Doxapram

Doxapram
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Overview

Doxapram is a respiratory stimulant that is FDA approved for the treatment of Postanesthesia, Drug-Induced Central Nervous System Depression and Chronic Pulmonary Disease Associated with Acute Hypercapnia. Common adverse reactions include {{{adverseReactions}}}.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

There is limited information regarding Doxapram FDA-Labeled Indications and Dosage (Adult) in the drug label.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Doxapram in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Doxapram in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Doxapram FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Doxapram in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Doxapram in pediatric patients.

Contraindications

• Doxapram is contraindicated in patients with known hypersensitivity to the drug or any of the injection components.
• Doxapram should not be used in patients with epilepsy or other convulsive disorders.
• Doxapram is contraindicated in patients with proven or suspected pulmonary embolism.
• Doxapram is contraindicated in patients with mechanical disorders of ventilation such as mechanical obstruction, muscle paresis (including neuromuscular blockade), flail chest, pneumothorax, acute bronchial asthma, pulmonary fibrosis, or other conditions resulting in restriction of the chest wall, muscles of respiration, or alveolar expansion.
• Doxapram is contraindicated in patients with evidence of head injury, cerebral vascular accident, or cerebral edema, and in those with significant cardiovascular impairment, uncompensated heart failure, severe coronary artery disease, or severe hypertension, including that associated with hyperthyroidism or pheochromocytoma.

Warnings

Doxapram should not be used in conjunction with mechanical ventilation. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources.

In Postanesthetic Use

Doxapram is neither an antagonist to muscle relaxant drugs nor a specific narcotic antagonist. More specific tests (eg, peripheral nerve stimulation, airway pressures, head lift, pulse oximetry, and end-tidal carbon dioxide) to assess adequacy of ventilation are recommended before administering doxapram. Doxapram should be administered with great care and only under careful supervision to patients with hypermetabolic states such as hyperthyroidism or pheochromocytoma. 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. In patients who have received general anesthesia utilizing a volatile agent known to sensitize the myocardium to catecholamines, administration of doxapram should be delayed until the volatile agent has been excreted in order to lessen the potential for arrhythmias, including ventricular tachycardia and ventricular fibrillation.

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 may be used as an adjunct to established supportive measures and resuscitative techniques.

In Chronic Obstructive Pulmonary Disease

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.

Adverse Reactions

Clinical Trials Experience

Adverse reactions reported coincident with the administration of DOPRAM (doxapram hydrochloride, USP) include:

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, hallucinations, headache, dizziness, hyperactivity, involuntary movements, muscle spasticity, muscle fasciculations, increased deep tendon reflexes, clonus, bilateral Babinski, and convulsions.

Respiratory

Dyspnea, cough, hyperventilation, tachypnea, laryngospasm, bronchospasm, hiccough, and rebound hypoventilation.

Cardiovascular

Phlebitis, variations in heart rate, lowered T-waves, arrhythmias (including ventricular tachycardia and ventricular fibrillation), 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.

Gastrointestinal

Nausea, vomiting, diarrhea, desire to defecate.

Genitourinary

Stimulation of urinary bladder with spontaneous voiding; urinary retention. Elevation of BUN and albuminuria.

Hemic and Lymphatic

Hemolysis with rapid infusion. 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.

Postmarketing Experience

There is limited information regarding Doxapram Postmarketing Experience in the drug label.

Drug Interactions

• Administration of doxapram to patients who are receiving sympathomimetic or monoamine oxidase inhibiting drugs may result in an additive pressor effect.
• In patients who have received neuromuscular blocking agents, doxapram may temporarily mask the residual effects of these drugs.
• In patients who have received general anesthesia utilizing a volatile agent known to sensitize the myocardium to catecholamines, administration of doxapram should be delayed until the volatile agent has been excreted in order to lessen the potential for arrhythmias, including ventricular tachycardia and ventricular fibrillation.
• There may be an interaction between doxapram and aminophylline and between doxapram and theophylline manifested by increased skeletal muscle activity, agitation, and hyperactivity.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): 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. Because 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.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Doxapram in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Doxapram during labor and delivery.

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 woman.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established. This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

Premature neonates given doxapram have developed hypertension, irritability, jitteriness, hyperglycemia, glucosuria, abdominal distension, increased gastric residuals, vomiting, bloody stools, necrotizing enterocolitis, erratic limb movements, excessive crying, disturbed sleep, premature eruption of teeth, and QT prolongation that has resulted in heart block. In premature neonates with risk factors such as a previous seizure, perinatal asphyxia, or intracerebral hemorrhage, seizures have occurred. In many instances, doxapram was administered following administration of xanthine derivatives such as caffeine, aminophylline or theophylline.

Geriatic Use

There is no FDA guidance on the use of Doxapram in geriatric settings.

Gender

There is no FDA guidance on the use of Doxapram with respect to specific gender populations.

Race

There is no FDA guidance on the use of Doxapram with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Doxapram in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Doxapram in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Doxapram in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Doxapram in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Doxapram Administration in the drug label.

Monitoring

There is limited information regarding Doxapram Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Doxapram and IV administrations.

Overdosage

Signs and Symptoms

Symptoms of overdosage are extensions of the pharmacologic effects of the drug. Excessive pressor effect, such as hypertension, 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.

Other effects may include agitation, confusion, sweating, cough, and dyspnea.

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 75 mg/kg and in the cat and dog were 40 to 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. Anticonvulsants, along with 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 or hypoventilation.

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.

Pharmacology

Mechanism of Action

There is limited information regarding Doxapram Mechanism of Action in the drug label.

Structure

Doxapram hydrochloride is a white to off-white, crystalline powder, sparingly soluble in water, alcohol and chloroform. Chemically, doxapram hydrochloride is 1-ethyl-4-2-(4-morpholinyl)ethyl-3,3-diphenyl-2-pyrrolidinone monohydrochloride, monohydrate.

The chemical structure is:

C24H31ClN2O2 • H2O M.W. 432.98

Pharmacodynamics

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 to 40 seconds with peak effect at 1 to 2 minutes. The duration of effect may vary from 5 to 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 state than in normovolemic state. 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.

Pharmacokinetics

Doxapram is metabolized via ring hydroxylation to ketodoxapram, an active metabolite readily detected in the plasma.

Nonclinical Toxicology

There is limited information regarding Doxapram Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Doxapram Clinical Studies in the drug label.

How Supplied

There is limited information regarding Doxapram How Supplied in the drug label.

Storage

There is limited information regarding Doxapram Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Doxapram Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Doxapram interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Doxapram Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Doxapram Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Doxapram

Clinical data
Routes of administration	Intravenous
ATC code	R07AB01 (WHO)
Identifiers
IUPAC name 1-ethyl-4- (2-morpholin-4-ylethyl)- 3,3-diphenyl-pyrrolidin-2-one
CAS Number	309-29-5
PubChem CID	3156
DrugBank	APRD00935
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C24H30N2O2
Molar mass	378.507 g/mol

Doxapram hydrochloride (marketed as Dopram®) is a respiratory stimulant. Administered intravenously, doxapram stimulates the respiratory rate, leading to an increase in tidal volume.

Mode of action

Doxapram stimulates chemoreceptors in the carotid arteries, which in turn, stimulates the respiratory centre in the brain stem.

Presentation

Doxapram is a white to off-white, odorless, crystalline powder that is stable in light and air. It is soluble in water, sparingly soluble in alcohol and practically insoluble in ether. Injectable products have a pH from 3.5-5. Benzyl alcohol or chlorobutanol is added as a preservative agent in the commercially available injections.

Uses

Doxapram is used in intensive care settings to stimulate the respiratory rate in patients with respiratory failure.

It is equally effective as pethidine in suppressing shivering after surgery.

Side effects

High blood pressure, panic attacks, tachycardia (rapid heart rate), tremor, sweating and vomiting may occur. Convulsions have been reported. It cannot be used in patients with coronary heart disease, epilepsy and high blood pressure. It is also contraindicated in newborns and small children, mainly due to the presence of benzyl alcohol.