Uniphyl (Theophylline)

UNIPHYL®

Purdue Frederick

Theophylline

Bronchodilator

Action And Clinical Pharmacology: Theophylline relaxes bronchial smooth muscle (particularly when the muscles are constricted); produces vasodilation except in cerebral vessels; stimulates the CNS including the respiratory center; stimulates cardiac muscle; produces diuresis and increases gastric acid secretion. In addition to its activity as a bronchodilator, theophylline may also stimulate mucociliary clearance, inhibit anaphylactic mediator release, suppress mediator induced inflammation and improve contractility of the diaphragm.

Uniphyl tablets are a sustained release formulation of theophylline. The release system consists of a homogeneous matrix of aliphatic alcohol, cellulose, and active drug. The proportion of these components in the formulation has been chosen to provide gradual, measured release of theophylline by diffusion through the tablet matrix and dissolution. The rate of release of active drug is dependent upon the drug’s partition coefficients between the components of the tablet matrix and the aqueous phase within the gastrointestinal tract. The controlled release of theophylline from these tablets has been demonstrated by both dissolution and pharmacokinetic studies.

Theophylline’s mechanism of action is not fully known and evidence exists indicating that phosphodiesterase inhibition, prostaglandin inhibition, effects on calcium flux and intracellular calcium distribution, and antagonism of endogenous adenosine may all contribute to its pharmacological effects.

Theophylline is usually well absorbed from the gastrointestinal tract, although there are some differences in the pharmacokinetic behavior of various sustained release formulations. Theophylline distributes to all body compartments and is approximately 50% protein bound. Elimination is primarily by hepatic biotransformation with approximately 50% excreted as 1,3-dimethyluric acid. Unchanged theophylline, 3-methylxanthine and 1-methyluric acid each account for 10% to 15% and 1-methylxanthine is excreted in smaller amounts.

The generally accepted optimal therapeutic serum theophylline concentrations are 10 to 20 mg/L (55 to 110 mol/L). Levels above 20 mg/L (110 mol/L) are usually associated with toxic reactions. The pharmacokinetics of theophylline are influenced by a number of variables such as age, concomitant medications, disease state and smoking (see Precautions). Therefore, each patient’s optimal therapeutic maintenance dosage should be determined by individual titration.

At steady state, Uniphyl tablets taken once daily produce peak theophylline levels between 8 and 12 hours post-dose, and trough levels almost always occur at the time of dosing. During once-daily dosing, the mean fluctuation between peak and trough theophylline levels is 130%. (Cmax-Cmin) % Fluctuation = x 100 Cmin

Indications And Clinical Uses: The symptomatic treatment of reversible bronchoconstriction associated with bronchial asthma, chronic obstructive pulmonary emphysema, chronic bronchitis and related bronchospastic disorders.

Contra-Indications: Should not be administered to patients with hypersensitivity to xanthines, to patients with coronary artery disease where cardiac stimulation might prove harmful, or to patients with active peptic ulcer. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: In clinical situations where immediate bronchodilation is required, such as status asthmaticus, Uniphyl tablets (a sustained release preparation) are not appropriate.

Theophylline has a narrow therapeutic index, the margin of safety above therapeutic doses is small.

Whenever signs of intolerance to theophylline develop, the therapy should be reassessed.

Theophylline clearance can be affected by various disease states, the age of the patient, concomitant use of other medication and lifestyle habits (see Precautions).

Children: A dosage schedule in the pediatric population has not been established. Use in children under 12 years of age is not recommended.

Precautions: General: There is a marked variation in serum levels achieved in different patients given the same dose of theophylline. Therefore, high serum levels may occur in some patients receiving doses considered to be conventional. The possibility of theophylline overdose should always be considered. Overdoses of theophylline may cause serious side effects such as tachycardia, arrhythmias, seizures, vascular collapse and even death. These may occur without warning and may not be preceded by less severe side effects such as nausea or restlessness.

The variability in serum levels is primarily due to differences in the rate of metabolism. Therefore, it is advisable to individualize the dosage regimen. Ideally, all patients should have serum theophylline levels measured which would enable doses and dosing regimens to be tailored for each patient in order to maintain therapeutic levels, ensure optimal clinical response and avoid toxicity. The incidence of adverse reactions increases at theophylline levels greater than 15 mg/L (82.5 mol/L) and levels above 20 mg/L (110 mol/L) are usually quite toxic in most adults.

Although Uniphyl tablets have pharmacokinetic properties similar to other sustained release theophylline formulations, it is not possible to ensure interchangeability between different formulations. Careful clinical monitoring is required when changing from one formulation to another. The equivalent content of anhydrous theophylline is the active ingredient that determines the blood concentration and clinical response. If a change in theophylline product is made and it involves a change in anhydrous theophylline equivalence, the dose should be adjusted accordingly.

Patients with Special Diseases and Conditions: Theophylline clearance is decreased, which may result in increased serum levels and resultant toxicity in patients: with impaired liver or kidney function; over 55 years of age, particularly males and those with chronic lung disease; with cardiac failure from any cause; with active influenza or other viral disease or after influenza immunization; with a high carbohydrate, low protein diet; patients taking certain drugs such as cimetidine, ciprofloxacin, norfloxacin, erythromycin and troleandomycin.

Laboratory monitoring of serum theophylline levels is especially appropriate in the above individuals in order to maintain the appropriate theophylline dosage.

Patients who are rapid metabolizers of theophylline, such as the young, smokers and some nonsmoking adults may not be suitable candidates for once-daily dosing. In rapid metabolizers, peak to trough fluctuations in theophylline levels may be greater than desirable or result in side effects at the time of maximum levels and/or the recurrence of symptoms toward the end of the 24 hour dose interval when levels are lowest. In such patients, dividing the total daily theophylline dose into 2 equal doses may be indicated.

Theophylline is known to stimulate gastric acid secretion and may also act as a local gastrointestinal irritant. Therefore, the drug should only be used with caution in patients with a history of peptic ulcer disease.

Theophylline may cause arrhythmia and/or worsen pre-existing arrhythmia. Any significant change in rate and/or rhythm warrants monitoring and further investigation.

Many patients who require theophylline may exhibit tachycardia due to their underlying disease process so that the cause/effect relationship to elevated serum theophylline concentrations may not be appreciated.

Use with caution in patients with severe cardiac disease, severe hypoxemia, hypertension, hyperthyroidism, acute myocardial injury, cor pulmonale, congestive heart failure, liver disease, in the elderly (especially males).

Drug Interactions: Pregnancy and Lactation: Theophylline crosses the placental barrier and also passes freely into breast milk, where concentrations are similar to plasma levels. Safe use in pregnancy has not been established relative to possible adverse effects on fetal development, but neither have adverse effects on fetal development been established. Therefore, use of theophylline in pregnant women and nursing mothers should be balanced against the risk of uncontrolled asthma.

Laboratory Test Interactions: When plasma levels are measured by spectrophotometric methods, coffee, tea, cola beverages, chocolate and acetaminophen contribute to falsely high values.

When high pressure liquid chromatography (HPLC) method is used, plasma theophylline concentration may be falsely increased by caffeine, some cephalosporins and sulfa medications.

Theophylline may cause elevation of urine catecholamines, plasma uric acid and free fatty acids.

Food Interaction: When immediate release theophylline formulations are administered with food, the rate of absorption is reduced but absorption remains complete. Various sustained release formulations, because of differences in their release mechanisms, may be affected in different ways by concomitant food intake.

Studies have shown that Uniphyl tablets are more completely absorbed when taken with food as opposed to under fasting conditions.

Adverse Reactions: The most common adverse reactions are gastric irritation, nausea, vomiting, epigastric pain, and tremor. These are usually early signs of toxicity, however, with high doses ventricular arrhythmias or seizures may be the first signs to appear.

Gastrointestinal: nausea, vomiting, epigastric pain, hematemesis, diarrhea, anorexia, intestinal bleeding and reactivation of peptic ulcer.

CNS: headache, irritability, restlessness, insomnia, twitching, convulsions and reflex hyperexcitability.

Cardiovascular: palpitations, tachycardia, hypotension, circulatory failure, ventricular arrhythmias, extrasystoles and flushing.

Renal: albuminuria, diuresis and hematuria.

Other: hyperglycemia, tachypnea and inappropriate ADH syndrome.

Symptoms And Treatment Of Overdose: Symptoms: Insomnia, restlessness, mild excitement or irritability and rapid pulse are the early symptoms, which may progress to mild delirium. Sensory disturbances such as tinnitus or flashes of light are common. Anorexia, nausea and vomiting are also frequently early observations of theophylline overdosage.

Fever, diuresis, dehydration and extreme thirst may be seen. Severe overdosage results in bloody, syrup-like “coffeeground” vomitus, tremors, tonic extensor spasm interrupted by clonic convulsions, extrasystoles, quickened respiration, stupor and finally coma.

Cardiovascular disorders and respiratory collapse, leading to shock, cyanosis and death follow gross overdosages.

Treatment: Monitoring Serum Theophylline Levels: It is important to note that, following the intake of Uniphyl tablets, the peak theophylline levels may not occur until 8 to 12 hours post ingestion. Moreover, patients ingesting overdoses of sustained release theophylline formulations may also have, after the initial rise in the blood theophylline, a secondary increase in theophylline levels (1 report on lethal self-poisoning has attributed this to compacted tablets in the gastrointestinal tract). Following initial treatment, longer careful clinical and laboratory monitoring is advisable after patients’ stabilization.

If a potential oral overdose is established and a seizure has not occurred, induce emesis. Administer a cathartic (this is particularly important when a sustained release preparation has been taken). Administer activated charcoal.

If patient is having a seizure, establish an airway. Administer oxygen. Treat the seizure with i.v. diazepam, 0.1 to 0.3 mg/kg up to 10 mg. Monitor vital signs, maintain blood pressure and provide adequate hydration.

Post Seizure Coma: Maintain airway and oxygenation. If a result of oral medication, follow the above recommendations to prevent absorption of the drug, but intubation and lavage will have to be performed instead of inducing emesis and the cathartic and charcoal will need to be introduced via a large bore gastric lavage tube. Continue to provide full supportive care and adequate hydration while waiting for the drug to be metabolized. In general, the drug is metabolized sufficiently rapidly so as not to warrant consideration of dialysis. However, if serum levels exceed 50 mg/L (275 mol/L) charcoal hemoperfusion may be indicated.

Dosage And Administration: Administration and dosing of theophylline should be individualized in respect of the patient’s clinical response and serum theophylline levels. There is considerable patient-to-patient variation in the daily theophylline dose required to achieve therapeutic and safe levels. Ideally, all patients should have serum theophylline levels measured which would enable doses and dosing regimens to be tailored in order to maintain therapeutic levels, ensure optimal clinical response and avoid toxicity. Therapeutic serum levels are generally considered to be between 10 and 20 mg/L (55 and 110 mol/L). Dosage calculations should be based on lean body mass (ideal body weight). A serum level of 20 mg/L (110 mol/L) is an important reference point in terms of toxicity (see Precautions).

Initial Adult Dose: For patients not currently receiving oral theophylline, the recommended initial dose is 400 to 600 mg once daily.

In patients currently controlled on oral theophylline, Uniphyl therapy should start at the same daily theophylline dosage (mg for mg basis) provided by the previous formulation. For example, a patient receiving 400 mg twice daily (800 mg daily dosage) would be given two 400 mg Uniphyl tablets once daily. A minimum of 12 hours should elapse between a patient’s last dose of the previous oral theophylline formulation and the first dose of Uniphyl.

It is recommended that once daily Uniphyl be taken in the evening. Studies have demonstrated that while the bioavailability and pharmacokinetics of Uniphyl tablets were not significantly different between morning and evening dosing, a better clinical response was obtained with evening dosing. Subsequent studies indicate that the clinical advantages of evening dosing are likely a result of the maximum theophylline levels occurring in the early morning hours, a time of greatest bronchoconstriction and symptoms for many asthmatics.

It is advisable that Uniphyl be taken with food, or within 1 to 2 hours of mealtime, as studies have suggested that absorption may be incomplete if taken under conditions of prolonged fasting.

Overall, therefore, it is recommended that most patients should take once daily Uniphyl with, or shortly following, the evening meal.

Dose Titration: Dosage adjustments should be based on the patient’s clinical response and/or serum theophylline levels, with increases of 1/2 tablet/day at 3 to 4 day intervals. Individual requirements vary considerably, therefore, the physician should be prepared to adjust each patient’s dose. Do not attempt to maintain any dosage that is poorly tolerated.

Monitoring serum theophylline levels is important, especially during initiation of therapy and dosage adjustment. For serum levels to be most useful, it is important that the patient not have missed or added any doses during the previous 3 days and that the dose intervals remained relatively constant. At steady state, Uniphyl tablets produce peak theophylline levels between 8 and 12 hours post-dose, and trough levels almost always occur at the time of dosing. During once daily dosing, the mean fluctuation between peak and trough theophylline levels is 130%.

The generally accepted optimal therapeutic range is 10 to 20 mg/L (55 to 110 mol/L), although some patients obtain a very good bronchodilator effect from serum levels less than 10 mg/L (55 mol/L). In cases where it is not possible to monitor theophylline levels, patients should be closely observed for signs of toxicity and dosages greater than 13 mg/kg/day (or 900 mg/day, whichever is less) should not be given.

Uniphyl tablets should not be chewed or crushed, they may be halved.

Availability And Storage: 400 mg: Each round, flat-faced, white, scored tablet, engraved š on one side and PF on the reverse, contains: theophylline 400 mg sustained release. Nonmedicinal ingredients: cetostearyl alcohol, hydroxyethyl cellulose, magnesium stearate, povidone and talc. Sodium- and tartrazine-free.

600 mg: Each capsule-shaped, concave-faced, white, scored tablet, engraved U 600 on one side and PF on the reverse, contains: theophylline 600 mg sustained release. Nonmedicinal ingredients: cetostearyl alcohol, hydroxyethyl cellulose, magnesium stearate, povidone and talc. Sodium- and tartrazine-free.

Opaque plastic bottles of 50. Dispense in amber or opaque containers. Store at room temperature, below 30°C. (Shown in Product Recognition Section)

UNIPHYL® Purdue Frederick Theophylline Bronchodilator

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