DOPRAM® INJECTION

INDICATIONS CONTRA-INDICATIONS DOSAGE SIDE-EFFECTS PREGNANCY OVERDOSE IDENTIFICATION PATIENT INFORMATION

DOPRAM® INJECTION

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

DOPRAM^® INJECTION

COMPOSITION:
Each 1 mL contains:
Doxapram hydrochloride USP 20 mg
Preservative: Benzyl alcohol NF 0,9% m/v
The structural and chemical formulas of doxapram hydrochloride are:
{structural formula illustrated here}

1-ethyl-4-(2-(4-morpholinyl)ethyl)-3,3-diphenyl-2-pyrrolidinone monohydrochloride monohydrate. The molecular weight is 432,99. Doxapram hydrochloride is a clear, colourless 2% aqueous solution with pH 3,5 to 5,0.

PHARMACOLOGICAL CLASSIFICATION:
A 1.4 –Respiratory Stimulant.

PHARMACOLOGICAL ACTION:
Doxapram hydrochloride produces respiratory stimulation mediated through the peripheral carotid chemoreceptors. As the dosage level is increased the central respiratory centres 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:

1.	Post-anaesthesia
	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 post-anaesthesia respiratory depression or apnoea 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 overdose.
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. The adequancy of ventilation must be assessed by measurements of arterial blood gases as well as careful monitoring of the cardiovascular indices.

CONTRA-INDICATIONS:

1.	General Contra-indications Doxapram is not recommended in the following conditions: epilepsy and other convulsive states; incompetence of the ventilatory mechanism due to muscle paresis; flail chest; pneumothorax; airway obstruction; and extreme dyspnea; severe hypertension and cerebrovascular accidents; hypersensitivity to doxapram; evidence of head injury.
2.	Contra-indications in pulmonary disease Doxapram is not recommended in the following conditions: strongly suspected or confirmed pulmonary embolism, pneumothorax, acute bronchial asthma, respiratory failure due to neuromuscular disorders, and in restrictive respiratory diseases such as pulmonary fibrosis.
3.	Contra-indications in cardiovascular disease Doxapram is not recommended in the following conditions: coronary artery disease, frank uncompensated heart failure.

DOSAGE AND DIRECTIONS FOR USE:

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 OR BICARBONATE WILL RESULT IN PRECIPITATION.
2.	In post-anaesthetic use
	a.	By I.V. injection (See Table 1.)

Table 1. Dosage for post-anaesthetic use - I.V.
IV Administration	Recommended dosage mg/kg	Maximum dose per single injection mg/kg	Maximum total dose mg/kg
Single injection	0,5 - 1,0	1,5	1,5
Repeat injection (5 min. intervals)	0,5 - 1,0	1,5	2,0
Infusion	0,5 - 1,0	-	4,0

	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, not to exceed 3 grams
3.	In the management of drug-induced CNS depression.(See Table II.)

Table II. Dosage for drug-induced CNS depression

Level of depression	METHOD ONE Priming dose single/ repeat (I.V.) injection mg/kg	METHOD TWO Rate of intermittent (I.V ) injection mg/kg/hr
Mild *	1,0	1,0 - 2,0
Moderate +	2,0	2,0 - 3,0

*	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.
	METHOD ONE: Using Single and/or Repeat Single I.V. injections.
	a.	Give priming dose of 2,0 mg/kg body weight and repeat in 5 minutes.
	b.	Repeat same dose every 1 to 2 hours 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 1-2 hourly injections until arousal is sustained, or total maximum daily dose (3 grams) is given. Allow patient to sleep until 24 hours have elapsed from first injection of Dopram using assisted or automatic respiration if necessary.
	d.	Repeat procedure 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 ½ to 2 hours and repeat Step b.
	d.		Do not exceed 3 grams.
4.	Chronic obstructive pulmonary disease associated with acute hypercapnia.
	a.		One vial of doxapram (400 mg) should be mixed with 180 mL of the intravenous solution (concentration of 2,0 mg/mL). The infusion should be started at 1-2 mg/minutes (½-1 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 ensure 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.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:

1.	Warning in post-anaesthetic 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 close supervision to patients with cerebral edema, history of bronchial asthma, severe tachycardia, cardiac arrhythmia, cardiac disease, 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 ½ to 1 hour.
2.	Warning 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.	Warning in chronic obstructive pulmonary disease.
	a.	In an attempt to low pCO₂, the rate of infusion of doxapram should not be increased in severely ill patients because of the associated increased work in breathing.
	b.	Doxapram should not be used in conjunction with mechanical ventilation.
4.	Warning in pregnancy. Clinically the safe use of doxapram in pregnancy has not been established. The physician must weigh the need against possible risks in using the drug in pregnant patients or in women of childbearing potential.
5.	Warning in children 12 years of age and under. Doxapram is not recommended for use in patients 12 years of age or under because studies to adequately evaluate its safety and efficacy have not been performed.

PRECAUTIONS:

1.	General precautions.
	a.	An adequate airway is essential.
	b.	Recommended dosages of doxapram should be employed and maximum total dosages should be 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, 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 and 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 Contra-indications).
	j.	If sudden hypotension of dyspnoea develops, doxapram should be stopped.
2.	Precautions in post-anaesthetic use.
	a.	In patients who have received muscle relaxants, doxapram may temporarily mask the residual effects of muscle relaxant drugs.
	b.	Since an increase in epinephrine release has been noted with doxapram, it is recommended that initiation of therapy be delayed for at least 10 minutes following the discontinuance of anaesthetics known to sensitize the myocardium to catecholamines, such as halothane, cyclopropane and enflurane.
	c.	The same consideration to pre-existing disease states should be exercised as in non-anaesthetized individuals. See Contra-indications 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.
3.	Precautions 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 ½ hour. Doxapram administration does not diminish the need for carefull monitoring of the patient or the need for supplemental oxygen in patients with acute repiratory failure. Doxapram should be stopped if the arterial blood gases deteriorate, and mechanical ventilation initiated.

ADVERSE REACTIONS: The following adverse reactions have been reported

1.	Central and autonomic nervous systems. Headache, dizziness, apprehension, disorientation, pupillary dilatation, hyperactivity, involuntary movements, convulsions, muscle spasticity, increased deep tendon reflexes, clonus, bilateral Babinski; pyrexia, flushing, sweating; pruritis and paresthesia such as a feeling of warmth, burning or hot sensation especially in the area of genitalia and perineum.
2.	Respiratory. Cough, dyspnoea, tachypnoea, laryngospasm, hiccough, and rebound hypoventialtion.
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. The elevation in blood pressure may be of concern only in hypertensive patients. (See Contra-indications).
4.	Gastro-intestinal. Nausea, vomiting, diarrhoea, desire to defecate.
5.	Genito-urinary. Urinary retention, stimulation of urinary bladder with spontaneous voiding.
6.	Laboratory determinations. A decrease in haemoglobin, haematocrit or red cell blood count has been observed in postoperative patients. In the presence of pre-existing leukopenia, a further decrease in WBC has been observed following anaesthesia and treatment with doxapram hydrochloride. Elevation of BUN and aluminuria 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.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Overdosage
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 but intravenous anticonvulsants, oxygen, and resuscitative equipment should be available.

IDENTIFICATION
Clear, colourless solution.

PRESENTATION
Dopram Injection (doxapram hydrochloride injection) is available in 20 mL rubber-stoppered vials containing 20 mg of doxapram hydrochloride per mL, (20 mg/mL) with benzyl alcohol 0,9% as the preservative.

STORAGE INSTRUCTIONS:
May be stored at room temperature below 25°C.
KEEP OUT OF REACH OF CHILDREN.

APPLICATION NUMBER:
B1547 (Act 101/1965)

NAME AND BUSINESS ADDRESS OF APPLICANT:
Intramed (Pty) Ltd
6 Gibaud Road
PORT ELIZABETH
6001

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
JANUARY 1978

	12-104/1-95
	Tradepak PE