ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Adverse reactions reported coincident with the administration of DOPRAM (doxapram hydrochloride, USP) include:1. Central and Autonomic Nervous SystemsPyrexia, flushing, sweating; pruritus and paresthesia, such as feeling of warmth, burning, or hot sensation, especially in the area of genitalia and perineum; apprehension, disorientation, pupillary dilatation, hallucinations, headache, dizziness, hyperactivity, involuntary movements, muscle spasticity, muscle fasciculations, increased deep tendon reflexes, clonus, bilateral Babinski, and convulsions.2. RespiratoryDyspnea, cough, hyperventilation, tachypnea, laryngospasm, bronchospasm, hiccough, and rebound hypoventilation.3. CardiovascularPhlebitis, variations in heart rate, lowered T-waves, arrhythmias (including ventricular tachycardia and ventricular fibrillation), chest pain, tightness in chest. mild to moderate increase in blood pressure is commonly noted and may be of concern in patients with severe cardiovascular diseases.4. GastrointestinalNausea, vomiting, diarrhea, desire to defecate.5. GenitourinaryStimulation of urinary bladder with spontaneous voiding; urinary retention. Elevation of BUN and albuminuria.6. Hemic and LymphaticHemolysis with rapid infusion. decrease in hemoglobin, hematocrit, or red blood cell count has been observed in postoperative patients. In the presence of pre-existing leukopenia, further decrease in WBC has been observed following anesthesia and treatment with doxapram hydrochloride.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE ADMINISTRATION. NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS) In Postanesthetic UseTable I. Dosage for postanesthetic use-I.V. and infusion. Dose not to exceed grams/24 hours. BY I.V. INJECTION(See Table I. Dosage for postanesthetic use--I.V.)The recommended dose for I.V. administration is 0.5 1 mg/kg for single injection and at 5-minute intervals. Careful observation of the patient during administration and for some time subsequently are advisable. The maximum total dosage by I.V. injection is mg/kg.BY INFUSIONThe solution is prepared by adding 250 mg of doxapram (12.5 mL) to 250 mL of dextrose 5% or 10% in water or normal saline solution. The infusion is initiated at rate of approximately mg/minute until satisfactory respiratory response is observed, and maintained at rate of to mg/minute. The rate of infusion should be adjusted to sustain the desired level of respiratory stimulation with minimum of side effects. The maximum total dosage by infusion is mg/kg, or approximately 300 mg for the average adult.In the Management of Drug-Induced CNS Depression(See Table II. Dosage for drug-induced CNS depression.)Table II. Dosage for drug-induced CNS depression. Mild Depression Class 0: Asleep, but can be aroused and can answer questions. Class 1: Comatose, will withdraw from painful stimuli, reflexes intact. Moderate Depression Class 2: Comatose, will not withdraw from painful stimuli, reflexes intact. Class 3: Comatose, reflexes absent, no depression of circulation or respiration. METHOD ONEUsing Single and/or Repeat Single I.V. InjectionsGive priming dose of mg/kg body weight and repeat in minutes. The priming dose for moderate depression is mg/kg and the priming dose for mild depression is mg/kg. Repeat same dose 1 to 2h until patient wakens. Watch for relapse into unconsciousness or development of respiratory depression, since DOPRAM does not affect the metabolism of CNS-depressant drugs. If relapse occurs, resume injections 1 to 2h until arousal is sustained, or total maximum daily dose (3 grams) is given. After maximum dose has been given (3 grams), allow patient to sleep until 24 hours have elapsed from first injection of DOPRAM, using assisted or automatic respiration if necessary. Repeat procedure the following day until patient breathes spontaneously and sustains desired level of consciousness, or until maximum dosage (3 grams) is given. Repetitive doses should be administered only to patients who have shown response to the initial dose. Failure to respond appropriately indicates the need for neurologic evaluation for possible central nervous system source of sustained coma. METHOD TWOBy Intermittent I.V. InfusionGive priming dose as in Method One. If patient wakens, watch for relapse; if no response, continue general supportive treatment for to hours and repeat priming dose of DOPRAM. If some respiratory stimulation occurs, prepare I.V. infusion by adding 250 mg of DOPRAM (12.5 mL) to 250 mL of saline or dextrose solution. Deliver at rate of to mg/min (60 to 180 mL/hr) according to size of patient and depth of coma. Discontinue DOPRAM if patient begins to waken or at end of hours. Continue supportive treatment for 1/2 to hours and repeat Step b. Do not exceed grams/day. Chronic Obstructive Pulmonary Disease Associated with Acute HypercapniaOne vial of doxapram (400 mg) should be mixed with 180 mL of dextrose 5% or 10% or normal saline solution (concentration of mg/mL). The infusion should be started at to mg/minute 1/2 to mL/minute); if indicated, increase to maximum of mg/minute. Arterial blood gases should be determined prior to the onset of doxaprams administration and at least every half hour during the two hours of infusion to insure against the insidious development of CO2-RETENTION AND ACIDOSIS. Alteration of oxygen concentration or flow rate may necessitate adjustment in the rate of doxapram infusion. Predictable blood gas patterns are more readily established with continuous infusion of doxapram. If the blood gases show evidence of deterioration, the infusion of doxapram should be discontinued. ADDITIONAL INFUSIONS BEYOND THE SINGLE MAXIMUM TWO HOUR ADMINISTRATION PERIOD ARE NOT RECOMMENDED. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.Diluent CompatibilityDoxapram hydrochloride is compatible with 5% and 10% dextrose in water or normal saline.IncompatibilityADMIXTURE OF DOXAPRAM WITH ALKALINE SOLUTIONS SUCH AS 2.5% THIOPENTAL SODIUM, SODIUM BICARBONATE, FUROSEMIDE, OR AMINOPHYLLINE WILL RESULT IN PRECIPITATION OR GAS FORMATION.Doxapram is also not compatible with ascorbic acid, cefoperazone sodium, cefotaxime sodium, cefotetan sodium, cefuroxime sodium, folic acid, dexamethasone disodium phosphate, diazepam, hydrocortisone sodium phosphate, methylprednisolone sodium, or hydrocortisone sodium succinate.Admixture of doxapram and ticarcillin disodium results in an 18% loss of doxapram in hours. When doxapram is mixed with minocycline hydrochloride, there is loss of 8% of doxapram in hours and 13% loss of doxapram in hours.. DOSAGE 1. DOSAGE 2.

OVERDOSAGE SECTION.

OVERDOSAGE. Signs and SymptomsSymptoms of overdosage are extensions of the pharmacologic effects of the drug. Excessive pressor effect, such as hypertension, tachycardia, skeletal muscle hyperactivity, and enhanced deep tendon reflexes may be early signs of overdosage. Therefore, the blood pressure, pulse rate, and deep tendon reflexes should be evaluated periodically and the dosage or infusion rate adjusted accordingly.Other effects may include agitation, confusion, sweating, cough, and dyspnea.Convulsive seizures are unlikely at recommended dosages. In unanesthetized animals, the convulsant dose is 70 times greater than the respiratory stimulant dose. Intravenous LD50 values in the mouse and rat were approximately 75 mg/kg and in the cat and dog were 40 to 80 mg/kg.Except for management of chronic obstructive pulmonary disease associated with acute hypercapnia, the maximum recommended dosage is GRAMS/24 HOURS. (See DOSAGE ADMINISTRATION.) ManagementThere is no specific antidote for doxapram. Management should be symptomatic. Anticonvulsants, along with oxygen and resuscitative equipment should be readily available to manage overdosage manifested by excessive central nervous system stimulation. Slow administration of the drug and careful observation of the patient during administration and for some time subsequently are advisable. These precautions are to assure that the protective reflexes have been restored and to prevent possible post-hyperventilation or hypoventilation.There is no evidence that doxapram is dialyzable; further, the half-life of doxapram makes it unlikely that dialysis would be appropriate in managing overdose with this drug.Close.

PRECAUTIONS SECTION.

PRECAUTIONS. GeneralAn adequate airway is essential and airway protection should be considered since doxapram may stimulate vomiting. Recommended dosages of doxapram should be employed and maximum total dosages should not be exceeded. In order to avoid side effects, it is advisable to use the minimum effective dosage. Monitoring of the blood pressure, pulse rate, and deep tendon reflexes is recommended to prevent overdosage. Vascular extravasation or use of single injection site over an extended period should be avoided since either may lead to thrombophlebitis or local skin irritation. Rapid infusion may result in hemolysis. Lowered pCO2 induced by hyperventilation produces cerebral vasoconstriction and slowing of the cerebral circulation. This should be taken into consideration on an individual basis. In certain patients pressor effect of doxapram on the pulmonary circulation may result in fall of the arterial pO2 probably due to worsening of ventilation perfusion-matching in the lungs despite an overall improvement in alveolar ventilation and fall in pCO2. Patients should be carefully supervised taking into account available blood gas measurements. There is risk that doxapram will produce adverse effects (including seizures) due to general central nervous system stimulation. Muscle involvement may range from fasciculation to spasticity. Anticonvulsants such as intravenous short-acting barbiturates, along with oxygen and resuscitative equipment should be readily available to manage overdosage manifested by excessive central nervous system stimulation. Slow administration of the drug and careful observation of the patient during administration and for some time subsequently are advisable. These precautions are to assure that the protective reflexes have been restored and to prevent possible post-hyperventilation or hypoventilation. Doxapram should be administered cautiously to patients receiving sympathomimetic or monoamine oxidase inhibiting drugs, since an additive pressor effect may occur. Blood pressure increases are generally modest but significant increases have been noted in some patients. Because of this, doxapram is not recommended for use in patients with severe hypertension (see CONTRAINDICATIONS). Cardiovascular effects may include various dysrhythmias. Patients receiving doxapram should be monitored for disturbance of their cardiac rhythm. If sudden hypotension or dyspnea develops, doxapram should be stopped. Doxapram should be administered with caution to patients with significantly impaired hepatic or renal function as reduction in the rate of metabolism or excretion of metabolites may alter the response. In Postanesthetic UseThe same consideration to pre-existing disease states should be exercised as in non-anesthetized individuals. See CONTRAINDICATIONS and WARNINGS covering use in hypertension, asthma, disturbances of respiratory mechanics including airway obstruction, CNS disorders including increased cerebrospinal fluid pressure, convulsive disorders, acute agitation, and profound metabolic disorders. See PRECAUTIONS, Drug Interactions. In Chronic Obstructive Pulmonary DiseaseArrhythmias seen in some patients in acute respiratory failure secondary to chronic obstructive pulmonary disease are probably the result of hypoxia. Doxapram should be used with caution in these patients. Arterial blood gases should be drawn prior to the initiation of doxapram infusion and oxygen administration, then at least every 1/2 hour during the infusion period to prevent development of CO2 retention and acidosis in patients with chronic obstructive pulmonary disease with acute hypercapnia. Doxapram administration does not diminish the need for careful monitoring of the patient or the need for supplemental oxygen in patients with acute respiratory failure. Doxapram should be stopped if the arterial blood gases deteriorate, and mechanical ventilation should be initiated. Drug InteractionsAdministration of doxapram to patients who are receiving sympathomimetic or monoamine oxidase inhibiting drugs may result in an additive pressor effect (see PRECAUTIONS, General). In patients who have received neuromuscular blocking agents, doxapram may temporarily mask the residual effects of these drugs.In patients who have received general anesthesia utilizing volatile agent known to sensitize the myocardium to catecholamines, administration of doxapram should be delayed until the volatile agent has been excreted in order to lessen the potential for arrhythmias, including ventricular tachycardia and ventricular fibrillation (see WARNINGS). There may be an interaction between doxapram and aminophylline and between doxapram and theophylline manifested by increased skeletal muscle activity, agitation, and hyperactivity.Carcinogenesis, Mutagenesis, Impairment of FertilityNo carcinogenic or mutagenic studies have been performed using doxapram. Doxapram did not adversely affect the breeding performance of rats.PregnancyPREGNANCY CATEGORY BReproduction studies have been performed in rats at doses up to 1.6 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to doxapram. There are, however, no adequate and well-controlled studies in pregnant women. Because the animals in the reproduction studies were dosed by the IM and oral routes and animal reproduction studies, in general, are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.Nursing MothersIt is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when doxapram hydrochloride is administered to nursing woman.Pediatric UseSafety and effectiveness in pediatric patients below the age of 12 years have not been established. This product contains benzyl alcohol as preservative. Benzyl alcohol, component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The gasping syndrome, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the gasping syndrome, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.Premature neonates given doxapram have developed hypertension, irritability, jitteriness, hyperglycemia, glucosuria, abdominal distension, increased gastric residuals, vomiting, bloody stools, necrotizing enterocolitis, erratic limb movements, excessive crying, disturbed sleep, premature eruption of teeth, and QT prolongation that has resulted in heart block. In premature neonates with risk factors such as previous seizure, perinatal asphyxia, or intracerebral hemorrhage, seizures have occurred. In many instances, doxapram was administered following administration of xanthine derivatives such as caffeine, aminophylline or theophylline.

WARNINGS SECTION.

WARNINGS. Doxapram should not be used in conjunction with mechanical ventilation.Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS, Pediatric Use). In Postanesthetic UseDoxapram is neither an antagonist to muscle relaxant drugs nor specific narcotic antagonist. More specific tests (eg, peripheral nerve stimulation, airway pressures, head lift, pulse oximetry, and end-tidal carbon dioxide) to assess adequacy of ventilation are recommended before administering doxapram. Doxapram should be administered with great care and only under careful supervision to patients with hypermetabolic states such as hyperthyroidism or pheochromocytoma. Since narcosis may recur after stimulation with doxapram, care should be taken to maintain close observation until the patient has been fully alert for 1/2 to hour. In patients who have received general anesthesia utilizing volatile agent known to sensitize the myocardium to catecholamines, administration of doxapram should be delayed until the volatile agent has been excreted in order to lessen the potential for arrhythmias, including ventricular tachycardia and ventricular fibrillation (see PRECAUTIONS, Drug Interactions). In Drug-Induced CNS and Respiratory DepressionDoxapram alone may not stimulate adequate spontaneous breathing or provide sufficient arousal in patients who are severely depressed either due to respiratory failure or to CNS depressant drugs, but may be used as an adjunct to established supportive measures and resuscitative techniques.In Chronic Obstructive Pulmonary DiseaseBecause of the associated increased work of breathing, do not increase the rate of infusion of doxapram in severely ill patients in an attempt to lower pCO2.