NUBAIN (nalbuphine hydrochloride) is a synthetic narcotic agonist-antagonist analgesic of the phenanthrene series. It is chemically related to both the widely used narcotic antagonist, naloxone, and the potent narcotic analgesic, oxymorphone.

NALBUPHINE HYDROCHLORIDE Nalbuphine hydrochloride is (-)-17-(cyclobutylmethyl)-4, 5alpha-epoxymorphinan-3,6alpha,14-triol hydrochloride. NUBAIN is available in two concentrations, 10 mg and 20 mg of nalbuphine hydrochloride per mL. Both strengths contain 0.94% sodium citrate hydrous, 1.26%
citric acid anhydrous, 0.1% sodium metabisulfite, and 0.2% of a 9:1 mixture of methylparaben and
propylparaben as preservatives; pH is adjusted, if necessary, with hydrochloric acid. The 10 mg/mL
strength contains 0.1% sodium chloride.

NUBAIN is also available in a sulfite and paraben-free formulation in two concentrations, 10 mg and
20 mg of nalbuphine hydrochloride per mL. One mL of each strength contains 0.94% sodium citrate
hydrous, 1.26% citric acid anhydrous; pH is adjusted, if necessary, with hydrochloric acid. The 10 mg/mL
strength contains 0.2% sodium chloride.

ACTIONS/CLINICAL PHARMACOLOGY:

NUBAIN is a potent analgesic. Its analgesic potency is essentially equivalent to that of morphine on a
milligram basis. Its onset of action occurs within 2 to 3 minutes Its onset of action occurs within 2 to 3
minutes after intravenous administration, and in less than 15 minutes following subcutaneous or
intramuscular injection. The plasma half-life of nalbuphine is 5 hours and in clinical studies the duration of
analgesic activity has been reported to range from 3 to 6 hours.

The narcotic antagonist activity of NUBAIN is one-fourth as potent as nalorphine and 10 times that of pentazocine.

INDICATIONS AND USAGE:

NUBAIN (nalbuphine hydrochloride) is indicated for the relief of moderate to severe pain. NUBAIN can
also be used as a supplement to balanced anesthesia, for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and delivery.

CONTRAINDICATIONS:

NUBAIN should not be administered to patients who are hypersensitive to it.

WARNINGS:

NUBAIN SHOULD BE ADMINISTERED AS A SUPPLEMENT TO GENERAL ANESTHESIA
ONLY BY PERSONS SPECIFICALLY TRAINED IN THE USE OF INTRAVENOUS
ANESTHETICS AND MANAGEMENT OF THE RESPIRATORY EFFECTS OF POTENT
OPIOIDS.

NALOXONE, RESUSCITATIVE AND INTUBATION EQUIPMENT AND OXYGEN SHOULD BE READILY AVAILABLE. DRUG DEPENDENCE NUBAIN has been shown to have a low abuse potential. When compared with drugs which are not mixed agonist-antagonists, it has been reported that
nalbuphine's potential for abuse would be less than that of codeine and propoxyphene. Psychological and physical dependence and tolerance may follow the abuse or misuse of nalbuphine. Therefore, caution should be observed in prescribing it for emotionally unstable patients, or for individuals with a history of
narcotic abuse. Such patients should be closely supervised when long-term therapy is contemplated.

Care should be taken to avoid increases in dosage or frequency of administration which in susceptible
individuals might result in physical dependence.

Abrupt discontinuation of NUBAIN following prolonged use has been followed by symptoms of narcotic
withdrawal, i.e., abdominal cramps, nausea and vomiting, rhinorrhea, lacrimation, restlessness, anxiety,
elevated temperature and piloerection.

USE IN AMBULATORY PATIENTS NUBAIN may impair the mental or physical abilities required for
the performance of potentially dangerous tasks such as driving a car or operating machinery. Therefore,
NUBAIN should be administered with caution to ambulatory patients who should be warned to avoid
such hazards.

USE IN EMERGENCY PROCEDURES Maintain patient under observation until recovered from
NUBAIN effects that would affect driving or other potentially dangerous tasks.

USE IN CHILDREN Clinical experience to support administration to patients under 18 years is not
available at present.

USE IN PREGNANCY (OTHER THAN LABOR)

Safe use of NUBAIN in pregnancy has not been established. Although animal reproductive studies have
not revealed teratogenic or embryotoxic effects, nalbuphine should only be administered to pregnant
women when, in the judgement of the physician, the potential benefits outweigh the possible hazards.

USE DURING LABOR AND DELIVERY

NUBAIN can produce respiratory depression in the neonate. It should be used with caution in women
delivering premature infants.

HEAD INJURY AND INCREASED INTRACRANIAL PRESSURE The possible respiratory
depressant effects and the potential of potent analgesics to elevate cerebrospinal fluid pressure (resulting
from vasodilation following CO2 retention) may be markedly exaggerated in the presence of head injury,
intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, potent analgesics can
produce effects which may obscure the clinical course of patients with head injuries. Therefore,
NUBAIN should be used in these circumstances only when essential, and then should be administered
with extreme caution.

INTERACTION WITH OTHER CENTRAL NERVOUS SYSTEM DEPRESSANTS Although
NUBAIN possesses narcotic antagonist activity, there is evidence that in nondependent patients it will not
antagonize a narcotic analgesic administered just before, concurrently, or just after an injection of
NUBAIN. Therefore, patients receiving a narcotic analgesic, general anesthetics, phenothiazines, or other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with NUBAIN may exhibit an additive effect. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

SULFITES SENSITIVITY NUBAIN 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.

PRECAUTIONS:

IMPAIRED RESPIRATION At the usual adult dose of 10 mg/70 kg, NUBAIN causes some respiratory
depression approximately equal to that produced by equal doses of morphine. However, in contrast to
morphine, respiratory depression is not appreciably increased with higher doses of NUBAIN. Respiratory
depression induced by NUBAIN can be reversed by NARCAN(R) (naloxone hydrochloride) when
indicated. NUBAIN should be administered with caution at low doses to patients with impaired
respiration (e.g., from other medication, uremia, bronchial asthma, severe infection, cyanosis or
respiratory obstructions).

IMPAIRED RENAL OR HEPATIC FUNCTION Because NUBAIN is metabolized in the liver and
excreted by the kidneys, patients with renal or liver dysfunction may over-react to customary doses.
Therefore, in these individuals, NUBAIN should be used with caution and administered in reduced
amounts. MYOCARDIAL INFARCTION As with all potent analgesics, NUBAIN should be used with
caution in patients with myocardial infarction who have nausea or vomiting.

BILIARY TRACT SURGERY As with all narcotic analgesics, NUBAIN should be used with caution in
patients about to undergo surgery of the biliary tract since it may cause spasm of the sphincter of Oddi.

CARDIOVASCULAR SYSTEM During evaluation of NUBAIN in anesthesia, a higher incidence of
bradycardia has been reported in patients who did not receive atropine pre-operatively or in the
pre-operative period.

DRUG INTERACTIONS:

INTERACTION WITH OTHER CENTRAL NERVOUS SYSTEM DEPRESSANTS Although
NUBAIN possesses narcotic antagonist activity, there is evidence that in nondependent patients it will not
antagonize a narcotic analgesic administered just before, concurrently, or just after an injection of
NUBAIN. Therefore, patients receiving a narcotic analgesic, general anesthetics, phenothiazines, or other
tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with
NUBAIN may exhibit an additive effect. When such combined therapy is contemplated, the dose of one
or both agents should be reduced. (See Also WARNINGS)

ADVERSE REACTIONS:

The most frequent adverse reaction in 1066 patients treated with NUBAIN is sedation 381(36%).

Less frequent reactions are: sweaty/clammy 99(9%), nausea/vomiting 68(6%), dizziness/vertigo 58(5%), dry mouth 44(4%), and headache 27(3%). Other adverse reactions which may occur (reported incidence of 1% or less) are: CNS EFFECTS Nervousness, depression, restlessness, crying, euphoria, floating, hostility, unusual dreams, confusion, faintness, hallucinations, dysphoria, feeling of heaviness, numbness, tingling, unreality. The incidence of psychotomimetic effects, such as unreality, depersonalization,
delusions, dysphoria and hallucinations has been shown to be less than that which occurs with
pentazocine.

CARDIOVASCULAR Hypertension, hypotension, bradycardia, tachycardia, pulmonary edema.

GASTROINTESTINAL Cramps, dyspepsia, bitter taste.

RESPIRATION Depression, dyspnea, asthma.

DERMATOLOGICAL Itching, burning, urticaria.

MISCELLANEOUS Speech difficulty, urinary urgency, blurred vision, flushing and warmth.

DRUG ABUSE AND DEPENDENCE:ATION

OVERDOSAGE:

MANAGEMENT OF OVERDOSAGE The immediate intravenous administration of NARCAN(R)
(naloxone hydrochloride) is a specific antidote. Oxygen, intravenous fluids, vasopressors and other
supportive measures should be used as indicated. supportive measures should be used as indicated.

The administration of single doses of 72 mg of NUBAIN subcutaneously to eight normal subjects has
been reported to have resulted primarily in symptoms of sleepiness and mild dysphoria.

DOSAGE AND ADMINISTRATION: The usual recommended adult dose is 10 mg for a 70 kg
individual, administered subcutaneously, intramuscularly or intravenously; this dose may be repeated every
3 to 6 hours as necessary. Dosage should be adjusted according to the severity of the pain, physical status
of the patient, and other medications which the patient may be receiving. (See Interaction with Other
Central Nervous System Depressants under WARNINGS). In non-tolerant individuals, the Central
Nervous System Depressants under WARNINGS). In non-tolerant individuals, the recommended single
maximum dose is 20 mg, with a maximum total daily dose of 160 mg.

The use of NUBAIN as a supplement to balanced anesthesia requires larger doses than those
recommended for analgesia. Induction doses of NUBAIN range from 0.3 mg/kg to 3.0 mg/kg
intravenously to be administered over a 10 to 15 minute period with maintenance doses of 0.25 to
0.50 mg/kg in single intravenous administrations as required. The use of NUBAIN may be followed by
respiratory depression which can be reversed with the narcotic antagonist NARCAN(R) (naloxone
hydrochloride).

PATIENTS DEPENDENT ON NARCOTICS Patients who have been taking narcotics chronically may
experience withdrawal symptoms can be controlled by the slow intravenous administration of small
increments of morphine, until relief occurs. If the previous analgesic was morphine, meperidine, codeine, or other narcotic with similar duration of activity, one-fourth of the anticipated dose of NUBAIN can be administered initially and the patient observed for signs of withdrawal, i.e., abdominal cramps, nausea and vomiting, lacrimation, rhinorrhea, anxiety, restlessness, elevation of temperature or piloerection. If
untoward symptoms do not occur, progressively larger doses may be tried at appropriate intervals until the
desired level of analgesia is obtained with NUBAIN.

HOW SUPPLIED: NUBAIN(R) (nalbuphine hydrochloride) for intramuscular, subcutaneous, or
intravenous use is available in:

NDC 0590-0385-10 10 mg/mL, 1 mL ampuls (box of 10)
NDC 0590-0386-01 10 mg/mL, 10 mL multiple dose vials (box of 1)
NDC 0590-0395-10 (sulfite/paraben-free) 10 mg/mL, 1 mL ampuls (box of 10)
NDC 0590-0396-10 20 mg/mL, 1 mL ampuls (box of 10)
NDC 0590-0396-15 20 mg/mL, 1 mL disposable pre-filled syringes (box of 10)
NDC 0590-0399-01 20 mg/mL, 10 mL multiple dose vials (box of 1)
NDC 0590-0398-10 (sulfite/paraben-free) 20 mg/mL, 1 mL ampuls (box of 10)
Store At Controlled Room Temperature (deg F, 15 deg-30 deg C).

CAUTION: Federal law prohibits dispensing without prescription.

DU PONT PHARMACEUTICALS Manati, Puerto Rico 00674 NUBAIN(R) is a Registered
Trademark of The Du Pont Merck Pharmaceutical Co. NARCAN(R) is a Registered Trademark of The
Du Pont Merck Pharmaceutical Co. 6109-12/Rev. Dec., 1990