Dopram

Generic Name: Doxapram Hydrochloride
Class: Respiratory and CNS Stimulants
VA Class: RE900
CAS Number: 7081-53-0

Introduction

CNS stimulant; a monohydrated pyrrolidinone derivative.128 a

Uses for Dopram

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

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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,100 101 102 103 104 105 106 107 108 120 121 123 124 125 principally in combination with theophylline104 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

Dopram 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 Dopram

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

Interactions for Dopram

Specific Drugs

Drug

Interaction

Comments

Anesthetics, inhalation (known to sensitize myocardium to catecholamines)

May increase potential for arrhythmias including ventricular tachycardia and ventricular fibrillation127 a

Increased BUN and albuminuria observeda

Delay administration of doxapram until anesthetic excreted127

Importance of observed increase in BUN and albuminuria not establisheda

CNS depressants

Increased BUN and albuminuria observeda

Importance not establisheda

MAO inhibitors

Possible synergistic pressor effect127 a

Use with caution127 a

Neuromuscular blocking agents

May temporarily mask residual effects of muscle relaxants127

Use with cautiona

Sympathomimetic agents

Possible synergistic pressor effect127 a

Use with caution127 a

Theophyllines (e.g., aminophylline)

Possible increased skeletal muscle activity, agitation, and hyperactivity127

Dopram 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

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Incompatible with strongly alkaline drugs or solutions.127 a

Solution Compatibility127 137

Compatible

Dextrose 5 or 10% in water

Sodium chloride 0.9%

Drug Compatibility
Admixture Compatibility127

Incompatible

Aminophylline

Furosemide

Sodium bicarbonate

Thiopental sodium

Ticarcillin

Y-Site Compatibility137

Compatible

Ampicillin sodium

Caffeine citrate

Calcium chloride

Calcium gluconate

Cefazolin sodium

Ceftazidime

Erythromycin lactobionate

Fentanyl citrate

Gentamicin sulfate

Heparin sodium

Metoclopramide HCl

Metronidazole

Oxacillin sodium

Phenobarbital sodium

Ranitidine HCl

Vancomycin HCl

Incompatible

Clindamycin phosphate

Drugs in Syringe Compatibility137

Compatible

Amikacin sulfate

Bumetanide

Chlorpromazine HCl

Cimetidine HCl

Cisplatin

Cyclophosphamide

Dopamine HCl

Doxycycline hyclate

Epinephrine HCl

Hydroxyzine HCl

Isoniazid

Lincomycin HCl

Methotrexate sodium

Phytonadione

Pyridoxine HCl

Terbutaline sulfate

Thiamine HCl

Tobramycin sulfate

Vincristine sulfate

Incompatible

Aminophylline

Ascorbic acid injection

Cefotaxime

Cefuroxime sodium

Dexamethasone sodium phosphate

Diazepam

Digoxin

Dobutamine HCl

Folic acid

Furosemide

Hydrocortisone sodium phosphate

Hydrocortisone sodium succinate

Ketamine HCl

Methylprednisolone sodium succinate

Thiopental sodium

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.

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

Doxapram Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

20 mg/mL*

Dopram (with benzyl alcohol 0.9%)

Baxter

Doxapram Hydrochloride Injection (with benzyl alcohol 0.9%)

Bedford

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 20, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

100. Burnard ED, Moore RG, Nichol H. A trial of doxapram in the recurrent apnea of prematurity. In: Stern L, Oh W, Friis-Hansen B, eds. Intensive care in the newborn. Vol. II. New York: Masson; 1978:143-8.

101. Alpan G, Eyal F, Sagi E et al. Doxapram in the treatment of idiopathic apnea of prematurity unresponsive to aminophylline. J Pediatr. 1984; 104:634-7. [IDIS 183784] [PubMed 6707826]

102. Hayakawa F, Hakamada S, Kuno K et al. Doxapram in the treatment of idiopathic apnea of prematurity: desirable dosage and serum concentrations. J Pediatr. 1986; 109:138-40. [IDIS 218527] [PubMed 3723234]

103. Barrington K, Torok-Both G, Finer N et al. Dose-response relationship of doxapram in refractory idiopathic apnea of prematurity. Am Rev Respir Dis. 1986; 133(Suppl):A105. [IDIS 213882] [PubMed 3963628]

104. Eyal F, Alpan G, Sagi E et al. Aminophylline versus doxapram in idiopathic apnea of prematurity: a double-blind controlled study. Pediatrics. 1985; 75:709-13. [IDIS 198191] [PubMed 3982903]

105. Sagi E, Eyal F, Alpan G et al. Idiopathic apnoea of prematurity treated with doxapram and aminophylline. Arch Dis Child. 1984; 59:281-3. [IDIS 184062] [PubMed 6424586]

106. Barrington KJ, Finer NN, Peters KL et al. Physiologic effects of doxapram in idiopathic apnea of prematurity. J Pediatr. 1986; 108:125-9.

107. Bairam A, Vert P. Low-dose doxapram for apnoea of prematurity. Lancet. 1986; 1:793-4. [IDIS 213923] [PubMed 2870280]

108. Martin RJ, Miller MJ, Carlo WA. Pathogenesis of apnea in preterm infants. J Pediatr. 1986; 109:733-41. [PubMed 3095518]

109. AH Robins Company. Dopram (doxapram hydrochloride) injection prescribing information. In: Huff BB, ed. Physicians’ desk reference. 43rd ed. Medical Economics Company Inc: Oradell, NJ; 1989:1693-5.

110. Food and Drug Administration. Parenteral drug products containing benzyl alcohol or other preservatives; intent and request for information. Notice of intent. [21 CFR Ch 1, Subchapter C; Docket No. 85N-0043] Fed Regist. 1985; 50:20233-5.

111. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356-8. [IDIS 175725] [PubMed 6889041]

112. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12(2):10-1.

113. Anon. Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982; 31:290-1. [IDIS 150868] [PubMed 6810084]

114. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982; 307:1384-8. [IDIS 160823] [PubMed 7133084]

115. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol. 1984; 1:288-92. [PubMed 6440575]

116. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol. 1984; 148:344-6. [IDIS 181207] [PubMed 6695984]

117. Jordan GD, Themelis NJ, Messerly SO et al. Doxapram and potential benzyl alcohol toxicity: a moratorium on clinical investigation? Pediatrics. 1986; 78:540-1. Letter. (IDIS 220422)

118. Jackson D. Doxapram and potential benzyl alcohol toxicity: a moratorium on clinical investigation? Pediatrics. 1986; 78:541. Reply. (IDIS 220423)

119. Cater G. Doxapram for apnea of prematurity. J Pediatr. 1987; 109:563.

120. Barrington KJ, Finer NN, Torok-Both G et al. Dose-response relationship of doxapram in the therapy for refractory idiopathic apnea of prematurity. Pediatrics. 1987; 80:22-7. [IDIS 231947] [PubMed 3110729]

121. Barrington KJ, Finer NN. Doxapram for apnea of prematurity. J Pediatr. 1987; 109:563.

122. Hiller JL, Benda GI, Rahatzad M et al. Benzyl alcohol toxicity: impact on mortality and intraventricular hemorrhage among very low birth weight infants. Pediatrics. 1986; 77:500-6. [IDIS 215931] [PubMed 3515306]

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137. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:574-76.

a. AHFS drug information 2007. McEvoy GK, ed. Doxapram hydrochloride. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2484-5.

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