Doxapram

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous, as hydrochloride:

Dopram: 20 mg/mL (20 mL) [contains benzyl alcohol]

Pharmacology

Mechanism of Action

Stimulates respiration through action on peripheral carotid chemoreceptors; respiratory center in medulla is also directly stimulated as dosage is increased

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: Neonates: 4 to 7.3 L/kg

Metabolism

Extensive in the liver to active metabolite (keto-doxapram)

Excretion

Clearance: Neonates, premature: 0.44 to 0.7 L/hour/kg

Onset of Action

Respiratory stimulation: Single IV injection: 20 to 40 seconds; Peak effect: Single IV injection: 1 to 2 minutes

Duration of Action

Single IV injection: 5 to 12 minutes

Half-Life Elimination

Serum: Neonates, premature: 6.6 to 12 hours; Adults: Mean: 3.4 hours (range: 2.4 to 4.1 hours)

Use: Labeled Indications

Respiratory stimulant for respiratory depression secondary to anesthesia, mild-to-moderate drug-induced respiratory and CNS depression; acute hypercapnia secondary to COPD

Note: In general, the use of doxapram as a respiratory stimulant in adults is limited; alternate therapies are preferred.

Contraindications

Hypersensitivity to doxapram or any component of the formulation; significant cardiovascular impairment (eg, uncompensated heart failure, severe coronary artery disease); severe hypertension (including severe hypertension associated with hyperthyroidism or pheochromocytoma); cerebral edema, cerebral vascular accident, epilepsy or other convulsive disorders, head injury; mechanical disorders of ventilation (eg, mechanical obstruction, muscle paresis, neuromuscular blockade, flail chest, pneumothorax, acute asthma, pulmonary fibrosis), pulmonary embolism (proven or suspected)

Dosage and Administration

Dosing: Adult

Note: Although manufacturer's dosing recommendations are presented for these FDA-approved indications, use of doxapram has largely been replaced by alternate preferred agents.

Respiratory depression following anesthesia: IV:

Intermittent injection: Initial: 0.5 to 1 mg/kg; may repeat at 5-minute intervals (only in patients who demonstrate initial response); maximum single injection dose: 1.5 mg/kg; maximum total dose: 2 mg/kg

IV infusion: Initial: 5 mg/minute until adequate response or adverse effects seen; decrease to 1 to 3 mg/minute; maximum total dose: 4 mg/kg

Drug-induced CNS depression: IV:

Intermittent injection: Initial: Priming dose of 1 to 2 mg/kg; repeat after 5 minutes (only in patients who demonstrate initial response); may repeat at 1 to 2 hour intervals (until sustained consciousness); maximum: 3000 mg/day. May repeat in 24 hours if necessary.

IV infusion: Initial: Priming dose of 1 to 2 mg/kg repeated in 5 minutes. If no response, wait 1 to 2 hours and repeat priming dose. If some stimulation is noted, initiate infusion at 1 to 3 mg/minute (depending on size of patient/depth of CNS depression); suspend infusion if patient begins to awaken. Infusion should not be continued for >2 hours. May reinstitute infusion as described above, including bolus, after rest interval of 30 minutes to 2 hours; maximum: 3000 mg/day.

Acute hypercapnia secondary to COPD: IV infusion: Initial: Initiate infusion at 1 to 2 mg/minute (depending on size of patient/depth of CNS depression); may increase to maximum rate of 3 mg/minute; infusion should not be continued for >2 hours. Additional infusions are not recommended (per manufacturer).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Although manufacturer's dosing recommendations are presented for these FDA-approved indications, use of doxapram has largely been replaced by alternate preferred agents.

Drug-induced CNS depression: Children ≥12 years and Adolescents:

IV: Initial: Priming dose of 1 to 2 mg/kg; repeat after 5 minutes; may repeat at 1 to 2 hour intervals (until sustained consciousness); if relapse occurs may resume repeat doses at 1 to 2 hour intervals until sustained consciousness or maximum dose reached; maximum daily dose: 3,000 mg/day. May repeat in 24 hours if necessary; repeat doses should only be given to patient who demonstrated a response to initial dose.

IV infusion: Initial: Priming dose of 1 to 2 mg/kg repeated in 5 minutes. If no response, wait 1 to 2 hours and repeat priming dose. If some stimulation is noted, initiate infusion at 1 to 3 mg/minute (depending on size of patient/depth of CNS depression); suspend infusion if patient begins to awaken. Infusion should not be continued for >2 hours. May reinstitute infusion as described above, including bolus, after rest interval of 30 minutes to 2 hours; maximum daily dose: 3,000 mg/day.

Respiratory depression following anesthesia: Children ≥12 years and Adolescents:

IV: Initial: 0.5 to 1 mg/kg; may repeat at 5-minute intervals; maximum total dose: 2 mg/kg

Continuous IV infusion: Initial: 5 mg/minute until adequate response or adverse effects seen; decrease to 1 to 3 mg/minute; maximum total dose: 4 mg/kg (in an average adult, ~300 mg total dose)

Reconstitution

To prepare an IV infusion:

Drug-induced CNS depression or postanesthesia: Mix doxapram 250 mg in 250 mL of D₅W, D₁₀W, or NS.

COPD-associated hypercapnia: Mix doxapram 400 mg in 180 mL of D₅W, D₁₀W, or NS (final concentration: 2 mg/mL).

Administration

IV: Administer IV as an intermittent bolus or as an IV infusion. Avoid rapid infusion. Avoid extravasation.

Storage

Store intact vials at 20°C to 25°C (68°F to 77°F).

Drug Interactions

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. Monitor therapy

Cocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Consider therapy modification

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Monitor therapy

Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Monitor therapy

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Consider therapy modification

Monoamine Oxidase Inhibitors: May enhance the hypertensive effect of Doxapram. Monitor therapy

Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Monitor therapy

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Monitor therapy

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Adverse Reactions

Frequency not defined.

Cardiovascular: Cardiac arrhythmia, change in pulse, chest pain, chest tightness, flattened T wave on ECG, flushing, increased blood pressure, phlebitis, ventricular fibrillation, ventricular tachycardia

Central nervous system: Apprehension, clonus, disorientation, dizziness, hallucination, headache, hyperactivity, hyperreflexia, involuntary muscle movements, paresthesia, positive Babinski sign, seizure

Dermatologic: Burning sensation of skin, diaphoresis, pruritus

Endocrine & metabolic: Albuminuria

Gastrointestinal: Bowel urgency, diarrhea, hiccups, nausea, vomiting

Genitourinary: Urinary incontinence, urinary retention

Hematologic & oncologic: Decreased hematocrit, decreased hemoglobin, hemolysis, decreased red blood cells

Neuromuscular & skeletal: Fasciculations, laryngospasm, muscle spasm

Ophthalmic: Mydriasis

Renal: Increased blood urea nitrogen

Respiratory: Bronchospasm, cough, dyspnea, hyperventilation, hypoventilation (rebound), tachypnea

Miscellaneous: Fever

<1%, postmarketing, and/or case reports: Agitation (emergence), prolonged Q-T interval on ECG (premature neonates), second degree atrioventricular block (premature neonates)

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: May cause dysrhythmias; monitor for disturbances of cardiac rhythm. If sudden hypotension develops during use, discontinue. Increases in blood pressure are generally modest; use is contraindicated in patients with severe hypertension.
• CNS stimulation: May cause severe CNS stimulation, including seizures; anticonvulsants (as well as oxygen and resuscitative equipment) should be available to manage potential excessive CNS stimulation.

Disease-related concerns:

• Cerebrovascular disease: Use with caution in patients with cerebrovascular disease; lowered pCO₂ induced by hyperventilation produces cerebral vasoconstriction and decreased circulation.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment.
• Respiratory disease: Do not use in patients on mechanical ventilation. Use with caution in treating pulmonary disease; a pressor effect on pulmonary circulation may result in a fall in arterial pO₂. If sudden dyspnea develops during use, discontinue. Doxapram causes patients to increase the work of breathing; therefore, do not increase the rate of infusion in an attempt to lower the pCO₂ in severely-ill COPD patients.

Concurrent drug therapy issues:

• MAO inhibitors (MAOIs): Use caution with coadministration; additive pressor effect may occur.
• Sympathomimetics: Use caution with coadministration; additive pressor effect may occur.
• Volatile anesthetics: If patient has received anesthesia with a volatile agent known to sensitize the myocardium to catecholamines, avoid use of doxapram until anesthetic has been eliminated to decrease the risk of ventricular tachycardia or ventricular fibrillation.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

Other warnings/precautions:

• Administration: Avoid extravasation; doxapram may cause thrombophlebitis or local skin irritation. Hemolysis may result from rapid infusion.
• Appropriate use: Adequate airway required prior to use; consider airway protection in case of vomiting. Resuscitative equipment (in addition to anticonvulsants and oxygen) should be readily available; doxapram alone may not be sufficient to stimulate spontaneous breathing or provide sufficient arousal. Doxapram is neither an antagonist to skeletal muscle relaxants nor an opioid antagonist. Use with caution in patients with hypermetabolic states (eg, hyperthyroidism, pheochromocytoma).

Monitoring Parameters

Heart rate, blood pressure, deep tendon reflexes, CNS status, ECG, arterial blood gases (COPD; prior to infusion initiation and at 30-minute intervals during infusion)

Pregnancy

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.