Doxapram (Monograph)

Brand name: Dopram
Drug class: Respiratory and CNS Stimulants
VA class: RE900
CAS number: 7081-53-0

Medically reviewed by Drugs.com on Nov 10, 2023. Written by ASHP.

Introduction

CNS stimulant; a monohydrated pyrrolidinone derivative.^{128 a}

Uses for Doxapram

Postanesthetic Respiratory Depression

Treatment of drug-induced postanesthetic respiratory depression or apnea not caused by skeletal muscle relaxants.^{127 a}

Other supportive therapy preferred due to questionable benefit and high potential for toxicity with doxapram.^a Limited role due to availability of safer and shorter-acting anesthetic agents.¹²⁸

Drug-induced CNS Depression

Has been used in conjunction with supportive measures to stimulate respiration and hasten arousal in patients with respiratory and CNS depression secondary to drug overdose (e.g., barbiturates, opiate analgesics, general anesthetics).^{127 a}

However, use as an analeptic is strongly discouraged by most clinicians;^a analeptic therapy largely abandoned in favor of intensive supportive care (e.g., mechanical ventilation, oxygenation, cardiovascular support) and specific antidotes (e.g., pure opiate antagonists).^{135 a}

Acute Hypercapnia Associated with COPD

Short-term use in patients with acute respiratory insufficiency associated with COPD.^{127 a}

Role in such patients is limited; other supportive therapy (i.e., noninvasive ventilation using either negative- or positive-pressure device) is preferred.^{132 133 134 a}

Neonatal Apnea

Has been used for the treatment of neonatal apnea^{† [off-label]},^{100 101 102 103 104 105 106 107 108 120 121 123 124 125} principally in combination with theophylline^{104 105 106 120} or caffeine.¹⁰⁷

Limited support for this use; no apparent advantage over methylxanthines and risk of substantial adverse effects with doxapram therapy.^{128 130 131} The commercially available injection contains benzyl alcohol; use of this preparation in neonates is not recommended.^{110 117 118 120 127 136} (See Pediatric Use under Cautions.)

Other Uses

Should not be used in conjunction with mechanical ventilation.¹²⁷

Doxapram Dosage and Administration

General

• Establish adequate airway and oxygenation prior to administration; take measures to prevent vomiting and aspiration.^{127 a}

• Use minimum effective dosage to avoid adverse effects.^{127 a}

• Monitor BP, heart rate, and deep tendon reflexes; adjust dosage or rate of infusion accordingly.¹²⁷ Monitor for recurrence of unconsciousness or development of respiratory depression; provide supportive care as required.¹²⁷

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV injection or IV infusion.^{127 a}

Predictable blood gas patterns in patients with COPD and acute hypercapnia are more readily established with IV infusion therapy.¹²⁷

Avoid extravasation and repeated use of a single injection site to minimize local reactions and thrombophlebitis.^{127 a}

Dilution

Prepare 1-mg/mL solution by adding 250 mg of doxapram hydrochloride (12.5 mL) to 250 mL of 5% dextrose, 10% dextrose, or 0.9% sodium chloride injection.¹²⁷

Prepare 2-mg/mL solution by adding 400 mg of doxapram hydrochloride (20 mL) to 180 mL of 5% dextrose, 10% dextrose, or 0.9% sodium chloride injection.¹²⁷

Rate of Administration

Rapid infusion may result in hemolysis; infuse diluted solution at slow rate.^{127 a}

Postanesthetic use: Initiate IV infusion with 1-mg/mL solution at a rate of approximately 5 mg/minute until desired response achieved; usual maintenance rate is 1–3 mg/minute.¹²⁷

Acute hypercapnia associated with COPD: Initiate IV infusion with 2-mg/mL solution at a rate of 1–2 mg/minute; may increase to maximum rate of 3 mg/minute.¹²⁷

Dosage

Available as doxapram hydrochloride; dosage expressed in terms of the salt.¹²⁷

Pediatric Patients

Postanesthetic Respiratory Depression

IV Injection

Children ≥12 years of age: 0.5–1 mg/kg as a single injection; may repeat every 5 minutes to a maximum total dosage of 2 mg/kg.¹²⁷

IV Infusion

Children ≥12 years of age: 0.5–1 mg/kg, up to a maximum dosage of 4 mg/kg.¹²⁷

Acute Hypercapnia Associated with COPD

IV Infusion

Children ≥12 years of age: Initiate at a rate of 1–2 mg/minute; increase to a maximum rate of 3 mg/minute if indicated.¹²⁷ Continuation beyond a single 2-hour infusion not recommended.^{127 a}

Adults

Postanesthetic Respiratory Depression

IV Injection

0.5–1 mg/kg as a single injection; may repeat every 5 minutes to a maximum total dosage of 2 mg/kg.¹²⁷

IV Infusion

0.5–1 mg/kg, up to a maximum dosage of 4 mg/kg.¹²⁷

Acute Hypercapnia Associated with COPD

IV Infusion

Initiate at a rate of 1–2 mg/minute; increase to a maximum rate of 3 mg/minute if indicated.¹²⁷ Continuation beyond a single 2-hour infusion not recommended.^{127 a}

Prescribing Limits

Pediatric Patients

Postanesthetic Respiratory Depression

IV Injection

Children ≥12 years of age: Maximum 1.5 mg/kg for a single injection, 2-mg/kg total dosage for repeat injections; do not exceed 3 g daily.¹²⁷

IV Infusion

Children ≥12 years of age: Maximum 4 mg/kg; do not exceed 3 g daily.¹²⁷

Acute Hypercapnia Associated with COPD

IV Infusion

Children ≥12 years of age: Maximum 3 mg/minute.¹²⁷ Limit use to a single 2-hour infusion.¹²⁷

Adults

Postanesthetic Respiratory Depression

IV Injection

Maximum 1.5 mg/kg for a single injection, 2-mg/kg total dosage for repeat injections; do not exceed 3 g daily.¹²⁷

IV Infusion

Maximum 4 mg/kg; do not exceed 3 g daily.¹²⁷

Acute Hypercapnia Associated with COPD

IV Infusion

Maximum 3 mg/minute.¹²⁷ Limit use to a single 2-hour infusion.¹²⁷

Special Populations

No special population dosage recommendations at this time.¹²⁷

Cautions for Doxapram

Contraindications

• Known hypersensitivity to doxapram or any ingredient in the formulation.^{127 a}

• Seizure disorders.^{127 a}

• Suspected or confirmed pulmonary embolism.^{127 a}

• Mechanical disorders of ventilation (e.g., mechanical obstruction, muscle paresis, flail chest, pneumothorax, acute bronchial asthma, pulmonary fibrosis or other restrictive lung diseases).^{127 a}

• Head injury, cerebrovascular accident, or cerebral edema.^{127 a}

• Substantial cardiovascular impairment (i.e., uncompensated heart failure, severe CAD).^{127 a}

• Severe hypertension including that associated with hyperthyroidism or pheochromocytoma.^{127 a} (See Postanesthetic Use under Cautions.)

Warnings/Precautions

Warnings

Benzyl Alcohol in Neonates

Doxapram hydrochloride injection contains benzyl alcohol as a preservative, which has been associated with toxicity (including deaths) in neonates.^{109 110 111 112 113 114 115 116 117 122 127} Use of this preparation in neonates is not recommended.^{110 117 118 120 127} (See Pediatric Use under Cautions.)

Mechanical Ventilation

Do notuse doxapram in conjunction with mechanical ventilation.^{127 a}

Postanesthetic Use

Doxapram is not an antagonist to muscle relaxants nor a specific opiate antagonist.¹²⁷ Assess adequacy of ventilation with specific tests (e.g., peripheral nerve stimulation, airway pressures, head lift, pulse oximetry, end-tidal carbon dioxide) prior to use.¹²⁷

Narcosis may recur; observe patient closely until fully alert for 0.5–1 hour.¹²⁷

Concomitant use with a volatile general anesthetic may increase potential for arrhythmias.¹²⁷ (See Specific Drugs under Interactions.)

Use with caution in patients with hypermetabolic states (e.g., hyperthyroidism, pheochromocytoma).¹²⁷

Drug-Induced CNS and Respiratory Depression

May not be effective in patients with severe CNS or respiratory depression; manufacturers state that doxapram may be used adjunctively with established supportive and resuscitative measures.¹²⁷

If no response, perform neurologic evaluation to identify other potential causes of sustained coma.¹²⁷

COPD

Do not increase rate of infusion to lower carbon dioxide tension.¹²⁷

Arrhythmias have been reported in patients with acute respiratory failure secondary to COPD.^{127 a} Use with caution in these patients.¹²⁷

To prevent respiratory acidosis in patients with COPD, monitor arterial blood gases at baseline and every 30 minutes. ¹²⁷ Discontinue drug and initiate mechanical ventilation if arterial blood gases deteriorate.¹²⁷

Use does not reduce need for supplemental oxygen.¹²⁷

General Precautions

Cardiovascular Effects

Possible changes in heart rate, lowered T-waves, and dysrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, QT interval prolongation).^{127 128 a} Use with caution and monitor cardiac rhythm.^{127 a}

Increases in BP usually are modest, but substantial increases reported.¹²⁷ Avoid use in patients with severe hypertension.¹²⁷ (See Contraindications under Cautions.)

Chest pain and tightness in chest also reported.^{127 a}

Discontinue drug if sudden hypotension develops.^{127 a}

Respiratory Effects

Establish and protect airways.¹²⁷

Discontinue drug if sudden dyspnea develops.¹²⁷

Lowered carbon dioxide tension induced by hyperventilation may cause cerebral vasoconstriction and decreased cerebral circulation.^{127 a} Pressor effect on pulmonary circulation may lead to decreased arterial oxygen tension.¹²⁷ Monitor arterial blood gases.¹²⁷

CNS Effects

May cause seizures and other adverse effects due to general CNS stimulation.^{127 a} Anticonvulsants, oxygen, and resuscitative equipment should be readily available; carefully observe patient and administer drug slowly if treatment continued.¹²⁷

Local Effects

Potential for local reactions including thrombophlebitis; administer dilute solutions at a slow rate, prevent extravasation, and avoid repeated use of a single injection site.^{127 a}

Hemolysis

Rapid infusion may result in hemolysis.^{127 a} (See Rate of Administration under Dosage and Administration.)

Specific Populations

Pregnancy

Category B.^{127 129}

Lactation

Not known whether doxapram is distributed into milk;¹²⁷ however, molecular weight of free base suggests drug may be distributed into milk.¹²⁹

Benzyl alcohol in commercial preparation is associated with toxicity in neonates; caution if used in nursing women.¹²⁷ (See Pediatric Use under Cautions.)

Pediatric Use

Safety and efficacy not established in children <12 years of age.^{127 a}

Each mL of doxapram hydrochloride injection contains 9 mg of benzyl alcohol;¹⁰⁹ use of this preparation in neonates is not recommended.^{110 117 118 120 127} Although a causal relationship has not been established, large amounts of benzyl alcohol (100–400 mg/kg daily) have been associated with toxicity in neonates.^{109 110 111 112 113 114 115 116 117 122 127}

Hepatic Impairment

Use with caution.¹²⁷ Possible decrease in rate of metabolism or clearance in patients with substantial hepatic impairment.¹²⁷

Renal Impairment

Use with caution.¹²⁷ Possible decrease in rate of metabolism or clearance in patients with substantial renal impairment.¹²⁷

Common Adverse Effects

Cough,^{127 128} dyspnea,^{127 128} tachypnea,^{127 128} headache,^{127 128} dizziness,^{127 128} apprehension,^{127 128} hypertension,^{127 128} flushing,^{127 128} sweating,^{127 128} nausea,^{127 128} vomiting,^{127 128} diarrhea,^{127 128} urinary retention,^{127 128} muscle spasticity.^{127 128}

Drug Interactions

Specific Drugs

Doxapram Pharmacokinetics

Absorption

Onset

Following single IV injection, onset of respiratory stimulation occurs within 20–40 seconds and peaks at 1–2 minutes.¹²⁷

Duration

Duration of respiratory stimulation may vary from 5–12 minutes following single IV injection.¹²⁷

Distribution

Extent

Doxapram and its metabolites are generally well distributed into tissues in animals.^a

Elimination

Metabolism

Rapidly metabolized following single IV dose.^{128 a} Undergoes hydroxylation to ketodoxapram, an active metabolite.¹³⁶

Elimination Route

Excreted mainly in urine and feces as metabolites within 24–48 hours following administration;^{128 a} following single IV dose, 40–50% of dose recovered in urine as metabolites;¹²⁸ small amounts of metabolites may continue to be excreted for up to 120 hours.^a

Half-life

Elimination half-life approximately 6.6–9.9 hours in premature neonates receiving IV infusions of doxapram.^{124 125 126}

Stability

Storage

Parenteral

Injection

20–25°C.¹²⁷

Compatibility

Parenteral

Incompatible with strongly alkaline drugs or solutions.^{127 a}

Solution Compatibility127 137

Drug Compatibility

Actions

• Stimulates peripheral carotid and aortic chemoreceptors and central respiratory centers in a dose-related manner.^{127 128 a} May cause tonic-clonic seizures with excessive CNS stimulation. ^a

• Transiently increases tidal volume with slight increase in respiratory rate.^{127 a}

• May elicit a pressor response due to improved cardiac output and increased release of catecholamines.¹²⁷ No direct effect on peripheral blood vessels.^a

• Does not antagonize the analgesic effects of opiates.¹²⁷

Advice to Patients

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, seizure disorders).¹²⁷

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.¹²⁷

• Importance of informing patients of other important precautionary information.¹²⁷ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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