crosomal enzymes. patients stabilized on corticosteroid therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen. griseofulvin: phenobarbital appears to interfere with the absorption of orally administered griseofulvin, thus decreasing its blood level. the effect of the resultant decreased blood levels of griseofulvin on therapeutic response has not been established. however, it would be preferable to avoid concomitant administration of these drugs. doxycycline: phenobarbital has been shown to shorten the half-life of doxycycline for as long as 2 weeks after barbiturate therapy is discontinued. this mechanism is probably through the induction of hepatic microsomal enzymes that metabolize the antibiotic. if phenobarbital and doxycycline are administered concurrently, the clinical response to doxycycline should be monitored closely. phenytoin, sodium valproate, valproic acid: the effect of barbiturates on the metabolism of phenytoin appears to be variable. some investigators report an accelerating effect, while others report no effect. because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be monitored more frequently if these drugs are given concurrently. sodium valproate and valproic acid appear to decrease barbiturate metabolism; therefore, barbiturate blood levels should be monitored and appropriate dosage adjustments made as indicated. central nervous system depressants: the concomitant use of other central nervous system depressants, including other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may produce additive depressant effects. monoamine oxidase inhibitors (maoi): maoi prolong the effects of barbiturates probably because metabolism of the barbiturate is inhibited. estradiol, estrone, progesterone and other steroidal hormones: pretreatment with or concurrent administration of phenobarbital may decrease the effect of estradiol by increasing its metabolism. there have been reports of patients treated with antiepileptic drugs (e.g., phenobarbital) who became pregnant while taking oral contraceptives. an alternate contraceptive method might be suggested to women taking phenobarbital.

nistration may cause respiratory depression, apnea, laryngospasm, or vasodilation with fall in blood pressure. acute or chronic pain: caution should be exercised when barbiturates are administered to patients with acute or chronic pain, because paradoxical excitement could be induced or important symptoms could be masked. however, the use of barbiturates as sedatives in the postoperative surgical period and as adjuncts to cancer chemotherapy is well established. use in pregnancy: barbiturates can cause fetal damage when administered to a pregnant woman. retrospective, case-controlled studies have suggested a connection between the maternal consumption of barbiturates and a higher than expected incidence of fetal abnormalities. following oral or parenteral administration, barbiturates readily cross the placental barrier and are distributed throughout fetal tissues with highest concentrations found in the placenta, fetal liver, and brain. fetal blood levels approach maternal blood levels following parenteral administration. withdrawal symptoms occur in infants born to mothers who receive barbiturates throughout the last trimester of pregnancy. (see " drug abuse and dependence " section.) if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. synergistic effects: the concomitant use of alcohol or other cns depressants may produce additive cns depressant effects. pediatric neurotoxicity: published animal studies demonstrate that the administration of anesthetic and sedation drugs that block nmda receptors and/or potentiate gaba activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. the clinical significance of these findings is not clear. however, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans (see " precautions-pregnancy and pediatric use " and " animal pharmacology and/or toxicology "). some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. these studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. anesthetic and sedation drugs are a necessary part of the care of children and pregnant women needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

erial injection may vary from transient pain to gangrene of the limb. any complaint of pain in the limb warrants stopping the injection.

routes are not feasible, either because the patient is unconscious (as in cerebral hemorrhage, eclampsia, or status epilepticus), or because the patient resists (as in delirium), or because prompt action is imperative. slow iv injection is essential, and patients should be carefully observed during administration. this requires that blood pressure, respiration, and cardiac function be maintained, vital signs be recorded, and equipment for resuscitation and artificial ventilation be available. the rate of iv injection should not exceed 50 mg/min for pentobarbital sodium. there is no average intravenous dose of pentobarbital sodium that can be relied on to produce similar effects in different patients. the possibility of overdose and respiratory depression is remote when the drug is injected slowly in fractional doses. a commonly used initial dose for the 70 kg adult is 100 mg. proportional reduction in dosage should be made for pediatric or debilitated patients. at least one minute is necessary to determine the full effect of intravenous pentobarbital. if necessary, additional small increments of the drug may be given up to a total of from 200 to 500 mg for normal adults. anticonvulsant use: in convulsive states, dosage of pentobarbital sodium should be kept to a minimum to avoid compounding the depression which may follow convulsions. the injection must be made slowly with due regard to the time required for the drug to penetrate the blood-brain barrier. special patient population: dosage should be reduced in the elderly or debilitated because these patients may be more sensitive to barbiturates. dosage should be reduced for patients with impaired renal function or hepatic disease. inspection: parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution containers permit. solutions for injection showing evidence of precipitation should not be used.

tipation. other reported reactions: headache, injection site reactions, hypersensitivity reactions (angioedema, skin rashes, exfoliative dermatitis), fever, liver damage, megaloblastic anemia following chronic phenobarbital use. to report suspected adverse reactions, contact sagent pharmaceuticals, inc. at 1-866-625-1618 or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

crosomal enzymes. patients stabilized on corticosteroid therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen. griseofulvin: phenobarbital appears to interfere with the absorption of orally administered griseofulvin, thus decreasing its blood level. the effect of the resultant decreased blood levels of griseofulvin on therapeutic response has not been established. however, it would be preferable to avoid concomitant administration of these drugs. doxycycline: phenobarbital has been shown to shorten the half-life of doxycycline for as long as 2 weeks after barbiturate therapy is discontinued. this mechanism is probably through the induction of hepatic microsomal enzymes that metabolize the antibiotic. if phenobarbital and doxycycline are administered concurrently, the clinical response to doxycycline should be monitored closely. phenytoin, sodium valproate, valproic acid: the effect of barbiturates on the metabolism of phenytoin appears to be variable. some investigators report an accelerating effect, while others report no effect. because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be monitored more frequently if these drugs are given concurrently. sodium valproate and valproic acid appear to decrease barbiturate metabolism; therefore, barbiturate blood levels should be monitored and appropriate dosage adjustments made as indicated. central nervous system depressants: the concomitant use of other central nervous system depressants, including other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may produce additive depressant effects. monoamine oxidase inhibitors (maoi): maoi prolong the effects of barbiturates probably because metabolism of the barbiturate is inhibited. estradiol, estrone, progesterone and other steroidal hormones: pretreatment with or concurrent administration of phenobarbital may decrease the effect of estradiol by increasing its metabolism. there have been reports of patients treated with antiepileptic drugs (e.g., phenobarbital) who became pregnant while taking oral contraceptives. an alternate contraceptive method might be suggested to women taking phenobarbital.

nistration of either isoflurane or propofol for 5 hours on gestation day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. with respect to brain development, this time period corresponds to the third trimester of gestation in the human. the clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits (see " warnings-pediatric neurotoxicity ", " precautions-pediatric use ", and " animal pharmacology and/or toxicology ").

ly 3 years of age in humans. in primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. the clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data (see " warnings-pediatric neurotoxicity ", " precautions-pregnancy ", and " animal pharmacology and/or toxicology ".)

the dose from 3 to 2 doses a day for 1 week). in studies, secobarbital sodium and pentobarbital sodium have been found to lose most of their effectiveness for both inducing and maintaining sleep by the end of 2 weeks of continued drug administration at fixed doses. the short-, intermediate-, and, to a lesser degree, long-acting barbiturates have been widely prescribed for treating insomnia. although the clinical literature abounds with claims that the short-acting barbiturates are superior for producing sleep while the intermediate-acting compounds are more effective in maintaining sleep, controlled studies have failed to demonstrate these differential effects. therefore, as sleep medications, the barbiturates are of limited value beyond short-term use. barbiturates have little analgesic action at subanesthetic doses. rather, in subanesthetic doses these drugs may increase the reaction to painful stimuli. all barbiturates exhibit anticonvulsant activity in anesthetic doses. however, of the drugs in this class, only phenobarbital, mephobarbital, and metharbital have been clinically demonstrated to be effective as oral anticonvulsants in subhypnotic doses. barbiturates are respiratory depressants. the degree of respiratory depression is dependent upon dose. with hypnotic doses, respiratory depression produced by barbiturates is similar to that which occurs during physiologic sleep with slight decrease in blood pressure and heart rate. studies in laboratory animals have shown that barbiturates cause reduction in the tone and contractility of the uterus, ureters, and urinary bladder. however, concentrations of the drugs required to produce this effect in humans are not reached with sedative-hypnotic doses. barbiturates do not impair normal hepatic function, but have been shown to induce liver microsomal enzymes, thus increasing and/or altering the metabolism of barbiturates and other drugs. (see " precautions - drug interactions " section). pharmacokinetics barbiturates are absorbed in varying degrees following oral, rectal, or parenteral administration. the salts are more rapidly absorbed than are the acids. the onset of action for oral or rectal administration varies from 20 to 60 minutes. for im administration, the onset of action is slightly faster. following iv administration, the onset of action ranges from almost immediately for pentobarbital sodium to 5 minutes for phenobarbital sodium. maximal cns depression may not occur until 15 minutes or more after iv administration for phenobarbital sodium. duration of action, which is related to the rate at which the barbiturates are redistributed throughout the body, varies among persons and in the same person from time to time. no studies have demonstrated that the different routes of administration are equivalent with respect to bioavailability. barbiturates are weak acids that are absorbed and rapidly distributed to all tissues and fluids with high concentrations in the brain, liver, and kidneys. lipid solubility of the barbiturates is the dominant factor in their distribution within the body. the more lipid soluble the barbiturate, the more rapidly it penetrates all tissues of the body. barbiturates are bound to plasma and tissue proteins to a varying degree with the degree of binding increasing directly as a function of lipid solubility. phenobarbital has the lowest lipid solubility, lowest plasma binding, lowest brain protein binding, the longest delay in onset of activity, and the longest duration of action. at the opposite extreme is secobarbital which has the highest lipid solubility, plasma protein binding, brain protein binding, the shortest delay in onset of activity, and the shortest duration of action. butabarbital is classified as an intermediate barbiturate. the plasma half-life for pentobarbital in adults is 15 to 50 hours and appears to be dose dependent. barbiturates are metabolized primarily by the hepatic microsomal enzyme system, and the metabolic products are excreted in the urine, and less commonly, in the feces. approximately 25 to 50 percent of a dose of aprobarbital or phenobarbital is eliminated unchanged in the urine, whereas the amount of other barbiturates excreted unchanged in the urine is negligible. the excretion of unmetabolized barbiturate is one feature that distinguishes the long-acting category from those belonging to other categories which are almost entirely metabolized. the inactive metabolites of the barbiturates are excreted as conjugates of glucuronic acid.

brain, liver, and kidneys. lipid solubility of the barbiturates is the dominant factor in their distribution within the body. the more lipid soluble the barbiturate, the more rapidly it penetrates all tissues of the body. barbiturates are bound to plasma and tissue proteins to a varying degree with the degree of binding increasing directly as a function of lipid solubility. phenobarbital has the lowest lipid solubility, lowest plasma binding, lowest brain protein binding, the longest delay in onset of activity, and the longest duration of action. at the opposite extreme is secobarbital which has the highest lipid solubility, plasma protein binding, brain protein binding, the shortest delay in onset of activity, and the shortest duration of action. butabarbital is classified as an intermediate barbiturate. the plasma half-life for pentobarbital in adults is 15 to 50 hours and appears to be dose dependent. barbiturates are metabolized primarily by the hepatic microsomal enzyme system, and the metabolic products are excreted in the urine, and less commonly, in the feces. approximately 25 to 50 percent of a dose of aprobarbital or phenobarbital is eliminated unchanged in the urine, whereas the amount of other barbiturates excreted unchanged in the urine is negligible. the excretion of unmetabolized barbiturate is one feature that distinguishes the long-acting category from those belonging to other categories which are almost entirely metabolized. the inactive metabolites of the barbiturates are excreted as conjugates of glucuronic acid.

cancer institute, 61:1031-1034, 1978).

ains. discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs. because some animal data suggest that the window of vulnerability includes the 3rd trimester of pregnancy, discuss with pregnant women the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs. (see " warnings-pediatric neurotoxicity ".)