Phenobarbital Sodium

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.

For injection: 100 mg of phenobarbital sodium as a white to off-white lyophilized powder in a single-dose vial for reconstitution. For injection: 100 mg of phenobarbital sodium lyophilized powder in a single-dose vial for reconstitution

SEZABY is contraindicated in patients with: acute porphyrias [see Warnings and Precautions (5.8)], or a history of hypersensitivity reaction to phenobarbital or other barbiturates [see Warnings and Precautions (5.7)] Acute porphyrias (4) Hypersensitivity to phenobarbital or other barbiturates (4)

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. […]

The following clinically significant adverse reactions are described elsewhere in the labeling: Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)] Dependence and Withdrawal Reactions After Use of SEZABY for a Longer Duration Than Recommended [see Warnings and Precautions (5.2)] Abuse, Misuse, and Addiction with Unapproved Use in Adolescents and Adults [see Warnings and Precautions (5.3)] Respiratory Depression or Insufficiency [see Warnings and Precautions (5.4)] Serious Dermatologic Reactions [see Warnings and Precautions (5.5)] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.6)] Hypersensitivity [see Warnings and Precautions (5.7)] Exacerbation of Porphyria [see Warnings and Precautions (5.8)] Injection Site Reactions [see Warnings and Precautions (5.9)] QT Prolongation [see Warnings and Precautions (5.10)] Embryofetal Toxicity with Unapproved Use in Adolescents and Adults [see Warnings and Precautions (5.11)] Neonatal Adverse Reactions from Unapproved Maternal Phenobarbital Use [see Warnings and Precautions (5.12)] Sedation, Respiratory Depression, and Withdrawal in Neonates Exposed to Phenobarbital Through Breast Milk [see Warnings and Precautions (5.13)] Suicidal Behavior and Ideation with Unapproved use in Adolescents and Adults [see Warnings and Precautions (5.14)] The most common adverse reactions (incidence > 5% patients overall) are abnormal respiration, sedation, feeding disorder, and hypotension. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 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 [see Clinical Studies (14)] . 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.

6.2 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

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.

8.4 Pediatric Use The safety and effectiveness of SEZABY have been established for the treatment of neonatal seizures in term and preterm infants, and the information on this use is discussed throughout the labeling. Juvenile Animal Studies In published studies, administration of antiepileptic drugs, including phenobarbital, to neonatal rats during the period of synaptogenesis has been reported to result in widespread apoptotic neurodegeneration in the developing brain and neurobehavioral deficits that persist into adulthood at doses associated with plasma exposures similar to those anticipated at the doses proposed for humans. The synaptogenetic period in rats is generally thought to correspond in humans to the third trimester of pregnancy through the first 3 to 4 years of life. In rodents, exposure to phenobarbital during the neonatal period has been reported in published literature to result in permanent alterations in male and female reproductive function. Administration of phenobarbital to neonatal rats or hamsters resulted in disruption of testosterone secretory profiles and estrous cyclicity, changes in steroidogenesis, altered sexual behavior, and impaired fertility in adulthood.