Pentobarbital

NEMBUTAL Sodium Solution (pentobarbital sodium injection, USP) is available in the following sizes:

20-mL multiple-dose vial, 1 g per vial (NDC 67386-501-52); and 50-mL multiple-dose vial, 2.5 g per vial (NDC 67386-501-55).

Each mL contains:

Pentobarbital Sodium, derivative of barbituric acid.......................................50 mg
Propylene glycol........................................................................................40% v/v
Alcohol ............................................................................................................10%
Water for Injection..............................................................................................qs (pH adjusted to approximately 9.5 with hydrochloric acid and/or sodium hydroxide.)

Vial stoppers are latex free.

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the product be stored at 20-25 C (68-77 F), however, brief excursions are permitted between 15-30 C (59-86 F). See USP Controlled Room Temperature.

Manufactured by: Hospira, Inc. Lake Forest, Illinois 60045, U.S.A. For: Ovation Pharmaceuticals Inc, Deerfield, Illinois, U.S.A. 60015. FDA Rev date: 5/10/2002

The following adverse reactions and their incidence were compiled from surveillance of thousands of hospitalized patients. Because such patients may be less aware of certain of the milder adverse effects of barbiturates, the incidence of these reactions may be somewhat higher in fully ambulatory patients.

More than 1 in 100 patients. The most common adverse reaction estimated to occur at a rate of 1 to 3 patients per 100 is: Nervous System: Somnolence.

Less than 1 in 100 patients. Adverse reactions estimated to occur at a rate of less than 1 in 100 patients listed below, grouped by organ system, and by decreasing order of occurrence are:

Nervous system: Agitation, confusion, hyperkinesia, ataxia, CNS depression, nightmares, nervousness, psychiatric disturbance, hallucinations, insomnia, anxiety, dizziness, thinking abnormality.

Respiratory system: Hypoventilation, apnea.

Cardiovascular system: Bradycardia, hypotension, syncope.

Digestive system: Nausea, vomiting, constipation.

Other reported reactions: Headache, injection site reactions, hypersensitivity reactions (angioedema, skin rashes, exfoliative dermatitis), fever, liver damage, megaloblastic anemia following chronic phenobarbital use.

Drug Abuse And Dependence

Pentobarbital sodium injection is subject to control by the Federal Controlled Substances Act under DEA schedule II.

Barbiturates may be habit forming. Tolerance, psychological dependence, and physical dependence may occur especially following prolonged use of high doses of barbiturates. Daily administration in excess of 400 milligrams (mg) of pentobarbital or secobarbital for approximately 90 days is likely to produce some degree of physical dependence. A dosage of from 600 to 800 mg taken for at least 35 days is sufficient to produce withdrawal seizures. The average daily dose for the barbiturate addict is usually about 1.5 grams. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than two-fold. As this occurs, the margin between an intoxicating dosage and fatal dosage becomes smaller.

Symptoms of acute intoxication with barbiturates include unsteady gait, slurred speech, and sustained nystagmus. Mental signs of chronic intoxication include confusion, poor judgment, irritability, insomnia, and somatic complaints.

Symptoms of barbiturate dependence are similar to those of chronic alcoholism. If an individual appears to be intoxicated with alcohol to a degree that is radically disproportionate to the amount of alcohol in his or her blood the use of barbiturates should be suspected. The lethal dose of a barbiturate is far less if alcohol is also ingested.

The symptoms of barbiturate withdrawal can be severe and may cause death. Minor withdrawal symptoms may appear 8 to 12 hours after the last dose of a barbiturate.

These symptoms usually appear in the following order: anxiety, muscle twitching, tremor of hands and fingers, progressive weakness, dizziness, distortion in visual perception, nausea, vomiting, insomnia, and orthostatic hypotension. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs. Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Individuals susceptible to barbiturate abuse and dependence include alcoholics and opiate abusers, as well as other sedative-hypnotic and amphetamine abusers.

Drug dependence to barbiturates arises from repeated administration of a barbiturate or agent with barbiturate-like effect on a continuous basis, generally in amounts exceeding therapeutic dose levels. The characteristics of drug dependence to barbiturates include: (a) a strong desire or need to continue taking the drug; (b) a tendency to increase the dose; (c) a psychic dependence on the effects of the drug related to subjective and individual appreciation of those effects; and (d) a physical dependence on the effects of the drug requiring its presence for maintenance of homeostasis and resulting in a definite, characteristic, and self-limited abstinence syndrome when the drug is withdrawn.

Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. In all cases withdrawal takes an extended period of time. One method involves substituting a 30 mg dose of phenobarbital for each 100 to 200 mg dose of barbiturate that the patient has been taking. The total daily amount of phenobarbital is then administered in 3 to 4 divided doses, not to exceed 600 mg daily. Should signs of withdrawal occur on the first day of treatment, a loading dose of 100 to 200 mg of phenobarbital may be administered IM in addition to the oral dose. After stabilization on phenobarbital, the total daily dose is decreased by 30 mg a day as long as withdrawal is proceeding smoothly. A modification of this regimen involves initiating treatment at the patient's regular dosage level and decreasing the daily dosage by 10 percent if tolerated by the patient.

Infants physically dependent on barbiturates may be given phenobarbital 3 to 10 mg/kg/day. After withdrawal symptoms (hyperactivity, disturbed sleep, tremors, hyperreflexia) are relieved, the dosage of phenobarbital should be gradually decreased and completely withdrawn over a 2-week period.

Since pentobarbital is often used only when needed, you may not be on a dosing schedule. If you are using the medication regularly, use the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to use the medicine and skip the missed dose. Do not use extra medicine to make up the missed dose.

Your pharmacist can provide more information about pentobarbital.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 5.02. Revision date: 12/15/2010.

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Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Pentobarbital falls into category D:

It has been shown that use of Pentobarbital in pregnant women caused some babies to be born with problems. However, in some serious situations, the benefit of using this medication may be greater than the risk of harm to the baby.

Absorption

Onset

Following IV administration, onset occurs within 1 minute.a b e

Following IM administration, onset occurs within 10–25 minutes.b

Duration

Variable;a patient-dependent and may vary occasionally within same patient.a About 15 minutes following IV administration.b

Plasma Concentrations

Plasma concentrations of 1–5 mcg/mL generally produce sedation and plasma concentrations of 5–15 mcg/mL generally produce sleep; however, plasma concentrations >10 mcg/mL may produce deep coma and those >30 mcg/mL are potentially lethal.b

Distribution

Extent

Rapidly distributed to all tissues and fluids,a e with high concentrations in the brain, liver, and kidneys.a e

Crosses the placenta and is distributed into milk.a e

Plasma Protein Binding

Approximately 35–45%.b

Elimination

Metabolism

Metabolized primarily by hepatic microsomal enzymes.a b e

Elimination Route

Excreted principally in urine, mostly as metabolites; excreted less commonly in the feces.a

Half-life

Biphasic; terminal half-life is 35–50 hours.b

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Potential for pentobarbital to impair mental alertness or physical coordination; do not drive or operate machinery until effects on individual are known.a e

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and alcohol consumption.a Importance of avoiding alcohol while taking the drug.a

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a

• Importance of informing patients of other important precautionary information.a (See Cautions.)

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling sleepy.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Krauss 2006: Children and Adults: Sedation: IM: 1 to 2 hours; IV: 15 to 45 minutes; Oral, Rectal: 1 to 4 hours

Half-Life Elimination

Terminal: Children: 26 ± 16 hours (Schaible 1982); Adults: Healthy: 22 hours (average) (Ehrnebo 1974); Range: 15 to 50 hours; dose dependent

Protein Binding

45% to 70%

There are no dosage adjustments provided in the manufacturer’s labeling. However, a reduced dosage is recommended.

Note: A risk of propylene glycol toxicity exists in patients receiving pentobarbital, especially in patients with renal impairment; monitor closely (eg, osmolal gap) if using for prolonged periods of time or at high doses (Miller 2008; Pillai 2014).

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Respiratory depression: May cause respiratory depression particularly when administered intravenously; use with caution in patients with respiratory disease. Intubation is typically required prior to treatment for seizures or traumatic brain injury (NCS [Brophy 2012]).

Disease-related concerns:

• Depression: Use with caution in patients with depression or suicidal tendencies.

• Hepatic impairment: Use with caution in patients with hepatic impairment; reduce dose as appropriate. Do not use in patients showing premonitory signs of hepatic coma.

• Renal impairment: Use with caution in patients with renal impairment; reduce dose as appropriate.

• Substance abuse: Use with caution in patients with a history of drug abuse; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Debilitated patients: Use with caution in patients who are debilitated; marked excitement, depression, and confusion may occur.

• Elderly: Use with caution in elderly patients; marked excitement, depression, and confusion may occur.

Dosage form specific issues:

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer’s labeling.

Other warnings/precautions:

• Acute or chronic pain: Use caution when administering to patients with acute or chronic pain; paradoxical excitement could be induced or important symptoms could be masked.

• Appropriate use: IV administration: Solution for injection is highly alkaline and extravasation may cause local tissue damage. Too rapid IV administration may cause respiratory depression, apnea, laryngospasm, or vasodilation with hypotension.

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.