PHENOBARBITAL: 6,483 Adverse Event Reports & Safety Profile

DESCRIPTION The barbiturates are nonselective central nervous system (CNS) depressants which are primarily used as sedative hypnotics and also anticonvulsants in subhypnotic doses. The barbiturates and their sodium salts are subject to control under the Federal Controlled Substances Act (CIV). Barbiturates are substituted pyrimidine derivatives in which the basic structure common to these drugs is barbituric acid, a substance which has no central nervous system activity. CNS activity is obtained by substituting alkyl, alkenyl or aryl groups on the pyrimidine ring.

Phenobarbital Sodium

Injection, USP is a sterile solution for intramuscular or slow intravenous administration as a long-acting barbiturate. Each mL contains phenobarbital sodium either 65 mg or 130 mg, alcohol 0.1 mL, propylene glycol 0.678 mL and benzyl alcohol 0.015 mL in Water for Injection; hydrochloric acid added, if needed, for pH adjustment. The pH range is 9.2-10.2. Chemically, phenobarbital sodium is 2,4,6(1 H ,3 H ,5 H )-Pyrimidinetrione,5-ethyl-5-phenyl-, monosodium salt and has the following structural formula: C 12 H 11 N 2 NaO 3 MW

254.22 The sodium salt of phenobarbital occurs as a white, slightly bitter powder, crystalline granules or flaky crystals; it is soluble in alcohol and practically insoluble in ether or chloroform.

Structural

Formula

INDICATIONS AND USAGE Parenteral a. Sedative. Sedation is obtainable within an hour, and in adequate dosage, the duration of action is more than six hours. Included in the more common conditions in which the sedative action of this class of drugs is desired are anxiety-tension states, hyperthyroidism, essential hypertension, nausea and vomiting of functional origin, motion sickness, acute labyrinthitis, pylorospasm in infants, chorea and cardiac failure. Phenobarbital is also a useful adjunct in treatment of hemorrhage from the respiratory or gastrointestinal tract. Phenobarbital controls anxiety, decreases muscular activity and lessens nervous excitability in hyperthyroid patients. However, thyrotoxic individuals occasionally react poorly to barbiturates. b. Hypnotic, for the short-term treatment of insomnia, since it appears to lose its effectiveness for sleep induction and sleep maintenance after 2 weeks (see CLINICAL PHARMACOLOGY ). c. Preanesthetic. d. Long-term anticonvulsant, (phenobarbital, mephobarbital and metharbital) for the treatment of generalized tonic-clonic and cortical focal seizures. And, in the emergency control of certain acute convulsive episodes, e.g., those associated with status epilepticus, cholera, eclampsia, cerebral hemorrhage, meningitis, tetanus, and toxic reactions to strychnine or local anesthetics. Phenobarbital sodium may be administered intramuscularly or intravenously as an anticonvulsant for emergency use. 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 the brain level to exceed that required to control the convulsions and lead to severe barbiturate-induced depression. e. Phenobarbital is indicated in pediatric patients as an anticonvulsant and as a sedative, including its preoperative and postoperative use.

DOSAGE AND ADMINISTRATION Dosages of barbiturates must be individualized with full knowledge of their particular characteristics and recommended rates of administration. Factors to consider are the patient's age, weight and condition. Suggested doses of phenobarbital sodium for specific indications follow: Pediatric Dosage Recommended by the American Academy of Pediatrics (intended as a guide)

Preoperative

Sedation: 1 to 3 mg/kg intramuscular or intravenous Anticonvulsion: 4 to 6 mg/kg/day for 7 to 10 days to blood level of 10 to 15 mcg/mL or 10 to 15 mg/kg/day intramuscular or intravenous Status Epilepticus: 15 to 20 mg/kg over 10 to 15 minutes intravenous Adult Dosage (intended as a guide)

Daytime

Sedation: 30 to 120 mg daily in 2 to 3 divided doses intramuscular or intravenous Bedtime Hypnosis: 100 to 320 mg intramuscular or intravenous Preoperative Sedation: intramuscular only - 100 to 200 mg 60 to 90 minutes before surgery Acute Convulsions: 20 to 320 mg intramuscular or intravenous, repeated in 6 hours as necessary Parenteral routes should be used only when oral administration is impossible or impractical. Intramuscular injection of the sodium salts of barbiturates should be made deeply into a large muscle and a volume of 5 mL should not be exceeded at any one site because of possible tissue irritation. Injection into or near peripheral nerves may result in permanent neurological deficit. After intramuscular injection of a hypnotic dose, the patient's vital signs should be monitored. Subcutaneous administration is not recommended (see CONTRAINDICATIONS ).

Intravenous Administration

Intravenous injection is restricted to conditions in which other routes are not feasible, either because the patient is unconscious (as in cerebral hemorrhage, eclampsia or status epilepticus), or because the patient resists (as in delirium) or because prompt action is imperative. Slow intravenous injection is essential, and patients should be carefully observed during administration. This requires that blood pressure, respiration and cardiac function be maintained, vital signs be recorded and equipment for resuscitation and artificial ventilation be available. The rate of intravenous injection for adults should not exceed 60 mg/min. for phenobarbital sodium. When given intravenously, do not use small veins, such as those on the dorsum of the hand or wrist. Preference should be given to a larger vein to minimize the risk of irritation with the possibility of resultant thrombosis. Avoid administration into varicose veins because circulation there is retarded. Inadvertent injection into or adjacent to an artery has resulted in gangrene requiring amputation of an extremity or a portion thereof. Careful technique, including aspiration, is necessary to avoid inadvertent intraarterial injection. (See below.) Treatment of Adverse Effects Due to Inadvertent Error in Administration Extravasation into subcutaneous tissues causes tissue irritation. This may vary from slight tenderness and redness to necrosis. Recommended treatment includes the application of moist heat and the injection of 0.5% procaine solution into the affected area. Intraarterial injection of any barbiturate must be avoided. The accidental intraarterial injection of a small amount of the solution may cause spasm and severe pain along the course of the artery. The injection should be terminated if the patient complains of pain or if other indications of accidental intraarterial injection occur, such as a white hand with cyanosed skin or patches of discolored skin and delayed onset of hypnosis. The consequences of intraarterial injection of phenobarbital can vary from transient pain to gangrene. It is not possible to formulate strict rules for management of such accidents. The following procedures have been suggested: 1) release of the tourniquet or restrictive garments to permit dilution of injected drug, 2) relief of arterial spasm by injecting 10 mL of a 1% procaine solution into the artery and, if considered necessary, brachial plexus block, 3) prevention of thrombosis by early anticoagulant therapy and 4) supportive treatment.

Anticonvulsant

Use A therapeutic anticonvulsant level of phenobarbital in the serum is 10 to 25 μg/mL. To achieve the blood levels considered therapeutic in children, higher per-kilogram dosages are generally necessary for phenobarbital and most other anticonvulsants. In children and infants, phenobarbital at loading doses of 15 to 20 mg/kg produces blood levels of about 20 μg/mL shortly after administration. In status epilepticus, it is imperative to achieve therapeutic blood levels of a barbiturate (or other anticonvulsants) as rapidly as possible. When administered intravenously, phenobarbital sodium may require 15 minutes or more to attain peak concentrations in the brain. If phenobarbital sodium is injected continuously until the convulsions stop, the brain concentration will continue to rise and can eventually exceed that required to control the seizures. Because a barbiturate-induced depression may occur along with a postictal depression once the seizures are controlled, it is important, therefore, to use the minimal amount required and to wait for the anticonvulsant effect to develop before administering a second dose. Phenobarbital has been used in the treatment and prophylaxis of febrile seizures. However, it has not been established that prevention of febrile seizures influences the subsequent development of epilepsy.

Special Patient Population

Dosage should be reduced in the elderly or debilitated because these patients may be more sensitive to barbiturates. Dosage should be reduced for patients with impaired renal function or hepatic disease. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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.

REACTIONS 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

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 <span class="opacity-50 text-xs">[see Drug Interactions (7.3)]</span> . 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 <span class="opacity-50 text-xs">[see Indications and Usage (1) and Dosage and Administration (2)]</span> , 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) <span class="opacity-50 text-xs">[see Drug Abuse and Dependence (9.3)]</span> . 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 <span class="opacity-50 text-xs">[see Drug Abuse and Dependence (9.2)]</span> .

5.4 Respiratory Depression or Insufficiency In Study 1, 25% of patients treated with phenobarbital developed abnormal respiration <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) and Clinical Studies (14)]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6)]</span> .

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 <span class="opacity-50 text-xs">[see Contraindications (4)]</span> .

5.9 Infusion Site Reactions SEZABY is highly alkaline <span class="opacity-50 text-xs">[see Description (11)]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2)]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.3)]</span> . 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.

PRECAUTIONS General Barbiturates may be habit forming. Tolerance and psychological and physical dependence may occur with continued use (see DRUG ABUSE AND DEPENDENCE ). Barbiturates should be administered with caution, if at all, to patients who are mentally depressed, have suicidal tendencies, or have a history of drug abuse. Elderly or debilitated patients may react to barbiturates with marked excitement, depression, or confusion. In some persons, especially children, barbiturates repeatedly produce excitement rather than depression. In patients with hepatic damage, barbiturates should be administered with caution and initially in reduced doses. Barbiturates should not be administered to patients showing the premonitory signs of hepatic coma. The systemic effects of exogenous and endogenous corticosteroids may be diminished by phenobarbital. Thus, this product should be administered with caution to patients with borderline hypoadrenal function, regardless of whether it is of pituitary or of primary adrenal origin. Information for Patients The following information and instructions should be given to patients receiving barbiturates. The use of barbiturates carries with it an associated risk of psychological and/or physical dependence. The patient should be warned against increasing the dose of the drug without consulting a physician. Barbiturates may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly. Alcohol should not be consumed while taking barbiturates. The concurrent use of the barbiturates with other CNS depressants (e.g., alcohol, narcotics, tranquilizers, and antihistamines) may result in additional CNS-depressant effects.

Laboratory Tests

Prolonged therapy with barbiturates should be accompanied by periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic systems (see General under PRECAUTIONS and ADVERSE REACTIONS ).

Drug Interactions

Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital. However, the application of these data to other barbiturates appears valid and warrants serial blood level determinations of the relevant drugs when there are multiple therapies. Anticoagulants . Phenobarbital lowers the plasma levels of dicumarol and causes a decrease in anticoagulant activity as measured by the prothrombin time. Barbiturates can induce hepatic microsomal enzymes resulting in increased metabolism and decreased anticoagulant response of oral anticoagulants (e.g., acenocoumarol, warfarin, dicumarol, and phenprocoumon). Patients stabilized on anticoagulant therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen. Corticosteroids . Barbiturates appear to enhance the metabolism of exogenous corticosteroids, probably through the induction of hepatic microsomal enzymes. Patients stabilized on corticosteroid therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen. Griseofulvin . Phenobarbital appears to interfere with the absorption of orally administered griseofulvin, thus decreasing its blood level. The effect of the resultant decreased blood levels of griseofulvin on therapeutic response has not been established. However, it would be preferable to avoid concomitant administration of these drugs. Doxycycline . Phenobarbital has been shown to shorten the half-life of doxycycline for as long as 2 weeks after barbiturate therapy is discontinued. This mechanism is probably through the induction of hepatic microsomal enzymes that metabolize the antibiotic. If phenobarbital and doxycycline are administered concurrently, the clinical response to doxycycline should be monitored closely. Phenytoin, Sodium Valproate, Valproic Acid . The effect of barbiturates on the metabolism of phenytoin appears to be variable. Some investigators report an accelerating effect, whereas others report no effect. Because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be monitored more frequently if these drugs are given concurrently. Sodium valproate and valproic acid increase the phenobarbital serum levels; therefore, phenobarbital blood levels should be closely monitored and appropriate dosage adjustments made as clinically indicated.

Cns

Depressants . The concomitant use of other CNS depressants, including other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may produce additive depressant effects.

Monoamine Oxidase

Inhibitors (MAOIs) . MAOIs prolong the effects of barbiturates, probably because metabolism of the barbiturate is inhibited. Estradiol, Estrone, Progesterone, and other Steroidal Hormones . Pretreatment with or concurrent administration of phenobarbital may decrease the effect of estradiol by increasing its metabolism. There have been reports of patients treated with antiepileptic drugs (e.g., phenobarbital) who become pregnant while taking oral contraceptives. An alternate contraceptive method might be suggested to women taking phenobarbital. Carcinogenesis, Mutagenesis, Impairment of Fertility Animal Data . Phenobarbital sodium is carcinogenic in mice and rats after lifetime administration. In mice, it produced benign and malignant liver cell tumors. In rats, benign liver cell tumors were observed very late in life.

Human

Data . In a 29-year epidemiological study of 9,136 patients who were treated on an anticonvulsant protocol that included phenobarbital, results indicated a higher than normal incidence of hepatic carcinoma. Previously, some of these patients had been treated with thorotrast, a drug which is known to produce hepatic carcinomas. Thus, this study did not provide sufficient evidence that phenobarbital sodium is carcinogenic in humans. A retrospective study of 84 children with brain tumors matched to 73 normal controls and 78 cancer controls (malignant disease other than brain tumors) suggested an association between exposure to barbiturates prenatally and an increased incidence of brain tumors.

Pregnancy

1.

Teratogenic Effects Pregnancy

Category D - See Usage in Pregnancy under WARNINGS . 2.

Nonteratogenic Effects

Reports of infants suffering from long-term barbiturate exposure in utero included the acute withdrawal syndrome of seizures and hyperirritability from birth to a delayed onset of up to 14 days (see DRUG ABUSE AND DEPENDENCE ). Labor and Delivery Hypnotic doses of barbiturates do not appear to impair uterine activity significantly during labor. Full anesthetic doses of barbiturates decrease the force and frequency of uterine contractions. Administration of sedative-hypnotic barbiturates to the mother during labor may result in respiratory depression in the newborn. Premature infants are particularly susceptible to the depressant effects of barbiturates. If barbiturates are used during labor and delivery, resuscitation equipment should be available. Data are not available to evaluate the effect of barbiturates when forceps delivery or other intervention is necessary or to determine the effect of barbiturates on the later growth, development, and functional maturation of the child.

Nursing Mothers

Caution should be exercised when phenobarbital is administered to a nursing woman, because small amounts of barbiturates are excreted in the milk.

General

Barbiturates may be habit forming. Tolerance and psychological and physical dependence may occur with continued use (see DRUG ABUSE AND DEPENDENCE ). Barbiturates should be administered with caution, if at all, to patients who are mentally depressed, have suicidal tendencies, or have a history of drug abuse. Elderly or debilitated patients may react to barbiturates with marked excitement, depression, or confusion. In some persons, especially children, barbiturates repeatedly produce excitement rather than depression. In patients with hepatic damage, barbiturates should be administered with caution and initially in reduced doses. Barbiturates should not be administered to patients showing the premonitory signs of hepatic coma. The systemic effects of exogenous and endogenous corticosteroids may be diminished by phenobarbital. Thus, this product should be administered with caution to patients with borderline hypoadrenal function, regardless of whether it is of pituitary or of primary adrenal origin.

Information for Patients The following information and instructions should be given to patients receiving barbiturates. The use of barbiturates carries with it an associated risk of psychological and/or physical dependence. The patient should be warned against increasing the dose of the drug without consulting a physician. Barbiturates may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly. Alcohol should not be consumed while taking barbiturates. The concurrent use of the barbiturates with other CNS depressants (e.g., alcohol, narcotics, tranquilizers, and antihistamines) may result in additional CNS-depressant effects.

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1)]</span> . Phenobarbital may cause sedation and respiratory depression <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.10) and Clinical Pharmacology (12.2)]</span> . Other products that may also prolong the QTc interval may have additive effects, and products that may increase concentrations of phenobarbital <span class="opacity-50 text-xs">[see Drug Interactions (7.1)]</span> 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.

INACTIVE INGREDIENT Inactive ingredients include: colloidal silicon dioxide, lactose anhydrous, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and stearic acid.