PHENOBARBITAL Drug Interactions: What You Need to Know

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Drug Interactions (FDA Label)

INTERACTIONS CYP2C9, 2C19, 2E1, UGT Inhibitors: Closely monitor and decrease SEZABY dosage, if needed. (7.1) CYP3A4, 2B6, 2C, UGT Substrates: Substrate dosage adjustment may be needed. (7.1) CNS depressants: Closely monitor for sedation and respiratory depression. (7.2) Drugs that Prolong the QT Interval : Avoid concomitant use. (7.3)

7.1 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 [see Clinical Pharmacology (12.3)] . 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 [see Clinical Pharmacology (12.3)] . 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) [see Clinical Pharmacology (12.3)] . It is likely that concomitant use in neonates will result in a decrease in the exposure of these substrates, which may reduce efficacy.

7.2 CNS Depressants Closely monitor for signs of sedation and respiratory depression with concomitant use of SEZABY with other CNS depressants, including opioids [see Warnings and Precautions (5.1)] . Phenobarbital may cause sedation and respiratory depression [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)] . Other products that may also cause these adverse reactions may have additive pharmacologic effect and may increase the risk of sedation and respiratory depression.

7.3 Drugs that Prolong QT Interval SEZABY may prolong the QT interval [see Warnings and Precautions (5.10) and Clinical Pharmacology (12.2)] . Other products that may also prolong the QTc interval may have additive effects, and products that may increase concentrations of phenobarbital [see Drug Interactions (7.1)] 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

CONTRAINDICATIONS Barbiturates are contraindicated in patients with known barbiturate sensitivity. Barbiturates are also contraindicated in patients with a history of manifest or latent porphyria, marked impairment of liver functions or with severe respiratory distress where dyspnea or obstruction is evident. Large doses are contraindicated in nephritic subjects. Barbiturates should not be administered to persons with known previous addiction to the sedative-hypnotic group since ordinary doses may be ineffectual and may contribute to further addiction. Intraarterial administration is contraindicated. Its consequences vary from transient pain to gangrene. Subcutaneous administration produces tissue irritation, ranging from tenderness and redness to necrosis and is not recommended. (See DOSAGE AND ADMINISTRATION, Treatment of Adverse Effects Due to Inadvertent Error in Administration .)

Phenobarbital Sodium

Injection contains the preservative benzyl alcohol and is not recommended for use in neonates. There have been reports of fatal 'gasping syndrome' in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse.

Habit Forming

Barbiturates may be habit forming. Tolerance and psychological and physical dependence may occur with continued use (see DRUG ABUSE AND DEPENDENCE and CLINICAL PHARMACOLOGY ). Patients who are psychologically dependent on barbiturates may increase the dosage or decrease the dosage interval without consulting a physician and may subsequently develop a physical dependence on barbiturates. To minimize the possibility of overdosage or the development of dependence, the prescribing and dispensing of sedative-hypnotic barbiturates should be limited to the amount required for the interval until the next appointment. Abrupt cessation after prolonged use in the dependent person may result in withdrawal symptoms, including delirium, convulsions and possibly death. Barbiturates should be withdrawn gradually from any patient known to be taking excessive dosage over long periods of time (see DRUG ABUSE AND DEPENDENCE ).

Dermatologic Reactions

Exfoliative dermatitis and Stevens-Johnson syndrome, possibly fatal, are rare hypersensitivity reactions to phenobarbital. Physicians should be alert to signs which may precede the onset of barbiturate- induced cutaneous lesions, and the drug should be discontinued whenever dermatological reactions occur.

Intravenous Administration

Too rapid administration may cause severe respiratory depression, apnea, laryngospasm, hypertension or vasodilation with fall in blood pressure. When administered intravenously, it may require 15 or more minutes before reaching peak concentrations in the brain. Therefore, injecting phenobarbital sodium until the convulsions stop may cause brain levels to exceed that required to control the convulsions and lead to severe barbiturate-induced depression. 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 harm 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. Phenobarbital may cause major fetal malformations. 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 ). Phenobarbital should be used during pregnancy only when clearly indicated. If phenobarbital is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Use in Children Phenobarbital has been reported to be associated with cognitive defects in children taking it for complicated febrile seizures.

Synergistic Effects

The concomitant use of alcohol or other CNS depressants may produce additive CNS depressant effects.

Related Warnings

AND PRECAUTIONS Respiratory Depression or Insufficiency: Abnormal respiration has been observed; careful respiratory monitoring is recommended during and after treatment. (5.4)

Serious Dermatologic

Reactions: Serious and sometimes fatal hypersensitivity reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome, have been reported. SEZABY should be discontinued at the first sign of a rash, unless the rash is clearly not drug related. (5.5)

Drug

Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity : DRESS can be fatal or life-threatening. If signs or symptoms of DRESS are present, evaluate the patient immediately. Discontinue if an alternative etiology cannot be established. (5.6)

Infusion Site

Reactions : SEZABY may cause tissue damage with necrosis; avoid perivascular extravasation or intra-arterial injection. Stop SEZABY if evidence of pain, swelling, discoloration, or temperature change in limb. (5.9) QT Prolongation : Avoid concomitant use of SEZABY in patients who are at significant risk of developing torsade de pointes and with products that may increase the risk of the QTc interval prolongation or products that may increase concentrations of SEZABY. (5.10)

5.1 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 [see Drug Interactions (7.3)] . 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.

5.2 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 [see Indications and Usage (1) and Dosage and Administration (2)] , 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) [see Drug Abuse and Dependence (9.3)] . 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.

5.3 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 [see Drug Abuse and Dependence (9.2)] .

5.4 Respiratory Depression or Insufficiency In Study 1, 25% of patients treated with phenobarbital developed abnormal respiration [see Adverse Reactions (6.1) and Clinical Studies (14)] . Careful respiratory monitoring is needed during and after the administration of SEZABY.

5.5 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 [see Warnings and Precautions (5.6)] .

5.6 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.

5.7 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.

5.8 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 [see Contraindications (4)] .

5.9 Infusion Site Reactions SEZABY is highly alkaline [see Description (11)] . 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 [see Clinical Pharmacology (12.2)] . 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 [see Drug Interactions (7.3)] . 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 [CI]: 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.

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