Perphyllone

Papaverine Hydrochloride:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Perphyllone (Papaverine Hydrochloride) reviews

Rx Only

This product is to be used by or under the direction of a physician.

Each vial contains a sufficient amount to permit withdrawal and administration of the volume specified on the label.

DESCRIPTION

Perphyllone (Papaverine Hydrochloride), USP, is the hydrochloride of an alkaloid obtained from opium or prepared synthetically. It belongs to the benzylisoquinoline group of alkaloids. It does not contain a phenanthrene group as do morphine and codeine.

Perphyllone (Papaverine Hydrochloride), USP, is 6,7-dimethoxy-1- veratrylisoquinoline hydrochloride and contains, on the dried basis, not less than 98.5% of C₂₀H₂₁NO₄-HCI. The molecular weight is 375.85. The structural formula is as shown.

Perphyllone (Papaverine Hydrochloride) occurs as white crystals or white crystalline powder. One gram dissolves in about 30 mL of water and in 120 mL of alcohol. It is soluble in chloroform and practically insoluble in ether.

Perphyllone (Papaverine Hydrochloride) Injection, USP, is a clear, colorless to pale-yellow solution.

Perphyllone (Papaverine Hydrochloride), for parenteral administration, is a smooth-muscle relaxant that is available in vials containing 30 mg/mL. Each vial also contains edetate disodium 0.005%. The 10 mL vials also contain chlorobutanol 0.5% as a preservative. pH may be adjusted with sodium citrate and/or citric acid.

Adobe Systems

CLINICAL PHARMACOLOGY

The most characteristic effect of papaverine is relaxation of the tonus of all smooth muscle, especially when it has been spasmodically contracted. Perphyllone (Papaverine Hydrochloride) apparently acts directly on the muscle itself. This relaxation is noted in the vascular system and bronchial musculature and in the gastrointestinal, biliary and urinary tracts.

The main actions of papaverine are exerted on cardiac and smooth muscle. Papaverine relaxes various smooth muscles, especially those of larger arteries; this relaxation may be prominent if spasm exists. The antispasmodic effect is a direct one and unrelated to muscle innervation, and the muscle still responds to drugs and other stimuli causing contraction. Papaverine has minimal actions on the central nervous system, although very large doses tend to produce some sedation and sleepiness in some patients. In certain circumstances, mild respiratory stimulation can be observed, but this is therapeutically inconsequential. Papaverine stimulates respiration by acting on carotid and aortic body chemoreceptors.

Papaverine relaxes the smooth musculature of the larger blood vessels, including the coronary, cerebral, peripheral, and pulmonary arteries. This action is particularly evident when such vessels are in spasm, induced reflexly or by drugs, and it provides the basis for the clinical use of papaverine in peripheral or pulmonary arterial embolism.

Experimentally in dogs, the alkaloid has been shown to cause fairly marked and long-lasting coronary vasodilatation and an increase in coronary blood flow. However, it also appears to have a direct inotropic effect and, when increased mechanical activity coincides with decreased systemic pressure, increases in coronary blood flow may not be sufficient to prevent brief periods of hypoxic myocardial depression.

Papaverine is effective by all routes of administration. A considerable fraction of the drug localizes in fat deposits and in the liver, with the remainder being distributed throughout the body. It is metabolized in the liver. About 90% of the drug is bound to plasma protein. Although estimates of its biologic half-life vary widely, reasonably constant plasma levels can be maintained with oral administration at 6 hour intervals. The drug is excreted in the urine in an inactive form.

INDICATIONS AND USAGE

Papaverine is recommended in various conditions accompanied by spasm of smooth muscle, such as vascular spasm associated with acute myocardial infarction (coronary occlusion), angina pectoris, peripheral and pulmonary embolism, peripheral vascular disease in which there is a vasospastic element, or certain cerebral angiospastic states; and visceral spasm, as in ureteral, biliary, or gastrointestinal colic.

CONTRAINDICATIONS

Intravenous injection of papaverine is contraindicated in the presence of complete atrioventricular heart block. When conduction is depressed, the drug may produce transient ectopic rhythms of ventricular origin, either premature beats or paroxysmal tachycardia.

Perphyllone (Papaverine Hydrochloride) is not indicated for the treatment of impotence by intracorporeal injection. The intracorporeal injection of Perphyllone (Papaverine Hydrochloride) has been reported to have resulted in persistent priapism requiring medical and surgical intervention.

PRECAUTIONS

General

Perphyllone Injection, USP, should not be added to Lactated Ringer’s Injection, because precipitation would result.

Perphyllone (Papaverine Hydrochloride) should be used with caution in patients with glaucoma. The medication should be discontinued if hepatic hypersensitivity with gastrointestinal symptoms, jaundice, or eosinophilia becomes evident or if liver function test values become altered.

Pregnancy

Pregnancy Category C - No teratogenic effects were observed in rats when Perphyllone (Papaverine Hydrochloride) was administered subcutaneously as a single agent. It is not known whether papaverine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Perphyllone (Papaverine Hydrochloride) should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Perphyllone is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children have not been established.

ADVERSE REACTIONS

The following side effects have been reported: general discomfort, nausea, abdominal discomfort, anorexia, constipation or diarrhea, skin rash, malaise, vertigo, headache, intensive flushing of the face, perspiration, increase in the depth of respiration, increase in heart rate, a slight rise in blood pressure, and excessive sedation.

Hepatitis, probably related to an immune mechanism, has been reported infrequently. Rarely, this has progressed to cirrhosis.

DRUG ABUSE AND DEPENDENCE

Drug dependence resulting from the abuse of many of the selective depressants, including Perphyllone (Papaverine Hydrochloride), has been reported.

OVERDOSAGE

Signs and Symptoms –

The symptoms of toxicity from Perphyllone often result from vasomotor instability and include nausea, vomiting, weakness, central nervous system depression, nystagmus, diplopia, diaphoresis, flushing, dizziness, and sinus tachycardia. In large overdoses, papaverine is a potent inhibitor of cellular respiration and a weak calcium antagonist. Following an oral overdose of 15 g, metabolic acidosis with hyperventilation, hyperglycemia, and hypokalemia have been reported. No information on toxic serum concentrations is available.

Following intravenous overdosing in animals, seizures, tachyarrhythmias, and ventricular fibrillation have been reported. The oral median lethal dose in rats is 360 mg/kg.

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 Physician’s 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 vital signs, blood gases, blood chemistry values, and other variables.

If convulsions occur, consider diazepam, phenytoin, or phenobarbital. If the seizures are refractory, general anesthesia with thiopental or halothane and paralysis with a neuromuscular blocking agent may be necessary.

For hypotension, consider intravenous fluids, elevation of the legs, and an inotropic vasopressor, such as dopamine or norepinephrine (levarterenol). Theoretically, calcium gluconate may be helpful in treating some of the toxic cardiovascular effects of papaverine; monitor the ECG and plasma calcium concentrations.

Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of Perphyllone (Papaverine Hydrochloride).

DOSAGE AND ADMINISTRATION

Perphyllone (Papaverine Hydrochloride) may be administered intravenously or intramuscularly. The intravenous route is recommended when an immediate effect is desired, but the drug must be injected slowly over the course of 1 or 2 minutes to avoid uncomfortable or alarming side effects.

Parenteral administration of Perphyllone (Papaverine Hydrochloride) in doses of 1 to 4 mL is repeated every 3 hours as indicated. In the treatment of cardiac extrasystoles, 2 doses may be given 10 minutes apart.

HOW SUPPLIED

Perphyllone (Papaverine Hydrochloride) Injection, USP, 30 mg/mL

0517-4002-25 2 mL Vial packaged in boxes of 25

0517-4010-01 10 mL Multiple Dose Vial* packaged individually

*The 10 mL Multiple Dose Vial contains chlorobutanol 0.5% as a preservative.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).

PROTECT FROM LIGHT. RETAIN IN CARTON UNTIL TIME OF USE.

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

IN4002

Rev. 1/09

Phenobarbital:

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

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

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

Carcinogenesis

• Animal Data. Perphyllone 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 Perphyllone (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 Perphyllone (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 Perphyllone (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 Perphyllone (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 Perphyllone (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 Perphyllone (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 Perphyllone (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 Perphyllone (Phenobarbital) use

DRUG ABUSE AND DEPENDENCE

Controlled Substance – Perphyllone (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 Perphyllone (Phenobarbital) for each 100- to 200-mg dose of barbiturate that the patient has been taking. The total daily amount of Perphyllone (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 Perphyllone (Phenobarbital) may be administered IM in addition to the oral dose. After stabilization on Perphyllone (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 Perphyllone (Phenobarbital), 3 to 10 mg/kg/day. After withdrawal symptoms (hyperactivity, disturbed sleep, tremors, and hyperreflexia) are relieved, the dosage of Perphyllone (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 Perphyllone (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 Perphyllone (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 Perphyllone (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 Perphyllone (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 Perphyllone (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 Perphyllone (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 Perphyllone (Phenobarbital) in the serum. To achieve the blood levels considered therapeutic in pediatric patients, higher per-kilogram dosages are generally necessary for Perphyllone (Phenobarbital) and most other anticonvulsants. In children and infants, Perphyllone (Phenobarbital) at a loading dose of 15 to 20 mg/kg produces blood levels of about 20 mcg/mL shortly after administration.

Perphyllone (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

Perphyllone (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

Perphyllone (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

Perphyllone (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

Perphyllone (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

Theophylline Hydrate:

• Description
• Clinical pharmacology
• Clinical studies
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Perphyllone (Theophylline Hydrate) reviews

DESCRIPTION

Perphyllone (Theophylline Hydrate)^® (theophylline, anhydrous) Tablets in a controlled-release system allows a 24-hour dosing interval for appropriate patients.

Perphyllone (Theophylline Hydrate) is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous Perphyllone (Theophylline Hydrate) has the chemical name 1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula:

The molecular formula of anhydrous Perphyllone (Theophylline Hydrate) is C₇H₈N₄O₂ with a molecular weight of 180.17.

Each controlled-release tablet for oral administration, contains 400 or 600 mg of anhydrous Perphyllone (Theophylline Hydrate).

Inactive Ingredients: cetostearyl alcohol, hydroxyethyl cellulose, magnesium stearate, povidone and talc.

Perphyllone (Theophylline Hydrate) 400 mg

CLINICAL PHARMACOLOGY

Mechanism of Action

Perphyllone has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of Perphyllone (Theophylline Hydrate) are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with Perphyllone (Theophylline Hydrate) appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).

Perphyllone (Theophylline Hydrate) increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.

Serum Concentration-Effect Relationship

Bronchodilation occurs over the serum Perphyllone (Theophylline Hydrate) concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Perphyllone (Theophylline Hydrate) concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Perphyllone (Theophylline Hydrate) concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Perphyllone (Theophylline Hydrate) concentrations between 10 and 15 mcg/mL will achieve most of the drug’s potential therapeutic benefit while minimizing the risk of serious adverse events.

Pharmacokinetics

Overview: Perphyllone is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Perphyllone (Theophylline Hydrate) does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of Perphyllone (Theophylline Hydrate) vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I ) and co-administration of other drugs (see Table II ) can significantly alter the pharmacokinetic characteristics of Perphyllone (Theophylline Hydrate). Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Perphyllone (Theophylline Hydrate) concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter Perphyllone (Theophylline Hydrate) clearance (see PRECAUTIONS, Laboratory Tests ).

Note: In addition to the factors listed above, Perphyllone (Theophylline Hydrate) clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of Perphyllone (Theophylline Hydrate).

Absorption

Perphyllone (Theophylline Hydrate)^® administered in the fed state is completely absorbed after oral administration.

In a single-dose crossover study, two 400 mg Perphyllone (Theophylline Hydrate) Tablets were administered to 19 normal volunteers in the morning or evening immediately following the same standardized meal (769 calories consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). There was no evidence of dose dumping nor were there any significant differences in pharmacokinetic parameters attributable to time of drug administration. On the morning arm, the pharmacokinetic parameters were AUC=241.9±83.0 mcg hr/mL, C_max=9.3±2.0 mcg/mL, T_max=12.8±4.2 hours. On the evening arm, the pharmacokinetic parameters were AUC=219.7±83.0 mcg hr/mL, C_max=9.2±2.0 mcg/mL, T_max=12.5±4.2 hours.

A study in which Perphyllone (Theophylline Hydrate) 400 mg Tablets were administered to 17 fed adult asthmatics produced similar Perphyllone (Theophylline Hydrate) level-time curves when administered in the morning or evening. Serum levels were generally higher in the evening regimen but there were no statistically significant differences between the two regimens.

A single-dose study in 15 normal fasting male volunteers whose Perphyllone (Theophylline Hydrate) inherent mean elimination half-life was verified by a liquid Perphyllone (Theophylline Hydrate) product to be 6.9±2.5 (SD) hours were administered two or three 400 mg Perphyllone (Theophylline Hydrate)^® Tablets. The relative bioavailability of Perphyllone (Theophylline Hydrate) given in the fasting state in comparison to an immediate-release product was 59%. Peak serum Perphyllone (Theophylline Hydrate) levels occurred at 6.9±5.2 (SD) hours, with a normalized (to 800 mg) peak level being 6.2±2.1 (SD). The apparent elimination half-life for the 400 mg Perphyllone (Theophylline Hydrate) Tablets was 17.2±5.8 (SD) hours.

Steady-state pharmacokinetics were determined in a study in 12 fasted patients with chronic reversible obstructive pulmonary disease. All were dosed with two 400 mg Perphyllone (Theophylline Hydrate) Tablets given once daily in the morning and a reference controlled-release BID product administered as two 200 mg tablets given 12 hours apart. The pharmacokinetic parameters obtained for Perphyllone (Theophylline Hydrate) Tablets given at doses of 800 mg once daily in the morning were virtually identical to the corresponding parameters for the reference drug when given as 400 mg BID. In particular, the AUC, C_max and C_min values obtained in this study were as follows:

Single-dose studies in which subjects were fasted for twelve (12) hours prior to and an additional four (4) hours following dosing, demonstrated reduced bioavailability as compared to dosing with food. One single-dose study in 20 normal volunteers dosed with two (2) 400 mg tablets in the morning, compared dosing under these fasting conditions with dosing immediately prior to a standardized breakfast (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). Under fed conditions, the pharmacokinetic parameters were: AUC=231.7±92.4 mcg hr/mL, C_max=8.4±2.6 mcg/mL, T_max=17.3±6.7 hours. Under fasting conditions, these parameters were AUC=141.2±6.53 mcg hr/mL, C_max=5.5±1.5 mcg/mL, T_max=6.5±2.1 hours.

Another single-dose study in 21 normal male volunteers, dosed in the evening, compared fasting to a standardized high calorie, high fat meal (870-1,020 calories, consisting of 33 grams protein, 55-75 grams fat, 58 grams carbohydrates). In the fasting arm subjects received one Perphyllone (Theophylline Hydrate)^® 400 mg Tablet at 8 p.m. after an eight hour fast followed by a further four hour fast. In the fed arm, subjects were again dosed with one 400 mg Perphyllone (Theophylline Hydrate) Tablet, but at 8 p.m. immediately after the high fat content standardized meal cited above. The pharmacokinetic parameters (normalized to 800 mg) fed were AUC=221.8±40.9 mcg hr/mL, C_max=10.9±1.7 mcg/mL, T_max=11.8±2.2 hours. In the fasting arm, the pharmacokinetic parameters (normalized to 800 mg) were AUC=146.4±40.9 mcg hr/mL, C_max=6.7±1.7 mcg/mL, T_max=7.3±2.2 hours.

Thus, administration of single Perphyllone (Theophylline Hydrate) doses to healthy normal volunteers, under prolonged fasted conditions (at least 10 hour overnight fast before dosing followed by an additional four (4) hour fast after dosing) results in decreased bioavailability. However, there was no failure of this delivery system leading to a sudden and unexpected release of a large quantity of Perphyllone (Theophylline Hydrate) with Perphyllone (Theophylline Hydrate) Tablets even when they are administered with a high fat, high calorie meal.

Similar studies were conducted with the 600 mg Perphyllone (Theophylline Hydrate) Tablet. A single-dose study in 24 subjects with an established Perphyllone (Theophylline Hydrate) clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Perphyllone (Theophylline Hydrate) Tablet and one and one-half 400 mg Perphyllone (Theophylline Hydrate) Tablets under fed (using a standard high fat diet) and fasted conditions. The results of this 4-way randomized crossover study demonstrate the bioequivalence of the 400 mg and 600 mg Perphyllone (Theophylline Hydrate) Tablets. Under fed conditions, the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=214.64±55.88 mcg hr/mL, C_max=10.58±2.21 mcg/mL and T_max=9.00±2.64 hours, and for the 600 mg tablet were AUC=207.85±48.9 mcg hr/mL, C_max=10.39±1.91 mcg/mL and T_max=9.58±1.86 hours. Under fasted conditions the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=191.85 ±51.1 mcg hr/mL, C_max= 7.37±1.83 mcg/mL and T_max=8.08±4.39 hours; and for the 600 mg tablet were AUC=199.39±70.27 mcg hr/mL, C_max=7.66±2.09 mcg/mL and T_max=9.67±4.89 hours.

In this study the mean fed/fasted ratios for the one and one-half 400 mg tablets and the 600 mg tablet were about 112% and 104%, respectively.

In another study, the bioavailability of the 600 mg Perphyllone (Theophylline Hydrate) Tablet was examined with morning and evening administration. This single-dose, crossover study in 22 healthy males was conducted under fed (standard high fat diet) conditions. The results demonstrated no clinically significant difference in the bioavailability of the 600 mg Perphyllone (Theophylline Hydrate) Tablet administered in the morning or in the evening. The results were: AUC=233.6±45.1 mcg hr/mL, C_max=10.6±1.3 mcg/mL and T_max=12.5±3.2 hours with morning dosing; AUC=209.8±46.2 mcg hr/mL, C_max=9.7±1.4 mcg/mL and T_max=13.7±3.3 hours with evening dosing. The PM/AM ratio was 89.3%.

The absorption characteristics of Perphyllone (Theophylline Hydrate)^® Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Perphyllone (Theophylline Hydrate) 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release Perphyllone (Theophylline Hydrate) product administered BID in fed subjects at 8 a.m. immediately after breakfast and 8 p.m. immediately after dinner (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat).

The pharmacokinetic parameters for Perphyllone (Theophylline Hydrate) 400 mg Tablets under these steady-state conditions were AUC=203.3±87.1 mcg hr/mL, C_max=12.1±3.8 mcg/mL, C_min=4.50±3.6, T_max=8.8±4.6 hours. For the reference BID product, the pharmacokinetic parameters were AUC=219.2±88.4 mcg hr/mL, C_max =11.0±4.1 mcg/mL, C_min=7.28±3.5, T_max=6.9±3.4 hours. The mean percent fluctuation [(C_max-C_min/C_min)x100]=169% for the once-daily regimen and 51% for the reference product BID regimen.

The bioavailability of the 600 mg Perphyllone (Theophylline Hydrate) Tablet was further evaluated in a multiple dose, steady-state study in 26 healthy males comparing the 600 mg Tablet to one and one-half 400 mg Perphyllone (Theophylline Hydrate) Tablets. All subjects had previously established Perphyllone (Theophylline Hydrate) clearances of ≤4 L/hr and were dosed once-daily for 6 days under fed conditions. The results showed no clinically significant difference between the 600 mg and one and one-half 400 mg Perphyllone (Theophylline Hydrate) Tablet regimens. Steady-state results were:

The bioavailability ratio for the 600/400 mg tablets was 98.8%. Thus, under all study conditions the 600 mg tablet is bioequivalent to one and one-half 400 mg tablets.

Studies demonstrate that as long as subjects were either consistently fed or consistently fasted, there is similar bioavailability with once-daily administration of Perphyllone (Theophylline Hydrate) Tablets whether dosed in the morning or evening.

Distribution

Once Perphyllone enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Perphyllone (Theophylline Hydrate) distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Perphyllone (Theophylline Hydrate) is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Perphyllone (Theophylline Hydrate) passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva Perphyllone (Theophylline Hydrate) concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of Perphyllone (Theophylline Hydrate), primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy. In such cases, the patient may show signs of toxicity at total (bound+unbound) serum concentrations of Perphyllone (Theophylline Hydrate) in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased Perphyllone (Theophylline Hydrate) binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum Perphyllone (Theophylline Hydrate) concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum Perphyllone (Theophylline Hydrate) concentration provides a more reliable means of dosage adjustment than measurement of total serum Perphyllone (Theophylline Hydrate) concentration. Generally, concentrations of unbound Perphyllone (Theophylline Hydrate) should be maintained in the range of 6-12 mcg/mL.

Metabolism

Following oral dosing, Perphyllone (Theophylline Hydrate) does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a Perphyllone (Theophylline Hydrate) dose is N-methylated to caffeine. Perphyllone (Theophylline Hydrate) demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.

Caffeine and 3-methylxanthine are the only Perphyllone (Theophylline Hydrate) metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Perphyllone (Theophylline Hydrate) and serum concentrations in adults with normal renal function are <1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized Perphyllone (Theophylline Hydrate) concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Perphyllone (Theophylline Hydrate) concentration and thus, exert a pharmacologic effect.

Both the N-demethylation and hydroxylation pathways of Perphyllone (Theophylline Hydrate) biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of Perphyllone (Theophylline Hydrate) metabolism, non-linearity of elimination may begin in some patients at serum Perphyllone (Theophylline Hydrate) concentrations <10 mcg/mL. Since this non-linearity results in more than proportional changes in serum Perphyllone (Theophylline Hydrate) concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum Perphyllone (Theophylline Hydrate) concentrations (see DOSAGE AND ADMINISTRATION, Table VI ). Accurate prediction of dose-dependency of Perphyllone (Theophylline Hydrate) metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady-state serum Perphyllone (Theophylline Hydrate) concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum Perphyllone (Theophylline Hydrate) concentration in response to dosage changes.

Excretion

In neonates, approximately 50% of the Perphyllone dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Perphyllone (Theophylline Hydrate) dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little Perphyllone (Theophylline Hydrate) is excreted unchanged in the urine and since active metabolites of Perphyllone (Theophylline Hydrate) (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, the large fraction of the Perphyllone (Theophylline Hydrate) dose excreted in the urine as unchanged Perphyllone (Theophylline Hydrate) and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Perphyllone (Theophylline Hydrate) concentrations in neonates with reduced renal function (See WARNINGS ).

Serum Concentrations at Steady-State

After multiple doses of Perphyllone (Theophylline Hydrate), steady-state is reached in 30-65 hours (average 40 hours) in adults. At steady-state, on a dosage regimen with 24-hour intervals, the expected mean trough concentration is approximately 50% of the mean peak concentration, assuming a mean Perphyllone (Theophylline Hydrate) half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid Perphyllone (Theophylline Hydrate) clearance. In these patients administration of Perphyllone (Theophylline Hydrate)^® may be required more frequently (every 12 hours).

Special Populations

Geriatric

The clearance of Perphyllone (Theophylline Hydrate) is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum Perphyllone (Theophylline Hydrate) concentrations are required in elderly patients (see WARNINGS ).

Pediatrics

The clearance of Perphyllone is very low in neonates (see WARNINGS ). Perphyllone (Theophylline Hydrate) clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged Perphyllone (Theophylline Hydrate) in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum Perphyllone (Theophylline Hydrate) concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION ).

Gender

Gender differences in Perphyllone (Theophylline Hydrate) clearance are relatively small and unlikely to be of clinical significance. Significant reduction in Perphyllone (Theophylline Hydrate) clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.

Race

Pharmacokinetic differences in Perphyllone clearance due to race have not been studied.

Renal Insufficiency

Only a small fraction, e.g., about 10%, of the administered Perphyllone (Theophylline Hydrate) dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little Perphyllone (Theophylline Hydrate) is excreted unchanged in the urine and since active metabolites of Perphyllone (Theophylline Hydrate) (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, approximately 50% of the administered Perphyllone (Theophylline Hydrate) dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum Perphyllone (Theophylline Hydrate) concentrations are required in neonates with decreased renal function (see WARNINGS ).

Hepatic Insufficiency

Perphyllone clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum Perphyllone (Theophylline Hydrate) concentrations are required in patients with reduced hepatic function (see WARNINGS ).

Congestive Heart Failure (CHF)

Perphyllone (Theophylline Hydrate) clearance is decreased by 50% or more in patients with CHF. The extent of reduction in Perphyllone (Theophylline Hydrate) clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since Perphyllone (Theophylline Hydrate) clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Careful attention to dose reduction and frequent monitoring of serum Perphyllone (Theophylline Hydrate) concentrations are required in patients with CHF (see WARNINGS ).

Smokers

Tobacco and marijuana smoking appears to increase the clearance of Perphyllone by induction of metabolic pathways. Perphyllone (Theophylline Hydrate) clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase Perphyllone (Theophylline Hydrate) clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in Perphyllone (Theophylline Hydrate) clearance. Careful attention to dose reduction and frequent monitoring of serum Perphyllone (Theophylline Hydrate) concentrations are required in patients who stop smoking (see WARNINGS ). Use of nicotine gum has been shown to have no effect on Perphyllone (Theophylline Hydrate) clearance.

Fever

Fever, regardless of its underlying cause, can decrease the clearance of Perphyllone (Theophylline Hydrate). The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of Perphyllone (Theophylline Hydrate) clearance. Precise data are lacking, but a temperature of 39°C (102°F) for at least 24 hours is probably required to produce a clinically significant increase in serum Perphyllone (Theophylline Hydrate) concentrations. Children with rapid rates of Perphyllone (Theophylline Hydrate) clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum Perphyllone (Theophylline Hydrate) concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever. Careful attention to dose reduction and frequent monitoring of serum Perphyllone (Theophylline Hydrate) concentrations are required in patients with sustained fever (see WARNINGS ).

Miscellaneous

Other factors associated with decreased Perphyllone (Theophylline Hydrate) clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum Perphyllone (Theophylline Hydrate) concentrations are required in patients with any of these conditions (see WARNINGS ). Other factors associated with increased Perphyllone (Theophylline Hydrate) clearance include hyperthyroidism and cystic fibrosis.

CLINICAL STUDIES

In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that Perphyllone (Theophylline Hydrate) decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-₂ agonists. Perphyllone (Theophylline Hydrate) has also been shown to reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators in asthmatics.

In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that Perphyllone (Theophylline Hydrate) decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.

INDICATIONS AND USAGE

Perphyllone (Theophylline Hydrate) is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

CONTRAINDICATIONS

Perphyllone (Theophylline Hydrate)^® is contraindicated in patients with a history of hypersensitivity to Perphyllone (Theophylline Hydrate) or other components in the product.

WARNINGS

Concurrent Illness

Perphyllone should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

Active peptic ulcer disease

Seizure disorders

Cardiac arrhythmias (not including bradyarrhythmias)

Conditions That Reduce Perphyllone (Theophylline Hydrate) Clearance

There are several readily identifiable causes of reduced Perphyllone (Theophylline Hydrate) clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Perphyllone (Theophylline Hydrate) toxicity can occur . Careful consideration must be given to the benefits and risks of Perphyllone (Theophylline Hydrate) use and the need for more intensive monitoring of serum Perphyllone (Theophylline Hydrate) concentrations in patients with the following risk factors:

Age

• Neonates (term and premature)
• Children <1 year
• Elderly (>60 years)

Concurrent Diseases

• Acute pulmonary edema
• Congestive heart failure
• Cor-pulmonale
• Fever; ≥102° for 24 hours or more; or lesser temperature elevations for longer periods
• Hypothyroidism
• Liver disease; cirrhosis, acute hepatitis
• Reduced renal function in infants <3 months of age
• Sepsis with multi-organ failure
• Shock

Cessation of Smoking

Drug Interactions

Adding a drug that inhibits Perphyllone metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances Perphyllone (Theophylline Hydrate) metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II ).

When Signs or Symptoms of Perphyllone (Theophylline Hydrate) Toxicity Are Present

Whenever a patient receiving Perphyllone (Theophylline Hydrate) develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with Perphyllone (Theophylline Hydrate) toxicity (even if another cause may be suspected), additional doses of Perphyllone (Theophylline Hydrate) should be withheld and a serum Perphyllone (Theophylline Hydrate) concentration measured immediately . Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the healthcare professional may instruct the patient to resume the drug at a lower dosage (see DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI ).

Dosage Increases

Increases in the dose of Perphyllone (Theophylline Hydrate) should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Perphyllone (Theophylline Hydrate) provides little added benefit to inhaled beta₂-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum Perphyllone (Theophylline Hydrate) concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the Perphyllone (Theophylline Hydrate) dose on the basis of a low serum concentration, the healthcare professional should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see PRECAUTIONS, Laboratory Tests ).

As the rate of Perphyllone (Theophylline Hydrate) clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum Perphyllone (Theophylline Hydrate) concentration (see DOSAGE AND ADMINISTRATION, Table VI ).

PRECAUTIONS

General

Careful consideration of the various interacting drugs and physiologic conditions that can alter Perphyllone clearance and require dosage adjustment should occur prior to initiation of Perphyllone (Theophylline Hydrate) therapy, prior to increases in Perphyllone (Theophylline Hydrate) dose, and during follow up (see WARNINGS ). The dose of Perphyllone (Theophylline Hydrate) selected for initiation of therapy should be low and, if tolerated , increased slowly over a period of a week or longer with the final dose guided by monitoring serum Perphyllone (Theophylline Hydrate) concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION , Table V).

Monitoring Serum Perphyllone (Theophylline Hydrate) Concentrations

Serum Perphyllone (Theophylline Hydrate) concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Perphyllone (Theophylline Hydrate) concentration should be measured as follows:

• When initiating therapy to guide final dosage adjustment after titration.
• Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.
• Whenever signs or symptoms of Perphyllone (Theophylline Hydrate) toxicity are present.
• Whenever there is a new illness, worsening of a chronic illness or a change in the patient’s treatment regimen that may alter Perphyllone (Theophylline Hydrate) clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued).

To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum Perphyllone (Theophylline Hydrate) concentration; 12 hours after an evening dose or 9 hours after a morning dose at steady-state. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum Perphyllone (Theophylline Hydrate) concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than 12 hours after the evening dose, or more than 9 hours after a morning dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of Perphyllone (Theophylline Hydrate) toxicity are present, a serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the healthcare professional without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound Perphyllone (Theophylline Hydrate) should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

Saliva concentrations of Perphyllone (Theophylline Hydrate) cannot be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests

As a result of its pharmacological effects, Perphyllone at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dL to 6 mg/dL), free fatty acids (from a mean of 451 µEq/L to 800 µEq/L, total cholesterol (from a mean of 140 vs 160 mg/dL), HDL (from a mean of 36 to 50 mg/dL), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Perphyllone (Theophylline Hydrate) at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dL after 4 weeks of Perphyllone (Theophylline Hydrate)). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Perphyllone (Theophylline Hydrate) in individual patients.

Information for Patients

The patient (or parent/caregiver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heartbeat occurs during treatment with Perphyllone (Theophylline Hydrate), even if another cause is suspected. The patient should be instructed to contact their healthcare professional if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another healthcare professional adds a new medication or discontinues a previously prescribed medication. Patients should be informed that Perphyllone (Theophylline Hydrate) interacts with a wide variety of drugs. The dietary supplement St. John’s Wort (Hypericum perforatum) should not be taken at the same time as Perphyllone (Theophylline Hydrate), since it may result in decreased Perphyllone (Theophylline Hydrate) levels. If patients are already taking St. John’s Wort and Perphyllone (Theophylline Hydrate) together, they should consult their healthcare professional before stopping the St. John’s Wort, since their Perphyllone (Theophylline Hydrate) concentrations may rise when this is done, resulting in toxicity. Patients should be instructed to inform all healthcare professionals involved in their care that they are taking Perphyllone (Theophylline Hydrate), especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their healthcare professional. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.

Perphyllone (Theophylline Hydrate)^® Tablets can be taken once a day in the morning or evening. It is recommended that Perphyllone (Theophylline Hydrate) be taken with meals. Patients should be advised that if they choose to take Perphyllone (Theophylline Hydrate) with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food.

Perphyllone (Theophylline Hydrate) Tablets are not to be chewed or crushed because it may lead to a rapid release of Perphyllone (Theophylline Hydrate) with the potential for toxicity. The scored tablet may be split. Patients receiving Perphyllone (Theophylline Hydrate) Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Perphyllone (Theophylline Hydrate).

Drug Interactions

Perphyllone interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to Perphyllone (Theophylline Hydrate) or another drug or occurrence of adverse effects without a change in serum Perphyllone (Theophylline Hydrate) concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of Perphyllone (Theophylline Hydrate) clearance is altered by another drug resulting in increased or decreased serum Perphyllone (Theophylline Hydrate) concentrations. Perphyllone (Theophylline Hydrate) only rarely alters the pharmacokinetics of other drugs.

The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with Perphyllone (Theophylline Hydrate). The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state Perphyllone (Theophylline Hydrate) regimen. If Perphyllone (Theophylline Hydrate) is being initiated in a patient who is already taking a drug that inhibits Perphyllone (Theophylline Hydrate) clearance (e.g., cimetidine, erythromycin), the dose of Perphyllone (Theophylline Hydrate) required to achieve a therapeutic serum Perphyllone (Theophylline Hydrate) concentration will be smaller. Conversely, if Perphyllone (Theophylline Hydrate) is being initiated in a patient who is already taking a drug that enhances Perphyllone (Theophylline Hydrate) clearance (e.g., rifampin), the dose of Perphyllone (Theophylline Hydrate) required to achieve a therapeutic serum Perphyllone (Theophylline Hydrate) concentration will be larger. Discontinuation of a concomitant drug that increases Perphyllone (Theophylline Hydrate) clearance will result in accumulation of Perphyllone (Theophylline Hydrate) to potentially toxic levels, unless the Perphyllone (Theophylline Hydrate) dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits Perphyllone (Theophylline Hydrate) clearance will result in decreased serum Perphyllone (Theophylline Hydrate) concentrations, unless the Perphyllone (Theophylline Hydrate) dose is appropriately increased.

The drugs listed in Table III have either been documented not to interact with Perphyllone (Theophylline Hydrate) or do not produce a clinically significant interaction (i.e., <15% change in Perphyllone (Theophylline Hydrate) clearance).

The listing of drugs in Tables II and III are current as of February 9, 1995. New interactions are continuously being reported for Perphyllone (Theophylline Hydrate), especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with Perphyllone (Theophylline Hydrate) if it is not listed in Table II. Before addition of a newly available drug in a patient receiving Perphyllone (Theophylline Hydrate), the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and Perphyllone (Theophylline Hydrate) has been reported.

Drug-Food Interactions

The bioavailability of Perphyllone (Theophylline Hydrate)^® Tablets (theophylline, anhydrous) has been studied with co-administration of food. In three single-dose studies, subjects given Perphyllone (Theophylline Hydrate) 400 mg or 600 mg Tablets with a standardized high-fat meal were compared to fasted conditions. Under fed conditions, the peak plasma concentration and bioavailability were increased; however, a precipitous increase in the rate and extent of absorption was not evident (see Pharmacokinetics , Absorption). The increased peak and extent of absorption under fed conditions suggests that dosing should be ideally administered consistently either with or without food.

The Effect of Other Drugs on Perphyllone Serum Concentration Measurements

Most serum Perphyllone (Theophylline Hydrate) assays in clinical use are immunoassays which are specific for Perphyllone (Theophylline Hydrate). Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs (e.g., cefazolin, cephalothin), however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum Perphyllone (Theophylline Hydrate) concentration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long term carcinogenicity studies have been carried out in mice and rats (oral doses 5-75 mg/kg). Results are pending.

Perphyllone (Theophylline Hydrate) has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.

In a 14 week continuous breeding study, Perphyllone (Theophylline Hydrate), administered to mating pairs of B6C3F₁ mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0-3.0 times the human dose on a mg/m² basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, Perphyllone (Theophylline Hydrate) was administered to F344 rats and B6C3F₁ mice at oral doses of 40-300 mg/kg (approximately 2.0 times the human dose on a mg/m² basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight.

Pregnancy: Teratogenic Effects: Category C

In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, Perphyllone (Theophylline Hydrate) produced teratogenic effects.

In studies with mice, a single intraperitoneal dose at and above 100 mg/kg (approximately equal to the maximum recommended oral dose for adults on a mg/m² basis) during organogenesis produced cleft palate and digital abnormalities. Micromelia, micrognathia, clubfoot, subcutaneous hematoma, open eyelids, and embryolethality were observed at doses that are approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis.

In a study with rats dosed from conception through organogenesis, an oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis) produced digital abnormalities. Embryolethality was observed with a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m² basis).

In a study in which pregnant rabbits were dosed throughout organogenesis, an intravenous dose of 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis), which caused the death of one doe and clinical signs in others, produced cleft palate and was embryolethal. Doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m² basis) increased the incidence of skeletal variations.

There are no adequate and well-controlled studies in pregnant women. Perphyllone (Theophylline Hydrate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Perphyllone is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of Perphyllone (Theophylline Hydrate) in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10-20 mcg/mL of Perphyllone (Theophylline Hydrate) per day is likely to receive 10-20 mg of Perphyllone (Theophylline Hydrate) per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Perphyllone (Theophylline Hydrate) concentrations.

Pediatric Use

Perphyllone (Theophylline Hydrate) is safe and effective for the approved indications in pediatric patients. The maintenance dose of Perphyllone (Theophylline Hydrate) must be selected with caution in pediatric patients since the rate of Perphyllone (Theophylline Hydrate) clearance is highly variable across the pediatric age range (see CLINICAL PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V ).

Geriatric Use

Elderly patients are at a significantly greater risk of experiencing serious toxicity from Perphyllone (Theophylline Hydrate) than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of Perphyllone (Theophylline Hydrate) is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Perphyllone (Theophylline Hydrate) clearance may be further reduced by concomitant diseases prevalent in the elderly, which further impair clearance of this drug and have the potential to increase serum levels and potential toxicity. These conditions include impaired renal function, chronic obstructive pulmonary disease, congestive heart failure, hepatic disease and an increased prevalence of use of certain medications (see PRECAUTIONS: Drug Interactions ) with the potential for pharmacokinetic and pharmacodynamic interaction. Protein binding may be decreased in the elderly resulting in an increased proportion of the total serum Perphyllone (Theophylline Hydrate) concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Perphyllone (Theophylline Hydrate) after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum Perphyllone (Theophylline Hydrate) concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Perphyllone (Theophylline Hydrate) Concentrations, and DOSAGE AND ADMINISTRATION ). The maximum daily dose of Perphyllone (Theophylline Hydrate) in patients greater than 60 years of age ordinarily should not exceed 400 mg/day unless the patient continues to be symptomatic and the peak steady-state serum Perphyllone (Theophylline Hydrate) concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Perphyllone (Theophylline Hydrate) doses greater than 400 mg/d should be prescribed with caution in elderly patients. Perphyllone (Theophylline Hydrate) should be prescribed with caution in elderly male patients with pre-existing partial outflow obstruction, such as prostatic enlargement, due to the risk of urinary retention.

ADVERSE REACTIONS

Adverse reactions associated with Perphyllone (Theophylline Hydrate) are generally mild when peak serum Perphyllone (Theophylline Hydrate) concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum Perphyllone (Theophylline Hydrate) concentrations exceed 20 mcg/mL, however, Perphyllone (Theophylline Hydrate) produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE ). The transient caffeine-like adverse reactions occur in about 50% of patients when Perphyllone (Theophylline Hydrate) therapy is initiated at doses higher than recommended initial doses (e.g., >300 mg/day in adults and >12 mg/kg/day in children beyond >1 year of age). During the initiation of Perphyllone (Theophylline Hydrate) therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of Perphyllone (Theophylline Hydrate) therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION, Table V ). In a small percentage of patients (<3% of children and <10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum Perphyllone (Theophylline Hydrate) concentrations within the therapeutic range (i.e., 10-20 mcg/mL). Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued Perphyllone (Theophylline Hydrate) therapy and the potential therapeutic benefit of alternative treatment.

Other adverse reactions that have been reported at serum Perphyllone (Theophylline Hydrate) concentrations <20 mcg/mL include abdominal pain, agitation, anaphylactic reaction, anaphylactoid reaction, anxiety, cardiac arrhythmias, diarrhea, dizziness, fine skeletal muscle tremors, gastric irritation, gastroesophageal reflux, hyperuricemia, irritability, palpitations, pruritus, rash, sinus tachycardia, restlessness, transient diuresis, urinary retention and urticaria. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum Perphyllone (Theophylline Hydrate) concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Perphyllone (Theophylline Hydrate) concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum Perphyllone (Theophylline Hydrate) concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Perphyllone (Theophylline Hydrate) concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Perphyllone (Theophylline Hydrate) concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Perphyllone (Theophylline Hydrate) concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).

OVERDOSAGE

General

The chronicity and pattern of Perphyllone overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: (1) acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg), as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient’s rate of Perphyllone (Theophylline Hydrate) clearance. The most common causes of chronic Perphyllone (Theophylline Hydrate) overdosage include patient or caregiver error in dosing, healthcare professional prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of Perphyllone (Theophylline Hydrate) clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Perphyllone (Theophylline Hydrate) concentration to determine whether a dose increase is safe.

Severe toxicity from Perphyllone (Theophylline Hydrate) overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of Perphyllone (Theophylline Hydrate) was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum Perphyllone (Theophylline Hydrate) concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum Perphyllone (Theophylline Hydrate) concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum Perphyllone (Theophylline Hydrate) concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from Perphyllone (Theophylline Hydrate) is seen principally at serum concentrations >30 mcg/mL.

Several studies have described the clinical manifestations of Perphyllone (Theophylline Hydrate) overdose and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum Perphyllone (Theophylline Hydrate) concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Perphyllone (Theophylline Hydrate) concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum Perphyllone (Theophylline Hydrate) concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum Perphyllone (Theophylline Hydrate) concentration compared to patients without the underlying disease.

The frequency of various reported manifestations of Perphyllone (Theophylline Hydrate) overdose according to the mode of overdose are listed in Table IV.

Other manifestations of Perphyllone (Theophylline Hydrate) toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy.

Seizures associated with serum Perphyllone (Theophylline Hydrate) concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from Perphyllone (Theophylline Hydrate) toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise.

Overdose Management

General Recommendations for Patients with Symptoms of Perphyllone (Theophylline Hydrate) Overdose or Serum Perphyllone (Theophylline Hydrate) Concentrations >30 mcg/mL (Note: Serum Perphyllone (Theophylline Hydrate) concentrations may continue to increase after presentation of the patient for medical care.)

• While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
• Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
• Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1-0.2 mg/kg every 1-3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30-60 minutes). Case reports of Perphyllone (Theophylline Hydrate) overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the healthcare professional should therefore be prepared to provide assisted ventilation. Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants. Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with Perphyllone (Theophylline Hydrate) overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by Perphyllone (Theophylline Hydrate). Enflurane appears less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain.
• Anticipate Need for Anticonvulsants In patients with Perphyllone (Theophylline Hydrate) overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum Perphyllone (Theophylline Hydrate) concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum Perphyllone (Theophylline Hydrate) concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient’s bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of Perphyllone (Theophylline Hydrate) (e.g., transfer of a high risk patient from one healthcare facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance Perphyllone (Theophylline Hydrate) clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline-induced generalized seizures and to increase the dose of Perphyllone (Theophylline Hydrate) required to induce seizures (i.e., markedly increases the LD₅₀). Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance Perphyllone (Theophylline Hydrate) clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.
• Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum Perphyllone (Theophylline Hydrate) concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.
• Gastrointestinal decontamination Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least once 1-2 hours after the first dose) is extremely effective in blocking the absorption of Perphyllone (Theophylline Hydrate) throughout the gastrointestinal tract, even when administered several hours after ingestion. If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. Phenothiazine antiemetics such as prochlorperazine or perphenazine should be avoided since they can lower the seizure threshold and frequently cause dystonic reactions. A single dose of sorbitol may be used to promote stooling to facilitate removal of Perphyllone (Theophylline Hydrate) bound to charcoal from the gastrointestinal tract. Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. Ipecac syrup should be avoided in Perphyllone (Theophylline Hydrate) overdoses. Although ipecac induces emesis, it does not reduce the absorption of Perphyllone (Theophylline Hydrate) unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal. Moreover, ipecac induced emesis may persist for several hours after a single dose and significantly decrease the retention and the effectiveness of oral activated charcoal.
• Serum Perphyllone (Theophylline Hydrate) Concentration Monitoring The serum Perphyllone (Theophylline Hydrate) concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum Perphyllone (Theophylline Hydrate) concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of Perphyllone (Theophylline Hydrate) from the gastrointestinal tract. Serial monitoring of serum Perphyllone (Theophylline Hydrate) serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels.
• General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum Perphyllone (Theophylline Hydrate) level has returned to a non-toxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL.
• Enhance clearance of Perphyllone (Theophylline Hydrate) Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of Perphyllone (Theophylline Hydrate) at least twofold by adsorption of Perphyllone (Theophylline Hydrate) secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed Perphyllone (Theophylline Hydrate) from the gastrointestinal tract. Sorbitol alone does not enhance clearance of Perphyllone (Theophylline Hydrate) and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of Perphyllone (Theophylline Hydrate) removal should be instituted (see OVERDOSAGE, Extracorporeal Removal ).

Specific Recommendations

Acute Overdose

• Serum Concentration >20<30 mcg/mL
  • Administer a single dose of oral activated charcoal.
  • Monitor the patient and obtain a serum Perphyllone concentration in 2-4 hours to insure that the concentration is not increasing.
• Serum Concentration >30<100 mcg/mL
  • Administer multiple dose oral activated charcoal and measures to control emesis.
  • Monitor the patient and obtain serial Perphyllone (Theophylline Hydrate) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
  • Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
• Serum Concentration>100 mcg/mL
  • Consider prophylactic anticonvulsant therapy.
  • Administer multiple-dose oral activated charcoal and measures to control emesis.
  • Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal ).
  • Monitor the patient and obtain serial Perphyllone (Theophylline Hydrate) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Chronic Overdosage

• Serum Concentration >20<30 mcg/mL (with manifestations of Perphyllone (Theophylline Hydrate) toxicity)
  • Administer a single dose of oral activated charcoal.
  • Monitor the patient and obtain a serum Perphyllone (Theophylline Hydrate) concentration in 2-4 hours to insure that the concentration is not increasing.
• Serum Concentration >30 mcg/mL in patients <60 years of age
  • Administer multiple-dose oral activated charcoal and measures to control emesis.
  • Monitor the patient and obtain serial Perphyllone (Theophylline Hydrate) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
  • Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
• Serum Concentration >30 mcg/mL in patients ≥ 60 years of age
  • Consider prophylactic anticonvulsant therapy.
  • Administer multiple-dose oral activated charcoal and measures to control emesis.
  • Consider extracorporeal removal even if the patient has not experienced a seizure.
  • Monitor the patient and obtain serial Perphyllone (Theophylline Hydrate) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal

Increasing the rate of Perphyllone (Theophylline Hydrate) clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing Perphyllone (Theophylline Hydrate) clearance up to sixfold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis. Serum Perphyllone (Theophylline Hydrate) concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of Perphyllone (Theophylline Hydrate) from the tissue compartment. Peritoneal dialysis is ineffective for Perphyllone (Theophylline Hydrate) removal; exchange transfusions in neonates have been minimally effective.

DOSAGE AND ADMINISTRATION

Perphyllone ^® 400 or 600 mg Tablets can be taken once a day in the morning or evening. It is recommended that Perphyllone (Theophylline Hydrate) be taken with meals. Patients should be advised that if they choose to take Perphyllone (Theophylline Hydrate) with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food.

Perphyllone (Theophylline Hydrate)^® Tablets are not to be chewed or crushed because it may lead to a rapid release of Perphyllone (Theophylline Hydrate) with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Perphyllone (Theophylline Hydrate) 400 or 600 mg Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Perphyllone (Theophylline Hydrate).

Stabilized patients, 12 years of age or older, who are taking an immediate-release or controlled-release Perphyllone (Theophylline Hydrate) product may be transferred to once-daily administration of 400 mg or 600 mg Perphyllone (Theophylline Hydrate) Tablets on a mg-for-mg basis.

It must be recognized that the peak and trough serum Perphyllone (Theophylline Hydrate) levels produced by the once-daily dosing may vary from those produced by the previous product and/or regimen.

General Considerations

The steady-state peak serum Perphyllone (Theophylline Hydrate) concentration is a function of the dose, the dosing interval, and the rate of Perphyllone (Theophylline Hydrate) absorption and clearance in the individual patient. Because of marked individual differences in the rate of Perphyllone (Theophylline Hydrate) clearance, the dose required to achieve a peak serum Perphyllone (Theophylline Hydrate) concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Perphyllone (Theophylline Hydrate) clearance (e.g., 400-1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). For a given population there is no single Perphyllone (Theophylline Hydrate) dose that will provide both safe and effective serum concentrations for all patients. Administration of the median Perphyllone (Theophylline Hydrate) dose required to achieve a therapeutic serum Perphyllone (Theophylline Hydrate) concentration in a given population may result in either sub-therapeutic or potentially toxic serum Perphyllone (Theophylline Hydrate) concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum Perphyllone (Theophylline Hydrate) concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients. The dose of Perphyllone (Theophylline Hydrate) must be individualized on the basis of peak serum Perphyllone (Theophylline Hydrate) concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments (see Table V ). Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum Perphyllone (Theophylline Hydrate) concentrations to reach the new steady-state. Dosage adjustment should be guided by serum Perphyllone (Theophylline Hydrate) concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION, Table VI ). Healthcare providers should instruct patients and caregivers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS ).

If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS ), serum Perphyllone (Theophylline Hydrate) concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum Perphyllone (Theophylline Hydrate) concentrations should be monitored at frequent intervals, e.g., every 24 hours.

Perphyllone (Theophylline Hydrate) distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.

Table V contains Perphyllone (Theophylline Hydrate) dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for Perphyllone (Theophylline Hydrate) dosage adjustment based upon serum Perphyllone (Theophylline Hydrate) concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum Perphyllone (Theophylline Hydrate) concentration.

Table V. Dosing initiation and titration (as anhydrous Perphyllone (Theophylline Hydrate)). *

• A. Children (12-15 years) and adults (16-60 years) without risk factors for impaired clearance.

• B. Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Perphyllone (Theophylline Hydrate) Concentrations:
  
  • In children 12-15 years of age, the Perphyllone (Theophylline Hydrate) dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced Perphyllone (Theophylline Hydrate) clearance (see WARNINGS ) or if it is not feasible to monitor serum Perphyllone (Theophylline Hydrate) concentrations.
    

  • In adolescents ≥16 years and adults, including the elderly, the Perphyllone (Theophylline Hydrate) dose should not exceed 400 mg/day in the presence of risk factors for reduced Perphyllone (Theophylline Hydrate) clearance (see WARNINGS ) or if it is not feasible to monitor serum Perphyllone (Theophylline Hydrate) concentrations.

*Patients with more rapid metabolism clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 12 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.

HOW SUPPLIED

Perphyllone (Theophylline Hydrate)^® (theophylline, anhydrous) Controlled-Release Tablets 400 mg are supplied in white, opaque plastic, child-resistant bottles containing 100 tablets (NDC 67781-251-01) or 500 tablets (NDC 67781-251-05). Each round, white 400 mg tablet bears the symbol PF on the scored side and U400 on the other side.

Perphyllone (Theophylline Hydrate)^® (theophylline, anhydrous) Controlled-Release Tablets 600 mg are supplied in white, opaque plastic, child-resistant bottles containing 100 tablets (NDC 67781-252-01). Each rectangular, concave, white 600 mg tablet bears the symbol PF on the scored side and U 600 on the other side.

Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F).

Dispense in a tight, light-resistant container.

©2011, Purdue Pharmaceutical Products L.P.

Dist. by: Purdue Pharmaceutical Products L.P.

Stamford, CT 06901-3431

Revised 10/2011

300945-0B

Perphyllone (Theophylline Hydrate) Tablets

400 mg Tablets

NDC 677781-251-01

Perphyllone (Theophylline Hydrate) Tablets 400 mg Tablets NDC 677781-251-01

Perphyllone (Theophylline Hydrate) Tablets

600 mg Tablets

NDC 677781-252-01

Perphyllone (Theophylline Hydrate) Tablets 600 mg Tablets NDC 677781-252-01