Phenobarbital

1. 
   
2. Phenobarb

Phenobarbital

 Generic name: phenobarbital (FEE noe BAR bi tal)

Brand name: Solfoton, Luminal
Dosage forms: oral elixir (20 mg/5 mL); oral tablet (100 mg; 15 mg; 16.2 mg; 30 mg; 32.4 mg; 60 mg; 64.8 mg; 97.2 mg)
Drug class: Barbiturate anticonvulsants, Barbiturates

What is phenobarbital?

Phenobarbital is a barbiturate that is available by various brand names including luminal and debritone. It is used in the treatment of patients with seizures (epilepsy), for sedation, and for the treatment of withdrawal symptoms associated with alcohol discontinuation.

Phenobarbital is a barbiturate (bar-BIT-chur-ate). Phenobarbital slows the activity of your brain and nervous system.

Phenobarbital is used to treat or prevent seizures. Phenobarbital is also used short-term as a sedative to help you relax.

Warnings

You should not use phenobarbital if you have severe liver disease, severe asthma or COPD, a personal or family history of porphyria, or a history of addiction to drugs similar to phenobarbital.

Indications of Phenobarbital:

• Sedation:

  • Used for sedation.

• Seizures:

  • Used in the management of generalized tonic-clonic, status epilepticus, and partial seizures.

• Off Label Use of Phenobarbital in Adults:

  • Alcohol withdrawal
  • Sedative/hypnotic withdrawal

Phenobarbital dose in adults:

Phenobarbital dose for sedation:

• Oral, IV, IM: 30 to 120 mg per 24 hours in 2 to 3 divided doses.
• maximum: 400 mg per 24 hours.

• Preoperative sedation:

  • IM: 100 to 200 mg 60 to 90 minutes prior to surgery.

Phenobarbital Dose in the treatment of Status epilepticus: IV:

• American Epilepsy Society recommendations:

  • 15 mg/kg as stat dose.
  • Note: Used only when the first-line options such as lorazepam, diazepam, or midazolam or other second line options (eg, fosphenytoin, valproic acid, levetiracetam) are not availble as per AES.

• Neurocritical Care Society recommendation:

  • 20 mg/kg (infused at 50 to 100 mg/minute); the dose may be repeated once after 10 minutes with an additional 5 to 10 mg/kg if required.

Note: May require additional respiratory support in case of concurrent sedation or maximizing the loading dose. Adequate time may not be allowed for achieving peak CNS concentration if repeat doses are administered sooner than 10 to 15 minutes and cause CNS depression.

Phenobarbital (Luminal) Dose in the treatment of Seizures:

• Maintenance dose:

  • Oral, IV: Usual dosage range (limited data available): 2 mg/kg per 24 hours in divided doses.
  • Note: Dosage should according to the individual based upon clinical response and serum concentration; a steady-state level of 20 mg/l is typically achieved by the dose of 2 mg/kg per 24 hours.

• Manufacturer’s labeling:

  • Oral: Current clinical practice may not be reflected by the dosing in the prescribing information. 60 to 200 mg per 24 hours or 50 to 100 mg twice or thrice daily.

Phenobarbital (Luminal) Dose in the treatmend of withdrawal of Alcohol (off-label):

• IV: Starting dose of 260 mg, followed by subsequent doses of 130 mg as required.
• Note: In clinical trials, Clinical Institute Withdrawal Assessment (CIWA) scores were evaluated at half-hour intervals.
• Oral:
  • On day 1, a Fixed-dose regimen of 60 mg QID,
  • On day 2, 60 mg TDS
  • On day 3, 60 mg BD,
  • On day 4, 30 mg BD
• Additional 60 mg may be given for breakthrough withdrawal symptoms.
• In case of substantial withdrawal symptoms including pulse more than 120/min, systolic BP more than 150 mmHg, severe agitation. Given130 mg intramuscular.

Phenobarbital (Luminal) dose in the treatment of Sedative/hypnotic withdrawal (off-label):

Several regimens have been evaluated:

• Taper following dosage conversion:

  • Initial daily requirement: Phenobarbital was substituted in an equivalent dose to the baseline medication (clonazepam 1 mg = phenobarbital 60 mg was used in the study). The calculated baseline total dose should be divided into 4 doses and administered every 6 hours for 48 hours; then the daily requirement should be decreased by 10% per day over the next 10 days.

• Fixed dose taper:

  • Start with 200 mg, followed by 100 mg every 4 hours for 5 doses, 60 mg every 4 hours for 4 doses, and then 60 mg every 8 hours for 3 doses.

 

Phenobarbital (Luminal) Dose in the treatment of Status epilepticus:

• Infants, Children, and Adolescents:

  • IV: Initial: 15-20 mg per kg.
  • Max dose: 1000 mg; may be repeated once after 10-15 minutes if required
  • Max total dose: 40 mg per kg; adequate time may not be allowed for achieving peak CNS concentration if repeat doses are administered sooner than 10 to 15 minutes and cause CNS depression.

Note: In case of maximizing loading dose or concurrent sedative therapy, additional respiratory support may be required.

Phenobarbital (Luminal) Dose in the maintenance therapy of Seizures:

Note:  12 hours are usually allowed to pass after the loading dose, for the administration of the maintenance dose.

Manufacturer’s labeling:

• • Infants, Children, and Adolescents: Oral: 3-6 mg/kg/day.

• Alternate dosing: Limited data available

  • Initial: Oral, IV:
    • Infants and Children ≤5 years: 3-5 mg/kg/day in 1-2 divided doses.
    • Children >5 years: 2-3 mg/kg/day in 1-2 divided doses.
    • Adolescents: 1-3 mg/kg/day in 1-2 divided doses.
  • Usual dosing range: Note: Manage dose according to the individual based upon clinical response and serum concentration; OD doses, in children and adolescents, is usually administered at bedtime. Some centers have used:
    • Infants: 5-6 mg/kg/day in 1-2 divided doses.
    • Children:
      • 1-5 years: 6-8 mg/kg/day in 1-2 divided doses.
      • 5-12 years: 4-6 mg/kg/day in 1-2 divided doses.
    • Adolescents: 1-3 mg/kg/day in 1-2 divided doses.

Phenobarbital (Luminal) Dose for Sedation:

Note: Prefer the newer, shorter-acting agents.

Manufacturer’s labeling:

• • Children and Adolescents: Oral: 2 mg/kg/dose thrice a day.
  • maximum dose: 40 mg.

• Alternate dosing: Limited data available:

  • Infants and Children: IM, Oral: 2-3 mg/kg/day in divided doses (twice or thrice a day).

Phenobarbital (Luminal) dose to treat Insomnia (hypnotic):

Limited data available; shorter-acting agents may be preferable:

• Infants and Children:

  • IM, Oral: 2-3 mg/kg/dose; dose may be repeated after 12-24 hours as per need
  • some centers have used: IM, IV: 3-5 mg/kg at night.

Phenobarbital (Luminal) dose to treat Hyperbilirubinemia: Limited data available:

• Infants and Children:

  • Oral: Usual range: 3-8 mg/kg/day in 2-3 divided doses; in case reports, doses up to 10 mg/kg/day have been used.
  • In Crigler Najjar Syndrome, a dose of 5 mg/kg/day has been used for treating hyperbilirubinemia and for reduction of serum bilirubin concentrations. Not to be used in biliary cirrhosis due to sedation and other adverse effects.

Phenobarbital (Luminal) Dose in the prevention of Sedative/hypnotic withdrawal;

conversion of Pentobarbital to Phenobarbital (Pentobarbital infusion, a total cumulative Pentobarbital dose ≥25 mg/kg or duration ≥5-7 days): Limited data available:

• Infants, Children, and Adolescents:

  • The following approach transitioning from pentobarbital to phenobarbital has been described: Pentobarbital infusion should be discontinued, half of the phenobarbital IV loading dose (see table) should be given over one hour followed 6 hours later by the remaining half of phenobarbital loading dose IV (over  one hour).
  • Give intravenous maintenance phenobarbital dose 6 hours after loading dose has been completed; the maintenance phenobarbital dose should be 1/3 of the initial loading dose and given every 12 hours. After the patient stabilizes he should be switched to oral therapy with weekly tapering of 10% to 20%.

Note: This conversion method is based on preliminary data in mechanically ventilated patients. Respiratory status should be monitored closely. Evaluation should be done for withdrawal symptoms.

Pentobarbital Infusion Rate (mg/kg/hour)	Phenobarbital IV Loading Dose (mg/kg)
1 to 2	8
2 to 3	15
3 to 4	20

 

Pregnancy Risk Factor D

• Phenobarbital crosses over the placenta.
• You can find barbiturates within the placenta and fetal liver as well as in the fetal brain. Parenteral administration may result in a similar blood concentration for the mother and the fetus.
• Increased incidence of fetal abnormalities may be due to maternal use.
• The neonate may experience withdrawal symptoms, including seizures and hyperirritability, if used during the third trimester. These withdrawal symptoms can last up to 14 days after the birth.
• While uterine activity is not affected if it is used during labor, it can cause respiratory depression in newborns. Therefore, arrange for resuscitation equipment specifically for premature infants.
• Pregnancy is a good time to avoid epilepsy treatment.
• For women exposed to phenobarbital during pregnancy, a registry is available: During pregnancy, they may enroll themselves into the North American Antiepileptic Drug (AED) Pregnancy Registry (888-2332334 or http://www.aedpregnancyregistry.org).

Use of phenobarbital while breastfeeding

• Breast milk contains phenobarbital.
• In utero exposure may cause a delayed interest in breastfeeding.
• Infantile spasms or other withdrawal symptoms can be caused by abrupt discontinuation of breast-feeding.
• The manufacturer suggests that nursing mothers be cautious when administering phenobarbital.

 

Phenobarbital (Luminal) Dose in Kidney Disease:

• No specific dosage adjustments have been provided in the manufacturer’s labeling; dosage reduction is recommended. Some clinicians have recommended the following guidelines.
  • CrCl ≥10 mL/minute: Dosage adjustment not necessary.
  • CrCl <10 mL/minute: Dose should be administered every 12 to 16 hours.
  • Hemodialysis (moderately dialyzable [20% to 50%]): 50 % dose should be given dose before dialysis and 50% after dialysis.
  • Peritoneal dialysis: 35% to 40% removed; 50% of normal dose should be given.
  • Continuous renal replacement therapy (CRRT): A normal dose should be given along with continuous monitoring of drug levels.

 

Dose in Liver disease:

No specific dosage adjustments have been provided in the manufacturer’s labeling; dosage reduction is recommended. Hepatic impairment increases the exposure of phenobarbital; use cautiously.

 

Side effects of Phenobarbital (Luminal):

• Cardiovascular:

  • Bradycardia
  • Hypotension
  • Syncope
  • Thrombophlebitis (IV)

• Central Nervous System:

  • Agitation
  • Anxiety
  • Ataxia
  • Central Nervous System Stimulation
  • Central Nervous System Depression
  • Confusion
  • Dizziness
  • Drowsiness
  • Hallucination
  • Hangover Effect
  • Headache
  • Impaired Judgement
  • Insomnia
  • Lethargy
  • Nervousness
  • Nightmares

• Dermatologic:

  • Exfoliative Dermatitis
  • Skin Rash
  • Stevens-Johnson Syndrome

• Gastrointestinal:

  • Constipation
  • Nausea
  • Vomiting

• Genitourinary:

  • Oliguria

• Hematologic & Oncologic:

  • Agranulocytosis
  • Thrombocytopenia
  • Megaloblastic Anemia

• Local:

  • Pain At Injection Site

• Neuromuscular & Skeletal:

  • Hyperkinesia
  • Laryngospasm

• Respiratory:

  • Apnea (Especially With Rapid IV Use)
  • Hypoventilation
  • Respiratory Depression

 

Contraindications to Phenobarbital (Luminal):

• Hypersensitivity to phenobarbital, barbiturates, or any other component of the formulation
• Hepatic impairment marked
• Dyspnea and airway obstruction
• Porphyria (manifest, latent)
• Intra-arterial administration
• Subcutaneous administration
• Patients who have a history of sedative/hypnotic dependence;
• Nephritic syndrome patients (large doses)

Warnings and Precautions

• CNS depression:

  • Patients should be aware that CNS depression can occur after using it, impairing mental or physical abilities.

• Hypersensitivity

  • Exfoliative dermatitis or Stevens-Johnson Syndrome can sometimes lead to death.
  • If you experience any allergic reactions, discontinue use.

• Paradoxical stimulatory response

  • Patients with chronic or acute pain, as well as pediatric patients, can experience paradoxical reactions, such as agitation or hyperactivity.

• Respiratory depression

  • Intravenous administration can cause respiratory depression. Use caution.

• Anemia:

  • Be careful when using it in anemic patients.

• Cardiac disease

  • Avoid use in patients with heart disease or hemodynamically unstable patients (hypotension and shock).

• Depression

  • Be careful in patients with depression.

• Diabetes:

  • Be careful in patients with diabetes.

• Use of drugs:

  • Be cautious as you may become dependent on drugs.
  • Tolerance, psychological and/or physical dependence may result from prolonged use.

• Hepatic impairment

  • Be careful. Patients with premonitory signs or symptoms of hepatic impairment should be avoided.

• Hyperthyroidism:

  • Be careful in patients with hyperthyroidism.

• Hypoadrenalism

  • Be careful in patients with adrenal insufficiency.

• Renal impairment

  • Be careful in patients with kidney impairment.

 

Monitoring parameters:

• Phenobarbital serum concentrations (as clinically indicated)
• CNS status
• CBC with differential
• Liver function tests
• Renal function tests
• Seizure activity
• Signs and symptoms of suicidality (eg, anxiety, depression, behavior changes)

IV use:

• Respiratory rate
• Pulse rate
• Bp
• IV site (stop the injection if patient develops of pain in the limb)

 

How to administer Phenobarbital (Luminal)?

Administer IV, IM, or orally.

As per the manufacturer the rapid IV administration >60 mg/minute should be avoided. The Neurocritical Care Society has recommended that in the setting of status epilepticus, it should be administered at a rate of 50 to 100 mg/minute.

Avoid extravasation and SubQ administration.

Contraindicated to be used as an intra-arterial injection.

IM injection should be injected deep into muscle. Do not exceed dose from 5 ml per injection site as it can cause tissue irritation.

 

Mechanism of action of Phenobarbital (Luminal):

It is a barbiturate that acts long-lastingly and has sedative, anticonvulsant, and hypnotic properties. Barbiturates can cause depression in the sensory cortex, lower motor activity, alter cerebellar functions, and induce drowsiness, sleepiness, and hypnosis. When used in high doses, barbiturates can cause respiratory depression due to their CNS depressant effects.

Start of action: It takes >=60 minutes for oral administration and 5 minutes for IV administration

Peak effect: IV: CNS Depression occurs in >=15 Minutes

Duration:  10 to 12 hours with oral administration & >6 hours with IV administration

Absorption: Rapid absorption when given orally

Distribution:

Neonates and Young Infants: V : 0.71 to 1.17 L/kg

Older Infants and Children: V : 0.57 to 0.7 L/kg

Adults: V : 0.54 to 0.73 L/kg

Protein binding:

Neonates: 36% to 43%

Adults: 50% to 60%

Metabolism: Metabolised in the liver mainly by oxidation via CYP2C9 and to a lesser extent via CYP2C19 and CYP2E1, and by N-glucosidation

Bioavailability: Adults: 95% to 100% when given orally

Half-life elimination:

• Neonates (<48 hours old)
• Infants, and Children: ~110 hours (60 to 180 hours)
• Adults: ~79 hours (range: 53 to 118 hours)

Time to peak, serum: 1.4 hours (0.5 to 4 hours) with oral administration

Excretion:

• 25% to 50% as unchanged drug in urine
• minimally excreted in feces

 

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of phenobarbital can be fatal.

Overdose symptoms may include slow or shallow breathing, weak pulse, cold or clammy skin, little or no urination, pinpoint pupils, feeling cold, or fainting.

What should I avoid while taking phenobarbital?

Drinking alcohol with phenobarbital can cause side effects.

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

International Brand Names of Phenobarbital:

• Alepsal
• Andral
• Aparoxal
• Aphenylbarbit
• Barbee
• Barbilettae
• Barbiphenyl
• Bialminal
• Carbital
• Comizial
• Dormital
• Edhanol
• Emgard
• Farmacoletas
• Farmaconal
• Fenemal
• Fenobarbital
• Fenobarbital FNA
• Fenobarbitale
• Fenobarbitale Sodico
• Fenocris
• Fenotal
• Fenros
• Fenton
• Garbital
• Gardenal
• Gardenal Sodium
• Gardenale
• Gardenale[inj.]
• Kaneuron
• Lethyl
• Luminal
• Luminale
• Luminaletas
• Luminalette
• Luminaletten
• Luminale[inj.]
• Luminalum
• Neurobiol
• Noberbar
• Pevalon
• Phenaemal
• Phenaemaletten
• Phenobal
• Phenobarbiton
• Phenobarbiton-natrium
• Phenobarbitone
• Phenobarbitone Injection
• Phenotal
• Phental
• Phincotomaline
• Sedabarb
• Sevenal
• Sevenaletta
• Sibital
• Solminotic
• Tridezibarbitur
• Uni-Feno

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