Apnea of prematurity, refractory: Limited data available: Note: Typically considered third-line agent.
Preterm neonates:
Loading dose: IV: 2.5 to 3 mg/kg (Ref).
Maintenance dose: Continuous IV infusion: Initial: 0.5 to 1.5 mg/kg/hour; increase in increments of 0.5 mg/kg/hour as needed to control apnea up to a maximum rate of 2.5 mg/kg/hour; once stable titrate to the lowest rate at which apnea is controlled; assess benzyl alcohol exposure particularly with higher doses or continued use (Ref).
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manufacturer's dosing recommendations are presented for these FDA-approved indications, use of doxapram has largely been replaced by alternate preferred agents.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:
Intermittent injection: 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; repeat after 5 minutes. If no response, wait 1 to 2 hours and repeat priming dose. If some respiratory 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:
Intermittent injection: Initial: 0.5 to 1 mg/kg; may repeat at 5-minute intervals; maximum single injection dose: 1.5 mg/kg; 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).
There are no dosage adjustments provided in manufacturer's labeling (has not been studied); however, use caution in severe impairment due to the potential for altered pharmacokinetics.
There are no dosage adjustments provided in manufacturer's labeling (has not been studied); however, use caution in severe impairment due to the potential for altered pharmacokinetics.
(For additional information see "Doxapram: Drug information")
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 chronic obstructive pulmonary disease: 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).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, use caution in severe impairment due to the potential for altered pharmacokinetics.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, use caution in severe impairment due to the potential for altered pharmacokinetics.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. 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 QT interval on ECG (premature neonates), second degree atrioventricular block (premature neonates)
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)
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; antiseizure medications (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 antiseizure medications 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).
Recommended doses of doxapram for treatment of neonatal apnea will deliver 5.4 to 27 mg/kg/day of benzyl alcohol; the use of doxapram should be reserved for neonates who are unresponsive to the treatment of apnea with therapeutic serum concentrations of theophylline or caffeine; monitor benzyl alcohol exposure, particularly with prolonged therapy or high doses.
Possible adverse effects on mental development (based on developmental scales and index scoring) have been reported in former premature neonates (Lando 2005, Sreenan 2001). A case-controlled trial of 80 children who weighed <1,250 g at birth (mean GA: ~26.5 weeks, corrected age at assessment: 18 months) reported a significant correlation between isolated adverse mental development and total cumulative dose of doxapram (mean: 2,233 mg [cases] vs 615 mg [controls]) and duration of therapy (mean: 45.2 days [cases] vs 19.4 days [controls]) (Sreenan 2001). Another report of 88 former premature neonates (GA <28 weeks) showed an association between doxapram therapy and lower developmental scores later in infancy and early childhood (age at assessment was 9 to 15 months corrected age) (Lando 2005).
Use with caution in premature neonates and infants; hypertension (dose related), irritability, jitteriness, erratic limb movements, excessive crying, sleep disturbances, abdominal distention, vomiting, necrotizing enterocolitis, increased gastric residuals, bloody stools, hyperglycemia, glycosuria, premature eruption of teeth, and QT prolongation resulting in heart block have been reported. Seizures have been reported in premature neonates who have additional seizure risk factors including a history of seizures, perinatal asphyxia, intracerebral hemorrhage or recent aminophylline, theophylline, or caffeine exposure.
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]
No
Solution (Dopram Intravenous)
20 mg/mL (per mL): $3.19
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Parenteral: IV: Administer as an intermittent bolus or as an IV infusion. Loading doses for apnea of prematurity have been infused over 15 minutes (Ref). Avoid rapid infusion. Avoid extravasation; irritating to tissues.
IV: Administer IV as an intermittent bolus or as an IV infusion. Avoid rapid infusion. Avoid extravasation.
Store intact vials at 20°C to 25°C (68°F to 77°F).
Respiratory stimulant for respiratory depression secondary to anesthesia, mild to moderate drug-induced respiratory and CNS depression, and acute hypercapnia secondary to chronic obstructive pulmonary disease (COPD) (FDA approved in ages ≥12 years and adults); has also been used to treat apnea of prematurity refractory to methylxanthine therapy.
Doxapram may be confused with doxazosin, doxepin, DOXOrubicin
Dopram® may be confused with DOPamine
Doxapram may be confused with Doxinate brand name for doxylamine and pyridoxine [Italy]
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Risk C: 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. Risk D: Consider therapy modification
Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Risk C: Monitor therapy
Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy
Kratom: May enhance the adverse/toxic effect of Sympathomimetics. Risk X: Avoid combination
Levothyroxine: May enhance the adverse/toxic effect of Sympathomimetics. Specifically, the risk of coronary insufficiency may be increased in patients with coronary artery disease. Levothyroxine may enhance the therapeutic effect of Sympathomimetics. Sympathomimetics may enhance the therapeutic effect of Levothyroxine. Risk C: Monitor therapy
Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Consider initial dose reductions of sympathomimetic agents, and closely monitor for enhanced blood pressure elevations, in patients receiving linezolid. Risk D: Consider therapy modification
Monoamine Oxidase Inhibitors: May enhance the hypertensive effect of Doxapram. Risk C: Monitor therapy
Ozanimod: May enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy
Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Sympathomimetics may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy
Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Adverse events have not been observed in animal reproduction studies.
Pulse oximetry, blood pressure, heart rate, ECG, arterial blood gases, deep tendon reflexes.
Apnea of prematurity: Data suggest a therapeutic serum concentration of at least 1.5 mg/L; toxicity becomes frequent at serum concentrations >4 to 5 mg/L (Barbé 1999; Barrington 1987).
Stimulates respiration through action on peripheral carotid chemoreceptors; respiratory center in medulla is also directly stimulated as dosage is increased
Onset of action: Respiratory stimulation: Single IV injection: 20 to 40 seconds.
Peak effect: Single IV injection: 1 to 2 minutes.
Duration: Single IV injection: 5 to 12 minutes.
Distribution: Vd: Neonates (GA: 24 to 32 weeks; PNA: 6 to 60 days): 7.33 ± 4.55 L/kg (Jamali 1988).
Metabolism: Extensive in the liver to active metabolite (keto-doxapram).
Half-life elimination, serum:
Neonates (GA: 24 to 32 weeks; PNA: 6 to 60 days): 8.17 ± 4.13 hours (Jamali 1988).
Adults: Mean: 3.4 hours (range: 2.4 to 4.1 hours) (Robson 1979).
Clearance: Neonates (GA: 24 to 32 weeks; PNA: 6 to 60 days): 0.7 ± 0.49 L/hour/kg (Jamali 1998).
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