Phyllocontin (Aminophylline)

PHYLLOCONTIN® PHYLLOCONTIN®-350

Purdue Frederick

Aminophylline

Bronchodilator

Action And Clinical Pharmacology: Aminophylline is the ethylenediamine salt of theophylline. The pharmacodynamics of Phyllocontin and Phyllocontin-350 tablets are a function of theophylline blood levels.

Theophylline is a xanthine structurally related to theobromine and caffeine. As with other xanthine derivatives, the precise mechanism of action of theophylline has not been determined. Theophylline stimulates the CNS and skeletal muscles, stimulates cardiac muscle, relaxes certain smooth muscles including those of the bronchi, produces diuresis, and causes an increase in gastric secretion.

Phyllocontin and Phyllocontin-350 tablets are sustained release tablets which produce peak blood levels of theophylline between 3 and 5 hours. Once the steady state level has been reached, the therapeutic blood levels persist for 12 hours.

Theophylline is usually readily absorbed following oral administration. The extent of absorption is negligibly influenced by food. Following absorption 55 to 65% of theophylline is reversibly bound to plasma protein. Theophylline is distributed in the extracellular fluids and uniformly to all tissues. The drug has a mean biological half-life of 5 hours in adults and 3.5 hours in children with great individual variability. Theophylline is metabolized in the liver. The major metabolites are 1,3-dimethyluric acid, 1-methyluric acid and 3-methylxanthine with only 7 to 13% excreted unchanged.

The enzymes involved in theophylline metabolism are unknown, but do not include xanthine oxidase. Serum uric acid concentrations are not increased during theophylline administration and the drug is not contraindicated in the presence of gout or allopurinol administration. Theophylline clearance is markedly increased in smokers, likely due to stimulation of the metabolizing enzymes.

Indications And Clinical Uses: 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 or ethylenediamine; to patients with coronary artery disease where cardiac stimulation might prove harmful or to patients with peptic ulcer.

Manufacturers’ Warnings In Clinical States: These sustained release tablets are not appropriate for use in an emergency where rapid relief of bronchospasm is required.

Children: Children are very sensitive to xanthines; the margin of safety above therapeutic doses is small. Not presently recommended for children under 12 years of age, as a dosage schedule in this age group has not been established.

Precautions: There is a marked variation in blood levels achieved in different patients given the same dose of theophylline. High serum levels may occur in some patients receiving doses considered to be conventional. Overdosage may lead to serious side effects such as tachycardia, arrhythmias, seizures, vascular collapse and even death, and may occur without warning signs such as nausea and vomiting. The variability in blood levels is primarily due to differences in the rate of metabolism. Therefore, it is important to individualize the dosage regimen.

Ideally, all individuals should have serum theophylline levels measured and a theophylline half-life calculated which would enable doses and dosing regimens to be tailored to each patient to maintain a therapeutic level, to ensure optimal clinical response and to avoid toxicity. The incidence of toxicity increases at serum theophylline levels greater than 82.5 µmol/L (15 µg/mL) and levels above 110 µmol/L (20 µg/mL) are usually quite toxic in most patients (adults). Concurrent tea, coffee or cocoa administration may interfere with analytical results.

The equivalent content of theophylline anhydrous is the active ingredient which determines clinical response. If there is a change in the theophylline product and if it involves a change in the theophylline anhydrous equivalence the physician should adjust the dosage to avoid overdosage or underdosage.

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 high carbohydrate, low protein diet; taking certain drugs (see Drug Interactions).

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

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, and in the elderly (especially males).

Drug Interactions: Theophylline pharmacokinetics are altered by the concurrent use of various drugs.

Pregnancy: 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 should be balanced against the risk of uncontrolled disease.

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.

Adverse reactions include: 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: palpitation, tachycardia, hypotension, circulatory failure, ventricular arrhythmias, extrasystoles and flushing.

Renal: albuminuria, diuresis and hematuria.

Others: 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 frequently early observations of theophylline overdosage.

Fever, diuresis, dehydration and extreme thirst may be seen. Severe poisoning results in bloody, syrup-like “coffee ground” 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: If potential oral overdosage is established, and seizure has not occurred, induce vomiting. Administer a cathartic (this is particularly important when a sustained release preparation has been taken). Administer activated charcoal.

If the patient is having a seizure, establish an airway. Administer oxygen. Treat the seizure with i.v. diazepam, 100 to 300 µg/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. 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 275 µmol/L (50 µg/mL) charcoal hemoperfusion may be indicated.

Dosage And Administration: Adults: The recommended initial dose is 225 to 350 mg every 12 hours (equivalent to 182.25 to 283.5 mg anhydrous theophylline).

Dosage adjustments should be based on the patient’s clinical response and/or serum theophylline levels, with increases of 1/2 tablet per dose at 3 to 4 day intervals. Individual requirements vary considerably; therefore, the physician should be prepared to adjust each patient’s dose. Doses greater than 1 125 mg/day should not be given unless serum theophylline levels are monitored. Monitoring serum theophylline levels is important, especially during dosage adjustment.

At steady state, Phyllocontin and Phyllocontin-350 tablets produce peak theophylline levels 3 to 5 hours after dosing. For serum levels to be most useful, it is important that the patient not have missed any doses during the previous 3 days. The optimum serum theophylline concentration is in the 44 to 110 µmol/L (8.0 to 20.0 µg/mL) range, depending on the severity of the condition. The incidence of adverse effects increases at levels greater than 82.5 µmol/L (15 µg/mL). In cases where it is not possible to monitor theophylline levels, patients should be closely observed for signs of toxicity.

Phyllocontin and Phyllocontin-350 tablets should not be chewed or crushed; they may be halved.

Availability And Storage: Phyllocontin: Each sustained release, round, flat-faced, off-white, scored tablet, engraved P on one side and PF on the reverse, contains: aminophylline USP 225 mg (equivalent to anhydrous theophylline 182.25 mg). Nonmedicinal ingredients: cetostearyl alcohol, hydroxyethyl cellulose, magnesium stearate, natural color, povidone and talc. Sodium- and tartrazine-free. Bottles of 100 and 500.

Phyllocontin-350: Each sustained release, square, off-white, scored tablet, engraved PF on one side and P 350 on the reverse, contains: aminophylline USP 350 mg (equivalent to anhydrous theophylline 283.5 mg). Nonmedicinal ingredients: cetostearyl alcohol, hydroxyethyl cellulose, magnesium stearate, natural color, povidone and talc. Sodium- and tartrazine-free. Bottles of 100 and 500.

PHYLLOCONTIN® PHYLLOCONTIN®-350 Purdue Frederick Aminophylline Bronchodilator

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