DESCRIPTION:
Doxapram (Doxapram Hydrochloride Injection, USP) is a clear, colorless,
sterile, non-pyrogenic, aqueous solution with pH 3.5--5.0, for intravenous
administration.
Each 1 mL contains:
Doxapram Hydrochloride, USP............................................. 20 mg
Benzyl Alcohol, NF (as preservative)..................................... 0.9%
Water for Injection, USP................................................. q.s.
Due to its benzyl alcohol content, Doxapram should not be used in
newborns.
Doxapram is a respiratory stimulant.
Doxapram hydrochloride is a white to off-white, crystalline powder, sparingly
soluble in water, alcohol and chloroform. It has the following chemical name:
1-ethyl-4-(2-(4-morpholinyl)ethyl)-3,3-diphenyl- 2-pyrrolidinone
monohydrochloride, monohydrate.
ACTIONS/CLINICAL PHARMACOLOGY:
Doxapram hydrochloride produces respiratory stimulation mediated through the
peripheral carotid chemoreceptors. As the dosage level is increased, the central
respiratory centers in the medulla are stimulated with progressive stimulation
of other parts of the brain and spinal cord.
The onset of respiratory stimulation following the recommended single
intravenous injection of doxapram hydrochloride usually occurs in 20-40 seconds
with peak effect at 1-2 minutes. The duration of effect may vary from 5-12
minutes.
The respiratory stimulant action is manifested by an increase in tidal volume
associated with a slight increase in respiratory rate.
A pressor response may result following doxapram administration. Provided there
is no impairment of cardiac function, the pressor effect is more marked in
hypovolemic than in normovolemic states. The pressor response is due to the
improved cardiac output rather than peripheral vasoconstriction. Following
doxapram administration an increased release of catecholamines has been noted.
Although opiate induced respiratory depression is antagonized by doxapram, the
analgesic effect is not affected.
INDICATIONS AND USAGE:
1. POSTANESTHESIA.
a. When the possibility of airway obstruction and/or hypoxia have been
eliminated, doxapram may be used to stimulate respiration in patients with drug-
induced postanesthesia respiratory depression or apnea other than that due to
muscle relaxant drugs.
b. To pharmacologically stimulate deep breathing in the so-called "stir-up"
regimen in the postoperative patient. (Simultaneous administration of oxygen is
desirable.)
2. DRUG-INDUCED CENTRAL NERVOUS SYSTEM DEPRESSION.
Exercising care to prevent vomiting and aspiration, doxapram may be used to
stimulate respiration, hasten arousal, and to encourage the return of
laryngopharyngeal reflexes in patients with mild to moderate respiratory and CNS
depression due to drug overdosage.
3. CHRONIC PULMONARY DISEASE ASSOCIATED WITH ACUTE HYPERCAPNIA.
Doxapram is indicated as a temporary measure in hospitalized patients with acute
respiratory insufficiency superimposed on chronic obstructive pulmonary disease.
Its use should be for a short period of time (approximately 2 hours) as an aid
in the prevention of elevation of arterial CO2 tension during the administration
of oxygen. It should not be used in conjunction with mechanical ventilation.
CONTRAINDICATIONS:
Due to its benzyl alcohol content, Doxapram should not be used in
newborns.
Doxapram should not be used in patients with epilepsy or other convulsive
disorders.
Doxapram is contraindicated in patients with mechanical disorders of ventilation
such as mechanical obstruction, muscle paresis, flail chest, pneumothorax, acute
bronchial asthma, pulmonary fibrosis or other conditions resulting in
restriction of chest wall, muscles of respiration or alveolar expansion.
Doxapram is contraindicated in patients with evidence of head injury or cerebral
vascular accident and in those with significant cardiovascular impairment,
severe hypertension, or known hypersensitivity to the drug.
WARNINGS:
1. IN POSTANESTHETIC USE.
a. Doxapram is neither an antagonist to muscle relaxant drugs nor a specific
narcotic antagonist. Adequacy of airway and oxygenation must be assured prior to
doxapram administration.
b. Doxapram should be administered with great care and only under careful
supervision to patients with hypermetabolic states such as hyperthyroidism or
pheochromocytoma.
c. Since narcosis may recur after stimulation with doxapram, care should be
taken to maintain close observation until the patient has been fully alert for
1/2 to 1 hour.
2. IN DRUG-INDUCED CNS AND RESPIRATORY DEPRESSION.
Doxapram alone may not stimulate adequate spontaneous breathing or provide
sufficient arousal in patients who are SEVERELY depressed either due to
respiratory failure or to CNS depressant drugs, but should be used as an adjunct
to established supportive measures and resuscitative techniques.
3. IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE.
a. Because of the associated increased work of breathing, do not increase the
rate of infusion of doxapram in severely ill patients in an attempt to lower
pCO2.
b. Doxapram should not be used in conjunction with mechanical ventilation.
PRECAUTIONS:
1. GENERAL.
a. An adequate airway is essential.
b. Recommended dosages of doxapram should be employed and maximum total dosages
should not be exceeded. In order to avoid side effects, it is advisable to use
the minimum effective dosage.
c. Monitoring of the blood pressure and deep tendon reflexes is recommended to
prevent overdosage.
d. Vascular extravasation or use of a single injection site over an extended
period should be avoided since either may lead to thrombophlebitis or local skin
irritation.
e. Rapid infusion may result in hemolysis.
f. Lowered pCO2 induced by hyperventilation produces cerebral vasoconstriction
and slowing of the cerebral circulation. This should be taken into consideration
on an individual basis.
g. Intravenous short-acting barbiturates, oxygen and resuscitative equipment
should be readily available to manage overdosage manifested by excessive central
nervous system stimulation. Slow administration of the drug, and careful
observation of the patient during administration and for some time subsequently
are advisable. These precautions are to assure that the protective reflexes have
been restored and to prevent possible post-hyperventilation hypoventilation.
h. Doxapram should be administered cautiously to patients receiving
sympathomimetic or monoamine oxidase inhibiting drugs, since an additive pressor
effect may occur.
i. Blood pressure increases are generally modest but significant increases have
been noted in some patients. Because of this doxapram is not recommended for use
in severe hypertension (see Contraindications).
j. If sudden hypotension or dyspnea develops, doxapram should be stopped.
2. IN POSTANESTHETIC USE.
a. The same consideration to pre-existing disease states should be exercised as
in non-anesthetized individuals. See Contraindications and Warnings covering use
in hypertension, asthma, disturbances of respiratory mechanics including airway
obstruction, CNS disorders including increased cerebrospinal fluid pressure,
convulsive disorders, acute agitation, and profound metabolic disorders.
b. See Drug Interactions.
3. IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE.
a. Arrhythmias seen in some patients in acute respiratory failure secondary to
chronic obstructive pulmonary disease are probably the result of hypoxia.
Doxapram should be used with caution in these patients.
b. Arterial blood gases should be drawn prior to the initiation of doxapram
infusion and oxygen administration, then at least every 1/2 hour. Doxapram
administration does not diminish the need for careful monitoring of the patient
or the need for supplemental oxygen in patients with acute respiratory failure.
Doxapram should be stopped if the arterial blood gases deteriorate, and
mechanical ventilation initiated.
DRUG INTERACTIONS: Administration of doxapram to patients who are receiving
sympathomimetic or monoamine oxidase inhibiting drugs may result in an additive
pressor effect. (See Precautions).
In patients who have received muscle relaxants, doxapram may temporarily mask
the residual effects of muscle relaxant drugs.
In patients who have received anesthetics known to sensitize the myocardium to
catecholamines, such as halothane, cyclopropane and enflurane, initiation of
doxapram therapy should be delayed for at least 10 minutes following
discontinuance of anesthesia, since an increase in epinephrine release has been
noted with doxapram.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY. No carcinogenic or
mutagenic studies have been performed using doxapram. Doxapram did not adversely
affect the breeding performance of rats.
PREGNANCY CATEGORY B. Reproduction studies have been performed in rats at doses
up to 1.6 times the human dose and have revealed no evidence of impaired
fertility or harm to the fetus due to doxapram. There are, however, no adequate
and well-controlled studies in pregnant women. Since the animals in the
reproduction studies were dosed by the IM and oral routes and animal
reproduction studies, in general, are not always predictive of human response,
this drug should be used during pregnancy only if clearly needed.
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
doxapram hydrochloride is administered to a nursing mother.
PEDIATRIC USE. The use of the preservative benzyl alcohol in the newborn has
been associated with metabolic, CNS, respiratory, circulatory, and renal
dysfunction. Safety and effectiveness in children below the age of 12 years have
not been established.
DRUG INTERACTIONS:
Administration of doxapram to patients who are receiving sympathomimetic or
monoamine oxidase inhibiting drugs may result in an additive pressor effect.
(See Precautions).
In patients who have received muscle relaxants, doxapram may temporarily mask
the residual effects of muscle relaxant drugs.
In patients who have received anesthetics known to sensitize the myocardium to
catecholamines, such as halothane, cyclopropane and enflurane, initiation of
doxapram therapy should be delayed for at least 10 minutes following
discontinuance of anesthesia, since an increase in epinephrine release has been
noted with doxapram.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The following adverse reactions have been reported:
1. CENTRAL AND AUTONOMIC NERVOUS SYSTEMS.
Pyrexia, flushing, sweating; pruritus and paresthesia, such as a feeling of
warmth, burning, or hot sensation, especially in the area of genitalia and
perineum; apprehension, disorientation, pupillary dilatation, headache,
dizziness, hyperactivity, involuntary movements, muscle spasticity, increased
deep tendon reflexes, clonus, bilateral Babinski, and convulsions.
2. RESPIRATORY.
Dyspnea, cough, tachypnea, laryngospasm, bronchospasm, hiccough, and rebound
hypoventilation.
3. CARDIOVASCULAR.
Phlebitis, variations in heart rate, lowered T- waves, arrhythmias, chest pain,
tightness in chest. A mild to moderate increase in blood pressure is commonly
noted and may be of concern in patients with severe cardiovascular diseases.
4. GASTROINTESTINAL.
Nausea, vomiting, diarrhea, desire to defecate.
5. GENITOURINARY.
Stimulation of urinary bladder with spontaneous voiding; urinary retention.
6. LABORATORY DETERMINATIONS.
A decrease in hemoglobin, hematocrit, or red blood cell count has been observed
in postoperative patients. In the presence of pre- existing leukopenia, a
further decrease in WBC has been observed following anesthesia and treatment
with doxapram hydrochloride. Elevation of BUN and albuminuria have also been
observed. As some of the patients cited above had received multiple drugs
concomitantly, a cause and effect relationship could not be determined.
OVERDOSAGE:
SIGNS AND SYMPTOMS. Symptoms of overdosage are extensions of the pharmacologic
effects of the drug. Excessive pressor effect, tachycardia, skeletal muscle
hyperactivity, and enhanced deep tendon reflexes may be early signs of
overdosage. Therefore, the blood pressure, pulse rate and deep tendon reflexes
should be evaluated periodically and the dosage or infusion rate adjusted
accordingly.
Convulsive seizures are unlikely at recommended dosages. In unanesthetized
animals, the convulsant dose is 70 times greater than the respiratory stimulant
dose. Intravenous LD50 values in the mouse and rat were approximately 75mg/kg
and in the cat and dog were 40-80 mg/kg.
Except for management of chronic obstructive pulmonary disease associated with
acute hypercapnia, the maximum recommended dosage is 3 GRAMS/24 HOURS. (See
Dosage and Administration.)
MANAGEMENT. There is no specific antidote for doxapram. Management should be
symptomatic. Short-acting intravenous barbiturates, oxygen and resuscitative
equipment should be used as needed for supportive treatment.
There is no evidence that doxapram is dialyzable; further, the half-life of
doxapram makes it unlikely that dialysis would be appropriate in managing
overdose with this drug.
DOSAGE AND ADMINISTRATION:
1. Doxapram hydrochloride is compatible with 5% and 10% dextrose in water or
normal saline. ADMIXTURE OF DOXAPRAM WITH ALKALINE SOLUTIONS SUCH AS 2.5%
THIOPENTAL SODIUM, BICARBONATE, OR AMINOPHYLLINE WILL RESULT IN PRECIPITATION OR
GAS FORMATION.
2. IN POSTANESTHETIC USE.
a. By i.v. injection (see Table I. Dosage for postanesthetic use--I.V.) Slow
administration of the drug and careful observation of the patient during
administration and for some time subsequently are advisable.
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TABLE I. DOXAPRAM DOSAGE FOR POSTANESTHETIC USE--I.V.
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I.V. RECOMMENDED MAXIMUM DOSE PER MAXIMUM
ADMINISTRATION DOSAGE SINGLE INJECTION TOTAL DOSE
MG/KG MG/LB MG/KG MG/LB MG/KG MG/LB
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Single 0.5-1.0 0.25-0.5 1.5 0.70 1.5 0.70
Injection
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Repeat 0.5-1.0 0.25-0.5 1.5 0.70 2.0 1.0
Injections
(5 min. intervals)
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Infusion 0.5-1.0 0.25-0.5 -- -- 4.0 2.0
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b. By infusion. The solution is prepared by adding 250 mg of doxapram (12.5 mL)
to 250 mL of dextrose or saline solution. The infusion is initiated at a rate of
approximately 5 mg/minute until a satisfactory respiratory response is observed,
and maintained at a rate of 1-3 mg/minute. The rate of infusion should be
adjusted to sustain the desired level of respiratory stimulation with a minimum
of side effects. The recommended total dosage by infusion is 4 mg/kg (2.0
mg/lb), or approximately 300 mg for the average adult.
3. IN THE MANAGEMENT OF DRUG-INDUCED CNS DEPRESSION.
(See Table II. Dosage for drug-induced CNS depression.)
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TABLE II. DOXAPRAM DOSAGE FOR DRUG-INDUCED CNS DEPRESSION.
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METHOD ONE METHOD TWO
PRIMING DOSE SINGLE/REPEAT RATE OF INTERMITTENT
LEVEL OF I.V. INJECTION I.V. INFUSION
DEPRESSION MG/KG MG/LB MG/KG/HR MG/LB/HR
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Mild* 1.0 0.5 1.0-2.0 0.5-1.0
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Moderate** 2.0 1.0 2.0-3.0 1.0-1.5
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* Mild Depression
Class 0: Asleep, but can be aroused and can answer questions.
Class 1: Comatose, will withdraw from painful stimuli, reflexes intact.
** Moderate Depression
Class 2: Comatose, will not withdraw from painful stimuli, reflexes intact.
Class 3: Comatose, reflexes absent, no depression of circulation or
respiration.
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METHOD ONE
Using Single and/or Repeat Single I.V. INJECTIONS.
a. Give priming dose of 1.0 mg/lb (2.0 mg/kg) body weight and repeat in 5
minutes.
b. Repeat same dose q1-2h until patient wakens. Watch for relapse into
unconsciousness or development of respiratory depression, since Dopram does not
affect the metabolism of CNS- depressant drugs.
c. If relapse occurs, resume injections q1-2h until arousal is sustained, or
total maximum daily dose (3 grams) is given. Allow patients to sleep until 24
hours have elapsed from first injection of Dopram, using assisted or automatic
respiration if necessary.
d. Repeat procedure the following day until patient breathes spontaneously and
sustains desired level of consciousness, or until maximum dosage (3 grams) is
given.
e. Repetitive doses should be administered only to patients who have shown
response to the initial dose.
f. Failure to respond appropriately indicates the need for neurologic evaluation
for a possible central nervous system source of sustained coma.
METHOD TWO
By Intermittent I.V. INFUSION.
a. Give priming dose as in Method One.
b. If patient wakens, watch for relapse; if no response, continue general
supportive treatment for 1-2 hours and repeat Dopram. If some respiratory
stimulation occurs, prepare I.V. infusion by adding 250 mg of Dopram (12.5 mL)
to 250 mL of saline or dextrose solution. Deliver at rate of 1-3 mg/min (60-180
mL/hr) according to size of patient and depth of coma. Discontinue Dopram if
patient begins to waken or at end of 2 hours.
c. Continue supportive treatment for 1/2 to 2 hours and repeat Step b.
d. Do not exceed 3 grams/day.
4. CHRONIC OBSTRUCTIVE PULMONARY DISEASE ASSOCIATED WITH ACUTE HYPERCAPNIA.
a. One vial of doxapram (400 mg) should be mixed with 180 mL of dextrose or
saline solution (concentration of 2.0 mg/mL). The infusion should be started at
1-2 mg/minute (1/2-1 mL/minute); if indicated, increase to a maximum of 3
mg/minute. Arterial blood gases should be determined prior to the onset of
doxapram's administration and at least every half hour during the two hours of
infusion to insure against the insidious development of CO2-RETENTION AND
ACIDOSIS. Alteration of oxygen concentration or flow rate may necessitate
adjustment in the rate of doxapram infusion.
b. Predictable blood gas patterns are more readily established with a continuous
infusion of doxapram. If the blood gases show evidence of deterioration, the
infusion of doxapram should be discontinued.
c. ADDITIONAL INFUSIONS BEYOND THE SINGLE MAXIMUM TWO HOUR ADMINISTRATION PERIOD
ARE NOT RECOMMENDED.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
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