PRODUCT MONOGRAPH

PrAPO-THEO ER

Theophylline sustained release tablets

Apotex Standard

400 mg and 600 mg

BRONCHODILATOR

Apotex Inc. Date of Revision:

150 Signet Drive February 15, 2019
Toronto, Ontario
M9L 1T9

Control Number: 224197

Page 1 of 28
 PRODUCT MONOGRAPH

NAME OF DRUG
PrAPO-THEO ER
(theophylline sustained release tablets 400 mg and 600 mg)

THERAPEUTIC CLASSIFICATION
Bronchodilator

ACTIONS

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.

APO-THEO ER (theophylline sustained release 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 APO-THEO ER has been
demonstrated by both dissolution and pharmacokinetic studies.

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

Theophylline is usually well absorbed from the G.I. tract, although there are some differences in
the pharmacokinetic behaviour of various sustained release formulations. Theophylline
distributes to all body compartments and is approximately 60% 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%
and 1-methylxanthine is excreted in smaller amounts.

The generally accepted optimal therapeutic serum theophylline concentrations are 5 to 15 mg/L
(27.5 to 82.5 mcmol / L). Levels above 20 mg/L (110 mcmol /L) are usually associated with
significant adverse drug reactions. The pharmacokinetics of theophylline are influenced by a
number of variables such as age, body weight, diet, concomitant medications, disease state and
smoking (see PRECAUTIONS). Therefore, each patient's optimal therapeutic maintenance
dosage should be determined by individual titration.

Page 2 of 28
At steady-state, theophylline 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%.

% Fluctuation = Cmax – Cmin x 100

Cmin

INDICATIONS

APO-THEO ER (theophylline sustained release tablets) is indicated for the symptomatic

treatment of reversible bronchoconstriction associated with bronchial asthma, chronic
obstructive pulmonary emphysema, chronic bronchitis and related bronchospastic disorders.

APO-THEO ER is not recommended for use in children under 12 years of age.

CONTRAINDICATIONS

APO-THEO ER (theophylline sustained release tablets) should not be administered to patients

with:
 hypersensitivity to theophylline, xanthines derivatives, or the excipients used in these
drug products
 coronary artery disease (where cardiac stimulation might prove harmful)
 peptic ulcers
 concomitant use with ephedrine in children

WARNINGS

In clinical situations where immediate bronchodilation is required, such as status asthmaticus,

APO-THEO ER (theophylline sustained release tablets) 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).

A dosage schedule in the pediatric population has not been established. Use of APO-THEO ER
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

Page 3 of 28
considered. Overdoses of theophylline may cause serious side effects such as tachycardia,
arrhythmias, seizures, vascuIar 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 mcmol/L) and levels above 20 mg/L (110 mcmol/L) are usually quite toxic in
most adults.

Although APO-THEO ER (theophylline sustained release 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 theophyIline product is made and it involves a change in anhydrous
theophylline equivalence, the dose should be adjusted accordingly.

Patients with Special Diseases and Conditions:

Due to potential decreased theophylline clearance, which may result in increased serum levels
and significant adverse drug reactions in patients, dose reduction and monitoring of serum
theophylline concentrations may be required in elderly patients and in patients:
- with impaired liver or kidney function
- over 55 years of age, particularly males and those with chronic lung disease
- with cardiac disease
- with active influenza or other viral disease or after influenza immunization
- with a high carbohydrate, low protein diet
- with hypothyroidism (and when starting acute treatment for hypothyroidism)
- with a sustained high fever

Due to potential increased theophylline clearance, dose increase and monitoring of serum
theophylline concentrations may be required in patients with hyperthyroidism (and when starting
acute hyperthyroidism treatment) and cystic fibrosis.

Particular care is advised in patients suffering from severe asthma who require acute
theophylline administration. It is recommended that serum theophylline concentrations are
monitored in such situations.

Patients who are rapid metabolizers of theophylline, such as the young, smokers and some
non-smoking 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 two equal doses may be indicated.

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

Page 4 of 28
 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,
porphyria, in elderly males with pre-existing partial urinary tract obstruction, such as prostatic
enlargement, due to risk of urinary retention.

Theophylline may exacerbate frequency and duration of seizures and therefore caution should
be exercised in patients with history of seizures.

Drug Interactions:
A. Theophylline pharmacokinetics are altered by the additional use of various drugs as
listed below:

Effect on
Theophylline
Clearance and Clinical Comments
Drug
Elimination Half-life
following co-
administration
Acyclovir, allopurinol, carbimazole, It may be necessary to reduce the
cimetidine, diltiazem, disulfiram, dosage of theophylline to avoid
fluconazole, interferon, isoniazid, adverse drug reactions. Monitoring
quinolone antibiotics (e.g., ciprofloxacin), of serum theophylline
macrolide antibiotics (e.g., erythromycin, concentrations may be required.
clarithromycin, troleandomycin), ↑ t½, ↓ clearance The concomitant use of
methotrexate, mexiletine, nizatidine, oral theophylline and fluvoxamine
contraceptives, propafenone, propanolol, should usually be avoided.
pentoxiphylline, selective serotonin re-
uptake inhibitors (e.g., fluvoxamine),
terbinafine*, thiabendazole, verapamil

It may be necessary to reduce the

dosage of theophylline to avoid
adverse drug reactions.
Alkalinizing agents ↑ t½, ↓ clearance
Monitoring of serum
theophylline concentrations may be
required.
It may be necessary to reduce the
dosage of theophylline to avoid
Treatments associated with adverse drug reactions.
↑ t½, ↓ clearance
hypothyroidism
Monitoring of serum theophylline
concentrations may be required.
Treatments associated with ↓ t½, ↑ clearance It may be necessary to increase

Page 5 of 28
 Effect on
Theophylline
Clearance and Clinical Comments
Drug
Elimination Half-life
following co-
administration
hyperthyroidism the dosage of theophylline to
ensure therapeutic effect.

Monitoring of serum theophylline

concentrations
may be required.
↑ t½, clearance
reported to be
Influenza vaccine
decreased or no
change
It may be necessary to increase
Aminoglutethimide, barbiturates,
the dosage of theophylline to
carbamazepine, hypericum perforatum
ensure therapeutic effect.
(St. John’s Wort), isoproterenol, ↓ t½, ↑ clearance
Monitoring of serum
phenytoin, rifampin, ritonavir,
theophylline concentrations may be
sulfinpyrazone
required.
Tobacco, alcohol ↓ t½, ↑ clearance
Acidifying agents ↓ t½, ↑ clearance
*Additional information provided in paragraphs below

Effect of Terbinafine on the Pharmacokinetics of Theophylline

Single dose terbinafine did not significantly alter the pharmacokinetics of theophylline in a
randomized, open-label, single-dose, three-period crossover study, in healthy male and female
adult subjects (n = 18) treated orally with 250 mg terbinafine, 375 mg theophylline, and 250 mg
terbinafine plus 375 mg theophylline.

Multiple dose terbinafine increased the AUC and half-life of theophylline by 16% and 24%,
respectively, and decreased the oral clearance of theophylline by 14%, in a randomized, open
label, two-period crossover study in healthy male and female adult subjects (n = 12) treated
orally with a single dose of 5 mg/kg theophylline alone (mean 345 mg, range 307 to 397 mg)
and 2 hours after the last of 4 daily doses of 250 mg terbinafine.

Effect of Theophylline on the Pharmacokinetics of Terbinafine

Theophylline increased the Cmax and AUC of terbinafine by 25% each, and decreased the oral
clearance of terbinafine by 24% in a randomized, open-label, single-dose, three-period
crossover study, in healthy male and female adult subjects (N = 18) treated orally with 250 mg
terbinafine, 375 mg theophylline, and 250 mg terbinafine plus 375 mg theophylline.

Page 6 of 28
B. Concurrent use of theophylline influences the actions of certain drugs:

Drug Influence of Theophylline Clinical Comment

Adenosine receptor Inhibits the effect of adenosine receptor Caution with
agonists agonists concomitant use
Caution with
Benzodiazepines Opposes the sedatory effects
concomitant use
Caution with
Digitalis glycosides ↑ cardiac effect
concomitant use
Caution with
Halothane Occurrence of arrhythmias
concomitant use
Caution with
Thiazides ↑ diuresis
concomitant use
Caution with
Nephrotoxic drugs ↑ nephrotoxicity
concomitant use
↑ ratio of lithium/creatinine clearance, Caution with
Lithium
thus a decrease in serum lithium levels concomitant use
Caution with
Lomustine Results in thrombocytopenia
concomitant use
Caution with
Sympathomimetic amines ↑ toxicity, ↑ CNS stimulation
concomitant use
↓ anticoagulant activity Caution with
↑ prothrombin and fibrinogen blood concomitant use
Coumarin anticoagulants
concentrations
↓ prothrombin time
Caution with
Allopurinol ↓ antihyperuricemic action
concomitant use
Probenecid and Caution with
↓ uricosuric action
pyrazolone derivatives concomitant use

For COPD patients, the concomitant use of theophylline and roflumilast should usually be
avoided.

Care should be taken with concomitant use of β -adrenergic agonists, glucagon and other
xanthine drugs, as these will potentiate the effects of theophylline. The incidence of toxic effects
may be enhanced by the concomitant use of ephedrine.

Hypokalemia resulting from β2 agonist therapy, steroids, diuretics and hypoxia may be
potentiated by xanthines. Particular care is advised in patients suffering from severe asthma
who require hospitalization. It is recommended that serum potassium concentrations are
monitored in such situations. Theophylline may decrease steady-state phenytoin levels.

Use in 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.
APO-THEO ER should not be administered during pregnancy unless considered essential by
the physician. Theophylline should be given to pregnant women or nursing mothers only when
the anticipated benefits outweigh the risk to the child.

Page 7 of 28
Laboratory Test Interactions: When plasma levels are measured by spectrophotometric
methods, coffee, tea, cola beverages, chocolate and acetaminophen contribute to falsely high
values.

When a high pressure liquid chromatography (HPLC) method is used, plasma theophylline
concentrations 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 theophylline tablets are more completely absorbed when taken with
food as opposed to under fasting conditions (see BIOAVAILABILITY AND CLINICAL DATA).

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 classified by body system include:

Gastrointestinal: Abdominal pain, anorexia, diarrhea, epigastric pain,

gastroesophageal reflux, hematemesis, intestinal bleeding,
nausea, reactivation of peptic ulcer and vomiting

Central Nervous System: Convulsions, dizziness, headache, irritability, reflex

hyperexcitability, restlessness, twitching and tremors

Cardiovascular: Atrial tachycardia, circulatory failure, extrasystoles, flushing,

hypotension, palpitations, sinus tachycardia and ventricular
arrhythmias

Skin and Subcutaneous: Pruritus and rash

Immune: Anaphylactic reaction, anaphylactoid reaction and hypersensitivity

Metabolic and Nutritional: Hyperuricemia, hyperglycemia

Psychiatric: Agitation, anxiety, insomnia, sleep disorder

Renal: Albuminuria, diuresis, hematuria and urinary retention (see

PRECAUTIONS, Patients with Special Diseases and Conditions).

Others: Tachypnea and inappropriate ADH syndrome

Page 8 of 28
 SYMPTOMS AND TREATMENT OF OVERDOSAGE

Symptoms of acute theophylline toxicity: Theophylline has a low therapeutic index.

Theophylline toxicity is most likely to occur when serum concentrations exceed 20 mcg/mL
(110 mcmol/L) and becomes progressively more severe at higher serum concentrations.

Symptoms:

Alimentary symptoms: Nausea, vomiting, abdominal pain and hematemesis

Cardiovascular symptoms: Sinus tachycardia, ventricular arrthymias and hypotension

Metabolic symptoms: Hyperglycemia, hypokalemia, acid/base disturbance and

rhabdomyolysis

Neurological symptoms: Restlessness, convulsion, seizure and coma in severe

cases

Treat symptoms on appearance, which may include hypokalemia, supraventricular and

ventricular arrhythmias, convulsions and seizures. Sustained release tablets may release
medication for hours, facilitated by formation of tablet aggregates, or bezoars, in the stomach.
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, acid/base disturbances, rhabdomyolysis, sinus
tachycardia and ventricular arrhythmias may be seen. Severe overdosage 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:

A. Monitoring Serum Theophylline Levels

It is important to note that, following the intake of APO-THEO ER (theophylline sustained

release tablets), the peak theophylline levels may not occur until eight to twelve 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 (one report on lethal self-poisoning has attributed this to
compacted tablets in the gastrointestinal tract). Following initial treatment, longer careful
clinical and laboratory monitoring, including electrocardiograms is advisable after the
patient's stabilization.

Page 9 of 28
B. If a potential oral overdose is established and a seizure has not occurred:

1) Administration of oral activated charcoal has been found to reduce high theophylline
serum concentrations. Multiple doses of activated charcoal should be also considered.
Seizure prophylaxis may be indicated for certain patients.

2) Administration of a cathartic can be considered in addition to oral activated charcoal.

Repeated doses of cathartic are not recommended due to possible adverse effects.

3) In severe poisoning or cases where gastric decontamination is not feasible,

extracorporeal removal (i.e., hemodialysis, charcoal-column hemoperfusion) can be
employed.

C. If patient is having a seizure:

1) Establish an airway.

2) Administer oxygen.

3) Intravenous benzodiazepines are generally considered as first line therapy although

some benzodiazepines may have reduced efficacy in theophylline overdose due to
suspected pharmacodynamics interactions. Second line agents should be used if
resistant, although phenytoin should be avoided.

4) Continue to provide full supportive care and monitoring.

D. Post Seizure Coma:

1) Maintain airway and oxygenation.

2) Consider the recommendations (B above, steps 1 to 3) to prevent absorption of the

drug. Note that an unprotected airway is a contraindication to activated charcoal
administration due to concerns of aspiration.

3) Continue to provide full supportive care and monitoring.

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 5
and 15 mg/L (27.5 to 82.5 mcmol/L). Theophylline distributes poorly into body fat,
therefore, mg/kg doses should be calculated on the basis of lean body mass (ideal body
weight). A serum level of 5 mcg/mL (27.5 mcmol/L) represents the lower level of clinical
effectiveness. Whereas the serum level of 20 mg/L (110 mcmol/L) is an important reference
point in terms of toxicity (see PRECAUTIONS).

Page 10 of 28
Monitoring of plasma theophylline concentrations may be required when:
 higher doses are prescribed
 patients have co-morbidities resulting in impaired clearance (see PRECAUTIONS,
Patients with Special Diseases and Conditions)
 theophylline is co-administered with medication that reduces theophylline clearance (see
PRECAUTIONS, Drug Interactions)

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, APO-THEO ER (theophylline sustained

release tablets) 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 APO-THEO ER 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 APO-THEO ER.

It is recommended that once-daily APO-THEO ER be taken in the evening. Studies have

demonstrated that while the bioavailability and the pharmacokinetics of theophylline 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 theophylline tablets 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 APO-THEO ER 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 ½ tablet per 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.

It is not possible to ensure interchangeability between different sustained release theophylline

products. Once titrated to an effective dose, patients should not be changed from one sustained
release theophylline product to another sustained release xanthine preparation without re-
titration and careful clinical monitoring.

Monitoring serum theophylIine 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, APO-THEO ER 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%.
(See BIOAVAILABILITY and CLINICAL DATA for further information on the time of peak
theophylline levels, and the relationship between a single level obtained 12 hours post-dose and
the actual peak level).

Page 11 of 28
The generally accepted optimal therapeutic range is 5 to 15 mg/L (27.5 to 82.5 mcmol/L),
although some patients obtain a very good bronchodilator effect from serum levels less than 10
mg/L (55 mcmol/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.

APO-THEO ER must be swallowed whole and should not be broken, chewed, dissolved or
crushed as this may lead to a rapid release of theophylline with the potential for toxicity. Tablets
may be halved.

AVAILABILITY

APO–THEO ER formulated as sustained–release tablets contains anhydrous theophylline with

no colour additives. APO–THEO ER is available in 400 mg and 600 mg strengths in bottles of
100.

APO–THEO ER 400 mg: White to off-white, round, flat-faced, bevelled-edge tablets. Engraved
“APO” on one side, “THE” over score “400” on the other side.

APO–THEO ER 600 mg: White to off-white, capsule shaped, flat-faced, bevelled-edge tablets.
Engraved “APO” on one side, “THE” over score “600” on the other side.

Store tablets at controlled room temperature 15°C to 30°C.

NON - MEDICINAL INGREDIENTS (all strengths): Colloidal silicon dioxide, hydroxypropyl

methylcellulose and magnesium stearate.

Page 12 of 28
 INFORMATION FOR THE CONSUMER
Pr
APO-THEO ER

Theophylline sustained release tablets

Your doctor has prescribed APO-THEO ER (theophylline sustained release tablets), which
contain the drug theophylline incorporated into a sustained release system. Theophylline opens
the airways in your lungs so that you may breathe more easily, and APO-THEO ER’s sustained
release mechanism gradually releases theophylline so that most patients need to take APO-
THEO ER only once per day.

When APO-THEO ER should not be used

APO-THEO ER should not be administered to patients with:

 hypersensitivity to xanthines
 an allergy to theophylline or the excipients used in the drug product
 heart disease
 peptic ulcers
 concomitant use with ephedrine in children

APO-THEO ER tablets, sustained release formulation, are not appropriate for use in an
emergency where rapid relief of bronchospasm is required.

APO-THEO ER is not recommended for use in children under 12 years of age.

You should also inform your doctor if you:

 start or stop smoking
 are breast-feeding, pregnant or want to become pregnant
 have impaired liver or kidney function
 are over 55 years of age, particularly male and with chronic lung disease
 have heart disease
 have influenza or other viral diseases or after influenza immunization
 have a high carbohydrate, low protein diet
 are taking certain drugs (see Drug Interactions, below)
 have thyroid disease
 suffered from seizures (fits or convulsions)
 have a continuous high fever
 have cystic fibrosis

In these situations, your dosage may need to be adjusted.

Drug Interactions
Many medications interact with theophylline, therefore it is important that your doctor knows all
the medications which you are taking and if you stop taking them. These include:
 acyclovir, adenosine receptor agonists, aminoglutethimide, antibiotics, ephedrine,
fluconazole, glucagon, halothane, interferons, lithium, lomustine, methotrexate, oral
contraceptives, terbinafine or xanthine drugs

Page 13 of 28
  if you have had or you are going to have flu injections
 medicines for alcoholism, asthma, epilepsy, gout, heart problems, insomnia (sleeping
problems), stomach ulcers, thyroid problems, tuberculosis
 St. John’s Wort (Hypericum perforatum)
 thiabendazole (a drug used for killing worms, for example threadworm and roundworm)
 selective serotonin re-uptake inhibitors, e.g., fluvoxamine (drugs used to treat
depression)
 ritonavir (used to treat HIV infection)
 roflumilast (used in patients with COPD). The concurrent use of this medication should
be avoided

How to take APO-THEO ER

It is important that you take your APO-THEO ER regularly, at the time and in the exact
quantity that your doctor has directed. Do not increase your APO-THEO ER dose unless
specifically directed to do so by your doctor.

To swallow APO-THEO ER more easily, and to ensure that the tablets promptly reach your
stomach, each dose should be taken with a full glass (120 to 180 mL; 4 to 6 fl. oz.) of water
while you are standing or sitting upright. Your tablets should be taken whole or halved (if a
dosage containing halved tablets was directed by your doctor), but do not break, crush,
dissolve or chew the tablets as this will affect the sustained release mechanism. Unless
directed otherwise by your doctor, APO-THEO ER should be taken with, or shortly following, the
evening meal.

Missed doses can cause your symptoms of asthma or bronchitis to reappear and taking more
APO-THEO ER than prescribed can lead to side effects such as headache, nausea or vomiting.
If these side effects occur at any time during APO-THEO ER therapy, you should contact your
doctor before taking any additional doses. If your symptoms become more severe and you have
been taking your medication regularly, you should also contact your doctor.

If you find that you have missed a dose, and less than 6 hours have elapsed since your
scheduled dosing time, take your regular dose immediately. If between 6 and 18 hours have
elapsed, take ½ your regular dose immediately then resume taking your full regular dose at your
next scheduled dosing time. If more than 18 hours have elapsed since your missed dose, wait
for your next scheduled dosing time and then resume your regular dosage regimen.

During a fever or viral infection (e.g., flu), your dosage of APO-THEO ER may need to be
adjusted. If you develop side effects during such an infection, do not take your next dose of
APO-THEO ER and call your doctor.

Side effects you may have while taking APO-THEO ER

When taking APO-THEO ER, you may feel sick, have an upset stomach, loss of appetite,
headache, tachycardia or palpitations (a fast, strong heart beat) or arrhythmia (an irregular heart
beat). You may also have problems sleeping or feel restless, irritable and shaky or develop a
rash and itching. Occasionally, convulsions (fits) have been reported. If any of these problems
bother you or you have any other problems, please contact your doctor immediately.

Page 14 of 28
Severe allergic reactions can occur while taking APO-THEO ER. If you develop a rash,
hives, swelling of the face, lips, tongue or throat, have difficulty swallowing or breathing,
stop taking APO-THEO ER and seek immediate emergency medical help.

Overdose

In the case of a drug overdose, contact a health care practitioner, hospital emergency
department or regional Poison Control Centre immediately, even if there are no symptoms.

Page 15 of 28
 CHEMISTRY

Structure:

Chemical Name: 1,3 Dimethylxanthine

Molecular Weight: 180.2 (anhydrous) g/mol

198.2 (monohydrate) g/mol

Description: Theophylline is a white, odorless, crystalline powder with a bitter taste.

TheophyIline is soluble 1:120 in water, 1:80 in alcohol and about 1:200 in
chloroform.

PHARMACOLOGY

Pharmacodynamics: The principal pharmacologic actions of theophyIline are to stimulate the

central nervous system, act on the kidney to produce diuresis, stimulate cardiac muscle and
relax smooth muscle, notably the bronchial muscle. The main therapeutic use of theophylline is
in the treatment of reversible airway obstruction.

Pharmacokinetics: Theophylline is usually readily absorbed following oral administration. The

drug is 60% bound to plasma proteins at the therapeutic plasma concentration range of 5 to 15
mg/L (27.5 to 82.5 mcmol/L); it is not likely to be subject to pronounced displacement effect. In
the case of sustained-release products, steady-state plasma concentrations are achieved within
3 days in most patients.

Theophylline is distributed into all body compartments and crosses the placental barrier
producing high fetal concentrations. It is also excreted in human breast milk.

Volume of distribution (Vd) ranges from 0.3 to 0.7 L per kg (30 to 70% ideal body weight) and
averages 0.45 L per kg among both children and adults. However, the mean Vd for premature
neonates, adults with hepatic cirrhosis or uncorrected acidemia, and the elderly is slightly larger
since protein binding is reduced in these patients.

TheophylIine is metabolized by the liver to 3-methylxanthine, 1-methyluric acid and

1,3-dimethyluric acid. About 10% of a dose is excreted unchanged in the urine. The mean
elimination half-life associated with theophylIine is approximately 7 hours.

Page 16 of 28
The enzymes responsible for theophylline metabolism are unknown but do not include xanthine
oxidase.

The half-life of theophylline is influenced by a number of known variables. It is prolonged in

patients suffering from chronic alcoholism, impaired hepatic or renal function, congestive heart
failure, and in patients receiving macrolide antibiotics and cimetidine. Older adults (over age 55)
and patients with chronic obstructive pulmonary disease, with or without cor pulmonale, may
also have much slower clearance rates. For such patients, the theophylline half-life may exceed
24 hours.

Newborns and neonates have extremely slow clearance rates compared to older infants (over 6
months) and children, and may also have a theophylline half-life of over 24 hours. High fever for
prolonged periods may also reduce the rate of theophylline elimination.
Administration of influenza vaccine and infection with influenza virus have been associated with
the impaired rate of theophylline elimination and consequent increases in serum theophylline
levels, sometimes with toxic symptoms.
The half-life of theophylline in smokers (one to two packs/day) averages four to five hours, much
shorter than the half-life in non-smokers which averages seven to nine hours. The increase in
theophylline clearance caused by smoking is probably the result of induction of drug-
metabolizing enzymes that do not readily normalize after cessation of smoking. It appears that
between three months and two years may be necessary for normalization of the effect of
smoking on theophylline pharmacokinetics.

BIOAVAILABILITY AND CLINICAL DATA

Bioavailability and Clinical Comparison to Twice-Daily Theophylline:

In a randomized, two-phase crossover trial, 12 asthmatic patients received two weeks therapy
with once-daily theophylline (dosed at 2000h) and a twice-daily reference theophylline (dosed at
0800h and 2000h). Asthma symptoms were recorded twice each day. At the end of each two-
week treatment, serum theophylline levels were measured every 2 hours over a 24 hour period
and spirometry was performed at 2000h, 0600h, and 0800h.
The pharmacokinetic parameters (mean ± SD) and serum theophylline vs. time profiles are
shown below:

Daily Dose Cmax Cmin Tmax AUC

mg mg/L mg/L hours mg.hr/L

Once daily 783 15.9 6.5 11.3 271

theophylline ±57 ±4.5 ±3.1 ±3.3 ±98
Twice daily 766 13.4 8.7 6.8 263
theophylline ±115 ±4.8 ±4.4 ±3.8 ±105

Page 17 of 28
 Serum theophylline levels from once-daily theophylline and
twice-daily theophylline (mean ± SE):

In comparing treatments, morning FEV1 and peak expiratory flow rates were significantly higher
during once-daily evening administration of theophylline than during twice-daily theophylline.
There were no statistically significant differences in evening FEV1 and PEFR values between
the two treatments.

Asthma symptom scores were significantly lower during once-daily theophylline as shown in the
following table.

Mean ± SEM Symptom Scores During Once-Daily Theophylline and Twice-Daily

Theophylline

Once-Daily Twice-Daily p Value

Symptom Theophylline Theophylline (between
Treatment Treatment treatments)
Dyspnea
Daytime 0.77 ± 0.2 1.22 ± 0.3 0.045
Nighttime 0.63 ± 0.2 1.14 ± 0.3 0.003
Wheeze
Daytime 0.63 ± 0.2 1.00 ± 0.3 0.036
Nighttime 0.62 ± 0.2 0.98 ± 0.3 0.002
Cough
Daytime 0.29 ± 0.2 0.52 ± 0.2 0.033
Nighttime 0.31 ± 0.2 0.53 ± 0.2 NS

The investigators concluded that once-daily theophylline resulted in better control of nighttime
symptoms without an increase in daytime symptoms or significant side effects and that optimal
timing of theophylline dosing is an important consideration in the management of asthma.

Page 18 of 28
Clinical Comparison to Twice-Daily Theophylline:

In a separate double-blind, two-phase, crossover trial, 22 adult asthmatics received 7 days

therapy with once-daily theophylline (dosing was at 2000h) and twice-daily theophylline (dosing
was at 0800h and 2000h). For each patient the total daily theophylline dose was the same
during both treatments. Asthma symptoms, drug side effects and PEFR were recorded at
0800h, 1600h, and 2000h each day. On the last 3 days of each treatment, serum theophylline
and spirometry were measured at 0800h, 1600h, and 2000h.

Once daily theophylline produced greater "peak" and lower "trough" theophylline levels than did
twice daily theophylline, although both drugs maintained levels within an acceptable therapeutic
range.

In contrast to the theophylline level results, once daily therapy was associated with less
fluctuation in pulmonary function throughout the day (see figure below), and significantly lower
symptom scores for wheeze. Both dosing therapies were well tolerated and only minimal side
effects were reported during the trial. The investigator concluded that once-daily theophylline
produced greater stabilization of the asthmatic patients' airway function than the twice-daily
formulation.

Mean ± SEM FEV1 over Three Consecutive Days In 22 Adult Asthmatics During
Once-Daily theophylline and Twice Daily theophylline

Effect of Morning vs Evening Dosing on Theophylline Bioavailability and Clinical Efficacy:

A double-blind, two-phase crossover trial compared the pharmacokinetics and clinical efficacy of
morning vs. evening dosing with once-daily theophylline in 17 asthmatic patients. After a pre-
study titration phase, patients were randomly allocated to receive active once daily theophylline
at either 0800h or 2200h, with an identical placebo taken at the opposite dosing time.
Symptoms and side effects were recorded in a daily diary and, after a minimum of 5 days
dosing, blood samples for theophylline analyses were obtained every 2 hours for 40 consecutive
hours. During the 40 hour period, spirometry was performed at 0800h, 1400h, 2200h and 0400h

Page 19 of 28
of the subsequent day. Patients then crossed-over to the opposite dosing time and repeated the
protocol.

There were no statistically significant differences in any of the pharmacologic parameters

between morning and evening dosing.

Mean ± SEM Steady-State Serum Theophylline Profiles After Once-Daily Theophylline

Mean ± SEM Pharmacokinetic Parameters During

Morning and Evening Dosing with Once-Daily Theophylline

Morning Dosing Evening Dosing

Cmax (mg/L) 14.5 ± 1.0 16.3 ± 1.1
Cmin 5.5 ± 0.7 5.0 ± 0.6
Tmax 8.1 ± 0.9 10.1 ± 1.0
AUC 235.5 ±18.7 256.0 ± 19.6

Evening dosing, but not morning dosing, resulted in a significant attenuation of the early
morning dip in pulmonary function. FEV1 (expressed as percent of daily best) demonstrated that
significantly better spirometric responses occurred at 0400h and 0800h during evening dosing.

Also, the early morning symptoms of wheezing, chest tightness and shortness of breath were
significantly lower during evening dosing. The spirometric and symptomatic benefits of evening
dosing were clearly perceived by the patients, and all of the patients who continued theophylline
post-study selected evening dosing.

Page 20 of 28
Effect of Food on Theophylline Bioavailability:

Multi-Dose Study
In a four-way crossover trial, the effect of a high-fat, high calorie meal on theophylline’s
bioavailability and pharmacokinetics was assessed in 20 adult asthmatics. After a minimum of 5
days continuous dosing (at 1800h), all patients received a theophylline dose under specified
fasting conditions and serum theophylline levels were measured every 2 hours for 24 hours.
The patient's next theophylline dose was given immediately following ingestion of a
standardized high-calorie (2040), high fat (115 g) meal and theophylline levels were again
measured over 24 hours. A week later the trial was repeated in the opposite sequence (i.e.,
dosing with food preceded fasting dosing).

The results were (Mean ± SD):

Fasted With Food p Value

AUC (mg.hr/L) 284 ± 93 313 ± 85 <0.01

Cmax (mg/L) 16.5 ±4.5 17.5 ± 4.5 NS
Tmax (hours) 8.5 ± 4.6 11.4 ± 3.6 <0.01
Cmin (mg/L) 7.0 ±3.0 7.7 ±3.1 <0.01

The overall mean serum theophylline vs. time profiles are shown below:

Single-Dose Study

In a three-way, randomized crossover study, 12 subjects received single doses of:

i. three 200 mg plain aminophylline tablets (total theophylline dose 480 mg) under fasting
conditions;
ii. two 400 mg theophylline tablets under fasting conditions;

Page 21 of 28
 iii. two 400 mg theophylline tablets immediately following ingestion of a high-fat breakfast.

All doses were administered in the morning and, following dosing, serum theophylline levels
were repeatedly measured up to 72 hours post-dose.

The results from the plain aminophylline tablets were used to calculate each subjects
theophylline disposition parameters and serve as a bioavailability reference.

Marked differences in theophylline’s pharmacokinetics and bioavailability were observed

between food and fasting administration as shown in the following table (Mean ± SD):

Fasted With Food p Value

AUC (mg.hr/L) 100 ± 51 179 ± 67 <0.001
Cmax (mg/L) 4.5 ± 0.9 8.6 ± 2.7 <0.05
Tmax (hours) 5.5 ± 1.7 12.0 ± 4.0 <0.01
Fraction absorbed (%) 53 ± 23 96 ± 46 <0.05

Comparison between the Multi-Dose and Single-Dose Studies

The results of the two studies are not consistent in respect of the bioavailability of theophylline
when taken in the fasting state. In the multi-dose study, the mean fasting AUC was 91% of the
food AUC whereas in the single dose study the fasting AUC was only 56% of the food AUC. The
reasons for these differences are not known but may relate to differences in the pre-dosing
fasting periods between the two studies. In the single-dose study, subjects fasted overnight for a
minimum of 10 hours whereas in the multi-dose study, the patients fasted for six hours,
beginning at noon.

Both studies indicate that theophylline is more completely absorbed when taken with food.
Therefore, until further information concerning the effects of prolonged fasting on theophylline
bioavailability is known, it is recommended that theophylline be taken within 1 to 2 hours of
mealtime.

Monitoring Serum Theophylline Levels:

When theophylline is taken in the evening with food, the time that peak levels most frequently
occur (under steady-state conditions) is 12 hours post-dose. Therefore, under such dosing
conditions, 12 hours post-dose is the optimal time to measure the theophylline level in order to
estimate the actual peak level. However, for patients whose actual peak level occurs at times
other than 12 hours post-dose, the 12 hour level will somewhat underestimate the actual peak.

The following figure shows the distribution of the difference between the serum theophylline
level measured at 12 hours post-dose and the actual peak level observed in a series of 91
steady-state serum theophylline vs. time profiles.

Page 22 of 28
 12 HOUR LEVEL vs. ACTUAL PEAK

Thus, while 90% of the 12 hour levels were within 4 mg/L of the actual peak level, the possibility
that an isolated 12 hour post-dose level may significantly underestimate the patient's actual
peak theophylline level should always be considered.

When theophylline tablets are taken in the morning, or in the evening under fasting conditions,
the time that peak levels most frequently occur is 8 hours post-dose.

Trough levels almost always occur at the time of dosing (i.e., 24 hours post-dose).

Clinical Studies

Comparative Bioavailability

Pursuant to current requirements, a comparative biostudy was conducted, under steady state
fasting conditions, between Nov.24/05 – Dec.6/05, under fasting conditions, between Mar.25/06
– Apr.19/06, and under fed conditions between Aug.16/05 – Aug.28/05, using APO-THEO ER
600mg, batch #XK379 and Uniphyl® Tablets 600mg, batch #30241. The studies consisted of
randomized, double-blind, single-dose, 2-way crossover, with wash-out periods of at least 7
days. The steady state fasting study consisted of twenty-nine (29) healthy male volunteers
fasting study consisted of twenty-six (26) healthy male volunteers, while the fed study consisted
of thirty (30) healthy male volunteers.

The results from the bioequivalence studies indicate that APO-THEO ER are bioequivalent to
Uniphyl® tablets. A summary containing comparative bioavailability data is provided in the
following tables:

Page 23 of 28
 Summary Table of the Comparative Bioavailability Data
Theophylline Sustained Release
(Multiple 600 mg dose: 7 x 600 mg tablets)
From Measured Data/Steady State Under Fasting Conditions
Geometric Mean ##
Arithmetic Mean (CV%)
Theophylline SR Uniphyl® Tablets Ratio of
95% Confidence
Parameter Tablets (Apotex (Purdue Pharma Geometric
Interval (%)##
Inc.) (Canada) Canada) Means (%)##
AUCtau 141.6670 134.3310 105.46 96.13 – 115.70
(mcg•h/mL) 145.8646 (23.50) 137.9830 (25.84)
C 8.2980 8.3830 98.98 90.18 – 108.64
max

(mcg/mL) 8.5157 (21.69) 8.5856 (23.98)

Cmin 3.0170 2.7200 110.92 93.23 – 131.97
(mcg/mL) 3.3966 (45.63) 2.8784 (35.45)
Tmax# (h) 6.2308 (40.43) 6.8077 (62.60)
Fluc# (%) 88.0042 (30.44) 101.1665 (17.34)
# Arithmetic mean (CV%) only.
## Based on the least squares estimate.
† Uniphyl® Tablets is manufactured by Purdue Pharma, Canada, and was purchased in Canada.

Summary Table of the Comparative Bioavailability Data

Theophylline Sustained Release
(A single 600 mg dose: 1 x 600 mg tablet)
From Measured Data/Fasting Conditions
Geometric Mean ##
Arithmetic Mean (CV%)
Theophylline SR Uniphyl® Tablets 95%
Ratio of Geometric
Parameter Tablets (Apotex Inc.) (Purdue Pharma Confidence
Means (%)##
(Canada) Canada) Interval (%)##

AUCt 133.778 131.339

(mcg•h/mL) 101.86 88.21 – 117.61
141.2028 (32.92) 139.7591 (36.80)
AUCinf 138.620 136.678
(mcg•h/mL) 101.42 88.39 – 116.74
145.8721 (32.04) 144.9577 (35.91)
Cmax 6.580 6.625
(mcg/mL) 99.31 90.65 – 108.79
6.6970 (18.91) 6.8363 (25.26)
Tmax# (h) 9.8621 (60.76) 7.2069 (60.18)
Thalf# (h) 6.9445 (19.11) 7.8286 (23.98)

Page 24 of 28
# Arithmetic mean (CV%) only.
## Based on the least squares estimate.
† Uniphyl® Tablets is manufactured by Purdue Pharma, Canada, and was purchased in Canada.

Summary Table of the Comparative Bioavailability Data

Theophylline Sustained Release
(A single 600 mg dose: 1 x 600 mg tablet)
From Measured Data/Fed Conditions
Geometric Mean ##
Arithmetic Mean (CV%)
Theophylline SR Uniphyl® Tablets 95%
Ratio of Geometric
Parameter Tablets (Apotex Inc.) (Purdue Pharma Confidence
Means (%)##
(Canada) Canada) Interval (%)##

AUCt 168.036 171.486

(mcg•h/mL) 97.99 86.20 – 111.38
177.6503 (33.00) 179.9892 (32.30)
AUCinf 172.184 175.950
(mcg•h/mL) 97.86 86.23 – 111.05
181.8155 (32.63) 184.3852 (31.79)
Cmax 8.309 8.492
(mcg/mL) 97.84 86.88 – 110.20
8.6243 (27.47) 8.6970 (23.95)
Tmax# (h) 11.7000 (47.62) 10.8000 (44.07)
Thalf# (h) 7.1013 (28.62) 7.4830 (27.89)
# Arithmetic mean (CV%) only.
## Based on the least squares estimate.
† Uniphyl® Tablets is manufactured by Purdue Pharma, Canada, and was purchased in Canada.

TOXICOLOGY

The human oral lethal dose is estimated to be from 50 to 500 mg/kg. Children are more
susceptible to the toxic effects of theophylline than adults.

The incidence of adverse reactions increases at serum concentrations over 15 mg/L

(82.5 mcmol/L). Levels in excess of (20 mg/L) 110 mcmol/L are usually quite toxic in most
patients, although a few patients can tolerate higher levels without significant side-effects.
Tolerance to some of the toxic effects of theophylline is known to occur.

Page 25 of 28
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