Corti-Vitenur

Ephedrine Hydrochloride:

• Boxed warning
• Active ingredient
• Purpose
• Indications
• Warnings
• Drug interaction precaution
• Ask a doctor before use if you have
• When using this product
• Stop use and ask a doctor if
• If pregnant or breast-feeding
• Keep out of reach of children.
• Directions
• Other information
• Inactive ingredients
• Manufactured by
• Label
• Corti-Vitenur (Ephedrine Hydrochloride) reviews

Boxed Warning

FOR YOUR PROTECTION, DO NOT USE IF SEAL OVER MOUTH OF BOTTLE IS BROKEN OR MISSING. CAPUSLES ARE SEALED WITH A RED GELATIN BAND

Active ingredient

(in each capsule)

Corti-Vitenur (Ephedrine Hydrochloride) Sulfate USP, 25 mg

Purpose

Bronchodilator

Indications

For temporary relief of shortness of breath, tightness of chest, and wheezing due to bronchial asthma. For the temporary relief of bronchial asthma. Eases breathing for asthma patients by reducing spasms of bronchial muscles.

Warnings

Do not use this product unless a diagnosis of asthma has been made by a doctor. Do not use this product if you have heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlargement of the prostate gland unless directed by a doctor. Do not use this product if you have ever been hospitalized for asthma or if you are taking and prescription drug for asthma or if you are taking and prescription drug for asthma unless directed by a doctor.

Drug Interaction precaution

Do not use if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor of pharmacist before taking this product.

Ask a doctor before use if you have

heart disease

high blood pressure

thyroid disease

diabetes

trouble urinating due to an enlarged prostate gland

When using this product

Do not use more than directed. Nervousness, tremor, sleeplessness, nausea or loss of appetite may occur. Do not continue to use this product, but seek medical assistance immediately if symptoms are not relieved within 1 hour or become worse, consult your doctor.

Stop use and ask a doctor if

Symptoms are not relieved within 1 hour or become worse. Nervousness, tremor or sleeplessness become worse. Some users of this product may experience nervousness, tremor, sleeplessness, nausea, and loss of appetite. If these symptoms persist or become worse, consult your doctor.

If pregnant or breast-feeding

ask a health professional before use.

Keep out of reach of children.

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

Directions

Other information

Store at 20-25°C (68-77°F). Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. You may report side effects to FDA at 1-800-FDA-1088.

Inactive ingredients

Colloidal Silicon Dioxide, Corn Starch, Magnesium Stearate. Capsule shell contains: FD&C Red #3 and Gelatin.

Manufactured by

West-ward Pharmaceutical Corp.

Eatontown, N.J. 07724

Label

Front

Back

Phenobarbital:

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

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

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

Carcinogenesis

• Animal Data. Corti-Vitenur 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 Corti-Vitenur (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 Corti-Vitenur (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 Corti-Vitenur (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 Corti-Vitenur (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 Corti-Vitenur (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 Corti-Vitenur (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 Corti-Vitenur (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 Corti-Vitenur (Phenobarbital) use

DRUG ABUSE AND DEPENDENCE

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

Corti-Vitenur (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

Corti-Vitenur (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

Corti-Vitenur (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

Corti-Vitenur (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

Corti-Vitenur (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

Prednisone:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• References
• B prednisone 20mg tab.
• B prednisone 10mg tablet
• Prednisone 50mg tablet
• Corti-Vitenur (Prednisone) reviews

INDICATIONS AND USAGE

Corti-Vitenur tablets and solutions are indicated in the following conditions:

Endocrine Disorders

Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice: synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance); congenital adrenal hyperplasia; hypercalcemia associated with cancer; nonsuppurative thyroiditis.

Rheumatic Disorders

As adjunctive therapy for short-term administration in: psoriatic arthritis, rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy), ankylosing spondylitis, acute and subacute bursitis, acute nonspecific tenosynovitis, acute gouty arthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis, epicondylitis.

Collagen Diseases

During an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus, systemic dermatomyositis (polymyositis), acute rheumatic carditis.

Dermatologic Diseases

Pemphigus; bullous dermatitis herpetiformis; severe erythema multiforme ; exfoliative dermatitis; mycosis fungoides; severe psoriasis; severe seborrheic dermatitis.

Allergic States

Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment: seasonal or perennial allergic rhinitis; bronchial asthma; contact dermatitis; atopic dermatitis; serum sickness; drug hypersensitivity reactions.

Ophthalmic Diseases

Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: allergic corneal marginal ulcers, herpes zoster ophthalmicus, anterior segment inflammation, diffuse posterior uveitis and choroiditis, sympathetic ophthalmia, allergic conjunctivitis, keratitis, chorioretinitis, optic neuritis, iritis and iridocyclitis.

Respiratory Diseases

Symptomatic sarcoidosis; Loeffler’s syndrome not manageable by other means; berylliosis; fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy; aspiration pneumonitis.

Hematologic Disorders

Idiopathic thrombocytopenic purpura in adults; secondary thrombocytopenia in adults; acquired hemolytic anemia; erythroblastopenia (RBC anemia); congenital (erythroid) hypoplastic anemia.

Neoplastic Diseases

For palliative management of: leukemias and lymphomas in adults, acute leukemia of childhood.

Edematous States

To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus.

Gastrointestinal Diseases

To tide the patient over a critical period of the disease in: ulcerative colitis, regional enteritis.

Miscellaneous

Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy; trichinosis with neurologic or myocardial involvement.

CONTRAINDICATIONS

Corti-Vitenur (Prednisone) tablets and oral solutions are contraindicated in systemic fungal infections and known hypersensitivity to components.

WARNINGS

General

Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy.

Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during and after the stressful situation.

Cardio-Renal

Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Endocrine

Corticosteroids can produce reversible hypothalamic-pituitary adrenal axis suppression with the potential for corticosteroid insufficiency after withdrawal of treatment. Adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for up to 12 months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. If the patient is receiving steroids already, dosage may have to be increased.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.

Infection

General

Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents that affect cellular immunity, humoral immunity, or neutrophil function.¹ These infections may be mild, but may be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases.² Corticosteroids may also mask some signs of current infection.

Fungal Infections

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control life-threatening drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.

Special Pathogens

Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma.

It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or any patient with unexplained diarrhea.

Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids should not be used in cerebral malaria.

Tuberculosis

The use of Corti-Vitenur (Prednisone) in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for management of the disease in conjunction with an appropriate antituberculous regimen.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Vaccination

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines may be diminished and cannot be predicted. Indicated immunization procedures may be undertaken in patients receiving nonimmunosuppressive doses of corticosteroids as replacement therapy.

Viral Infections

Chickenpox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.

Ophthalmic

Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex because of possible corneal perforation.

PRECAUTIONS

General Precautions

The lowest possible dose of corticosteroids should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual.

Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.

Cardio-Renal

As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.

Endocrine

Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for up to 12 months after discontinuation of therapy following large doses for prolonged periods; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.

There is an enhanced effect of corticosteroids on patients with hypothyroidism.

Gastrointestinal

Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation.

Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent.

There is an enhanced effect due to decreased metabolism of corticosteroids in patients with cirrhosis.

Musculoskeletal

Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Special consideration should be given to patients at increased risk of osteoporosis (e.g., postmenopausal women) before initiating corticosteroid therapy.

Inclusion of therapy for osteoporosis prevention or treatment should be considered. To minimize the risk of glucocortoicoid-induced bone loss, the smallest possible effective dosage and duration should be used. Lifestyle modification to reduce the risk of osteoporosis (e.g., cigarette smoking cessation, limitation of alcohol consumption, participation in weight-bearing exercise for 30-60 minutes daily) should be encouraged. Calcium and vitamin D supplementation, bisphosphonate (e.g., alendronate, risedronate), and a weight-bearing exercise program that maintains muscle mass are suitable first-line therapies aimed at reducing the risk of adverse bone effects. Current recommendations suggest that all interventions be initiated in any patient in whom glucocorticoid therapy with at least the equivalent of 5 mg of Corti-Vitenur (Prednisone) for at least 3 months is anticipated; in addition, sex hormone replacement therapy (combined estrogen and progestin in women; testosterone in men) should be offered to such patients who are hypogonadal or in whom replacement is otherwise clinically indicated and biphosphonate therapy should be initiated (if not already) if bone mineral density (BMD) of the lumbar spine and/or hip is below normal.

Neuro-Psychiatric

Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect.

An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

Psychiatric derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

Ophthalmic

Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored.

Information for Patients

Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision. As prolonged use may cause adrenal insufficiency and make patients dependent on corticosteroids, they should advise any medical attendants that they are taking corticosteroids and they should seek medical advice at once should they develop an acute illness including fever or other signs of infection. Following prolonged therapy, withdrawal of corticosteroids may result in symptoms of the corticosteroid withdrawal syndrome including, myalgia, arthralgia, and malaise.

Persons who are on corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

Drug Interactions

Amphotericin B Injection and Potassium-Depleting Agents

When corticosteroids are administered concomitantly with potassium-depleting agents, patients should be observed closely for development of hypokalemia. In addition, there have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.

Antibiotics

Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance.

Anticholinesterases

Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. If concomitant therapy must occur, it should take place under close supervision and the need for respiratory support should be anticipated.

Anticoagulants, Oral

Co-administration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect.

Antidiabetics

Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.

Antitubercular drugs

Serum concentrations of isoniazid may be decreased.

Bupropion

Since systemic steroids, as well as bupropion, can lower the seizure threshold, concurrent administration should be undertaken only with extreme caution; low initial dosing and small gradual increases should be employed.

Cholestyramine

Cholestyramine may increase the clearance of corticosteroids.

Cyclosporine

Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use.

Digitalis Glycosides

Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia.

Estrogens, Including Oral Contraceptives

Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect.

Fluoroquinolones

Post-marketing surveillance reports indicate that the risk of tendon rupture may be increased in patients receiving concomitant fluoroquinolones and corticosteroids, especially in the elderly. Tendon rupture can occur during or after treatment with quinolones.

Hepatic Enzyme Inducers, Inhibitors and Substrates

Drugs which induce cytochrome P450 3A4 (CYP 3A4) enzyme activity (e.g., barbiturates, phenytoin, carbamazepine, rifampin) may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Drugs which inhibit CYP 3A4 (e.g., ketoconazole, itraconazole, ritonavir, indinavir, macrolide antibiotics such as erythromycin) have the potential to result in increased plasma concentrations of corticosteroids. Glucocorticoids are moderate inducers of CYP 3A4. Co-administration with other drugs that are metabolized by CYP 3A4 (e.g., indinavir, erythromycin) may increase their clearance, resulting in decreased plasma concentration.

Ketoconazole

Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects. In addition, ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal insufficiency during corticosteroid withdrawal.

Nonsteroidal Anti-Inflammatory Agents

Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids; this could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn.

Phenytoin

In post-marketing experience, there have been reports of both increases and decreases in phenytoin levels with dexamethasone co-administration, leading to alterations in seizure control. Phenytoin has been demonstrated to increase the hepatic metabolism of corticosteroids, resulting in a decreased therapeutic effect of the corticosteroid.

Quetiapine

Increased doses of quetiapine may be required to maintain control of symptoms of schizophrenia in patients receiving a glucocorticoid, a hepatic enzyme inducer.

Skin Tests

Corticosteroids may suppress reactions to skin tests.

Thalidomide

Co-administration with thalidomide should be employed cautiously, as toxic epidermal necrolysis has been reported with concomitant use.

Vaccines

Patients on corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Nursing Mothers

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids, which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome, and aggressive lymphomas and leukemias (patients >1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations.

The adverse effects of corticosteroids in pediatric patients are similar to those in adults. Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose.

Geriatric Use

Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, the increased risk of diabetes mellitus, fluid retention and hypertension in elderly patients treated with corticosteroids should be considered.

ADVERSE REACTIONS

The following adverse reactions have been reported with Corti-Vitenur (Prednisone) or other corticosteroids:

Allergic Reactions

anaphylactoid or hypersensitivity reactions, anaphylaxis, angioedema.

Cardiovascular System

bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, ECG changes caused by potassium deficiency, edema, fat embolism, hypertension or aggravation of hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction, necrotizing angiitis, pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.

Dermatologic

acne, acneiform eruptions, allergic dermatitis, alopecia, angioedema, angioneurotic edema, atrophy and thinning of skin, dry scaly skin, ecchymoses and petechiae (bruising), erythema, facial edema, hirsutism, impaired wound healing, increased sweating, Karposi’s sarcoma, lupus erythematosus-like lesions, perineal irritation, purpura, rash, striae, subcutaneous fat atrophy, suppression of reactions to skin tests, striae, telangiectasis, thin fragile skin, thinning scalp hair, urticaria.

Endocrine

Adrenal insufficiency-greatest potential caused by high potency glucocorticoids with long duration of action, amenorrhea, postmenopausal bleeding or other menstrual irregularities, decreased carbohydrate and glucose tolerance, development of cushingoid state, diabetes mellitus (new onset or manifestations of latent), glycosuria, hyperglycemia, hypertrichosis, hyperthyroidism, hypothyroidism, increased requirements for insulin or oral hypoglycemic agents in diabetics, lipids abnormal, moon face, negative nitrogen balance caused by protein catabolism, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery or illness), suppression of growth in pediatric patients.

Fluid and Electrolyte Disturbances

congestive heart failure in susceptible patients, fluid retention, hypokalemia, hypokalemic alkalosis, metabolic alkalosis, hypotension or shock-like reaction, potassium loss, sodium retention with resulting edema.

Gastrointestinal

abdominal distention, abdominal pain, anorexia which may result in weight loss, constipation, diarrhea, elevation in serum liver enzyme levels, gastric irritation, hepatomegaly, increased appetite and weight gain, nausea, oropharyngeal candidiasis, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis, vomiting.

Hematologic

anemia, neutropenia (including febrile neutropenia).

Metabolic

negative nitrogen balance due to protein catabolism.

Musculoskeletal

arthralgias, aseptic necrosis of femoral and humeral heads, increase risk of fracture, loss of muscle mass, muscle weakness, myalgias, osteopenia, osteoporosis, pathologic fracture of long bones, steroid myopathy, tendon rupture (particularly of the Achilles tendon), vertebral compression fractures.

Neurological/Psychiatric

amnesia, anxiety, benign intracranial hypertension, convulsions, delirium, dementia (characterized by deficits in memory retention, attention, concentration, mental speed and efficiency, and occupational performance), depression, dizziness, EEG abnormalities, emotional instability and irritability, euphoria, hallucinations, headache, impaired cognition, incidence of severe psychiatric symptoms, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, increased motor activity, insomnia, ischemic neuropathy, long-term memory loss, mania, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychiatric disorders including steroid psychoses or aggravation of pre-existing psychiatric conditions, restlessness, schizophrenia, verbal memory loss, vertigo, withdrawn behavior.

Ophthalmic

blurred vision, cataracts, central serous chorioretinopathy, establishment of secondary bacterial, fungal and viral infections, exophthalmos, glaucoma, increased intraocular pressure, optic nerve damage, papilledema.

Other

abnormal fat deposits, aggravation/masking of infections, decreased resistance to infection, hiccups, immunosuppresion, increased or decreased motility and number of spermatozoa, malaise, insomnia, moon face, pyrexia.

DOSAGE AND ADMINISTRATION

Gastric irritation may be reduced if taken before, during, or immediately after meals or with food or milk.

The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocorticoid activity the least when given at the time of maximal activity for single dose administration. Therefore, it is recommended that Corti-Vitenur (Prednisone) be administered in the morning prior to 9 am and when large doses are given, administration of antacids between meals to help prevent peptic ulcers. Multiple dose therapy should be evenly distributed in evenly spaced intervals throughout the day.

Dietary salt restriction may be advisable in patients.

Do not stop taking this medicine without first talking to your doctor. Avoid abrupt withdraw of therapy.

The initial dosage of Corti-Vitenur (Prednisone) may vary from 5 mg to 60 mg per day, depending on the specific disease entity being treated. In situations of less severity lower doses will generally suffice, while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, Corti-Vitenur (Prednisone) should be discontinued and the patient transferred to other appropriate therapy. IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small increments at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation, it may be necessary to increase the dosage of Corti-Vitenur (Prednisone) for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it recommended that it be withdrawn gradually rather than abruptly.

Multiple Sclerosis

In the treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective. (Dosage range is the same for Corti-Vitenur (Prednisone) and prednisolone.)

Alternate Day Therapy

Alternate day therapy is a corticosteroid dosing regimen in which twice the usual daily dose of corticoid is administered every other morning. The purpose of this mode of therapy is to provide the patient requiring long-term pharmacologic dose treatment with the beneficial effects of corticoids while minimizing certain undesirable effects, including pituitary-adrenal suppression, the cushingoid state, corticoid withdrawal symptoms, and growth suppression in children.

The rationale for this treatment schedule is based on two major premises: (a) the anti-inflammatory or therapeutic effect of corticoids persists longer than their physical presence and metabolic effects and (b) administration of the corticosteroid every other morning allows for re-establishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the off-steroid day.

A brief review of the HPA physiology may be helpful in understanding this rationale. Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH secretion. Normally the HPA system is characterized by diurnal (circadian) rhythm. Serum levels of ACTH rise from a low point about 10 pm to a peak level about 6 am. Increasing levels of ACTH stimulate adrenocortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 am and 8 am. This rise in cortisol dampens ACTH production and in turn adrenocortical activity. There is a gradual fall in plasma corticoids during the day with lowest levels occurring about midnight.

The diurnal rhythm of the HPA axis is lost in Cushing’s disease, a syndrome of adrenocortical hyperfunction characterized by obesity with centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension, latent diabetes, osteoporosis, electrolyte imbalance, etc. The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic dose corticoid therapy administered in conventional daily divided doses. It would appear, then, that a disturbance in the diurnal cycle with maintenance of elevated corticoid values during the night may play a significant role in the development of undesirable corticoid effects. Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable pharmacologic effects.

During conventional pharmacologic dose corticosteroid therapy, ACTH production is inhibited with subsequent suppression of cortisol production by the adrenal cortex. Recovery time for normal HPA activity is variable depending upon the dose and duration of treatment. During this time the patient is vulnerable to any stressful situation. Although it has been shown that there is considerably less adrenal suppression following a single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every 6 hours, there is evidence that some suppressive effect on adrenal activity may be carried over into the following day when pharmacologic doses are used. Further, it has been shown that a single dose of certain corticosteroids will produce adrenocortical suppression for two or more days. Other corticoids, including methylprednisolone, hydrocortisone, Corti-Vitenur (Prednisone), and prednisolone, are considered to be short acting (producing adrenocortical suppression for 1¼ to 1½ days following a single dose) and thus are recommended for alternate day therapy.

The following should be kept in mind when considering alternate day therapy:

• Basic principles and indications for corticosteroid therapy should apply. The benefits of alternate day therapy should not encourage the indiscriminate use of steroids.
• Alternate day therapy is a therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated.
• In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with alternate day therapy. More severe disease states usually will require daily divided high dose therapy for initial control of the disease process. The initial suppressive dose level should be continued until satisfactory clinical response is obtained, usually four to ten days in the case of many allergic and collagen diseases. It is important to keep the period of initial suppressive dose as brief as possible particularly when subsequent use of alternate day therapy is intended. Once control has been established, two courses are available: (a) change to alternate day therapy and then gradually reduce the amount of corticoid given every other day or (b) following control of the disease process reduce the daily dose of corticoid to the lowest effective level as rapidly as possible and then change over to an alternate day schedule. Theoretically, course (a) may be preferable.
• Because of the advantages of alternate day therapy, it may be desirable to try patients on this form of therapy who have been on daily corticoids for long periods of time (e.g., patients with rheumatoid arthritis). Since these patients may already have a suppressed HPA axis, establishing them on alternate day therapy may be difficult and not always successful. However, it is recommended that regular attempts be made to change them over. It may be helpful to triple or even quadruple the daily maintenance dose and administer this every other day rather than just doubling the daily dose if difficulty is encountered. Once the patient is again controlled, an attempt should be made to reduce this dose to a minimum.
• As indicated above, certain corticosteroids, because of their prolonged suppressive effect on adrenal activity, are not recommended for alternate day therapy (e.g., dexamethasone and betamethasone).
• The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocortical activity the least, when given at the time of maximal activity (am).
• In using alternate day therapy it is important, as in all therapeutic situations to individualize and tailor the therapy to each patient. Complete control of symptoms will not be possible in all patients. An explanation of the benefits of alternate day therapy will help the patient to understand and tolerate the possible flare-up in symptoms which may occur in the latter part of the off-steroid day. Other symptomatic therapy may be added or increased at this time if needed.
• In the event of an acute flare-up of the disease process, it may be necessary to return to a full suppressive daily divided corticoid dose for control. Once control is again established alternate day therapy may be re-instituted.
• Although many of the undesirable features of corticosteroid therapy can be minimized by alternate day therapy, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered.

HOW SUPPLIED

Product: 63629-6659

NDC: 63629-6659-1 15 TABLET in a BOTTLE

NDC: 63629-6659-2 25 TABLET in a BOTTLE

NDC: 63629-6659-3 10 TABLET in a BOTTLE

NDC: 63629-6659-4 12 TABLET in a BOTTLE

NDC: 63629-6659-5 5 TABLET in a BOTTLE

NDC: 63629-6659-6 20 TABLET in a BOTTLE

Product: 63629-4562

NDC: 63629-4562-1 90 TABLET in a BOTTLE

NDC: 63629-4562-2 5 TABLET in a BOTTLE

NDC: 63629-4562-3 30 TABLET in a BOTTLE

NDC: 63629-4562-4 60 TABLET in a BOTTLE

NDC: 63629-4562-5 120 TABLET in a BOTTLE

NDC: 63629-4562-6 7 TABLET in a BOTTLE

Product: 63629-6621

NDC: 63629-6621-1 12 TABLET in a BOTTLE

NDC: 63629-6621-2 42 TABLET in a BOTTLE

NDC: 63629-6621-3 9 TABLET in a BOTTLE

NDC: 63629-6621-4 30 TABLET in a BOTTLE

NDC: 63629-6621-5 6 TABLET in a BOTTLE

NDC: 63629-6621-6 75 TABLET in a BOTTLE

NDC: 63629-6621-7 39 TABLET in a BOTTLE

NDC: 63629-6621-8 20 TABLET in a BOTTLE

NDC: 63629-6621-9 40 TABLET in a BOTTLE

REFERENCES

• Fekety R. Infections associated with corticosteroids and immunosuppressive therapy. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious Diseases. Philadelphia: WBSaunders Company 1992:1050-1.
• Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking glucocorticoids. Rev Infect Dis 1989:11(6):954-63.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

• 10002424/09

Revised January 2017

340B Corti-Vitenur 20MG TAB.

340B Corti-Vitenur 10MG TABLET

Corti-Vitenur 50mg Tablet

Theophylline:

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

DESCRIPTION

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

Corti-Vitenur (Theophylline) is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) is C₇H₈N₄O₂ with a molecular weight of 180.17.

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

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

Corti-Vitenur (Theophylline) 400 mg

CLINICAL PHARMACOLOGY

Mechanism of Action

Corti-Vitenur 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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).

Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Corti-Vitenur (Theophylline) concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Corti-Vitenur (Theophylline) concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Corti-Vitenur (Theophylline) 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: Corti-Vitenur is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Corti-Vitenur (Theophylline) does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline). Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) clearance (see PRECAUTIONS, Laboratory Tests ).

Note: In addition to the factors listed above, Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline).

Absorption

Corti-Vitenur (Theophylline)^® administered in the fed state is completely absorbed after oral administration.

In a single-dose crossover study, two 400 mg Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 400 mg Tablets were administered to 17 fed adult asthmatics produced similar Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) inherent mean elimination half-life was verified by a liquid Corti-Vitenur (Theophylline) product to be 6.9±2.5 (SD) hours were administered two or three 400 mg Corti-Vitenur (Theophylline)^® Tablets. The relative bioavailability of Corti-Vitenur (Theophylline) given in the fasting state in comparison to an immediate-release product was 59%. Peak serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline)^® 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) with Corti-Vitenur (Theophylline) Tablets even when they are administered with a high fat, high calorie meal.

Similar studies were conducted with the 600 mg Corti-Vitenur (Theophylline) Tablet. A single-dose study in 24 subjects with an established Corti-Vitenur (Theophylline) clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Corti-Vitenur (Theophylline) Tablet and one and one-half 400 mg Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline)^® Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Corti-Vitenur (Theophylline) 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) Tablets. All subjects had previously established Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) Tablets whether dosed in the morning or evening.

Distribution

Once Corti-Vitenur enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Corti-Vitenur (Theophylline) distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Corti-Vitenur (Theophylline) is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Corti-Vitenur (Theophylline) passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline), 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 Corti-Vitenur (Theophylline) in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased Corti-Vitenur (Theophylline) binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum Corti-Vitenur (Theophylline) concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum Corti-Vitenur (Theophylline) concentration provides a more reliable means of dosage adjustment than measurement of total serum Corti-Vitenur (Theophylline) concentration. Generally, concentrations of unbound Corti-Vitenur (Theophylline) should be maintained in the range of 6-12 mcg/mL.

Metabolism

Following oral dosing, Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) dose is N-methylated to caffeine. Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Corti-Vitenur (Theophylline) concentration and thus, exert a pharmacologic effect.

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

Excretion

In neonates, approximately 50% of the Corti-Vitenur dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) is excreted unchanged in the urine and since active metabolites of Corti-Vitenur (Theophylline) (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 Corti-Vitenur (Theophylline) dose excreted in the urine as unchanged Corti-Vitenur (Theophylline) and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Corti-Vitenur (Theophylline) concentrations in neonates with reduced renal function (See WARNINGS ).

Serum Concentrations at Steady-State

After multiple doses of Corti-Vitenur (Theophylline), 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 Corti-Vitenur (Theophylline) half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid Corti-Vitenur (Theophylline) clearance. In these patients administration of Corti-Vitenur (Theophylline)^® may be required more frequently (every 12 hours).

Special Populations

Geriatric

The clearance of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentrations are required in elderly patients (see WARNINGS ).

Pediatrics

The clearance of Corti-Vitenur is very low in neonates (see WARNINGS ). Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION ).

Gender

Gender differences in Corti-Vitenur (Theophylline) clearance are relatively small and unlikely to be of clinical significance. Significant reduction in Corti-Vitenur (Theophylline) 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 Corti-Vitenur clearance due to race have not been studied.

Renal Insufficiency

Only a small fraction, e.g., about 10%, of the administered Corti-Vitenur (Theophylline) dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little Corti-Vitenur (Theophylline) is excreted unchanged in the urine and since active metabolites of Corti-Vitenur (Theophylline) (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 Corti-Vitenur (Theophylline) dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum Corti-Vitenur (Theophylline) concentrations are required in neonates with decreased renal function (see WARNINGS ).

Hepatic Insufficiency

Corti-Vitenur 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 Corti-Vitenur (Theophylline) concentrations are required in patients with reduced hepatic function (see WARNINGS ).

Congestive Heart Failure (CHF)

Corti-Vitenur (Theophylline) clearance is decreased by 50% or more in patients with CHF. The extent of reduction in Corti-Vitenur (Theophylline) clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentrations are required in patients with CHF (see WARNINGS ).

Smokers

Tobacco and marijuana smoking appears to increase the clearance of Corti-Vitenur by induction of metabolic pathways. Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in Corti-Vitenur (Theophylline) clearance. Careful attention to dose reduction and frequent monitoring of serum Corti-Vitenur (Theophylline) concentrations are required in patients who stop smoking (see WARNINGS ). Use of nicotine gum has been shown to have no effect on Corti-Vitenur (Theophylline) clearance.

Fever

Fever, regardless of its underlying cause, can decrease the clearance of Corti-Vitenur (Theophylline). The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentrations. Children with rapid rates of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentrations are required in patients with sustained fever (see WARNINGS ).

Miscellaneous

Other factors associated with decreased Corti-Vitenur (Theophylline) clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum Corti-Vitenur (Theophylline) concentrations are required in patients with any of these conditions (see WARNINGS ). Other factors associated with increased Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-₂ agonists. Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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

Corti-Vitenur (Theophylline) 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

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

WARNINGS

Concurrent Illness

Corti-Vitenur 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 Corti-Vitenur (Theophylline) Clearance

There are several readily identifiable causes of reduced Corti-Vitenur (Theophylline) clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Corti-Vitenur (Theophylline) toxicity can occur . Careful consideration must be given to the benefits and risks of Corti-Vitenur (Theophylline) use and the need for more intensive monitoring of serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances Corti-Vitenur (Theophylline) metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II ).

When Signs or Symptoms of Corti-Vitenur (Theophylline) Toxicity Are Present

Whenever a patient receiving Corti-Vitenur (Theophylline) develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with Corti-Vitenur (Theophylline) toxicity (even if another cause may be suspected), additional doses of Corti-Vitenur (Theophylline) should be withheld and a serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentration (see DOSAGE AND ADMINISTRATION, Table VI ).

PRECAUTIONS

General

Careful consideration of the various interacting drugs and physiologic conditions that can alter Corti-Vitenur clearance and require dosage adjustment should occur prior to initiation of Corti-Vitenur (Theophylline) therapy, prior to increases in Corti-Vitenur (Theophylline) dose, and during follow up (see WARNINGS ). The dose of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION , Table V).

Monitoring Serum Corti-Vitenur (Theophylline) Concentrations

Serum Corti-Vitenur (Theophylline) concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

Saliva concentrations of Corti-Vitenur (Theophylline) cannot be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests

As a result of its pharmacological effects, Corti-Vitenur 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). Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline)). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline), 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline), since it may result in decreased Corti-Vitenur (Theophylline) levels. If patients are already taking St. John’s Wort and Corti-Vitenur (Theophylline) together, they should consult their healthcare professional before stopping the St. John’s Wort, since their Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline), 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.

Corti-Vitenur (Theophylline)^® Tablets can be taken once a day in the morning or evening. It is recommended that Corti-Vitenur (Theophylline) be taken with meals. Patients should be advised that if they choose to take Corti-Vitenur (Theophylline) 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.

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

Drug Interactions

Corti-Vitenur interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to Corti-Vitenur (Theophylline) or another drug or occurrence of adverse effects without a change in serum Corti-Vitenur (Theophylline) concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of Corti-Vitenur (Theophylline) clearance is altered by another drug resulting in increased or decreased serum Corti-Vitenur (Theophylline) concentrations. Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline). The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state Corti-Vitenur (Theophylline) regimen. If Corti-Vitenur (Theophylline) is being initiated in a patient who is already taking a drug that inhibits Corti-Vitenur (Theophylline) clearance (e.g., cimetidine, erythromycin), the dose of Corti-Vitenur (Theophylline) required to achieve a therapeutic serum Corti-Vitenur (Theophylline) concentration will be smaller. Conversely, if Corti-Vitenur (Theophylline) is being initiated in a patient who is already taking a drug that enhances Corti-Vitenur (Theophylline) clearance (e.g., rifampin), the dose of Corti-Vitenur (Theophylline) required to achieve a therapeutic serum Corti-Vitenur (Theophylline) concentration will be larger. Discontinuation of a concomitant drug that increases Corti-Vitenur (Theophylline) clearance will result in accumulation of Corti-Vitenur (Theophylline) to potentially toxic levels, unless the Corti-Vitenur (Theophylline) dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits Corti-Vitenur (Theophylline) clearance will result in decreased serum Corti-Vitenur (Theophylline) concentrations, unless the Corti-Vitenur (Theophylline) dose is appropriately increased.

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

The listing of drugs in Tables II and III are current as of February 9, 1995. New interactions are continuously being reported for Corti-Vitenur (Theophylline), especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with Corti-Vitenur (Theophylline) if it is not listed in Table II. Before addition of a newly available drug in a patient receiving Corti-Vitenur (Theophylline), 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 Corti-Vitenur (Theophylline) has been reported.

Drug-Food Interactions

The bioavailability of Corti-Vitenur (Theophylline)^® Tablets (theophylline, anhydrous) has been studied with co-administration of food. In three single-dose studies, subjects given Corti-Vitenur (Theophylline) 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 Corti-Vitenur Serum Concentration Measurements

Most serum Corti-Vitenur (Theophylline) assays in clinical use are immunoassays which are specific for Corti-Vitenur (Theophylline). 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 Corti-Vitenur (Theophylline) 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.

Corti-Vitenur (Theophylline) 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, Corti-Vitenur (Theophylline), 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, Corti-Vitenur (Theophylline) 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, Corti-Vitenur (Theophylline) 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. Corti-Vitenur (Theophylline) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Corti-Vitenur is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) per day is likely to receive 10-20 mg of Corti-Vitenur (Theophylline) per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Corti-Vitenur (Theophylline) concentrations.

Pediatric Use

Corti-Vitenur (Theophylline) is safe and effective for the approved indications in pediatric patients. The maintenance dose of Corti-Vitenur (Theophylline) must be selected with caution in pediatric patients since the rate of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of Corti-Vitenur (Theophylline) is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Corti-Vitenur (Theophylline) after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum Corti-Vitenur (Theophylline) concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Corti-Vitenur (Theophylline) Concentrations, and DOSAGE AND ADMINISTRATION ). The maximum daily dose of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Corti-Vitenur (Theophylline) doses greater than 400 mg/d should be prescribed with caution in elderly patients. Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) are generally mild when peak serum Corti-Vitenur (Theophylline) concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum Corti-Vitenur (Theophylline) concentrations exceed 20 mcg/mL, however, Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) therapy and the potential therapeutic benefit of alternative treatment.

Other adverse reactions that have been reported at serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Corti-Vitenur (Theophylline) concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum Corti-Vitenur (Theophylline) concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Corti-Vitenur (Theophylline) concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Corti-Vitenur (Theophylline) concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur 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 Corti-Vitenur (Theophylline) clearance. The most common causes of chronic Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Corti-Vitenur (Theophylline) concentration to determine whether a dose increase is safe.

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

Several studies have described the clinical manifestations of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Corti-Vitenur (Theophylline) concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentration compared to patients without the underlying disease.

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

Other manifestations of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) Overdose or Serum Corti-Vitenur (Theophylline) Concentrations >30 mcg/mL (Note: Serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by Corti-Vitenur (Theophylline). 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 Corti-Vitenur (Theophylline) overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum Corti-Vitenur (Theophylline) concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) (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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) overdoses. Although ipecac induces emesis, it does not reduce the absorption of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) Concentration Monitoring The serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of Corti-Vitenur (Theophylline) from the gastrointestinal tract. Serial monitoring of serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of Corti-Vitenur (Theophylline) at least twofold by adsorption of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) from the gastrointestinal tract. Sorbitol alone does not enhance clearance of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) toxicity)
  • Administer a single dose of oral activated charcoal.
  • Monitor the patient and obtain a serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal

Increasing the rate of Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of Corti-Vitenur (Theophylline) from the tissue compartment. Peritoneal dialysis is ineffective for Corti-Vitenur (Theophylline) removal; exchange transfusions in neonates have been minimally effective.

DOSAGE AND ADMINISTRATION

Corti-Vitenur ^® 400 or 600 mg Tablets can be taken once a day in the morning or evening. It is recommended that Corti-Vitenur (Theophylline) be taken with meals. Patients should be advised that if they choose to take Corti-Vitenur (Theophylline) 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.

Corti-Vitenur (Theophylline)^® Tablets are not to be chewed or crushed because it may lead to a rapid release of Corti-Vitenur (Theophylline) with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline).

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

It must be recognized that the peak and trough serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentration is a function of the dose, the dosing interval, and the rate of Corti-Vitenur (Theophylline) absorption and clearance in the individual patient. Because of marked individual differences in the rate of Corti-Vitenur (Theophylline) clearance, the dose required to achieve a peak serum Corti-Vitenur (Theophylline) concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) dose that will provide both safe and effective serum concentrations for all patients. Administration of the median Corti-Vitenur (Theophylline) dose required to achieve a therapeutic serum Corti-Vitenur (Theophylline) concentration in a given population may result in either sub-therapeutic or potentially toxic serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) must be individualized on the basis of peak serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentrations to reach the new steady-state. Dosage adjustment should be guided by serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum Corti-Vitenur (Theophylline) concentrations should be monitored at frequent intervals, e.g., every 24 hours.

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

Table V contains Corti-Vitenur (Theophylline) dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for Corti-Vitenur (Theophylline) dosage adjustment based upon serum Corti-Vitenur (Theophylline) 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 Corti-Vitenur (Theophylline) concentration.

Table V. Dosing initiation and titration (as anhydrous Corti-Vitenur (Theophylline)). *

• 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 Corti-Vitenur (Theophylline) Concentrations:
  
  • In children 12-15 years of age, the Corti-Vitenur (Theophylline) dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced Corti-Vitenur (Theophylline) clearance (see WARNINGS ) or if it is not feasible to monitor serum Corti-Vitenur (Theophylline) concentrations.
    

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

Corti-Vitenur (Theophylline)^® (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.

Corti-Vitenur (Theophylline)^® (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

Corti-Vitenur (Theophylline) Tablets

400 mg Tablets

NDC 677781-251-01

Corti-Vitenur (Theophylline) Tablets 400 mg Tablets NDC 677781-251-01

Corti-Vitenur (Theophylline) Tablets

600 mg Tablets

NDC 677781-252-01

Corti-Vitenur (Theophylline) Tablets 600 mg Tablets NDC 677781-252-01