Phenobarbital for Dizziness and Vertigo

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.

WARNINGS 1 . Habit Forming –Phenobarbital may be habit forming. Tolerance and psychological and physical dependence may occur with continued use ( see DRUG ABUSE AND DEPENDENCE and Pharmacokinetics under CLINICAL PHARMACOLOGY). Patients who have psychologic dependence on barbiturates may increase the dosage or decrease the dosage interval without consulting a physician and may subsequently develop a physical dependence on barbiturates. In order 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 a person who is dependent on the drug may result in withdrawal symptoms, including delirium, convulsions, and possibly death. Barbiturates should be withdrawn gradually from any patient known to be taking excessive doses over long periods of time ( see DRUG ABUSE AND DEPENDENCE). 2. 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. 3 . Usage in Pregnancy –Barbiturates can cause fetal damage 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. Barbiturates readily cross the placental barrier and are distributed throughout fetal tissues; the highest concentrations are 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 women who receive barbiturates throughout the last trimester of pregnancy ( see DRUG ABUSE AND DEPENDENCE). If phenobarbital is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 4. Usage in Children –Phenobarbital has been reported to be associated with cognitive deficits in children taking it for complicated febrile seizures. 5 . Synergistic Effects –The concomitant use of alcohol or other CNS depressants may produce additive CNS depressant effects. 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. 1. 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. 2. 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. 3. 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 this data to other barbiturates appears valid and warrants serial blood level determinations of the relevant drugs when there are multiple therapies. 1. 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., warfarin, acenocoumarol, dicumarol, and phenprocoumon). Patients stabilized on anticoagulant therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen. 2. 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. 3. 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. 4. 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. 5. 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. 6. CNS Depressants –The concomitant use of other CNS depressants, including other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may produce additive depressant effects. 7. Monoamine Oxidase Inhibitors (MAOIs)– MAOIs prolong the effects of barbiturates, probably because metabolism of the barbiturate is inhibited. 8. 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– 1 . 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 tumo

DRUG 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.

ADVERSE 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