Antisacer Comp.

Atropine Sulfate:

• Antisacer Comp. (Atropine Sulfate) reviews

Indication: For the treatment of poisoning by susceptible organophosphorous nerve agents having cholinesterase activity as well as organophosphorous or carbamate insecticides.

Antisacer Comp. (Atropine Sulfate), a naturally occurring belladonna alkaloid, is a racemic mixture of equal parts of d- and l-hyoscyamine, whose activity is due almost entirely to the levo isomer of the drug. Antisacer Comp. (Atropine Sulfate) is commonly classified as an anticholinergic or antiparasympathetic (parasympatholytic) drug. More precisely, however, it is termed an antimuscarinic agent since it antagonizes the muscarine-like actions of acetylcholine and other choline esters. Adequate doses of Antisacer Comp. (Atropine Sulfate) abolish various types of reflex vagal cardiac slowing or asystole. The drug also prevents or abolishes bradycardia or asystole produced by injection of choline esters, anticholinesterase agents or other parasympathomimetic drugs, and cardiac arrest produced by stimulation of the vagus. Antisacer Comp. (Atropine Sulfate) may also lessen the degree of partial heart block when vagal activity is an etiologic factor. Antisacer Comp. (Atropine Sulfate) in clinical doses counteracts the peripheral dilatation and abrupt decrease in blood pressure produced by choline esters. However, when given by itself, Antisacer Comp. (Atropine Sulfate) does not exert a striking or uniform effect on blood vessels or blood pressure.

Caffeine Citrate:

• Antisacer Comp. (Caffeine Citrate) reviews

Active ingredient (in each tablet)

Antisacer Comp. (Caffeine Citrate) 200mg

Purpose

Alertness aid

Use

• helps restore mental alertness or wakefulness when experiencing fatigue or drowsiness

Warnings

For occasional use only

Do not use

• in children under 12 years of age
• as a substitute for sleep

When using this product limit the use of Antisacer Comp. (Caffeine Citrate) containing medications, foods, or beverages because too much Antisacer Comp. (Caffeine Citrate) may cause nervousness, irritability, sleeplessness, and occasionally, rapid heartbeat. The recommended dose of this product contains about as much Antisacer Comp. (Caffeine Citrate) as a cup of coffee.

Stop use and ask a doctor if fatigue or drowsiness persists or continues to recur

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

Directions

• adults and children 12 years of age and over: take 1 tablet not more often than every 3 to 4 hours.

Other information

• store at room temperature
• avoid excessive heat (greater than 100°F) or humidity

Inactive ingredients

carnauba wax, colloidal silicon dioxide, D&C yellow #10 aluminum lake, dextrose, FD&C yellow #6 aluminum lake, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, starch, titanium dioxide

Questions or comments?

Call toll-free 1-855-874-0970 weekdays

Display Panel Antisacer Comp. (Caffeine Citrate): 16 ct. Package

Antisacer Comp. (Caffeine Citrate)^®

CAFFEINE ALERTNESS AID

16 TABLETS

200mg each

FUNCTIONAL Antisacer Comp. (Caffeine Citrate)^® for Mental Alertness

SAFE & EFFECTIVE

One tablet is equal to about a cup of coffee

Antisacer Comp. (Caffeine Citrate)^®

Making the Most of Every Day.^®

Tamper Evident Feature: individually sealed in foil for your protection. Do not

use if foil or plastic bubble is torn or punctured.

Vivarin®, Vivarin® and design, stylization and trade dress, and FUNCTIONAL

CAFFEINE® are registered trademarks of Meda AB.

Distributed by:

Meda Consumer Healthcare Inc.

Marietta, GA 30062 ©2011 Meda AB

www.vivarin.com

16 ct. Package

Display Panel Antisacer Comp. (Caffeine Citrate): 40 ct. Package

SAFE & EFFECTIVE

FUNCTIONAL Antisacer Comp. (Caffeine Citrate)^® for Mental Alertness

Antisacer Comp. (Caffeine Citrate)^®

Antisacer Comp. (Caffeine Citrate) ALERTNESS AID

40 Tablets

200mg each

FUNCTIONAL Antisacer Comp. (Caffeine Citrate)^® for Mental Alertness

Tamper Evident Feature: Individually sealed in foil for your protection. Do not use if foil or plastic bubble is torn or punctured.

VIVARIN® helps restore mental alertness or wakefulness when experiencing fatigue or drowsiness (FDA approved uses), so you can accomplish all the things you want to do and all the things you need to do.

Vivarin®, Vivarin® and design, stylization and trade dress, and FUNCTIONAL

CAFFEINE® are registered trademarks of Meda AB.

Made in the U.S.A.

Antisacer Comp. (Caffeine Citrate)^®

Making the Most of Every Day.^®

Distributed by:

Meda Consumer Healthcare Inc.

Marietta, GA 30062 ©2013 Meda AB

www.vivarin.com

40 ct. Package

Phenobarbital:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Antisacer Comp. (Phenobarbital) reviews

INDICATIONS AND USAGE

• Sedative
• Anticonvulsant – For the treatment of generalized and partial seizures.

CONTRAINDICATIONS

Antisacer Comp. (Phenobarbital) is contraindicated in patients who are hypersensitive to barbiturates, in patients with a history of manifest or latent porphyria, and in patients with marked impairment of liver function or respiratory disease in which dyspnea or obstruction is evident.

WARNINGS

• Habit Forming. Antisacer Comp. (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 ).
• 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.
• 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 Antisacer Comp. (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.
• Usage in Pediatric Patients. Antisacer Comp. (Phenobarbital) has been reported to be associated with cognitive deficits 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.

PRECAUTIONS

General

Barbiturates may be habit forming. Tolerance and psychological and physical dependence may occur with continued use. 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 Antisacer Comp. (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.

Drug Interactions

Most reports of clinically significant drug interactions occurring with the barbiturates have involved Antisacer Comp. (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. Antisacer Comp. (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. Antisacer Comp. (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. Antisacer Comp. (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 Antisacer Comp. (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 Antisacer Comp. (Phenobarbital) serum levels; therefore, Antisacer Comp. (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 Antisacer Comp. (Phenobarbital) may decrease the effect of estradiol by increasing its metabolism. There have been reports of patients treated with antiepileptic drugs (e.g., Antisacer Comp. (Phenobarbital)) who become pregnant while taking oral contraceptives. An alternate contraceptive method might be suggested to women taking Antisacer Comp. (Phenobarbital).

Carcinogenesis

• Animal Data. Antisacer Comp. 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 Antisacer Comp. (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 Antisacer Comp. (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.

Usage in Pregnancy

• Teratogenic Effects. Pregnancy Category D – See Usage in Pregnancy under WARNINGS.
• 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 Antisacer Comp. (Phenobarbital) is administered to a nursing woman, because small amounts of barbiturates are excreted in the milk.

ADVERSE REACTIONS

The following adverse reactions have been reported:

CNS Depression – Residual sedation or “hangover”, drowsiness, lethargy, and vertigo. Emotional disturbances and phobias may be accentuated. In some persons, barbiturates such as Antisacer Comp. (Phenobarbital) repeatedly produce excitement rather than depression, and the patient may appear to be inebriated. Irritability and hyperactivity can occur in children. Like other nonanalgesic hypnotic drugs, barbiturates such as Antisacer Comp. (Phenobarbital), when given in the presence of pain, may cause restlessness, excitement, and even delirium. Rarely, the use of barbiturates results in localized or diffuse myalgic, neuralgic, or arthritic pain, especially in psychoneurotic patients with insomnia. The pain may appear in paroxysms, is most intense in the early morning hours, and is most frequently located in the region of the neck, shoulder girdle, and upper limbs. Symptoms may last for days after the drug is discontinued.

Respiratory/Circulatory – Respiratory depression, apnea, circulatory collapse.

Allergic – Acquired hypersensitivity to barbiturates consists chiefly in allergic reactions that occur especially in persons who tend to have asthma, urticaria, angioedema, and similar conditions. Hypersensitivity reactions in this category include localized swelling, particularly of the eyelids, cheeks, or lips, and erythematous dermatitis. Rarely, exfoliative dermatitis (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) may be caused by Antisacer Comp. (Phenobarbital) and can prove fatal. The skin eruption may be associated with fever, delirium, and marked degenerative changes in the liver and other parenchymatous organs. In a few cases, megaloblastic anemia has been associated with the chronic use of Antisacer Comp. (Phenobarbital).

Other – Nausea and vomiting; headache, osteomalacia.

The following adverse reactions and their incidence were compiled from surveillance of thousands of hospitalized patients who received barbiturates. Because such patients may be less aware of the milder adverse effects of barbiturates, the incidence of these reactions may be somewhat higher in fully ambulatory patients.

More than 1 in 100 Patients: The most common adverse reaction, estimated to occur at a rate of 1 to 3 patients per 100, is:

Nervous System: Somnolence

Less than 1 in 100 Patients: Adverse reactions estimated to occur at a rate of less than 1 in 100 patients are listed below, grouped by organ system and by decreasing order of occurrence:

Nervous System: Agitation, confusion, hyperkinesia, ataxia, CNS depression, nightmares, nervousness, psychiatric disturbance, hallucinations, insomnia, anxiety, dizziness, abnormality in thinking

Respiratory System: Hypoventilation, apnea

Cardiovascular System: Bradycardia, hypotension, syncope

Digestive System: Nausea, vomiting, constipation

Other Reported Reactions: Headache, injection site reactions, hypersensitivity reactions (angioedema, skin rashes, exfoliative dermatitis), fever, liver damage, megaloblastic anemia following chronic Antisacer Comp. (Phenobarbital) use

DRUG ABUSE AND DEPENDENCE

Controlled Substance – Antisacer Comp. (Phenobarbital) is a Schedule IV drug.

Dependence – Barbiturates may be habit forming. Tolerance, psychological dependence, and physical dependence may occur, especially following prolonged use of high doses of barbiturates. Daily administration in excess of 400 mg of pentobarbital or secobarbital for approximately 90 days is likely to produce some degree of physical dependence. A dosage of 600 to 800 mg taken for at least 35 days is sufficient to produce withdrawal seizures. The average daily dose for the barbiturate addict is usually about 1.5 g. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than twofold. As this occurs, the margin between intoxicating dosage and fatal dosage becomes smaller.

Symptoms of acute intoxication with barbiturates include unsteady gait, slurred speech, and sustained nystagmus. Mental signs of chronic intoxication include confusion, poor judgment, irritability, insomnia, and somatic complaints.

Symptoms of barbiturate dependence are similar to those of chronic alcoholism. If an individual appears to be intoxicated with alcohol to a degree that is radically disproportionate to the amount of alcohol in his or her blood, the use of barbiturates should be suspected. The lethal dose of a barbiturate is far less if alcohol is also ingested.

The symptoms of barbiturate withdrawal can be severe and may cause death. Minor withdrawal symptoms may appear 8 to 12 hours after the last dose of a barbiturate. These symptoms usually appear in the following order: anxiety, muscle twitching, tremor of hands and fingers, progressive weakness, dizziness, distortion in visual perception, nausea, vomiting, insomnia, and orthostatic hypotension. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of barbiturates. The intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Individuals susceptible to barbiturate abuse and dependence include alcoholics and opiate abusers as well as other sedative-hypnotic and amphetamine abusers.

Drug dependence on barbiturates arises from repeated administration of a barbiturate or agent with barbiturate-like effect on a continuous basis, generally in amounts exceeding therapeutic dose levels. The characteristics of drug dependence on barbiturates include: (a) a strong desire or need to continue taking the drug; (b) a tendency to increase the dose; (c) a psychic dependence on the effects of the drug related to subjective and individual appreciation of those effects; and (d) a physical dependence on the effects of the drug, requiring its presence for maintenance of homeostasis and resulting in a definite, characteristic, and self-limited abstinence syndrome when the drug is withdrawn.

Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. In all cases, withdrawal requires an extended period of time. One method involves substituting a 30-mg dose of Antisacer Comp. (Phenobarbital) for each 100- to 200-mg dose of barbiturate that the patient has been taking. The total daily amount of Antisacer Comp. (Phenobarbital) is then administered in 3 or 4 divided doses, not to exceed 600 mg daily. If signs of withdrawal occur on the first day of treatment, a loading dose of 100 to 200 mg of Antisacer Comp. (Phenobarbital) may be administered IM in addition to the oral dose. After stabilization on Antisacer Comp. (Phenobarbital), the total daily dose is decreased by 30 mg/day as long as withdrawal is proceeding smoothly. A modification of this regimen involves initiating treatment at the patient’s regular dosage level and decreasing the daily dosage by 10% if tolerated by the patient.

Infants who are physically dependent on barbiturates may be given Antisacer Comp. (Phenobarbital), 3 to 10 mg/kg/day. After withdrawal symptoms (hyperactivity, disturbed sleep, tremors, and hyperreflexia) are relieved, the dosage of Antisacer Comp. (Phenobarbital) should be gradually decreased and completely withdrawn over a 2-week period.

OVERDOSAGE

Signs and Symptoms – The onset of symptoms following a toxic oral exposure to Antisacer Comp. (Phenobarbital) may not occur until several hours following ingestion. The toxic dose of barbiturates varies considerably. In general, an oral dose of 1 g of most barbiturates produces serious poisoning in an adult. Death commonly occurs after 2 to 10 g of ingested barbiturate. The sedated, therapeutic blood levels of Antisacer Comp. (Phenobarbital) range between 5 to 40 mcg/mL; the usual lethal blood level ranges from 100 to 200 mcg/mL. Barbiturate intoxication may be confused with alcoholism, bromide intoxication, and various neurologic disorders. Potential tolerance must be considered when evaluating significance of dose and plasma concentration.

The manifestations of a long-acting barbiturate in overdose include nystagmus, ataxia, CNS depression, respiratory depression, hypothermia, and hypotension. Other findings may include absent or depressed reflexes and erythematous or hemorrhagic blisters (primarily at pressure points). Following massive exposure to Antisacer Comp. (Phenobarbital), pulmonary edema, circulatory collapse with loss of peripheral vascular tone, cardiac arrest, and death may occur.

In extreme overdose, all electrical activity in the brain may cease, in which case a “flat” EEG normally equated with clinical death should not be accepted. This effect is fully reversible unless hypoxic damage occurs.

Consideration should be given to the possibility of barbiturate intoxication even in situations that appear to involve trauma.

Complications such as pneumonia, pulmonary edema, cardiac arrhythmias, congestive heart failure, and renal failure may occur. Uremia may increase CNS sensitivity to barbiturates if renal function is impaired. Differential diagnosis should include hypoglycemia, head trauma, cerebrovascular accidents, convulsive states, and diabetic coma.

Treatment – To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.

Alkalinization of urine hastens Antisacer Comp. (Phenobarbital) excretion, but dialysis and hemoperfusion are more effective and cause less troublesome alterations in electrolyte equilibrium. If the patient has chronically abused sedatives, withdrawal reactions may be manifest following acute overdose.

DOSAGE AND ADMINISTRATION

The dose of Antisacer Comp. (Phenobarbital) must be individualized with full knowledge of its particular characteristics. Factors of consideration are the patient’s age, weight, and condition.

Sedation:

For sedation, the drug may be administered in single dose of 30 to 120 mg repeated at intervals: frequency will be determined by the patient’s response. It is generally considered that no more than 400 mg of Antisacer Comp. (Phenobarbital) should be administered during a 24-hour period.

Adults:

Daytime Sedation: 30 to 120 mg daily in 2 to 3 divided doses.

Oral Hypnotic: 100 to 200 mg.

Anticonvulsant Use – Clinical laboratory reference values should be used to determine the therapeutic anticonvulsant level of Antisacer Comp. (Phenobarbital) in the serum. To achieve the blood levels considered therapeutic in pediatric patients, higher per-kilogram dosages are generally necessary for Antisacer Comp. (Phenobarbital) and most other anticonvulsants. In children and infants, Antisacer Comp. (Phenobarbital) at a loading dose of 15 to 20 mg/kg produces blood levels of about 20 mcg/mL shortly after administration.

Antisacer Comp. (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.

Adults: 60 to 200 mg/day.

Pediatric Patients: 3 to 6 mg/kg/day.

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.

HOW SUPPLIED

Antisacer Comp. (Phenobarbital) Tablets, USP 16.2 mg are white, round, biconvex, scored tablets, debossed “5011” and “V” on one side and plain on the reverse side, and supplied as follows:

• Bottles of 100 NDC 0603-5165-21
• Bottles of 1000 NDC 0603-5165-32

Antisacer Comp. (Phenobarbital) Tablets, USP 32.4 mg are white, round, biconvex, scored tablets, debossed “5012” and “V” on one side and plain on the reverse side, and supplied as follows:

• Bottles of 30 NDC 0603-5166-16
• Bottles of 60 NDC 0603-5166-20
• Bottles of 90 NDC 0603-5166-02
• Bottles of 100 NDC 0603-5166-21
• Bottles of 120 NDC 0603-5166-22
• Bottles of 1000 NDC 0603-5166-32

Antisacer Comp. (Phenobarbital) Tablets, USP 64.8 mg are white, round, biconvex, scored tablets, debossed “5013” and “V” on one side and plain on the reverse side, and supplied as follows:

• Bottles of 100 NDC 0603-5167-21
• Bottles of 1000 NDC 0603-5167-32

Antisacer Comp. (Phenobarbital) Tablets, USP 97.2 mg are white, round, biconvex, scored tablets, debossed “5014” and “V” on one side and plain on the reverse side, and supplied as follows:

• Bottles of 100 NDC 0603-5168-21
• Bottles of 1000 NDC 0603-5168-32

Manufactured for:

QUALITEST PHARMACEUTICALS

Huntsville, AL 35811

8180067

Rev 7/14

R4

Phenytoin Sodium:

• Description section
• Clinical pharmacology section
• Indications & usage section
• Contraindications section
• Warnings section
• Precautions section
• Adverse reactions section
• Overdosage section
• Dosage & administration section
• How supplied section
• Spl medguide section
• Antisacer Comp. (Phenytoin Sodium) reviews

DESCRIPTION SECTION

Antisacer Comp. (Phenytoin Sodium), USP is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is sodium 5,5-diphenyl-2,4-imidazolidinedione, having the following structural formula:

Each extended Antisacer Comp. (Phenytoin Sodium) capsule, USP contains 100 mg Antisacer Comp. (Phenytoin Sodium), USP. Each capsule also contains the following inactive ingredients: D&C Red #28, D&C Red #33, FD&C Blue #1, gelatin, hydroxypropyl cellulose, mannitol, magnesium stearate, talc and titanium dioxide. Product in vivo performance is characterized by a slow and extended rate of absorption with peak blood concentrations expected in 4 to 12 hours as contrasted to Prompt Antisacer Comp. (Phenytoin Sodium) Capsules, USP with a rapid rate of absorption with peak blood concentration expected in 1½ to 3 hours.

CLINICAL PHARMACOLOGY SECTION

Mechanism of Action

Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post tetanic potentiation at synapses. Loss of post tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures.

Pharmacokinetics and Drug Metabolism

The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5 to 7 half-lives) after initiation of therapy with recommended doses of 300 mg/day.

When serum level determinations are necessary, they should be obtained at least 5 to 7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient’s next scheduled dose. Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For extended Antisacer Comp. (Phenytoin Sodium) capsules, peak serum levels occur 4 to 12 hours after administration.

Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin.

In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal.

Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but more importantly by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more.

Special Populations

Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations.

Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20 to 30 years of age). Phenytoin dosing requirements are highly variable and must be individualized.

Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics.

Pediatrics: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day).

INDICATIONS & USAGE SECTION

Extended Antisacer Comp. (Phenytoin Sodium) capsules, USP are indicated for the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.

Phenytoin serum level determinations may be necessary for optimal dosage adjustments.

CONTRAINDICATIONS SECTION

Phenytoin, USP is contraindicated in those patients with a history of hypersensitivity to phenytoin, USP, its inactive ingredients, or other hydantoins.

Coadministration of extended Antisacer Comp. (Phenytoin Sodium) is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

WARNINGS SECTION

Effects of Abrupt Withdrawal

Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. In the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including extended Antisacer Comp. (Phenytoin Sodium), increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to 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 patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing extended Antisacer Comp. (Phenytoin Sodium) or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Serious Dermatologic Reactions

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Extended Antisacer Comp. (Phenytoin Sodium) 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 this drug 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.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B*1502.

The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities and the level of dermatologic monitoring have not been studied.

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 extended Antisacer Comp. (Phenytoin Sodium). Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash and/or lymphadenopathy, 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. Extended Antisacer Comp. (Phenytoin Sodium) should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Hypersensitivity

Extended Antisacer Comp. (Phenytoin Sodium) and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity. Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides and oxazolidinediones (e.g., trimethadione) 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 extended Antisacer Comp. (Phenytoin Sodium).

Hepatic Injury

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with extended Antisacer Comp. (Phenytoin Sodium). These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, extended Antisacer Comp. (Phenytoin Sodium) should be immediately discontinued and not readministered.

Hematopoietic System

Hematopoietic complications, some fatal, have occasionally been reported in association with administration of extended Antisacer Comp. (Phenytoin Sodium). These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis and pancytopenia with or without bone marrow suppression.

There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma and Hodgkin’s disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS.

In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

Effects on Vitamin D and Bone

The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis and osteomalacia) and bone fractures. Phenytoin induces hepatic metabolizing enzymes. This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia and hypophosphatemia. Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines.

Effects of Alcohol Use on Phenytoin Serum Levels

Acute alcoholic intake may increase phenytoin serum levels, while chronic alcohol use may decrease serum levels.

Exacerbation of Porphyria

In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.

Usage In Pregnancy:

Clinical:

• 
  

  Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage. However, postpartum restoration of the original dosage will probably be indicated.
  

• 
  

  Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus.
  

Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly) and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs.

Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy.

Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

Preclinical:

Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.

PRECAUTIONS SECTION

General:

The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.

A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. If early signs of dose-related CNS toxicity develop, plasma levels should be checked immediately.

Hyperglycemia, resulting from the drug’s inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients.

Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated.

Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed.

Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended.

Information for Patients

Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking extended Antisacer Comp. (Phenytoin Sodium). Instruct patients to take extended Antisacer Comp. (Phenytoin Sodium) only as prescribed.

Patients taking phenytoin should be advised of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc.

Patients should be made aware of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use.

Patients should also be cautioned on the use of other drugs or alcoholic beverages without first seeking the physician’s advice.

The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications.

Patients, their caregivers, and families should be counseled that AEDs, including extended Antisacer Comp. (Phenytoin Sodium), may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334.

Do not use capsules which are discolored.

Laboratory Tests:

Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL).

Drug Interactions:

Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected.

The most commonly occurring drug interactions are listed below:

Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted.

Drugs that affect phenytoin concentrations:

• Drugs that may increase phenytoin serum levels include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, diazepam, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone and warfarin.
• Drugs that may decrease phenytoin levels, include: anti-cancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate) carbamazepine, chronic alcohol abuse, folic acid, fosamprenavir, nelfinavir, reserpine, ritonavir, St. John’s Wort, sucralfate and vigabatrin.
• Administration of phenytoin with preparations that increase gastric pH (e.g., supplements or antacids containing calcium carbonate, aluminum hydroxide and magnesium hydroxide) may affect the absorption of phenytoin. In most cases where interactions were seen, the effect is a decrease in phenytoin levels when the drugs are taken at the same time. When possible, phenytoin and these products should not be taken at the same time of day.
• Drugs that may either increase or decrease phenytoin serum levels, include: phenobarbital, sodium valproate and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable.
• The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.

Drugs affected by phenytoin:

• Drugs that should not be coadministered with phenytoin: Delavirdine.
• Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline and vitamin D.
• Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.
• Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents (felbamate, topiramate, oxcarbazepine, quetiapine) atorvastatin, cyclosporine, digoxin, fluvastatin, folic acid, mexiletine, nisoldipine, praziquantel and simvastatin.
• Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir.
• Resistance to the neuromuscular blocking action of the non-depolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
• The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.

Drug Enteral Feeding/Nutritional Preparations Interaction:

Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients.

Drug/Laboratory Test Interactions:

Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline phosphatase and gamma glutamyl transpeptidase (GGT).

Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations.

Carcinogenesis:

See WARNINGS section for information on carcinogenesis.

Pregnancy: Pregnancy Category D; See WARNINGS section.

To provide information regarding the effects of in utero exposure to extended Antisacer Comp. (Phenytoin Sodium), physicians are advised to recommend that pregnant patients taking extended Antisacer Comp. (Phenytoin Sodium) enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Nursing Mothers:

Infant breast-feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk.

Pediatric Use: See DOSAGE AND ADMINISTRATION section.

Geriatric Use: Phenytoin clearance tends to decrease with increasing age.

ADVERSE REACTIONS SECTION

Body as a Whole: Allergic reactions in the form of rash and rarely more serious forms and DRESS have been observed. Anaphylaxis has also been reported.

There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa and immunoglobulin abnormalities.

Nervous System: The most common manifestations adverse reactions encountered with phenytoin therapy are referable to this nervous system reactions and are usually dose-related. These Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias and headaches have also been observed. There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs.

A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, Nnausea, vomiting, constipation, enlargement of the lips,and gingival hyperplasia, toxic hepatitis and liver damage.

Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. There have also been reports of hypertrichosis.

Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma and Hodgkin’s disease have been reported.

Special Senses: Altered taste sensation including metallic taste.

Urogenital: Peyronie’s disease.

OVERDOSAGE SECTION

The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression.

There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL; dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery.

Treatment:

Treatment is nonspecific since there is no known antidote.

The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients.

In acute overdosage, the possibility of other CNS depressants, including alcohol, should be borne in mind.

DOSAGE & ADMINISTRATION SECTION

Serum concentrations should be monitored in changing from extended Antisacer Comp. (Phenytoin Sodium) capsules, USP to Prompt Antisacer Comp. (Phenytoin Sodium) Capsules, USP, and from the sodium salt to the free acid form.

Extended Antisacer Comp. (Phenytoin Sodium) capsules, USP are formulated with the sodium salt of phenytoin. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.

General:

Dosage should be individualized to provide maximum benefit. In some cases, serum blood level determinations may be necessary for optimal dosage adjustments-the clinically effective serum level is usually 10 to 20 mcg/mL. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.

Adult

Dosage:

Divided daily

Dosage:

Patients who have received no previous treatment may be started on one 100-mg extended Antisacer Comp. (Phenytoin Sodium) capsule, USP three times daily and the dosage then adjusted to suit individual requirements. For most adults, the satisfactory maintenance dosage will be one capsule three to four times a day. An increase up to two capsules three times a day may be made, if necessary.

Once-a-day

Dosage:

In adults, if seizure control is established with divided doses of three 100-mg extended Antisacer Comp. (Phenytoin Sodium) capsules, USP daily, once-a-day dosage with 300 mg of extended Antisacer Comp. (Phenytoin Sodium) capsules, USP may be considered. Studies comparing divided doses of 300 mg with a single daily dose of this quantity indicated absorption, peak plasma levels, biologic half-life, difference between peak and minimum values, and urinary recovery were equivalent. Once-a-day dosage offers a convenience to the individual patient or to nursing personnel for institutionalized patients and is intended to be used only for patients requiring this amount of drug daily. A major problem in motivating noncompliant patients may also be lessened when the patient can take this drug once a day. However, patients should be cautioned not to miss a dose, inadvertently.

Only extended Antisacer Comp. (Phenytoin Sodium) capsules, USP are recommended for once-a-day dosing. Inherent differences in dissolution characteristics and resultant absorption rates of phenytoin due to different manufacturing procedures and/or dosage forms preclude such recommendation for other phenytoin products. When a change in the dosage form or brand is prescribed, careful monitoring of phenytoin serum levels should be carried out.

Loading dose:

Some authorities have advocated use of an oral loading dose of phenytoin in adults who require rapid steady-state serum levels and where intravenous administration is not desirable. This dosing regimen should be reserved for patients in a clinic or hospital setting where phenytoin serum levels can be closely monitored. Patients with a history of renal or liver disease should not receive the oral loading regimen.

Initially, one gram of extended Antisacer Comp. (Phenytoin Sodium) capsules, USP is divided into three doses (400 mg, 300 mg, 300 mg) and administered at two-hour intervals. Normal maintenance dosage is then instituted 24 hours after the loading dose, with frequent serum level determinations.

Dosing in Special Populations

Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations.

Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.

Pediatric: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years old and adolescents may require the minimum adult dose (300 mg/day).

HOW SUPPLIED SECTION

Extended Antisacer Comp. (Phenytoin Sodium) Capsules, USP 100 mg are supplied as white opaque / light lavender opaque, hard gelatin capsules imprinted with "IP 212" on both cap and body.

They are available as follows:

Bottles of 30: NDC 65162-212-03

Bottles of 100: NDC 65162-212-10

Bottles of 500: NDC 65162-212-50

Bottles of 1000: NDC 65162-212-11

Store at 20° to 25°C (68° to 77°F). Preserve in tight, light-resistant containers. Protect from moisture.

Rx only

SPL MEDGUIDE SECTION

Extended Phenytoin (FEN-i-toyn) Sodium Capsules


Read this Medication Guide before you start taking extended Antisacer Comp. (Phenytoin Sodium) capsules and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about extended Antisacer Comp. (Phenytoin Sodium) capsules, ask your healthcare provider or pharmacist.


What is the most important information I should know about extendedphenytoin sodium capsules?


Do not stop taking extended Antisacer Comp. (Phenytoin Sodium) capsules without first talking to your healthcare provider. Stopping extended Antisacer Comp. (Phenytoin Sodium) capsules suddenly can cause serious problems.


Extended Antisacer Comp. (Phenytoin Sodium) capsules can cause serious side effects including:


1. Like other antiepileptic drugs, extended Antisacer Comp. (Phenytoin Sodium) capsules may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.


Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:


• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood



How can I watch for early symptoms of suicidal thoughts and actions?


• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.



Call your healthcare provider between visits as needed, especially if you are worried about


symptoms.


Do not stop taking extended Antisacer Comp. (Phenytoin Sodium) capsules without first talking to a healthcare provider.


Stopping extended Antisacer Comp. (Phenytoin Sodium) capsules suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).


Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal


thoughts or actions, your healthcare provider may check for other causes.


2. Extended Antisacer Comp. (Phenytoin Sodium) capsules may harm your unborn baby.


• If you take extended Antisacer Comp. (Phenytoin Sodium) capsules during pregnancy, your baby is at risk for serious birth defects.
• Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors.
• If you take extended Antisacer Comp. (Phenytoin Sodium) capsules during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this.
• All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of extended Antisacer Comp. (Phenytoin Sodium) capsules. If the decision is made to use extended Antisacer Comp. (Phenytoin Sodium) capsules, you should use effective birth control (contraception) unless you are planning to become pregnant.
• Tell your healthcare provider right away if you become pregnant while taking extended Antisacer Comp. (Phenytoin Sodium) capsules. You and your healthcare provider should decide if you will take extended Antisacer Comp. (Phenytoin Sodium) capsules while you are pregnant.
• Pregnancy Registry: If you become pregnant while taking extended Antisacer Comp. (Phenytoin Sodium) capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.



3. Swollen glands (lymph nodes)


4. Allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Symptoms can include any of the following:


• swelling of your face, eyes, lips, or tongue
• trouble swallowing or breathing
• a skin rash
• hives
• fever, swollen glands (lymph nodes), or sore throat that do not go away or come and go
• painful sores in the mouth or around your eyes
• yellowing of your skin or eyes
• bruising or bleeding
• severe fatigue or weakness
• severe muscle pain
• frequent infections or an infection that does not go away
• loss of appetite (anorexia)
• nausea or vomiting



Call your healthcare provider right away if you have any of the symptoms listed above.


What are extended Antisacer Comp. (Phenytoin Sodium) capsules?


Extended Antisacer Comp. (Phenytoin Sodium) capsules are a prescription medicine used to treat tonic-clonic (grand mal), complex partial (psychomotor or temporal lobe) seizures, and to prevent and treat seizures that happen during or after brain surgery.


Who should not take extended Antisacer Comp. (Phenytoin Sodium) capsules?


Do not take extended Antisacer Comp. (Phenytoin Sodium) capsules if you:


• are allergic to phenytoin or any of the ingredients in extended Antisacer Comp. (Phenytoin Sodium) capsules. See the end of this leaflet for a complete list of ingredients in extended Antisacer Comp. (Phenytoin Sodium) capsules.
• have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin).
• take delavirdine



What should I tell my healthcare provider before taking extended Antisacer Comp. (Phenytoin Sodium) capsules?


Before you take extended Antisacer Comp. (Phenytoin Sodium) capsules, tell your healthcare provider if you:


• Have or had liver disease
• Have or had porphyria
• Have or had diabetes
• Have or have had depression, mood problems, or suicidal thoughts or behavior
• Are pregnant or plan to become pregnant. If you become pregnant while taking extended Antisacer Comp. (Phenytoin Sodium) capsules, the level of extended Antisacer Comp. (Phenytoin Sodium) in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of extended Antisacer Comp. (Phenytoin Sodium) capsules.
• Are breast feeding or plan to breastfeed. Extended Antisacer Comp. (Phenytoin Sodium) can pass into breast milk. You and your healthcare provider should decide if you will take extended Antisacer Comp. (Phenytoin Sodium) capsules or breastfeed. You should not do both.



Tell your healthcare provider about all the medicines you take, including prescription and


• 
  

  non-prescription medicines, vitamins and herbal supplements.
  

  Taking extended Antisacer Comp. (Phenytoin Sodium) capsules with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.
  

  +Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
  

  How should I take extended Antisacer Comp. (Phenytoin Sodium) capsules?
  

• 
  

  Take extended Antisacer Comp. (Phenytoin Sodium) capsules exactly as prescribed. Your healthcare provider will tell you how much extended Antisacer Comp. (Phenytoin Sodium) capsules to take.
  

• Your healthcare provider may change your dose. Do not change your dose of extended Antisacer Comp. (Phenytoin Sodium) capsules without talking to your healthcare provider.
• Extended Antisacer Comp. (Phenytoin Sodium) capsules can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking extended Antisacer Comp. (Phenytoin Sodium) capsules can help prevent this.
• If you take too much extended Antisacer Comp. (Phenytoin Sodium) capsules, call your healthcare provider or local Poison Control Center right away.
• Do not stop taking extended Antisacer Comp. (Phenytoin Sodium) capsules without first talking to your healthcare provider. Stopping extended Antisacer Comp. (Phenytoin Sodium) capsules suddenly can cause serious problems.



What should I avoid while taking extended Antisacer Comp. (Phenytoin Sodium) capsules?


• Do not drink alcohol while you take extended Antisacer Comp. (Phenytoin Sodium) capsules without first talking to your healthcare provider. Drinking alcohol while taking extended Antisacer Comp. (Phenytoin Sodium) capsules may change your blood levels of extended Antisacer Comp. (Phenytoin Sodium) capsules which can cause serious problems.
• Do not drive, operate heavy machinery, or do other dangerous activities until you know how extended Antisacer Comp. (Phenytoin Sodium) capsules affect you. Extended Antisacer Comp. (Phenytoin Sodium) capsules can slow your thinking and motor skills.



What are the possible side effects of extended Antisacer Comp. (Phenytoin Sodium) capsules?


See “What is the most important information I should know about extended Antisacer Comp. (Phenytoin Sodium) capsules?”


Extended Antisacer Comp. (Phenytoin Sodium) capsules may cause other serious side effects including:


• Softening of your bones (osteopenia, osteoporosis and osteomalacia). This can cause broken bones.
  

  Call your healthcare provider right away, if you have any of the symptoms listed above.
  

  The most common side effects of extended Antisacer Comp. (Phenytoin Sodium) capsules include:
  

• problems with walking and coordination
• slurred speech
• confusion
• dizziness
• trouble sleeping
• nervousness
• tremor
• headache
• nausea
• vomiting
• constipation
• rash



These are not all the possible side effects of extended Antisacer Comp. (Phenytoin Sodium) capsules. For more information, ask your healthcare provider or pharmacist.


Tell your healthcare provider if you have any side effect that bothers you or that does not go away.


Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.


How should I store extended Antisacer Comp. (Phenytoin Sodium) capsules?


• Store extended Antisacer Comp. (Phenytoin Sodium) capsules at room temperature between 68°F to 77°F (20°C to 25°C) in tight, light-resistant containers. Protect from moisture.



Keep extended phenytoin sodiumcapsules and all medicines out of the reach of children.


General information about extended Antisacer Comp. (Phenytoin Sodium) capsules


Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use extended Antisacer Comp. (Phenytoin Sodium) capsules for a condition for which it was not prescribed. Do not give extended Antisacer Comp. (Phenytoin Sodium) capsules to other people, even if they have the same symptoms that you have. It may harm them.


This Medication Guide summarizes the most important information about extended Antisacer Comp. (Phenytoin Sodium) capsules. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about extended Antisacer Comp. (Phenytoin Sodium) capsules that was written for healthcare professionals.


For more information about extended Antisacer Comp. (Phenytoin Sodium) capsules, visit www.amneal.com or call 1-877-835-5472.


What are the ingredients in extended Antisacer Comp. (Phenytoin Sodium) capsules?


Extended Oral Capsule


Extended Antisacer Comp. (Phenytoin Sodium) capsule 100mg: White opaque/lavender opaque, hard gelatin capsules imprinted “IP 212” on both cap and body.


Active ingredient: 100 mg Antisacer Comp. (Phenytoin Sodium)


Inactive ingredients: D&C Red #28, D&C Red #33, FD&C Blue #1, gelatin, hydroxypropyl cellulose, mannitol, magnesium stearate, talc and titanium dioxide.


This Medication Guide has been approved by the U.S. Food and Drug Administration.


Close

815

Potassium Bromide:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Antisacer Comp. (Potassium Bromide) reviews

Antisacer Comp. (Potassium Bromide) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The Antisacer Comp. (Potassium Bromide) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Antisacer Comp. (Potassium Bromide) chloride containing 1500 mg of microencapsulated Antisacer Comp. (Potassium Bromide) chloride, USP equivalent to 20 mEq of Antisacer Comp. (Potassium Bromide) in a tablet.

These formulations are intended to slow the release of Antisacer Comp. (Potassium Bromide) so that the likelihood of a high localized concentration of Antisacer Comp. (Potassium Bromide) chloride within the gastrointestinal tract is reduced.

Antisacer Comp. (Potassium Bromide) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Antisacer Comp. (Potassium Bromide) chloride, and the structural formula is KCl. Antisacer Comp. (Potassium Bromide) chloride, USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.

Antisacer Comp. (Potassium Bromide) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Antisacer Comp. (Potassium Bromide) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Antisacer Comp. (Potassium Bromide) Chloride Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of Antisacer Comp. (Potassium Bromide) chloride.

Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.

CLINICAL PHARMACOLOGY

The Antisacer Comp. (Potassium Bromide) ion is the principal intracellular cation of most body tissues. Antisacer Comp. (Potassium Bromide) ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.

The intracellular concentration of Antisacer Comp. (Potassium Bromide) is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

Antisacer Comp. (Potassium Bromide) is a normal dietary constituent and under steady-state conditions the amount of Antisacer Comp. (Potassium Bromide) absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of Antisacer Comp. (Potassium Bromide) is 50 to 100 mEq per day.

Antisacer Comp. (Potassium Bromide) depletion will occur whenever the rate of Antisacer Comp. (Potassium Bromide) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of Antisacer Comp. (Potassium Bromide) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of Antisacer Comp. (Potassium Bromide) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Antisacer Comp. (Potassium Bromide) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Antisacer Comp. (Potassium Bromide) depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

If Antisacer Comp. (Potassium Bromide) depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental Antisacer Comp. (Potassium Bromide) in the form of high Antisacer Comp. (Potassium Bromide) food or Antisacer Comp. (Potassium Bromide) chloride may be able to restore normal Antisacer Comp. (Potassium Bromide) levels.

In rare circumstances (eg, patients with renal tubular acidosis) Antisacer Comp. (Potassium Bromide) depletion may be associated with metabolic acidosis and hyperchloremia. In such patients Antisacer Comp. (Potassium Bromide) replacement should be accomplished with Antisacer Comp. (Potassium Bromide) salts other than the chloride, such as Antisacer Comp. (Potassium Bromide) bicarbonate, Antisacer Comp. (Potassium Bromide) citrate, Antisacer Comp. (Potassium Bromide) acetate, or Antisacer Comp. (Potassium Bromide) gluconate.

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Antisacer Comp. (Potassium Bromide) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT Antisacer Comp. (Potassium Bromide) PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.

2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.

The use of Antisacer Comp. (Potassium Bromide) salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum Antisacer Comp. (Potassium Bromide) should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with Antisacer Comp. (Potassium Bromide) salts may be indicated.

CONTRAINDICATIONS

Antisacer Comp. (Potassium Bromide) supplements are contraindicated in patients with hyperkalemia since a further increase in serum Antisacer Comp. (Potassium Bromide) concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).

Controlled-release formulations of Antisacer Comp. (Potassium Bromide) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Antisacer Comp. (Potassium Bromide) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Antisacer Comp. (Potassium Bromide) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of Antisacer Comp. (Potassium Bromide) chloride are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.

WARNINGS

Hyperkalemia (see OVERDOSAGE )

In patients with impaired mechanisms for excreting Antisacer Comp. (Potassium Bromide), the administration of Antisacer Comp. (Potassium Bromide) salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given Antisacer Comp. (Potassium Bromide) by the intravenous route but may also occur in patients given Antisacer Comp. (Potassium Bromide) orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Antisacer Comp. (Potassium Bromide) salts in patients with chronic renal disease, or any other condition which impairs Antisacer Comp. (Potassium Bromide) excretion, requires particularly careful monitoring of the serum Antisacer Comp. (Potassium Bromide) concentration and appropriate dosage adjustment.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of Antisacer Comp. (Potassium Bromide) salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.

Interaction with Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some Antisacer Comp. (Potassium Bromide) retention by inhibiting aldosterone production. Antisacer Comp. (Potassium Bromide) supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of Antisacer Comp. (Potassium Bromide) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Antisacer Comp. (Potassium Bromide) chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Antisacer Comp. (Potassium Bromide) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Antisacer Comp. (Potassium Bromide) chloride and thus to minimize the possibility of a high local concentration of Antisacer Comp. (Potassium Bromide) near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral Antisacer Comp. (Potassium Bromide) chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of Antisacer Comp. (Potassium Bromide) chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release Antisacer Comp. (Potassium Bromide) chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Antisacer Comp. (Potassium Bromide) Chloride Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.

Metabolic Acidosis

Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing Antisacer Comp. (Potassium Bromide) salt such as Antisacer Comp. (Potassium Bromide) bicarbonate, Antisacer Comp. (Potassium Bromide) citrate, Antisacer Comp. (Potassium Bromide) acetate, or Antisacer Comp. (Potassium Bromide) gluconate.

PRECAUTIONS

General

The diagnosis of Antisacer Comp. depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for Antisacer Comp. (Potassium Bromide) depletion. In interpreting the serum Antisacer Comp. (Potassium Bromide) level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body Antisacer Comp. (Potassium Bromide) while acute acidosis per se can increase the serum Antisacer Comp. (Potassium Bromide) concentration into the normal range even in the presence of a reduced total body Antisacer Comp. (Potassium Bromide). The treatment of Antisacer Comp. (Potassium Bromide) depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.

Information for Patients

Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  

  1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  

  2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
  

  3. Stir for about half a minute after the tablet(s) has disintegrated.
  

  4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  

  5. Add another 1 fluid ounce of water, swirl, and consume immediately.
  

  6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Antisacer Comp. (Potassium Bromide) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Antisacer Comp. (Potassium Bromide) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.

To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

Laboratory Tests

When blood is drawn for analysis of plasma Antisacer Comp. it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.

Drug Interactions

Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (see WARNINGS ).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Antisacer Comp. is a normal dietary constituent.

Pregnancy Category C

Animal reproduction studies have not been conducted with Antisacer Comp. (Potassium Bromide) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that Antisacer Comp. (Potassium Bromide) supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal Antisacer Comp. ion content of human milk is about 13 mEq per liter. Since oral Antisacer Comp. (Potassium Bromide) becomes part of the body Antisacer Comp. (Potassium Bromide) pool, so long as body Antisacer Comp. (Potassium Bromide) is not excessive, the contribution of Antisacer Comp. (Potassium Bromide) chloride supplementation should have little or no effect on the level in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Antisacer Comp. (Potassium Bromide) Chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection; and it may be useful to monitor renal function.

ADVERSE REACTIONS

One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral Antisacer Comp. (Potassium Bromide) salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.

OVERDOSAGE

The administration of oral Antisacer Comp. (Potassium Bromide) salts to persons with normal excretory mechanisms for Antisacer Comp. (Potassium Bromide) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if Antisacer Comp. (Potassium Bromide) is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum Antisacer Comp. (Potassium Bromide) concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).

Treatment measures for hyperkalemia include the following:

• Patients should be closely monitored for arrhythmias and electrolyte changes.
• Elimination of foods and medications containing Antisacer Comp. (Potassium Bromide) and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
• Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
• Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
• Correction of acidosis, if present, with intravenous sodium bicarbonate.
• Use of exchange resins, hemodialysis, or peritoneal dialysis.

In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum Antisacer Comp. (Potassium Bromide) concentration can produce digitalis toxicity.

The extended release feature means that absorption and toxic effects may be delayed for hours.

Consider standard measures to remove any unabsorbed drug.

DOSAGE AND ADMINISTRATION

The usual dietary intake of Antisacer Comp. (Potassium Bromide) by the average adult is 50 to 100 mEq per day. Antisacer Comp. (Potassium Bromide) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of Antisacer Comp. (Potassium Bromide) from the total body store.

Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of Antisacer Comp. (Potassium Bromide) depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

Each Antisacer Comp. (Potassium Bromide) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of Antisacer Comp. (Potassium Bromide) chloride.

Antisacer Comp. (Potassium Bromide) Chloride Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).

Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  • Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  • Allow approximately 2 minutes for the tablet(s) to disintegrate.
  • Stir for about half a minute after the tablet(s) has disintegrated.
  • Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  • Add another 1 fluid ounce of water, swirl, and consume immediately.
  • Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Antisacer Comp. (Potassium Bromide) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Antisacer Comp. (Potassium Bromide) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

Antisacer Comp. (Potassium Bromide) Chloride Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.

Storage Conditions

Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).

Manufactured by:

Eurand, Inc.

Vandalia, OH 45377 USA

Distributed by:

Watson Pharma, Inc.

Rev. Date (01/09) 173714

Antisacer Comp. (Potassium Bromide) chloride 20 Meq