetaminophen have been reported, as
manifested by skin rashes, thrombocytopenic purpura, rarely hemolytic anemia and
agranulocytosis. Occasional individuals respond to ordinary doses with nausea
and vomiting and diarrhea.
DRUG ABUSE AND DEPENDENCE:
Controlled Substance. FORTWIN is a Schedule IV controlled substance.
Abuse And Dependence. There have been some reports of dependence and of
withdrawal symptoms with orally administered pentazocine. There have been
recorded instances of psychological and physical dependence in patients using
parenteral pentazocine. Abrupt discontinuance following the extended use of
parenteral pentazocine has resulted in withdrawal symptoms. Patients with a
history of drug dependence should be under close supervision while receiving
FORTWIN. There have been rare reports of possible abstinence syndromes in
newborns after prolonged use of pentazocine during pregnancy.
Some tolerance to the analgesic and subjective effects of pentazocine develops
with frequent and repeated use.
Drug addicts who are given closely spaced doses of pentazocine (e.g., 60 mg to
90 mg every 4 hours) develop physical dependence which is demonstrated by abrupt
withdrawal or by administration of naloxone. The withdrawal symptoms exhibited
after chronic doses of more than 500 mg of pentazocine per day have similar
characteristics, but to a lesser degree, of opioid withdrawal and may be
associated with drug seeking behavior.
OVERDOSAGE:
Manifestations. Clinical experience with FORTWIN has been insufficient to define
the signs of overdosage with this product. It may be assumed that signs and
symptoms of FORTWIN overdose would be a combination of those observed with
pentazocine overdose and acetaminophen overdose.
For pentazocine alone in single doses above 60 mg there have been reports of the
occurrence of nalorphine-like psychotomimetic effects such as anxiety,
nightmares, strange thoughts, and hallucinations. Marked respiratory depression
associated with increased blood pressure and tachycardia have also resulted from
excessive doses as have dizziness, nausea, vomiting, lethargy, and paresthesias.
The respiratory depression is antagonized by naloxone (see Treatment).
There have been reports of glycosuria and impaired glucose tolerance, but
hypoglycemia may also occur. Metabolic acidosis and metabolic alkalosis have
been reported. Cerebral edema and nonspecific myocardial depression have also
been noted. Biopsy reveals centrolobular necrosis with sparing of the periportal
area. The hepatic lesions are reversible over a period of weeks or months in
nonfatal cases.
Treatment. Oxygen, intravenous fluids, vasopressors, and other supportive
measures should be employed as indicated. Assisted or controlled ventilation
should also be considered. For respiratory depression due to overdosage or
unusual sensitivity to FORTWIN, parenteral naloxone is a specific and effective
antagonist.
Vigorous supportive therapy is required in severe intoxication. Procedures to
limit the continuing absorption of the drug must be readily performed since the
hepatic injury is dose dependent and occurs early in the course of intoxication.
Induction of vomiting or gastric lavage, followed by oral administration of
activated charcoal should be done in all cases.
If hemodialysis can be initiated within the first 12 hours, it is advocated for
patients with a plasma acetaminophen concentration exceeding 120 mcgm/mL at 4
hours after ingestion of the drug.
DOSAGE AND ADMINISTRATION:
Adult. The usual adult dose is 1 caplet every 4 hours as needed for pain relief,
up to a maximum of 6 caplets per day.
The usual duration of therapy is dependent upon the condition being treated but
in any case should be reviewed regularly by the physician.