Introduction

CNS stimulant; a monohydrated pyrrolidinone derivative.

Uses for Doxapram

Postanesthetic Respiratory Depression

Treatment of drug-induced postanesthetic respiratory depression or apnea not caused by skeletal muscle relaxants.

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

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).

However, use as an analeptic is strongly discouraged by most clinicians; 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).

Acute Hypercapnia Associated with COPD

Short-term use in patients with acute respiratory insufficiency associated with COPD.

Role in such patients is limited; other supportive therapy (i.e., noninvasive ventilation using either negative- or positive-pressure device) is preferred.

Neonatal Apnea

Has been used for the treatment of neonatal apnea^{† [off-label]}, principally in combination with theophylline or caffeine.

Limited support for this use; no apparent advantage over methylxanthines and risk of substantial adverse effects with doxapram therapy. The commercially available injection contains benzyl alcohol; use of this preparation in neonates is not recommended. (See Pediatric Use under Cautions.)

Other Uses

Should not be used in conjunction with mechanical ventilation.

Doxapram Dosage and Administration

General

• Establish adequate airway and oxygenation prior to administration; take measures to prevent vomiting and aspiration.

• Use minimum effective dosage to avoid adverse effects.

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

Administration

IV Administration

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

Administer by IV injection or IV infusion.

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

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

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.

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.

Rate of Administration

Rapid infusion may result in hemolysis; infuse diluted solution at slow rate.

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.

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.

Dosage

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

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.

IV Infusion

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

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. Continuation beyond a single 2-hour infusion not recommended.

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.

IV Infusion

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

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. Continuation beyond a single 2-hour infusion not recommended.

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.

IV Infusion

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

Acute Hypercapnia Associated with COPD

IV Infusion

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

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.

IV Infusion

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

Acute Hypercapnia Associated with COPD

IV Infusion

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

Special Populations

No special population dosage recommendations at this time.

Contraindications

• Known hypersensitivity to doxapram or any ingredient in the formulation.

• Seizure disorders.

• Suspected or confirmed pulmonary embolism.

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

• Head injury, cerebrovascular accident, or cerebral edema.

• Substantial cardiovascular impairment (i.e., uncompensated heart failure, severe CAD).

• Severe hypertension including that associated with hyperthyroidism or pheochromocytoma. (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. Use of this preparation in neonates is not recommended. (See Pediatric Use under Cautions.)

Mechanical Ventilation

Do notuse doxapram in conjunction with mechanical ventilation.

Postanesthetic Use

Doxapram is not an antagonist to muscle relaxants nor a specific opiate antagonist. 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.

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

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

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

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.

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

COPD

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

Arrhythmias have been reported in patients with acute respiratory failure secondary to COPD. Use with caution in these patients.

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

Use does not reduce need for supplemental oxygen.

General Precautions

Cardiovascular Effects

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

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

Chest pain and tightness in chest also reported.

Discontinue drug if sudden hypotension develops.

Respiratory Effects

Establish and protect airways.

Discontinue drug if sudden dyspnea develops.

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

CNS Effects

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

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.

Hemolysis

Rapid infusion may result in hemolysis. (See Rate of Administration under Dosage and Administration.)

Specific Populations

Pregnancy

Category B.

Lactation

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

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

Pediatric Use

Safety and efficacy not established in children <12 years of age.

Each mL of doxapram hydrochloride injection contains 9 mg of benzyl alcohol; use of this preparation in neonates is not recommended. 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.

Hepatic Impairment

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

Renal Impairment

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

Common Adverse Effects

Cough, dyspnea, tachypnea, headache, dizziness, apprehension, hypertension, flushing, sweating, nausea, vomiting, diarrhea, urinary retention, muscle spasticity.

General

• Establish adequate airway and oxygenation prior to administration; take measures to prevent vomiting and aspiration.

• Use minimum effective dosage to avoid adverse effects.

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

Administration

IV Administration

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

Administer by IV injection or IV infusion.

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

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

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.

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.

Rate of Administration

Rapid infusion may result in hemolysis; infuse diluted solution at slow rate.

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.

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.

Dosage

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

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.

IV Infusion

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

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. Continuation beyond a single 2-hour infusion not recommended.

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.

IV Infusion

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

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. Continuation beyond a single 2-hour infusion not recommended.

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.

IV Infusion

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

Acute Hypercapnia Associated with COPD

IV Infusion

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

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.

IV Infusion

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

Acute Hypercapnia Associated with COPD

IV Infusion

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

Special Populations

No special population dosage recommendations at this time.

Specific Drugs