Sezaby Drug Information
Generic name: PHENOBARBITAL SODIUM
Uses of Sezaby
is indicated for the treatment of neonatal seizures in term and preterm infants. SEZABY is a barbiturate indicated for the treatment of neonatal seizures in term and preterm infants.
Dosage & Administration of Sezaby
| First loading dose | 20 mg/kg |
|---|---|
| Second loading dose (If clinically indicated)1 | Preterm Infants |
| Term Infants | 20 mg/kg |
| Option 1 | 1.5 mg/kg every 8 hours |
| Option 2 | 2.25 mg/kg every 12 hours |
Side Effects of Sezaby
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The Study 1 was a multicenter, randomized, double-blind, active-controlled study in neonates who were experiencing seizures . Patients were infants younger than 14 days of age with gestational ages between 36 and 44 weeks. Overall, 106 neonates (51 female and 55 male) were randomized to receive either phenobarbital (N=42) or levetiracetam (N=64) as their initial treatment.
Patients received up to two 15-minute infusions of their initially assigned treatment (loading dose(s)) followed by maintenance treatment of up to 5 days. Mean durations of phenobarbital and levetiracetam treatments were 4.3 and 4 days, respectively. Table 2 summarizes the adverse reactions that occurred in 2% or more of neonates in Study 1. Incidences are displayed for neonates who received phenobarbital only and for neonates who received levetiracetam only.
Because patients in Study 1 were neonates, adverse reactions that are verbally reported could not be assessed in this study. Table 2: Adverse Reactions That Occurred in At Least 2% of Neonates Overall in Study 1 by Treatment Received Phenobarbital (N = 32)* % Levetiracetam (N = 19) % Respiration abnormal 25 5 Sedation 16 5 Feeding disorder 16 5 Hypotension 16 0 Bradycardia 3 0 Hyponatremia 3 0 Sepsis 3 0 * Fifty-five neonates received both phenobarbital and levetiracetam and they had a similar adverse reaction profile as neonates who received only phenobarbital.
Postmarketing Experience
The following adverse reactions associated with the use of phenobarbital in neonates were identified in the literature. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular System : Bradycardia, patent ductus arteriosus Dermatologic Reactions : Eczema Hepatic : Abnormal liver function Musculoskeletal : Hypotonia, absent deep tendon reflexes Nervous System : Impaired consciousness, neurological impairment Renal : Abnormal kidney function Respiratory System : Bronchial secretion, respiratory depression
Warnings & Cautions for Sezaby
Risks from
Concomitant Use with Opioids Concomitant use of phenobarbital products, including SEZABY, and opioids may result in profound sedation, respiratory depression, coma, and death . Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. If a decision is made for concomitant use of these drugs, limit dosages and durations to the minimum required, and follow patients for signs and symptoms of respiratory depression and sedation. Practitioners administering SEZABY must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.
Dependence and Withdrawal Reactions After Use of
SEZABY for a Longer Duration Than Recommended The continued use of phenobarbital may lead to clinically significant physical dependence. Although SEZABY is indicated only for short-term use , if used for a longer duration than recommended, abrupt discontinuation or rapid dosage reduction of SEZABY may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) . To reduce the risk of withdrawal reactions in patients receiving SEZABY for a longer duration than recommended, use a gradual taper to discontinue SEZABY (a patient-specific plan should be used to taper the dose). Patients at an increased risk of withdrawal adverse reactions after phenobarbital discontinuation or rapid dosage reduction include those who received higher dosages, or those who had longer durations of use.
Abuse, Misuse, and Addiction with Unapproved Use in Adolescents and Adults
SEZABY is not approved for use in adolescents or adults. The unapproved use of SEZABY in adolescents and adults exposes them to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of barbiturates, including phenobarbital, often (but not always) involve the use of doses exceeding the doses used in clinical practice and commonly involve concomitant use of other drugs, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death .
Respiratory Depression or Insufficiency
In Study 1, 25% of patients treated with phenobarbital developed abnormal respiration . Careful respiratory monitoring is needed during and after the administration of SEZABY.
Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal
necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with the use of phenobarbital. SEZABY should be discontinued at the first sign of a rash, unless the rash is clearly not drug related. If signs or symptoms suggest SJS/TEN, use of SEZABY should not be resumed and alternative therapy should be considered.
If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms .
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with
Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenobarbital. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection.
Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.
If such signs or symptoms are present, the patient should be evaluated immediately. SEZABY should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Hypersensitivity Reactions Phenobarbital-associated hypersensitivity reactions may include symptoms and signs such as
rash, fever, facial or limb edema, and lymphadenopathy. SEZABY is contraindicated in patients who have experienced hypersensitivity to phenobarbital or other barbiturates. Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine) and hydantoins (e.g., phenytoin) in these same patients.
Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to SEZABY. If signs or symptoms of hypersensitivity reactions are present in a patient treated with SEZABY, the patient should be evaluated immediately and SEZABY should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Exacerbation of Porphyria
SEZABY may precipitate acute attacks in patients with acute porphyrias. These episodes may be life-threatening, and include symptoms and signs such as anxiety, confusion, limb or abdominal pain, hyponatremia, seizures, and muscle weakness. Therefore, SEZABY is contraindicated in patients with acute porphyrias .
Infusion Site Reactions
SEZABY is highly alkaline . Therefore, extreme care should be taken to avoid perivascular extravasation or intra-arterial injection. Extravascular injection may cause local tissue damage with subsequent necrosis; consequences of intraarterial injection may vary from transient pain to gangrene of the limb. Any evidence of pain, swelling, discoloration, or temperature change in the limb warrants stopping the injection. 5.10 QT Prolongation SEZABY may prolong the QT interval . Avoid use of SEZABY in patients who are at significant risk of developing torsade de pointes, including those with congenital long QT syndrome, uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, AV block, aortic stenosis, or uncontrolled hypothyroidism.
If use cannot be avoided in these patients, collect ECGs during treatment at specified intervals as clinically indicated, and monitor serum electrolytes and correct abnormalities. Avoid the concomitant use of products that may increase the risk of QTc interval prolongation or products that may increase concentrations of phenobarbital . If concomitant use of a product that also prolongs the QTc interval or that increases SEZABY concentrations is unavoidable, monitor patients for increased risk of QTc interval prolongation. 5.11 Embryofetal Toxicity with Unapproved Use in Adolescents and Adults SEZABY is not approved for use in adolescents or adults. Based on findings from prospective controlled trials, cohort studies, pregnancy registries, and randomized controlled-trials, phenobarbital can cause fetal harm when administered during pregnancy.
Data from observational studies suggest an increased risk of major congenital malformations in infants of mothers who received phenobarbital during pregnancy. 5.12 Neonatal Adverse Reactions from Unapproved Maternal Phenobarbital Use SEZABY is not approved for use in adolescents or adults. Phenobarbital crosses the placenta and may produce respiratory depression, hypotonia, and sedation in neonates of mothers who received phenobarbital during pregnancy. The use of SEZABY late in pregnancy can result in the following adverse reactions in neonates: Sedation (respiratory depression, lethargy, hypotonia) and/or Withdrawal reactions (hyperreflexia, irritability, restlessness, tremors, inconsolable crying and feeding difficulties). Neonatal coagulation defects have also been reported within the first 24 hours in neonates exposed to phenobarbital during pregnancy. 5.13 Sedation, Respiratory Depression, and Withdrawal in Neonates Exposed to Phenobarbital Through Breast Milk SEZABY is not approved for use in adolescents or adults.
Phenobarbital is present and may accumulate in breast milk. Phenobarbital has been detected in some neonates exposed to breast milk from phenobarbital-treated mothers. There are reports of sedation, respiratory depression and withdrawal in infants exposed to phenobarbital through breast milk. 5.14 Suicidal Behavior and Ideation with Unapproved Use in Adolescents and Adults SEZABY is not approved for use in adolescents or adults.
Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in adolescents and adults. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that adult patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval : 1.2, 2.7) of suicidal thinking or behavior compared to adult patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated adult patients was 0.43%, compared to 0.24% among 16,029 placebo-treated adult patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 adult patients treated.
There were four suicides in drug-treated adult patients in the trials and none in placebo-treated adult patients, but the number was too small to allow any conclusion about AED effect on suicide. The increased risk of suicidal thoughts or behavior in adults with AEDs was observed as early as one week after starting AED treatment and persisted for the duration of treatment assessed.
Drug Interactions with Sezaby
Cytochrome P450- or Uridine 5’-diphospho-glucuronosyltransferase (UGT)-Based Interactions
The drug interaction information in Table 3 is based upon published literature in non-neonatal populations, in vitro studies, and the mechanistic knowledge of phenobarbital metabolic pathways . Although the data from the published literature regarding these drug interactions are from non-neonatal populations and the magnitude of the potential drug interactions in neonates have not been characterized, this information still warrants consideration given the potential impact of these possible drug interactions on the safety and efficacy of phenobarbital and CYP2B6, 2C9, 2C19, or UGT substrates in neonates. Table 3: Drug Interactions with SEZABY Effects of Other Drugs on SEZABY CYP2C9, 2C19, 2E1, Uridine 5'-diphospho-glucuronosyltransferases ( UGT) Inhibitors or Inducers Prevention or Management Closely monitor for adverse reactions (e.g., over sedation, prolonged QTc interval, etc.) when used concomitantly with inhibitors of these enzymes and reduced efficacy (e.g., breakthrough seizure) when used with inducers of these enzymes. Consider titration of the SEZABY maintenance dosage accordingly if concomitant use is unavoidable.
Clinical Effect(s) Phenobarbital is a substrate of CYP2C9, CYP2C19, CYP2E1, and UGTs . It is likely that concomitant use will result in an increase in phenobarbital exposure when used with these inhibitors and a reduction when used with these inducers, which may increase the risk of SEZABY adverse reactions or reduce efficacy, respectively when concomitant use in neonates. Effects of Other Drugs on Sezaby CYP3A, 2B6, 2C(s), UGTs Substrates Prevention or Management Closely monitor neonates when SEZABY is used concurrently with substrates of these enzymes and consider increasing the dosage of the substrate accordingly, unless otherwise advised in its Prescribing Information, if concomitant use is unavoidable. Clinical Effect(s) Phenobarbital is an inducer of CYP3A, CYP2B6, CYP2C(s), and UGT(s) . It is likely that concomitant use in neonates will result in a decrease in the exposure of these substrates, which may reduce efficacy.
CNS Depressants
Closely monitor for signs of sedation and respiratory depression with concomitant use of SEZABY with other CNS depressants, including opioids . Phenobarbital may cause sedation and respiratory depression . Other products that may also cause these adverse reactions may have additive pharmacologic effect and may increase the risk of sedation and respiratory depression.
Drugs that Prolong QT Interval
SEZABY may prolong the QT interval . Other products that may also prolong the QTc interval may have additive effects, and products that may increase concentrations of phenobarbital may increase the QT prolongation risk; therefore, avoid concomitant use of SEZABY and these products. If concomitant use of a product that also prolongs the QTc interval or that increases SEZABY concentrations is unavoidable, monitor patients for increased risk of QTc interval prolongation.
Contraindications for Sezaby
is contraindicated in patients with: acute porphyrias, or a history of hypersensitivity reaction to phenobarbital or other barbiturates Acute porphyrias Hypersensitivity to phenobarbital or other barbiturates
Overdosage Information for Sezaby
Overdosage of barbiturates, including phenobarbital, is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur.
In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of barbiturates, particularly in combination with other CNS depressants (including alcohol and opioids) may be fatal . Markedly elevated blood pressure, heart rate, or respiratory rate raise the concern that additional drugs are involved in the overdosage. In managing SEZABY overdosage, employ general supportive measures, including intravenous fluids, pressors, and airway maintenance.
Consider contacting a poison center (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.
Clinical Studies of Sezaby
The effectiveness of phenobarbital for the treatment of neonatal seizures was established in a randomized, double-blind, active-controlled study in neonates who were experiencing seizures (Study 1; NCT01720667). Patients were neonates younger than 14 days of age with gestational ages between 36 and 44 weeks. Fifty-two percent of patients were male. Fifty-six percent of patients were White, 9% were Native Hawaiian or other Pacific Islander, 5% were Black or African American, 5% were Asian, 4% were mixed race, 1% were American Indian or Alaska Native, and 22% were identified as other, or were missing or unknown.
Twenty-six percent of patients were Hispanic or Latino, 60% were not Hispanic or Latino, and 14% were not reported, missing, or unknown. Eligible patients who experienced electrographically-confirmed seizures were randomized to receive either intravenous phenobarbital (N=42) or levetiracetam (N=64). Patients received an initial 15-minute infusion (loading dose) of either 20 mg/kg phenobarbital or 40 mg/kg levetiracetam. If electroencephalographic seizures persisted or recurred any time 15 minutes after the initial infusion completion, an additional infusion of the same treatment was administered (the second loading dose was 20 mg/kg infused over 15 minutes for both drugs). After loading dose(s) of phenobarbital or levetiracetam were administered, maintenance dosing of that treatment was administered regardless of whether seizures subsided.
Maintenance regimens of 1.5 mg/kg/dose of phenobarbital and/or 10 mg/kg/dose of levetiracetam were administered via infusion every 8 hours and continued for up to 5 days. Mean durations of phenobarbital and levetiracetam treatments were 4.3 and 4 days, respectively. If seizures persisted or recurred any time 15 minutes after the second loading dose was completed, the patient also received alternate treatment.
The primary endpoint in Study 1 was the percentage of neonates whose seizures were terminated for at least 24 hours without the need for a second drug for the treatment of their seizures. A total of 94 patients who had neurophysiologist-confirmed seizures were included in the efficacy analysis. Efficacy Results A statistically significantly greater percentage of phenobarbital-treated patients met Study 1’s primary efficacy endpoint, compared to levetiracetam-treated patients.
Table 5 presents the results of the trial’s primary and secondary efficacy analyses. Table 5: Seizure Efficacy Results in Neonates (Study 1) Phenobarbital (N=33) Levetiracetam (N=61) P-value* Primary Endpoint Percentage of patients with seizure termination > 24 hours 1 73% 25% <0.001 Secondary Endpoints Percentage of patients with seizure termination > 48 hours 1 55% 13% <0.001 Percentage of patients with seizure termination > 1 hour 1 85% 43% <0.001** 1 Without need for a second drug to treat seizures N = Total number of patients in each treatment group. *P-value was based on two-sided Fisher’s Exact Test for categorical variables comparing phenobarbital and levetiracetam groups. **Nominal: not controlled for Type I error The outcome of 11 patients who had missing data (3 in the phenobarbital group and 8 in the levetiracetam group) was imputed as not successfully terminating seizures.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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