Phenobarbital

Phenobarbital (fee-noe-bar-bih-tal) is a generic medication manufactured by several companies. It is the oldest epilepsy medicine still in use. In 1912, two independent teams of chemists created the drug under the name of Luminal.

Phenobarbital (fee-noe-bar-bih-tal) is a generic medication manufactured by several companies. It is the oldest epilepsy medicine still in use. In 1912, two independent teams of chemists created the drug under the name of Luminal.

Phenobarbital is a barbiturate, a class of medicines used to bring on sedation or sleepiness. This can be a disadvantage, along with behavioral changes and the risk of withdrawal seizures.

The advantages of phenobarbital are its long history of use, low cost, and effectiveness. It has a long half-life, which keeps the level of medication in the blood relatively stable over the course of the day even when it is taken in only one daily dose (often at bedtime).

Phenobarbital
Tablet
15mg Phenobarbital

15mg

30mg Phenobarbital

30mg

60mg Phenobarbital

60mg

100mg Phenobarbital

100mg

Liquid Solution

20 mg per 5 mL (milliliters)

Indications

Phenobarbital is approved in the United States by the Food and Drug Administration (FDA) for add-on therapy for partial and tonic-clonic seizures. It has been used alone for more than 80 years, however, to treat partial and tonic-clonic seizures. It is also used for treatment of status epilepticus.

Forms

Phenobarbital is available in several forms. The name or appearance may differ from country to country, or even from manufacturer to manufacturer, but usually the dose will be the same. In the United States, several companies sell generic phenobarbital, in these forms:

How to take and store Phenobarbital?

Phenobarbital can be taken either with food or without food, but patients should be consistent each day in whether they take it with food or not.

Phenobarbital is usually taken just once a day. Most people find that sleepiness is less of a problem if they take the phenobarbital 30 to 60 minutes before bedtime.

If needed, tablets may be crushed and put in foods for children. A liquid (elixir) is available for those who cannot swallow pills, however. This liquid can be given with water, milk, or juice. Patients should use the same standard-size medicine spoon or dropper each time to get an accurate dose.

Patients should be cautioned if you write a new prescription using a different strength of phenobarbital. For example, if you've been prescribing 30-mg tablets and the new prescription is for 60-mg tablets, advise the patient about how many phenobarbital tablets should now be taken.

Phenobarbital should be stored at room temperature, away from heat, direct light, and dampness. The liquid form should be prevented from freezing. Advise patients to keep phenobarbital out of the reach of children, since overdose is especially dangerous in children.

Don't use more than the doctor prescribes. If one or two extra tablets or an extra spoonful of liquid are taken, call the doctor for advice. For a larger overdose, call your local poison control center or emergency room right away unless you have other specific directions from your doctor.

Missed Doses

Missed doses of phenobarbital should be taken right away unless it is almost time for the next dose. In that case, patients should skip the forgotten dose (rather than taking a double dose) or call for further instructions.

Patients who often forget doses may benefit from using a special pillbox or watch with an alarm.

Mechanisms of actions of Phenobarbital

The primary action of phenobarbital is to enhance the inhibitory actions of gamma-aminobutyric acid (GABA) on neurons.

Clinical Pharmacology of Phenobarbital

Phenobarbital is metabolized in the liver and renally excreted. Mysoline is ~45% protein-bound. Phenobarbital is rapidly and nearly completely absorbed following oral and intramuscular administration. Peak serum concentrations are reached in approximately 3 hours. The half-life in adults is 80-100 hours.

Efficacy of Phenobarbital

Phenobarbital has been used to treat epilepsy since the early decades of the 20th century. It is still commonly used throughout the world because it is both effective and low in cost. Also, most people need to take it only once a day, so they are less likely to miss doses.

When given intravenously, it is effective in stopping status epilepticus.

Phenobarbital is useful in controlling focal aware and focal impaired awareness seizures and generalized tonic-clonic seizures in patients of all ages. It has traditionally been considered the first choice to treat neonatal seizures (seizures in newborn infants). Most studies have found that phenobarbital controls these seizures in about one-third of the infants.

Phenobarbital also has been widely used to prevent recurrent febrile seizures (seizures accompanying a high fever in infants or young children). Because 2 days or more may be required to achieve a high enough level of medication in the blood to control seizures, giving phenobarbital after a fever begins will not be effective. Instead, it must be given daily. One study found that 4% of children treated with an adequate daily dose had a repetition of these seizures, compared to 20% of untreated children. Because febrile seizures usually cause no lasting harm, however, most children should not be given medication for them.

Studies have compared phenobarbital with other antiepileptic medications for treatment of newly diagnosed epilepsy. For instance, one large study compared phenobarbital with carbamazepine (Tegretol, Carbatrol), phenytoin (Dilantin, Phenytek), and primidone (Mysoline). All four medications were about equally effective when used alone to control tonic-clonic seizures in adults. (phenobarbital and phenytoin completely controlled them in 43% of patients, compared to 48% for Carbamazepine.) Carbamazepine more often succeeded in completely controlling partial seizures, however. One-third of those who continued to take phenobarbital for 18 months had complete control of their partial seizures, compared to nearly two-thirds of those who took carbamazepine.

Some doctors hesitate to prescribe phenobarbital because it has a reputation for causing unwanted side effects, especially drowsiness in adults and behavioral or learning problems in children. Side effects are much more likely to be troublesome if high doses are given—60 to 90 mg per day may be enough for an adult—or if too high a dose is given to start. It may be necessary to increase the dosage very slowly over several months. Drowsiness is more common when phenobarbital is first taken or when the dose is increased, but not everyone is affected and some people can take higher doses without trouble.

Phenobarbital is often used in combination with other seizure medicines if one medication does not fully control the patient's seizures. No single combination is perfect for all patients. Sometimes a series of combinations must be tried before finding what is best for the individual. Phenobarbital does interact with many other medications, so the dosages may need to be adjusted.

Common side effects of Phenobarbital

During the past several decades, most doctors have recommended phenobarbital only after trying several other seizure medicines because its side effects often outweigh its benefits (except for certain groups such as very young children). Because of its low cost, however, it may be used more frequently in situations where cost is a critical issue, such as in developing countries.

Because phenobarbital is a barbiturate, it depresses brain function, reduces the breathing and heart rate, and decreases blood pressure and body temperature. As a result, the most common side effect of phenobarbital is sleepiness or fatigue. Patients should be cautioned about driving, operating machinery, or any other dangerous activity until they see how they react to this medication.

Other side effects include:

  • depression
  • hyperactivity (in children)
  • impaired attention (in children and adults)
  • dizziness
  • memory problems
  • decreased sexual interest (libido)
  • impotence
  • slurred speech
  • nausea
  • anemia
  • folate deficiency
  • rash
  • fever
  • low calcium levels, bone loss

Phenobarbital also has been found to reduce the effectiveness of oral contraceptives (birth control pills), so women who could become pregnant may want to consider another form of birth control.

Some studies have found greater problems with behavior and thinking in children taking phenobarbital than in children taking other seizure medicines. Some studies have found that phenobarbital worsens pre-existing hyperactivity and aggressive tendencies. Many physicians believe that phenobarbital sedates children, with a greater effect at higher doses. A number of studies have not found any sedation, however, perhaps because some children become extra alert and their scores cancel out those of sedated children. Nevertheless, the problems with phenobarbital should not be overestimated.

Taking supplements of both calcium and vitamin D may help to prevent bone loss. Patients who have been taking phenobarbital for more than 5 years should be considered for a bone density test.

Long-term use of phenobarbital can lead to changes in the soft tissues, including:

  • joint pains mimicking rheumatism
  • heel and knuckle pads
  • frozen shoulder
  • Dupuytren's contractures
  • fibromas (fibrous tumors) of the bottom of the foot
  • Peyronie's disease (hardening of a portion of the penis)
Serious Side effects of Phenobarbital

Barbiturates like phenobarbital can be addictive because of their sedative-hypnotic and anti-anxiety effects, but psychological dependence (a psychological craving after long-term use) is rare in people taking phenobarbital to treat epilepsy.

Physical dependence, on the other hand, is common. With physical dependence, a withdrawal syndrome occurs if the medication is stopped suddenly or if the dosage is sharply reduced. These withdrawal symptoms may include:

  • anxiety
  • increased heart rate
  • sweating
  • confusion
  • seizures
  • death (very rarely)

It is therefore important to taper patients off phenobarbital gradually to avoid withdrawal symptoms.

Women who may become pregnant should be aware that studies have suggested a connection between phenobarbital and a higher-than-expected incidence of birth defects. There also is a danger to the baby from withdrawal symptoms if the mother has taken phenobarbital in the last few months of pregnancy, since barbiturates cross the placenta into the baby.

In general, it is wise for patients to avoid alcohol while taking phenobarbital.

On July 10, 2008, an advisory panel was convened by the Food and Drug Administration (FDA) to review data that the FDA had previously collected from drug studies showing an association between many of the antiepileptic drugs (AEDs) and suicidal ideation and behavior, which together are called suicidality. According to the FDA's Alert, among the patients with epilepsy in these drug studies, 1 out of 1000 people taking the placebo (inactive substance) showed suicidality compared to approximately 3.5 out of 1000 people who took an AED. The FDA advisory panel voted to accept the FDA's data at its meeting on July 10.

  • Taking antiepileptic medicines may increase the risk of having suicidal thoughts or actions;
  • Do not make any changes to the medication regimen without first talking with the responsible healthcare professional;
  • Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.
  • Be aware of common warning signs that might be a signal for risk of suicide. Some of these are:
    • Talking or thinking about wanting to hurt yourself or end your life
    • Withdrawing from friends and family
    • Becoming depressed or having your depression get worse
    • Becoming preoccupied with death and dying
    • Giving away prized possessions

We again urge patients and families to contact their doctor before stopping an epilepsy medication because this may possibly lead to seizures and worsening of mood.

Impact of Phenobarbital on bone health

Please see package insert.

Phenobarbital Interactions with other medications

Effects of phenobarbital on other drugs
Because phenobarbital accelerates hepatic metabolism, it will increase the clearance of:

  • oral contraceptives
  • valproate
  • phenytoin
  • primidone
  • carbamazepine
  • topiramate
  • lamotrigine
  • tiagabine
  • zonisamide
  • theophylline
  • warfarin
  • steroids

Effects of other drugs on Phenobarbital
Valproate will increase the serum concentration of phenobarbital by inhibiting its hepatic metabolism.

On the other hand, drugs that accelerate hepatic metabolism will lower serum concentrations of phenobarbital. These include:

  • phenytoin
  • carbamazepine
  • primidone
  • oxcarbazepine
  • felbamate

AED Interaction Sheets:
Seizure drugs are often affected by drug-drug interactions. Print these informative sheets for practical help.

Phenobarbital effects on Children

Phenobarbital is useful in controlling simple and complex partial seizures and generalized tonic-clonic seizures in children. It has traditionally been considered the first choice to treat neonatal seizures (seizures in newborn infants). Most studies have found that phenobarbital controls these seizures in about one-third of the infants.

Phenobarbital also has been widely used to prevent recurrent febrile seizures (seizures accompanying a high fever in infants or young children). Because 2 days or more may be required to achieve a high enough level of medication in the blood to control seizures, giving phenobarbital after a fever begins will not be effective. Instead, it must be given daily. One study found that 4% of children treated with an adequate daily dose had a repetition of these seizures, compared to 20% of untreated children. Because febrile seizures usually cause no lasting harm, however, most children should not be given medication for them.

Some doctors hesitate to prescribe phenobarbital for children because it has a reputation for causing behavioral or learning problems in children. Some studies have found that phenobarbital worsens pre-existing hyperactivity and aggressive tendencies. Many physicians believe that phenobarbital sedates children, with a greater effect at higher doses. A number of studies have not found any sedation, however, perhaps because some children become extra alert and their scores cancel out those of sedated children. Nevertheless, the problems with phenobarbital should not be overestimated.

Nevertheless, some studies have found subtle learning impairments in children who are given phenobarbital over a long period, so other seizure medicines may be preferred as a first choice for long-term use in children.

Side effects are much more likely to be troublesome if high doses are given or if too high a dose is given to start. It may be necessary to increase the dosage very slowly over several months. Dosages for children are based on weight: the usual dose for children is 1 to 6 mg per kilogram (2.2 pounds) of body weight per day.

Phenobarbital and Pregnancy

Women who may become pregnant should be aware that studies have suggested a connection between phenobarbital and a higher-than-expected incidence of birth defects.

The risk of defects is higher for women who take several medicines, and for women with a family history of birth defects.

Women who are capable of becoming pregnant should be advised to take 400 mcg (0.4 mg) of folic acid (folate) daily to help prevent neural tube defects. Women at high risk, such as those with a history of a neural tube defect in a previous pregnancy, should take 4000 mcg (4 mg) daily, beginning before they become pregnant.

Check the levels of Mysoline in the woman's blood at intervals during pregnancy, since changes in her body may affect them. Dosage adjustments may be needed to prevent seizures or side effects.

During the last month of pregnancy, the woman should take 10 mg per day of vitamin K to prevent a bleeding disorder that affects some babies born to mothers who are taking anticonvulsants.

No studies have been performed to demonstrate the effect of specific AEDs during labor and delivery. Possible causes of seizures include:

  • failure or inability to take medication
  • sleep deprivation
  • hyperventilation
  • stress
  • pain

There also is a danger to the baby from withdrawal symptoms if the mother has taken phenobarbital in the last few months of pregnancy, since phenobarbital crosses the placenta into the baby.

Since phenobarbital reduces the effectiveness of oral contraceptives (birth control pills), women of childbearing potential should be especially cautious.

Phenobarbital effects on Seniors

Seniors are at particular risk for the following problems with phenobarbital:

  • More possibilities for drug interactions. Usually seniors can continue to take all their medications, including phenobarbital, if the dosages are changed to compensate for the effects of interactions.
  • Greater susceptibility to side effects. Some common side effects of phenobarbital, such as sleepiness or unsteadiness, may exacerbate pre-existing problems.
  • Greater danger of injury from falls or other accidents resulting from side effects.

Lower doses are generally required.

Phenobarbital Dosing and titration

The usual starting dose in adults is 60 mg/day, with additional 30-mg increases every 2-4 weeks to a target dose of 90-120 mg/day, or higher if clinically tolerated.

The usual dose for children is 1 to 6 mg per kilogram (2.2 pounds) of body weight per day.

Phenobarbital References for Professionals

Abstracts of articles relevant to this topic are available through PubMed, a service of the National Library of Medicine:

Herranz JL, Armijo JA, Arteaga R. Clinical side effects of phenobarbital, primidone, phenytoin, carbamazepine, and valproate during monotherapy in children. Epilepsia. 1988 Nov-Dec;29(6):794-804. PMID: 3142761.

In this study of almost 400 children, 64% of those who took phenobarbital had some kind of side effect but only 4% had to stop taking the medication. The children who took phenobarbital had more behavioral disorders than the other children, including excitement at low blood levels and depression at high levels.

Vining EP, Mellitis ED, Dorsen MM. Psychologic and behavioral effects of antiepileptic drugs in children: a double-blind comparison between phenobarbital and valproic acid. Pediatrics. 1987 Aug;80(2):165-74. PMID: 3112727.

In this study, 21 children with epilepsy each took phenobarbital and valproic acid (Depakote) during separate 6-month periods. The researchers found subtle but significant changes in intellectual function and behavior. While taking phenobarbital, the children did not seem to be sedated but they did significantly less well on tests of thinking than when they were taking Depakote. They also showed more hyperactivity and worse behavior.

Mattson, RH, Cramer, JA, et al. Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondarily generalized tonic clonic seizures. New England Journal of Medicine313:145-151, 1985. PMID: 3925335.

Phenobarbital was as effective as the other medications for generalized tonic-clonic seizures in adults, but it was less likely than carbamazepine (Tegretol, Carbatrol) to completely control partial seizures. It had fewer intolerable side effects than primidone (Mysoline).

Mitchell WG, Chavez JM. Carbamazepine versus phenobarbital for partial onset seizures in children. Epilepsia. 1987 Jan-Feb;28(1):56-60. PMID: 3098555.

Some individuals taking each medication showed changes in behavior or cognition, but overall the groups of children taking one of these two medicines did not differ significantly.

Phenobarbital References for Professionals

In the United States, companies that manufacture medicines are required to publish certain kinds of information about each product. This document is commonly known as a “package insert” because it is usually included with each package of the medicine.

You can also read these documents (also called "prescribing information") online. The U.S. package insert for phenobarbital is found at:

Some of the information may differ in other countries.

The summary of package characteristics can be obtained in any European language from:

Find out how to read and understand a package insert.

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