DOPRAM

DOPRAM Injection (doxapram hydrochloride injection, USP) is a clear, colorless, sterile, non-pyrogenic, aqueous solution with pH 3.5 to 5, for intravenous administration. Each 1 mL contains: Doxapram Hydrochloride, USP ................................................................. 20 mg Benzyl Alcohol, NF (as preservative) ......................................................... 0.9% Water for Injection, USP ...........…................................................................. q.s. Doxapram Injection is a respiratory stimulant. Doxapram hydrochloride is a white to off-white, crystalline powder, sparingly soluble in water, alcohol and chloroform. Chemically, doxapram hydrochloride is 1-ethyl-4-[2-(4-morpholinyl)ethyl]-3,3-diphenyl-2-pyrrolidinone monohydrochloride, monohydrate. The chemical structure is: C 24 H 31 ClN 2 O 2 • H 2 O M.W. 432.98 Structural Formula

Postanesthesia When the possibility of airway obstruction and/or hypoxia have been eliminated, doxapram may be used to stimulate respiration in patients with drug-induced postanesthesia respiratory depression or apnea other than that due to muscle relaxant drugs. To pharmacologically stimulate deep breathing in the postoperative patient. (A quantitative method of assessing oxygenation, such as pulse oximetry, is recommended.) Drug-Induced Central Nervous System Depression Exercising care to prevent vomiting and aspiration, doxapram may be used to stimulate respiration, hasten arousal, and to encourage the return of laryngopharyngeal reflexes in patients with mild to moderate respiratory and CNS depression due to drug overdosage. Chronic Pulmonary Disease Associated with Acute Hypercapnia Doxapram is indicated as a temporary measure in hospitalized patients with acute respiratory insufficiency superimposed on chronic obstructive pulmonary disease. Its use should be for a short period of time (see DOSAGE AND ADMINISTRATION ) as an aid in the prevention of elevation of arterial CO 2 tension during the administration of oxygen. It should not be used in conjunction with mechanical ventilation.

NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS ) In Postanesthetic Use Table I. Dosage for postanesthetic use-I.V. and infusion. I.V. Administration Recommended Dosage mg/kg Maximum dose per single injection mg/kg Maximum total dose Dose not to exceed 3 grams/24 hours. mg/kg Single Injection 0.5-1 1.5 1.5 Repeat Injections (5 min. intervals) 0.5-1 1.5 2 Infusion 0.5-1 – 4 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 a 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 2 mg/kg. BY INFUSION The 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 a rate of approximately 5 mg/minute until a satisfactory respiratory response is observed, and maintained at a rate of 1 to 3 mg/minute. The rate of infusion should be adjusted to sustain the desired level of respiratory stimulation with a minimum of side effects. The maximum total dosage by infusion is 4 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. METHOD ONE Priming dose single/repeat I.V. Injection METHOD TWO Rate of Intermittent I.V. Infusion Level of Depression mg/kg mg/kg/hr Mild Mild Depression Class 0: Asleep, but can be aroused and can answer questions. Class 1: Comatose, will withdraw from painful stimuli, reflexes intact. 1 1-2 Moderate Moderate Depression Class 2: Comatose, will not withdraw from painful stimuli, reflexes intact. Class 3: Comatose, reflexes absent, no depression of circulation or respiration. 2 2-3 METHOD ONE Using Single and/or Repeat Single I.V. Injections Give priming dose of 2 mg/kg body weight and repeat in 5 minutes. The priming dose for moderate depression is 2 mg/kg and the priming dose for mild depression is 1 mg/kg. Repeat same dose q 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 q 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 a possible central nervous system source of sustained coma. METHOD TWO By Intermittent I.V. Infusion Give priming dose as in Method One. If patient wakens, watch for relapse; if no response, continue general supportive treatment for 1 to 2 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 1 to 3 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 2 hours. Continue supportive treatment for ½ to 2 hours and repeat Step b. Do not exceed 3 grams/day. Chronic Obstructive Pulmonary Disease Associated with Acute Hypercapnia One vial of doxapram (400 mg) should be mixed with 180 mL of dextrose 5% or 10% or normal saline solution (concentration of 2 mg/mL). The infusion should be started at 1 to 2 mg/minute (½ to 1 mL/minute); if indicated, increase to a maximum of 3 mg/minute. Arterial blood gases should be determined prior to the onset of doxapram’s administration and at least every half hour during the two hours of infusion to insure against the insidious development of CO 2 -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 a 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 Compatibility Doxapram hydrochloride is compatible with 5% and 10% dextrose in water or normal saline. Incompatibility ADMIXTURE 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 3 hours. When doxapram is mixed with minocycline hydrochloride, there is a loss of 8% of doxapram in 3 hours and a 13% loss of doxapram in 6 hours.

Doxapram is contraindicated in patients with known hypersensitivity to the drug or any of the injection components. Doxapram should not be used in patients with epilepsy or other convulsive disorders. Doxapram is contraindicated in patients with proven or suspected pulmonary embolism. Doxapram is contraindicated in patients with mechanical disorders of ventilation such as mechanical obstruction, muscle paresis (including neuromuscular blockade), flail chest, pneumothorax, acute bronchial asthma, pulmonary fibrosis, or other conditions resulting in restriction of the chest wall, muscles of respiration, or alveolar expansion. Doxapram is contraindicated in patients with evidence of head injury, cerebral vascular accident, or cerebral edema, and in those with significant cardiovascular impairment, uncompensated heart failure, severe coronary artery disease, or severe hypertension, including that associated with hyperthyroidism or pheochromocytoma. (See WARNINGS .)

Adverse reactions reported coincident with the administration of DOPRAM (doxapram hydrochloride, USP) include: 1. Central and Autonomic Nervous Systems Pyrexia, flushing, sweating; pruritus and paresthesia, such as a 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. Respiratory Dyspnea, cough, hyperventilation, tachypnea, laryngospasm, bronchospasm, hiccough, and rebound hypoventilation. 3. Cardiovascular Phlebitis, variations in heart rate, lowered T-waves, arrhythmias (including ventricular tachycardia and ventricular fibrillation), chest pain, tightness in chest. A mild to moderate increase in blood pressure is commonly noted and may be of concern in patients with severe cardiovascular diseases. 4. Gastrointestinal Nausea, vomiting, diarrhea, desire to defecate. 5. Genitourinary Stimulation of urinary bladder with spontaneous voiding; urinary retention. Elevation of BUN and albuminuria. 6. Hemic and Lymphatic Hemolysis with rapid infusion. A decrease in hemoglobin, hematocrit, or red blood cell count has been observed in postoperative patients. In the presence of pre-existing leukopenia, a further decrease in WBC has been observed following anesthesia and treatment with doxapram hydrochloride.

Administration 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 a 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.