THEOPHYLLINE - theophylline tablet, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
THEOPHYLLINE ANHYDROUS (UNII: 0I55128JYK) (THEOPHYLLINE ANHYDROUS - UNII:0I55128JYK)
Available from:
Physicians Total Care, Inc.
INN (International Name):
THEOPHYLLINE ANHYDROUS
Composition:
THEOPHYLLINE ANHYDROUS 100 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Theophylline extended-release tablets are 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. Theophylline extended-release tablets are contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.
Product summary:
Theophylline Extended-Release Tablets 100 mg – White to off white, round, biconvex, uncoated tablets debossed with PLIVA and 483 bisected by a score line on one side and unscored on the other side in 200 mg – White to off white, Oval shaped, biconvex, uncoated tablets debossed with PLIVA and 482 on one side and scored on the other side in 300 mg – White to off white, capsule shaped, biconvex, uncoated tablets debossed with PLIVA and 459 on one side and scored on the other side in Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. Manufactured In India By: EMCURE PHARMACEUTICALS LTD. Hinjwadi, Pune, India Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 Relabeling and Repackaging by: Physicians Total Care, Inc. Tulsa, OK     74146 Rev. A 6/2010
Authorization status:
Abbreviated New Drug Application
Authorization number:
54868-0028-1, 54868-0028-2, 54868-0028-6, 54868-0029-2, 54868-0029-5, 54868-0029-6, 54868-0029-7, 54868-1461-1, 54868-1461-2

THEOPHYLLINE - theophylline tablet, extended release

Physicians Total Care, Inc.

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Theophylline Extended-Release Tablets

DESCRIPTION

Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline

powder with a bitter taste. Anhydrous theophylline has the chemical name 1H-Purine-2,6-dione,3,7-

dihydro-1,3-dimethyl-, and is represented by the following structural formula:

C H N O M.W. 180.17

This product allows a 12-hour dosing interval for a majority of patients and a 24-hour dosing interval

for selected patients (see DOSAGE AND ADMINISTRATION section for description of appropriate

patient populations).

Each extended-release tablet for oral administration contains either 100 mg, 200 mg, 300 mg or 450 mg

of anhydrous theophylline. Tablets also contain as inactive ingredients: hypromellose, anhydrous

lactose, magnesium stearate and povidone.

CLINICAL PHARMACOLOGY

Mechanism of Action

Theophylline 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 theophylline are not

known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of

two isozymes of phosphodiesterase (PDE lll 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 lll or antagonism of adenosine receptors. Some of the adverse effects

associated with theophylline appear to be mediated by inhibition of PDE lll (e.g., hypotension,

tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral

blood flow).

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 theophylline concentration range of 5 to 20 mcg/mL. Clinically

important improvement in symptom control has been found in most studies to require peak serum

theophylline concentrations >10 mcg/mL, but patients with mild disease may benefit from lower

concentrations. At serum theophylline concentrations >20 mcg/mL, both the frequency and severity of

adverse reactions increase. In general, maintaining peak serum 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

Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-

release solid oral dosage form. 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 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 theophylline. Within-subject variability in

metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore,

recommended that serum 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 to 12 month

intervals. More frequent measurements should be made in the presence of any condition that may

significantly alter theophylline clearance (see PRECAUTIONS, Laboratory Tests).

Table I. Mean and range of total body clearance and half-life of

theophylline related to age and altered physiological states.

Population Characteristics

Age

Total body

clearance

mean (range)

(mL/kg/min)

Half-life

mean

(range)

(hr)

Premature neonates

postnatal age 3 to 15 days

postnatal age 25 to 57 days

0.29 (0.09 to 0.49)

0.64 (0.04 to 1.2)

30 (17 to 43)

20 (9.4 to

30.6)

Term infants

postnatal age 1 to 2 days

postnatal age 3 to 30 weeks

25.7 (25 to

26.5)

11 (6 to 29)

Children

1 to 4 years

4 to 12 years

13 to 15 years

6 to 17 years

1.7 (0.5 to 2.9)

1.6 (0.8 to 2.4)

0.9 (0.48 to 1.3)

1.4 (0.2 to 2.6)

3.4 (1.2 to

5.6)

3.7 (1.5 to

5.9)

Adults (16 to 60 years)

otherwise healthy

nonsmoking asthmatics

0.65 (0.27 to 1.03)

8.7 (6.1 to

12.8)

Elderly (>60 years)

nonsmokers with normal cardiac,

liver, and renal function

0.41 (0.21 to 0.61)

9.8 (1.6 to

Concurrent illness or

altered physiological state

Acute pulmonary edema

0.33 (0.07 to

2.45)

19 (3.1 to

COPD->60 years, stable

nonsmoker > 1 year

0.54 (0.44 to 0.64)

11 (9.4 to

12.6)

COPD with cor pulmonale

0.48 (0.08 to 0.88) NR

Cystic fibrosis (14 to 28 years)

Fever associated with acute viral

respiratory illness (children 9 to 15

years)

1.25 (0.31 to 2.2)

6.0 (1.8 to

10.2)

7.0 (1.0 to 13)

Liver disease - cirrhosis

acute hepatitis

cholestasis

0.31 (0.1 to 0.7)

0.35 (0.25 to 0.45)

0.65 (0.25 to 1.45)

32 (10 to 56)

19.2 (16.6 to

21.8)

14.4 (5.7 to

31.8)

Pregnancy - 1st trimester

2nd trimester

3rd trimester

8.5 (3.1 to

13.9)

8.8 (3.8 to

13.8)

13.0 (8.4 to

17.6)

Sepsis with multi-organ failure

Thyroid disease - hypothyroid

hyperthyroid

0.47 (0.19 to 1.9)

0.38 (0.13 to 0.57)

0.8 (0.68 to 0.97)

18.8 (6.3 to

24.1)

11.6 (8.2 to

4.5 (3.7 to

5.6)

NOTE: In addition to the factors listed above, 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 theophylline.

Absorption

Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-

release solid oral dosage form. After a single dose immediate release theophylline of 5 mg/kg in adults,

a mean peak serum concentration of about 10 mcg/mL (range 5 to 15 mcg/mL) can be expected 1 to 2

hours after the dose. Co-administration of theophylline with food or antacids does not cause clinically

significant changes in the absorption of theophylline from immediate-release dosage forms.

Single-Dose Study

(450 mg)

Reported range or estimated range (mean +/- 2 SD) where actual range not

reported.

NR = not reported or not reported in a comparable format.

Median.

A single-dose, two-way crossover study was conducted in sixteen healthy male volunteers under

fasting conditions, with one 450 mg tablet being administered at 7 a.m. with a 6 oz. glass of water. No

food or liquid (other than water) was allowed for 4 hours after which a standard lunch was served.

Mean peak theophylline serum level (C

) was 6.69 mcg/mL and mean time of peak serum

concentration (T

) was 8.31 hours.

(300 mg)

A single-dose crossover study was conducted in twelve healthy male volunteers to compare

pharmacokinetic parameters when theophylline extended-release tablets were administered with and

without food. Subjects were fasted overnight and received a single 300 mg tablet early the following

morning.

When dosing was done under fed conditions, the subjects received a standard breakfast consisting of 2

fried eggs, 2 strips of bacon, 4 oz. hash brown potatoes, 1 slice of toast with a pat of butter, and 8 oz.

whole milk 15 minutes pre-dosing. No food was allowed for five hours post-dosing, then a standard

lunch was served; at ten hours post-dosing a standard supper was served. Mean peak theophylline serum

levels for the two treatments were 3.7 mcg/mL (fasting) and 4.4 mcg/mL (with food). The time of peak

serum level varied from subject to subject, occurring from 4 to 14 hours after dosing. However, 92%

of the subjects had serum levels at least 75% of the maximum value at 4 to 8 hours after dosing, during

each phase.

Thus, blood samples taken 4 to 8 hours post-dosing should reference the peak serum level for most

patients. The mean Tmax was 6.2 hours (fasting) and 8.7 hours (with food). The respective AUC (0-inf.)

for these treatments were 73.3 mcg x hr/mL and 82.2 mcg x hr/mL, respectively.

Multiple-Dose Study

(300 mg)

A multiple-dose, steady-state study was conducted under fed conditions. Three high fat content meals

were served at 6:30 a.m., 12 noon and 6:30 p.m. Nineteen normal subjects were dosed at 300 mg every

12 hours (7 p.m. and 7 a.m.) for eight doses. Dosing began one-half hour after the evening meal with the

test dose occurring one-half hour after breakfast. At steady-state, the mean peak concentration was 8.8

mcg/mL and the mean trough concentration was 5.9 mcg/mL.

The time of peak concentration (T

) was 6.2 hours. The average percent fraction of fluctuation

) x 100] was 49% for this formulation and dosing regimen.

The subjects used for this study exhibited a mean half-life of 8.3 hours (range 5.2 to 12.2) and a mean

clearance of 3.5 L/hour (range 2.3 to 5.6) as determined in a separate single-dose clearance study using

500 mg of immediate-release theophylline, prior to this multiple-dose study.

(200 mg)

A multiple-dose, steady-state study was conducted in sixteen normal subjects, with one 200 mg tablet

given every 12 hours for eight doses. Three high fat content meals were served at 6:30 a.m., 12 noon

and 6:30 p.m. Dosing began one-half hour after the evening meal with the test dose occurring one-half

hour after breakfast. At steady-state following the eighth dose, the mean C

was 5.1 mcg/mL and the

mean C

was 3.7 mcg/mL. The mean time to peak concentration was 6.2 hours. The average percent

fraction of fluctuation was 39%.

The subjects used for this study exhibited a mean half-life of 8.7 hours (range 5.0 to 14.6) and a mean

clearance of 3.6 L/hour (range 2.2 to 6.1).

(100 mg)

A multiple-dose, steady-state study was conducted in sixteen normal subjects, with three 100 mg tablets

given every 12 hours for eight doses. Three high fat content meals were served at 6:30 a.m.,12 noon

and 6:30 p.m. Dosing began one-half hour after the evening meal with the test dose occurring one-half

hour after breakfast. At steady-state following the eighth dose, the mean C

was 8.1 mcg/mL and the

mean C

was 5.6 mcg/mL. The mean time to peak concentration was 6.2 hours. The average percent

fraction of fluctuation was 45%.

The subjects used for this study were the same as those used in the previously cited 200 mg study.

Once-a-Day Dosing

A multiple-dose, steady-state study was conducted under fed conditions with once-a-day dosing. Fed

conditions were the same as those previously cited. Sixteen subjects were dosed at 2 x 300 mg tablets

every morning at 8 a.m. for five doses. At steady-state, the mean C

was 11.7 mcg/mL, and the mean

was 3.4 mcg/mL. The average percent fraction of fluctuation was 244%. The mean T

was 8.7

hours.

The subjects used in the above study exhibited a mean half-life of 7.9 hours (range 5.3 to 13.4) and a

mean clearance of 3.8 L/hour (range 2.3 to 5.7).

Distribution

Once theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily

albumin. Unbound theophylline distributes throughout body water, but distributes poorly into body fat.

The apparent volume of distribution of theophylline is approximately 0.45 L/kg (range 0.3 to 0.7 L/kg)

based on ideal body weight. Theophylline passes freely across the placenta, into breast milk and into the

cerebrospinal fluid (CSF). Saliva 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 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 theophylline in the therapeutic range (10

to 20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly,

a patient with decreased 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

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 theophylline

concentration provides a more reliable means of dosage adjustment than measurement of total serum

theophylline concentration. Generally, concentrations of unbound theophylline should be maintained in

the range of 6 to 12 mcg/mL.

Metabolism

Following oral dosing, 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 theophylline dose is N-methylated to caffeine. 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-methyl-

xanthine 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 theophylline metabolites with pharmacologic activity. 3-

methylxanthine has approximately one tenth the pharmacologic activity of 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

theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of

renal function. In neonates, caffeine may accumulate to concentrations that approximate the

unmetabolized theophylline concentration and thus, exert a pharmacologic effect.

Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-

limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of

elimination may begin in some patients at serum theophylline concentrations >10 mcg/mL. Since this

non-linearity results in more than proportional changes in serum 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 theophylline concentrations (see DOSAGE AND

ADMINISTRATION, Table VI). Accurate prediction of dose-dependency of theophylline metabolism

in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady-

state serum theophylline concentrations at above average doses) have the greatest likelihood of

experiencing large changes in serum theophylline concentration in response to dosage changes.

Excretion

In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the

first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the

urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35 to 40%), 1-methyluric

acid (20 to 25%) and 3-methylxanthine (15 to 20%). Since little theophylline is excreted unchanged in

the urine and since active metabolites of 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 theophylline dose excreted in the urine as unchanged theophylline and caffeine in

neonates requires careful attention to dose reduction and frequent monitoring of serum theophylline

concentrations in neonates with reduced renal function (see WARNINGS).

Serum Concentrations at Steady-State

After multiple doses of theophylline, steady-state is reached in 30 to 65 hours (average 40 hours) in

adults. At steady-state, on a dosage regimen with 6-hour intervals, the expected mean trough

concentration is approximately 60% of the mean peak concentration, assuming a mean theophylline half-

life of 8 hours. The difference between peak and trough concentrations is larger in patients with more

rapid theophylline clearance. In patients with high theophylline clearance and half-lives of about 4 to 5

hours, such as children age 1 to 9 years, the trough serum theophylline concentration may be only 30%

of peak with a 6-hour dosing interval. In these patients a slow-release formulation would allow a longer

dosing interval (8 to 12 hours) with a smaller peak/trough difference.

Special Populations (see Table I for mean clearance and half-life values)

Geriatric

The clearance of 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

theophylline concentrations are required in elderly patients (see WARNINGS).

Pediatrics

The clearance of theophylline is very low in neonates (see WARNINGS). 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 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 theophylline concentrations are required in pediatric patients (see WARNINGS and DOSAGE

AND ADMINISTRATION).

Gender

Gender differences in theophylline clearance are relatively small and unlikely to be of clinical

significance. Significant reduction in 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 theophylline clearance due to race have not been studied.

Renal Insufficiency

Only a small fraction, e.g., about 10%, of the administered theophylline dose is excreted unchanged in

the urine of children greater than three months of age and adults. Since little theophylline is excreted

unchanged in the urine and since active metabolites of 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 theophylline dose is excreted unchanged in the urine in

neonates. Careful attention to dose reduction and frequent monitoring of serum theophylline

concentrations are required in neonates with decreased renal function (see WARNINGS).

Hepatic Insufficiency

Theophylline 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 theophylline concentrations are required in patients with reduced hepatic function (see

WARNINGS).

Congestive Heart Failure (CHF)

Theophylline clearance is decreased by 50% or more in patients with CHF. The extent of reduction in

theophylline clearance in patients with CHF appears to be directly correlated to the severity of the

cardiac disease. Since 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 theophylline concentrations are required in

patients with CHF (see WARNINGS).

Smokers

Tobacco and marijuana smoking appears to increase the clearance of theophylline by induction of

metabolic pathways. 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

nonsmoking subjects. Passive smoke exposure has also been shown to increase theophylline clearance

by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately

40% in theophylline clearance. Careful attention to dose reduction and frequent monitoring of serum

theophylline concentrations are required in patients who stop smoking (see WARNINGS). Use of

nicotine gum has been shown to have no effect on theophylline clearance.

Fever

Fever, regardless of its underlying cause, can decrease the clearance of theophylline. The magnitude

and duration of the fever appear to be directly correlated to the degree of decrease of 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 theophylline concentrations. Children with

rapid rates of 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 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 theophylline concentrations are

required in patients with sustained fever (see WARNINGS).

Miscellaneous

Other factors associated with decreased 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 theophylline concentrations are required in patients with any of these

conditions (see WARNINGS). Other factors associated with increased 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 theophylline decreases the

frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed”

use of inhaled beta-2 agonists. 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

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

Theophylline extended-release tablets are 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

Theophylline extended-release tablets are contraindicated in patients with a history of hypersensitivity

to theophylline or other components in the product.

WARNINGS

Concurrent Illness

Theophylline 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 Theophylline Clearance

There are several readily identifiable causes of reduced theophylline clearance.If the total daily dose is

not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline

toxicity can occur. Careful consideration must be given to the benefits and risks of theophylline use and

the need for more intensive monitoring of serum theophylline concentrations in patients with the

following risk factors:

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), reduced renal function in infants <3 months of age,

sepsis with multi-organ failure, and shock.

Cessation of Smoking

Drug Interactions

Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping

a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin).

(see PRECAUTIONS, Drug Interactions, Table II).

When Signs or Symptoms of Theophylline Toxicity Are Present

Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive

vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause

may be suspected), additional doses of theophylline should be withheld and a serum 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 clinician 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 theophylline should not be made in response to an acute exacerbation of

symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-

selective agonists and systemically administered cortico-steroids in this circumstance and increases the

risk of adverse effects. A peak steady-state serum 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 theophylline dose on the basis of a low serum concentration, the

clinician 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 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 theophylline concentration (see DOSAGE AND ADMINISTRATION, Table VI).

PRECAUTIONS

General

Careful consideration of the various interacting drugs and physiologic conditions that can alter

theophylline clearance and require dosage adjustment should occur prior to initiation of theophylline

therapy, prior to increases in theophylline dose, and during follow up (see WARNINGS). The dose of

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 theophylline concentrations

and the patient’s clinical response (see DOSAGE AND ADMINISTRATION, Table V).

Monitoring Serum Theophylline Concentrations

Serum theophylline concentration measurements are readily available and should be used to determine

whether the dosage is appropriate. Specifically, the serum theophylline concentration should be

measured as follows:

measured as follows:

1. When initiating therapy to guide final dosage adjustment after titration.

2. Before making a dose increase to determine whether the serum concentration is subtherapeutic in a

patient who continues to be symptomatic.

3. Whenever signs or symptoms of theophylline toxicity are present.

4. Whenever there is a new illness, worsening of a chronic illness or a change in the patient’s treatment

regimen that may alter 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

theophylline concentration: 6 to 7 hours after a 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 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

seven hours after the 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 theophylline toxicity are

present, the serum sample should be obtained as soon as possible, analyzed immediately, and the result

reported to the clinician 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

theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6 to 12

mcg/mL.

Saliva concentrations of theophylline cannot be used reliably to adjust dosage without special

techniques.

Effects on Laboratory Tests

As a result of its pharmacological effects, theophylline at serum concentrations within the 10 to 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 µεq/L to 800 µεq/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).

Theophylline at serum concentrations within the 10 to 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 theophylline). The clinical importance of these changes should be weighed against the potential

therapeutic benefit of theophylline in individual patients.

Information for Patients

The patient (or parent/care giver) should be instructed to seek medical advice whenever nausea,

vomiting, persistent headache, insomnia or rapid heart beat occurs during treatment with theophylline,

even if another cause is suspected. The patient should be instructed to contact their clinician 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 clinician adds a new

medication or discontinues a previously prescribed medication. Patients should be instructed to inform

all clinicians involved in their care that they are taking 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 clinician. 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.

Theophylline extended-release tablets should not be chewed or crushed. When dosing on a once daily

(q24h) basis, tablets should be taken whole and not split.

Drug Interactions

Drug-Drug Interactions

Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e.,

alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects

without a change in serum theophylline concentration. More frequently, however, the interaction is

pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased

or decreased serum theophylline concentrations. 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 theophylline. The information in the “Effect” column of Table II

assumes that the interacting drug is being added to a steady-state theophylline regimen. If theophylline

is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g.,

cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum

theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient

who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of

theophylline required to achieve a therapeutic serum theophylline concentration will be larger.

Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation

of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced.

Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased

serum theophylline concentrations, unless the theophylline dose is appropriately increased.

The drugs listed in Table III have either been documented not to interact with theophylline or do not

produce a clinically significant interaction (i.e., <15% change in 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 theophylline, especially with new chemical entities. The clinician

should not assume that a drug does not interact with theophylline if it is not listed in Table II. Before

addition of a newly available drug in a patient receiving 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

theophylline has been reported.

Table II. Clinically significant drug interactions with theophylline.

Drug

Type of Interaction

Effect

Adenosine

Theophylline blocks

adenosine receptors.

Higher doses of

adenosine may be

required to achieve

desired effect.

Alcohol

A single large dose of

alcohol (3 mL/kg of

whiskey) decreases

theophylline clearance for

up to 24 hours.

30% increase

Allopurinol

Decreases theophylline

clearance at allopurinol

doses ≥600 mg/day.

25% increase

Aminoglutethimide

Increases theophylline

clearance by induction of

microsomal enzyme

activity.

25% decrease

Carbamazepine

Similar to

aminoglutethimide.

30% decrease

Cimetidine

Decreases theophylline

clearance by inhibiting

cytochrome P450 1A2.

70% increase

Ciprofloxacin

Similar to cimetidine.

40% increase

Clarithromycin

Similar to erythromycin.

25% increase

Diazepam

Benzodiazepines increase

CNS concentrations of

adenosine, a potent CNS

depressant, while

theophylline blocks

adenosine receptors.

Larger diazepam

doses may be

required to produce

desired level of

sedation.

Discontinuation of

theophylline without

reduction of

diazepam dose may

result in respiratory

depression.

Disulfiram

Decreases theophylline

clearance by inhibiting

hydroxylation and

demethylation.

50% increase

Enoxacin

Similar to cimetidine.

300% increase

Ephedrine

Synergistic CNS effects

Increased frequency

of nausea,

nervousness, and

insomnia.

Erythromycin

Erythromycin metabolite

decreases theophylline

clearance by inhibiting

cytochrome P450 3A3.

35% increase.

Erythromycin steady-

state serum

concentrations

decrease by a similar

amount.

Estrogen

Estrogen containing oral

contraceptives decrease

theophylline clearance in a

dose-dependent fashion.

The effect of

progesterone on

theophylline clearance is

unknown.

30% increase

Flurazepam

Similar to diazepam.

Similar to diazepam.

Fluvoxamine

Similar to cimetidine.

Similar to cimetidine.

Halothane

Halothane sensitizes the

myocardium to

catecholamines,

theophylline increases

release of endogenous

catecholamines.

Increased risk of

ventricular

arrhythmias.

Interferon, human

recombinant alpha-A

Decreases theophylline

clearance.

100% increase

Isoproterenol (IV)

Increase theophylline

clearance.

20% increase

Ketamine

Pharmacologic

May lower

theophylline seizure

threshold.

Lithium

Theophylline increases

renal lithium clearance.

Lithium dose

required to achieve a

therapeutic serum

concentration

increased an average

of 60%.

Lorazepam

Similar to diazepam.

Similar to diazepam.

Methotrexate

(MTX)

Decreases theophylline

clearance.

20% increase after

low dose MTX,

higher dose MTX

may have a greater

effect.

Mexiletine

Similar to disulfiram.

80% increase

Midazolam

Similar to diazepam.

Similar to diazepam.

Moricizine

Increases theophylline

clearance.

25% decrease

Pancuronium

Theophylline may

antagonize non-

depolarizing

neuromuscular blocking

effects; possibly due to

phosphodiesterase

inhibition.

Larger dose of

pancuronium may be

required to achieve

neuromuscular

blockade.

Pentoxifylline

Decreases theophylline

clearance.

30% increase

Phenobarbital (PB)

Similar to

aminoglutethimide.

25% decrease after

two weeks of

concurrent PB.

Phenytoin

Phenytoin increases

theophylline clearance by

increasing microsomal

enzyme activity.

Theophylline decreases

phenytoin absorption.

Serum theophylline

and phenytoin

concentrations

decrease about 40%.

Propafenone

Decreases theophylline

clearance and

pharmacologic interaction.

40% increase. Beta-

2 blocking effect

may decrease

efficacy of

theophylline.

Propranolol

Similar to cimetidine and

pharmacologic interaction.

100% increase.

Beta-2 blocking

effect may decrease

efficacy of

theophylline.

Rifampin

Increases theophylline

clearance by increasing

cytochrome P450 1A2 and

3A3 activity.

20 to 40% decrease

Sulfinpyrazone

Increase theophylline

clearance by increasing

demethylation and

hydroxylation. Decreases

renal clearance of

theophylline.

20% increase

Tacrine

Similar to cimetidine, also

increases renal clearance

of theophylline.

90% increase

Thiabendazole

Decreases theophylline

clearance.

190% increase

Ticlopidine

Decreases theophylline

clearance.

60% increase

Troleandomycin

Similar to erythromycin.

33 to 100% increase

depending on

troleandomycin dose.

Verapamil

Similar to disulfiram.

20% increase

Table III. Drugs that have been documented not to interact

with theophylline or drugs that produce no clinically

significant interaction with theophylline.

albuterol,

famotidine

nizatidine

systemic and

inhaled

felodipine

norfloxacin

amoxicillin

finasteride

ofloxacin

ampicillin,

hydrocortisone

omeprazole

with or without

isoflurane

prednisone,

prednisolone

sulbactam

isoniazid

ranitidine

atenolol

isradipine

rifabutin

azithromycin

influenza vaccine

roxithromycin

caffeine,

ketoconazole

sorbitol

dietary ingestion

lomefloxacin

(purgative doses do

cefaclor

mebendazole

inhibit theophylline

co-trimoxazole

medroxyprogesterone absorption)

(trimethoprim and

methylprednisolone

sucralfate

sulfamethoxazole)

metronidazole

terbutaline, systemic

diltiazem

metoprolol

terfenadine

dirithromycin

nadolol

tetracycline

enflurane

nifedipine

tocainide

Drug-Food Interactions

Taking theophylline extended-release tablets immediately after ingesting a high fat content meal (45 g

fat, 55 g carbohydrates, 28 g protein, 789 calories) may result in a somewhat higher Cmax and delayed

, and a somewhat greater extent of absorption when compared to taking it in the fasting state. The

influence of the type and amount of other foods, as well as the time interval between drug and food, has

not been studied.

The Effect of Other Drugs on Theophylline Serum Concentration Measurements

Most serum theophylline assays in clinical use are immunoassays which are specific for 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 theophylline concentration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term carcinogenicity studies have been carried out in mice (oral doses 30 to 150 mg/kg) and rats

(oral doses 5 to 75 mg/kg). Results are pending.

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, theophylline, administered to mating pairs of B6C3F1 mice at

oral doses of 120, 270 and 500 mg/kg (approximately 1.0 to 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,

theophylline was administered to F344 rats and B6C3F1 mice at oral doses of 40 to 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

Category C

There are no adequate and well-controlled studies in pregnant women. Additionally, there are no

teratogenicity studies in non-rodents (e.g., rabbits). Theophylline was not shown to be teratogenic in

CD-1 mice at oral doses up to 400 mg/kg, approximately 2.0 times the human dose on a mg/m basis or

in CD-1 rats at oral doses up to 260 mg/kg, approximately 3.0 times the recommended human dose on a

mg/m basis. At a dose of 220 mg/kg, embryotoxicity was observed in rats in the absence of maternal

toxicity.

Nursing Mothers

Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in

nursing human infants. The concentration of theophylline in breast milk is about equivalent to the

maternal serum concentration. An infant ingesting a liter of breast milk containing 10 to 20 mcg/mL of

theophylline a day is likely to receive 10 to 20 mg of theophylline per day. Serious adverse effects in

the infant are unlikely unless the mother has toxic serum theophylline concentrations.

Pediatric Use

Theophylline is safe and effective for the approved indications in pediatric patients. The maintenance

dose of theophylline must be selected with caution in pediatric patients since the rate of theophylline

clearance is highly variable across the age range of neonates to adolescents (see CLINICAL

PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V).

Geriatric Use

Elderly patients are at significantly greater risk of experiencing serious toxicity from theophylline than

younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging.

Theophylline clearance is reduced in patients greater than 60 years of age, resulting in increased serum

theophylline concentrations in response to a given theophylline dose. Protein binding may be decreased

in the elderly resulting in a larger proportion of the total serum theophylline concentration in the

pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic

effects of theophylline after chronic overdosage than younger patients. For these reasons, the maximum

daily dose of 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 theophylline

concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION). Theophylline doses greater

than 400 mg/d should be prescribed with caution in elderly patients.

ADVERSE REACTIONS

Adverse reactions associated with theophylline are generally mild when peak serum 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 theophylline concentrations exceed 20

mcg/mL, however, 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 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 theophylline therapy, caffeine-like adverse

effects may transiently alter patient behavior, especially in school age children, but this response rarely

persists. Initiation of 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 theophylline concentrations within the therapeutic range (i.e., 10 to 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 theophylline therapy

and the potential therapeutic benefit of alternative treatment.

Other adverse reactions that have been reported at serum theophylline concentrations <20 mcg/mL

include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. In patients

with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum

theophylline concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum

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 theophylline concentrations

<20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total

serum theophylline concentration in the pharmacologically active unbound form. The clinical

characteristics of the seizures reported in patients with serum theophylline concentrations <20 mcg/mL

have generally been milder than seizures associated with excessive serum 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).

Table IV. Manifestations of theophylline toxicity. Percentage

of patients reported with sign or symptom

Acute Overdose

(Large Single

Inges tion)

Chronic Overdosage

(Multiple Excessive

Dos es )

Sign/Symptom

As ymotomatic

Gas tointes tinal

Study 1 Study 2

(n = 157) (n = 14)

NR 0

Study 1 Study 2

(n = 92) (n = 102)

NR 6

Vomiting

Abdominal Pain

Diarrhea

Hematemesis

73 93

NR 21

NR 0

NR 0

30 61

NR 12

NR 14

NR 2

Metabolic/Other

Hypokalemia

Hyperglycemia

Acid/base disturbance

Rhabdomyolysis

85 79

98 NR

34 21

NR 7

44 43

18 NR

9 5

NR 0

Cardiovascular

Sinus tachycardia

Other supraventricular

tachycardias

Ventricular premature

beats

Atrial fibrillation or

flutter

Multifocal atrial

tachycardia

Ventricular arrhythmias

hemodynamic instability

Hypotension/shock

100 86

2 21

3 21

1 NR

0 NR

7 14

NR 21

100 62

12 14

10 19

12 NR

2 NR

40 0

NR 8

Neurologic

Nervousness

Tremors

Disorientation

Seizures

Death

NR 64

38 29

NR 7

5 14

3 21

NR 21

16 14

NR 11

14 5

10 4

OVERDOSAGE

General

The chronicity and pattern of theophylline 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 theophylline clearance. The most common causes of chronic

theophylline overdosage include patient or care giver error in dosing, clinician prescribing of an

excessive dose or a normal dose in the presence of factors known to decrease the rate of theophylline

clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring

the serum theophylline concentration to determine whether a dose increase is safe.

Severe toxicity from theophylline overdose is a relatively rare event. In one health maintenance

organization, the frequency of hospital admissions for chronic overdosage of theophylline was about 1

per 1000 person-years exposure. In another study, among 6000 blood samples obtained for

measurement of serum theophylline concentration, for any reason, from patients treated in an emergency

department, 7% were in the 20 to 30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-

thirds of the patients with serum theophylline concentrations in the 20 to 30 mcg/mL range had one or

more manifestations of toxicity while >90% of patients with serum theophylline concentrations >30

mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from theophylline is

seen principally at serum concentrations >30 mcg/mL.

Several studies have described the clinical manifestations of 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 theophylline concentration is >100 mcg/mL. After a chronic

NR = Not reported in a comparable manner.

overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum

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 theophylline concentration; patients >60

years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Preexisting 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 theophylline

concentration compared to patients without the underlying disease.

The frequency of various reported manifestations of theophylline overdose according to the mode of

overdose are listed in Table IV.

Other manifestations of 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 theophylline concentrations >30 mcg/mL are often resistant to

anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from

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 Theophylline Overdose or Serum

Theophylline Concentrations >30 mcg/mL (Note: Serum theophylline concentrations may

continue to increase after presentation of the patient for medical care.)

1. While simultaneously instituting treatment, contact a regional poison center to obtain updated

information and advice on individualizing the recommendations that follow.

2. Institute supportive care, including establishment of intravenous access, maintenance of the airway,

and electrocardiographic monitoring.

3. 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 to 0.2 mg/kg every

1 to 3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading

dose of phenobarbital (20 mg/kg infused over 30 to 60 minutes). Case reports of 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 clinician 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 theophylline overdose because fluorinated volatile

anesthetics may sensitize the myocardium to endogenous catecholamines released by 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.

4. Anticipate need for anticonvulsants: In patients with theophylline overdose who are at high risk

for theophylline-induced seizures, e.g., patients with acute overdoses and serum theophylline

concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum

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 theophylline (e.g., transfer of a high risk patient from one health care

facility to another for extracorporeal removal) and clinical circumstances that significantly interfere

with efforts to enhance 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 theophylline required to induce seizures (i.e., markedly increases the LD ).

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 theophylline clearance are continued. Phenobarbital may cause respiratory

depression, particularly in elderly patients and patients with COPD.

5. 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 theophylline concentrations.

Other arrhythmias, especially those associated with hemodynamic compromise, should be treated

with antiarrhythmic therapy appropriate for the type of arrhythmia.

6. Gastrointestinal decontamination : Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least

once 1 to 2 hours after the first dose) is extremely effective in blocking the absorption of

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 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 theophylline overdoses. Although ipecac induces emesis, it does

not reduce the absorption of 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.

7. Serum theophylline concentration monitoring: The serum theophylline concentration should be

measured immediately upon presentation, 2 to 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

theophylline concentrations may continue to increase after presentation of the patient for medical

care as a result of continued absorption of theophylline from the gastrointestinal tract. Serial

monitoring of serum theophylline serum concentrations should be continued until it is clear that the

concentration is no longer rising and has returned to nontoxic levels.

8. General monitoring procedures: Electrocardiographic monitoring should be initiated on

presentation and continued until the serum theophylline level has returned to a nontoxic 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.

9. Enhance clearance of theophylline: Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20

g, every two hours) increases the clearance of theophylline at least twofold by absorption of

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

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

theophylline from the gastrointestinal tract. Sorbitol alone does not enhance clearance of

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 theophylline removal should be instituted (see

OVERDOSAGE, Extracorporeal Removal).

Specific Recommendations

Acute Overdose

A. Serum Concentration >20 <30 mcg/mL

1. Administer a single dose of oral activated charcoal.

2. Monitor the patient and obtain a serum theophylline concentration in 2 to 4 hours to insure

that the concentration is not increasing.

B. Serum Concentration >30 <100 mcg/mL

1. Administer multiple-dose oral activated charcoal and measures to control emesis.

2. Monitor the patient and obtain serial theophylline concentrations every 2 to 4 hours to gauge

the effectiveness of therapy and to guide further treatment decisions.

3. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be

adequately controlled (see OVERDOSAGE, Extracorporeal Removal).

C. Serum Concentration >100 mcg/mL

1. Consider prophylactic anticonvulsant therapy.

2. Administer multiple-dose oral activated charcoal and measures to control emesis.

3. Consider extracorporeal removal, even if the patient has not experienced a seizure (see

OVERDOSAGE, Extracorporeal Removal).

4. Monitor the patient and obtain serial theophylline concentrations every 2 to 4 hours to gauge

the effectiveness of therapy and to guide further treatment decisions.

Chronic Overdosage

A. Serum Concentration >20 <30 mcg/mL (with manifestations of theophylline toxicity)

1. Administer a single dose of oral activated charcoal.

2. Monitor the patient and obtain a serum theophylline concentration in 2 to 4 hours to insure that

the concentration is not increasing.

B. Serum Concentration >30 mcg/mL in patients <60 years of age

1. Administer multiple-dose oral activated charcoal and measures to control emesis.

2. Monitor the patient and obtain serial theophylline concentrations every 2 to 4 hours to gauge

the effectiveness of therapy and to guide further treatment decisions.

3. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be

adequately controlled (see OVERDOSAGE, Extracorporeal Removal).

C. Serum Concentration >30 mcg/mL in patients >60 years of age

1. Consider prophylactic anticonvulsant therapy.

2. Administer multiple-dose oral activated charcoal and measures to control emesis.

3. Consider extracorporeal removal even if the patient has not experienced a seizure (see

OVERDOSAGE, Extracorporeal Removal).

4. Monitor the patient and obtain serial theophylline concentrations every 2 to 4 hours to gauge

the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal

Increasing the rate of 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 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 theophylline

concentrations may rebound 5 to 10 mcg/mL after discontinuation of charcoal hemoperfusion or

hemodialysis due to redistribution of theophylline from the tissue compartment. Peritoneal dialysis is

ineffective for theophylline removal; exchange transfusions in neonates have been minimally effective.

DOSAGE AND ADMINISTRATION

Taking theophylline extended-release tablets immediately after a high-fat content meal may result in a

somewhat higher C

and delayed T

, and somewhat greater extent of absorption. However, the

differences are usually not great and this product may normally be administered without regard to meals

(see CLINICAL PHARMACOLOGY, Drug Interactions, Drug-Food Interactions).

Theophylline extended-release tablets are recommended for chronic or long-term management and

prevention of symptoms, and not for use in treating acute symptoms of asthma and reversible

bronchospasm.

General Considerations

The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval,

and the rate of theophylline absorption and clearance in the individual patient. Because of marked

individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum

theophylline concentration in the 10 to 20 mcg/mL range varies fourfold among otherwise similar

patients in the absence of factors known to alter theophylline clearance (e.g., 400 to 1600 mg/day in

adults <60 years old and 10 to 36 mg/kg/day in children 1 to 9 years old). For a given population there

is no single theophylline dose that will provide both safe and effective serum concentrations for all

patients. Administration of the median theophylline dose required to achieve a therapeutic serum

theophylline concentration in a given population may result in either subtherapeutic or potentially toxic

serum 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 to 9 years, the steady-state peak serum theophylline concentration

will be <10 mcg/mL in about 30% of patients, 10 to 20 mcg/mL in about 50% and 20 to 30 mcg/mL in

about 20% of patients. The dose of theophylline must be individualized on the basis of peak serum

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

theophylline concentrations to reach the new steady state. Dosage adjustment should be guided by serum

theophylline concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND

ADMINISTRATION, Table VI). Health care providers should instruct patients and care givers 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

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 theophylline concentrations should be

monitored at frequent intervals, e.g. every 24 hours.

Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis

of ideal body weight.

Table V contains theophylline dosing titration schema recommended for patients in various age groups

and clinical circumstances. Table VI contains recommendations for theophylline dosage adjustment

based upon serum 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 theophylline concentration.

Table V. Dosing initiation and titration (as anhydrous

theophylline).

A.

Children (6 to 15 years) and adults (16 to 60 years)

without risk factors for impaired clearance.

Titration Step

Children <45 kg

Children >45 kg and

adults

Starting Dosage

12 to 14 mg/kg/day

to a maximum of

300 mg/day divided

Q12 hrs

300 mg/day divided

Q12 hrs

After 3 days,

if tolerated,

increase dose to:

16 mg/kg/day up

to a maximum of

400 mg/day divided

Q12 hrs

400 mg/day divided

Q12 hrs

After 3 more days,

if tolerated,

increase dose to:

20 mg/kg/day up to

a maximum of

600 mg/day

divided Q12 hrs

600 mg/day divided

Q12 hrs

B.

Patients With Risk Factors For Impaired Clearance, The

Elderly (>60 Years), And Those In Whom It Is Not

Feasible To Monitor Serum Theophylline Concentrations:

In children 6 to 15 years of age, the final 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

theophylline clearance (see WARNINGS) or if it is not

feasible to monitor serum theophylline concentrations.

*

In adolescents ≥16 years and adults, including the elderly, the

final theophylline dose should not exceed 400 mg/day in the

presence of risk factors for reduced theophylline clearance

(see WARNINGS) or if it is not feasible to monitor serum

theophylline concentrations.

Table VI. Dosage adjustment guided by serum theophylline

concentration.

Peak Serum

Concentration

Dosage Adjustment

<9.9 mcg/mL

If symptoms are not controlled and current dosage is

tolerated, increase dose about 25%. Recheck serum

concentration after three days for further dosage

adjustment.

10 to 14.9

mcg/mL

If symptoms are controlled and current dosage is

tolerated, maintain dose and recheck serum

concentration at 6 to 12 month intervals.

If symptoms are not controlled and current dosage is

tolerated consider adding additional medication(s) to

treatment regimen.

15 to 19.9

mcg/mL

Consider 10% decrease in dose to provide greater

margin of safety even if current dosage is tolerated.

20 to 24.9

mcg/mL

Decrease dose by 25% even if no adverse effects are

present. Recheck serum concentration after 3 days to

guide further dosage adjustment.

25 to 30

mcg/mL

Skip next dose and decrease subsequent doses at least

25% even if no adverse effects are present. Recheck

serum concentration after 3 days to guide further

dosage adjustment. If symptomatic, consider whether

overdose treatment is indicated (see recommendations

for chronic overdosage).

>30 mcg/mL

Treat overdose as indicated (see recommendations for

chronic overdosage). If theophylline is subsequently

resumed, decrease dose by at least 50% and recheck

serum concentration after 3 days to guide further

dosage adjustment.

Once-Daily Dosing

The slow absorption rate of this preparation may allow once-daily administration in adult non-smokers

with appropriate total body clearance and other patients with low dosage requirements. Once-daily

dosing should be considered only after the patient has been gradually and satisfactorily titrated to

therapeutic levels with q12h dosing. Once-daily dosing should be based on twice the q12h dose and

Patients with more rapid metabolism, clinically identified by higher than

average dose requirements, should receive a smaller dose more

frequently (every 8 hours) to prevent breakthrough symptoms resulting

from low trough concentrations before the next dose.

Dose reduction and/or serum theophylline concentration measurement is

indicated whenever adverse effects are present, physiologic abnormalities

that can reduce theophylline clearance occur (e.g., sustained fever), or a

drug that interacts with theophylline is added or discontinued (see

WARNINGS).

should be initiated at the end of the last q12h dosing interval. The trough concentration (C

) obtained

following conversion to once-daily dosing may be lower (especially in high clearance patients) and the

peak concentration (C

) may be higher (especially in low clearance patients) than that obtained with

q12h dosing. If symptoms recur, or signs of toxicity appear during the once-daily dosing interval,

dosing on the q12h basis should be reinstituted.

It is essential that serum theophylline concentrations be monitored before and after transfer to once-

daily dosing.

Food and posture, along with changes associated with circadian rhythm, may influence the rate of

absorption and/or clearance rates of theophylline from extended-release dosage forms administered at

night. The exact relationship of these and other factors to nighttime serum concentrations and the

clinical significance of such findings require additional study. Therefore, it is not recommended that

theophylline extended-release once-daily dosing be administered at night.

HOW SUPPLIED

Theophylline Extended-Release Tablets

100 mg – White to off white, round, biconvex, uncoated tablets debossed with PLIVA and 483 bisected

by a score line on one side and unscored on the other side in

Bottles of

NDC 54868-

1461-1

Bottles of

NDC 54868-

1461-2

200 mg – White to off white, Oval shaped, biconvex, uncoated tablets debossed with PLIVA and 482 on

one side and scored on the other side in

Bottles of

NDC 54868-

0028-6

Bottles of

NDC 54868-

0028-1

Bottles of

NDC 54868-

0028-2

300 mg – White to off white, capsule shaped, biconvex, uncoated tablets debossed with PLIVA and 459

on one side and scored on the other side in

Bottles of

NDC 54868-

0029-6

Bottles of

NDC 54868-

0029-5

Bottles of

NDC 54868-

0029-7

Bottles of

NDC 54868-

0029-2

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as

required).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Manufactured In India By:

EMCURE PHARMACEUTICALS LTD.

Hinjwadi, Pune, India

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Relabeling and Repackaging by:

Physicians Total Care, Inc.

Tulsa, OK 74146

Rev. A 6/2010

PRINCIPAL DISPLAY PANEL

Theophylline ER Tablets 100mg Label Text

THEOPHYLLINE

EXTENDED-RELEASE

Tablets

100 mg

Rx only

PRINCIPAL DISPLAY PANEL

Theophylline ER Tablets 200mg Label Text

THEOPHYLLINE

EXTENDED-RELEASE

Tablets

200 mg

Rx only

PRINCIPAL DISPLAY PANEL

Theophylline ER Tablets 300mg Label Text

THEOPHYLLINE

EXTENDED-RELEASE

Tablets

300 mg

Rx only

THEOPHYLLINE

theophylline tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:548 6 8 -146 1(NDC:50 111-48 3)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

THEO PHYLLINE ANHYDRO US (UNII: 0 I55128 JYK) (THEOPHYLLINE ANHYDROUS -

UNII:0 I55128 JYK)

THEOPHYLLINE

ANHYDROUS

10 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

HYPRO MELLO SE 2 2 0 8 ( 10 0 MPA.S) (UNII: B1QE5P712K)

HYPRO MELLO SE 2 2 0 8 ( 10 0 0 0 0 MPA.S) (UNII: VM7F0 B23ZI)

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO VIDO NE K3 0 (UNII: U725QWY32X)

Product Characteristics

Color

WHITE (white to o ff white)

S core

2 pieces

S hap e

ROUND

S iz e

10 mm

Flavor

Imprint Code

PLIVA;48 3

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:548 6 8 -146 1-1

30 in 1 BOTTLE

2

NDC:548 6 8 -146 1-2

9 0 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 8 9 8 0 7

0 7/0 4/20 0 7

THEOPHYLLINE

theophylline tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:548 6 8 -0 0 28 (NDC:50 111-48 2)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

THEO PHYLLINE ANHYDRO US (UNII: 0 I55128 JYK) (THEOPHYLLINE ANHYDROUS -

UNII:0 I55128 JYK)

THEOPHYLLINE

ANHYDROUS

20 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

HYPRO MELLO SE 2 2 0 8 ( 10 0 MPA.S) (UNII: B1QE5P712K)

HYPRO MELLO SE 2 2 0 8 ( 10 0 0 0 0 MPA.S) (UNII: VM7F0 B23ZI)

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO VIDO NE (UNII: FZ9 8 9 GH9 4E)

Product Characteristics

Color

WHITE (white to o ff white)

S core

2 pieces

S hap e

OVAL

S iz e

12mm

Flavor

Imprint Code

PLIVA;48 2

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:548 6 8 -0 0 28 -1

6 0 in 1 BOTTLE

2

NDC:548 6 8 -0 0 28 -2

10 0 in 1 BOTTLE

3

NDC:548 6 8 -0 0 28 -6

30 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 8 9 8 0 8

12/19 /19 9 6

THEOPHYLLINE

theophylline tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:548 6 8 -0 0 29 (NDC:50 111-459 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

THEO PHYLLINE ANHYDRO US (UNII: 0 I55128 JYK) (THEOPHYLLINE ANHYDROUS -

UNII:0 I55128 JYK)

THEOPHYLLINE

ANHYDROUS

30 0 mg

Physicians Total Care, Inc.

Inactive Ingredients

Ingredient Name

Stre ng th

HYPRO MELLO SE 2 2 0 8 ( 10 0 MPA.S) (UNII: B1QE5P712K)

HYPRO MELLO SE 2 2 0 8 ( 10 0 0 0 0 MPA.S) (UNII: VM7F0 B23ZI)

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO VIDO NE (UNII: FZ9 8 9 GH9 4E)

Product Characteristics

Color

WHITE (white to o ff white)

S core

2 pieces

S hap e

OVAL (capsule shaped)

S iz e

14mm

Flavor

Imprint Code

PLIVA;459

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:548 6 8 -0 0 29 -2

10 0 in 1 BOTTLE

2

NDC:548 6 8 -0 0 29 -5

6 0 in 1 BOTTLE

3

NDC:548 6 8 -0 0 29 -6

30 in 1 BOTTLE

4

NDC:548 6 8 -0 0 29 -7

9 0 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 8 9 76 3

0 9 /17/20 0 7

Labeler -

Physicians T otal Care, Inc. (194123980)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Physicians To tal Care, Inc.

19 41239 8 0

relabel, repack

Revised: 9/2011

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