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Phyloday® (theophylline, anhydrous) Tablets in a controlled-release system allows a 24-hour dosing interval for appropriate patients.
Phyloday is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous Phyloday has the chemical name 1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula:
The molecular formula of anhydrous Phyloday is C7H8N4O2 with a molecular weight of 180.17.
Each controlled-release tablet for oral administration, contains 400 or 600 mg of anhydrous Phyloday.
Inactive Ingredients: cetostearyl alcohol, hydroxyethyl cellulose, magnesium stearate, povidone and talc.
Phyloday has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of Phyloday are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with Phyloday appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).
Phyloday increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.
Bronchodilation occurs over the serum Phyloday concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Phyloday concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Phyloday concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Phyloday 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.
Overview: Phyloday is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Phyloday does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.
The pharmacokinetics of Phyloday 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 and co-administration of other drugs (see Table II ) can significantly alter the pharmacokinetic characteristics of Phyloday. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Phyloday concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter Phyloday clearance (see PRECAUTIONS, Laboratory Tests ).
|Population Characteristics||Total body clearance* |
|Half-life mean (range)†† |
|¶For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples.|
|*Clearance represents the volume of blood completely cleared of Phyloday by the liver in one minute. Values listed were generally determined at serum Phyloday concentrations <20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics.|
|††Reported range or estimated range (mean ±2 SD) where actual range not reported.|
|†NR=not reported or not reported in a comparable format.|
|postnatal age 3-15 days||0.29 (0.09-0.49)||30 (17-43)|
|postnatal age 25-57 days||0.64 (0.04-1.2)||20 (9.4-30.6)|
|postnatal age 1-2 days||NR†||25.7 (25-26.5)|
|postnatal age 3-30 weeks||NR†||11 (6-29)|
|1-4 years||1.7 (0.5-2.9)||3.4 (1.2-5.6)|
|4-12 years||1.6 (0.8-2.4)||NR†|
|13-15 years||0.9 (0.48-1.3)||NR†|
|6-17 years||1.4 (0.2-2.6)||3.7 (1.5-5.9)|
|Adults (16-60 years)|
|non-smoking asthmatics||0.65 (0.27-1.03)||8.7 (6.1-12.8)|
|Elderly (>60 years)|
|non-smokers with normal |
liver, and renal function
|0.41 (0.21-0.61)||9.8 (1.6-18)|
|Concurrent illness or altered physiological state|
|Acute pulmonary edema||0.33** (0.07-2.45)||19** (3.1-82)|
|COPD->60 years, stable|
|non-smoker >1 year||0.54 (0.44-0.64)||11 (9.4-12.6)|
|COPD with cor pulmonale||0.48 (0.08-0.88)||NR†|
|Cystic fibrosis (14-28 years)||1.25 (0.31-2.2)||6.0 (1.8-10.2)|
|Fever associated with|
|acute viral respiratory illness|
|(children 9-15 years)||NR†||7.0 (1.0-13)|
|cirrhosis||0.31** (0.1-0.7)||32** (10-56)|
|acute hepatitis||0.35 (0.25-0.45)||19.2 (16.6-21.8)|
|cholestasis||0.65 (0.25-1.45)||14.4 (5.7-31.8)|
|1st trimester||NR†||8.5 (3.1-13.9)|
|2nd trimester||NR†||8.8 (3.8-13.8)|
|3rd trimester||NR†||13.0 (8.4-17.6)|
|Sepsis with multi-organ failure||0.47 (0.19-1.9)||18.8 (6.3-24.1)|
|hypothyroid||0.38 (0.13-0.57)||11.6 (8.2-25)|
|hyperthyroid||0.8 (0.68-0.97)||4.5 (3.7-5.6)|
Note: In addition to the factors listed above, Phyloday 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 Phyloday.
Phyloday® administered in the fed state is completely absorbed after oral administration.
In a single-dose crossover study, two 400 mg Phyloday Tablets were administered to 19 normal volunteers in the morning or evening immediately following the same standardized meal (769 calories consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). There was no evidence of dose dumping nor were there any significant differences in pharmacokinetic parameters attributable to time of drug administration. On the morning arm, the pharmacokinetic parameters were AUC=241.9±83.0 mcg hr/mL, Cmax=9.3±2.0 mcg/mL, Tmax=12.8±4.2 hours. On the evening arm, the pharmacokinetic parameters were AUC=219.7±83.0 mcg hr/mL, Cmax=9.2±2.0 mcg/mL, Tmax=12.5±4.2 hours.
A study in which Phyloday 400 mg Tablets were administered to 17 fed adult asthmatics produced similar Phyloday level-time curves when administered in the morning or evening. Serum levels were generally higher in the evening regimen but there were no statistically significant differences between the two regimens.
|AUC (0-24 hrs) (mcg hr/mL)||236.0±76.7||256.0±80.4|
A single-dose study in 15 normal fasting male volunteers whose Phyloday inherent mean elimination half-life was verified by a liquid Phyloday product to be 6.9±2.5 (SD) hours were administered two or three 400 mg Phyloday® Tablets. The relative bioavailability of Phyloday given in the fasting state in comparison to an immediate-release product was 59%. Peak serum Phyloday levels occurred at 6.9±5.2 (SD) hours, with a normalized (to 800 mg) peak level being 6.2±2.1 (SD). The apparent elimination half-life for the 400 mg Phyloday Tablets was 17.2±5.8 (SD) hours.
Steady-state pharmacokinetics were determined in a study in 12 fasted patients with chronic reversible obstructive pulmonary disease. All were dosed with two 400 mg Phyloday Tablets given once daily in the morning and a reference controlled-release BID product administered as two 200 mg tablets given 12 hours apart. The pharmacokinetic parameters obtained for Phyloday Tablets given at doses of 800 mg once daily in the morning were virtually identical to the corresponding parameters for the reference drug when given as 400 mg BID. In particular, the AUC, Cmax and Cmin values obtained in this study were as follows:
|Phyloday Tablets |
|Reference Drug |
|AUC, (0-24 hours), mcg hr/mL||288.9±21.5||283.5±38.4|
Single-dose studies in which subjects were fasted for twelve (12) hours prior to and an additional four (4) hours following dosing, demonstrated reduced bioavailability as compared to dosing with food. One single-dose study in 20 normal volunteers dosed with two (2) 400 mg tablets in the morning, compared dosing under these fasting conditions with dosing immediately prior to a standardized breakfast (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). Under fed conditions, the pharmacokinetic parameters were: AUC=231.7±92.4 mcg hr/mL, Cmax=8.4±2.6 mcg/mL, Tmax=17.3±6.7 hours. Under fasting conditions, these parameters were AUC=141.2±6.53 mcg hr/mL, Cmax=5.5±1.5 mcg/mL, Tmax=6.5±2.1 hours.
Another single-dose study in 21 normal male volunteers, dosed in the evening, compared fasting to a standardized high calorie, high fat meal (870-1,020 calories, consisting of 33 grams protein, 55-75 grams fat, 58 grams carbohydrates). In the fasting arm subjects received one Phyloday® 400 mg Tablet at 8 p.m. after an eight hour fast followed by a further four hour fast. In the fed arm, subjects were again dosed with one 400 mg Phyloday Tablet, but at 8 p.m. immediately after the high fat content standardized meal cited above. The pharmacokinetic parameters (normalized to 800 mg) fed were AUC=221.8±40.9 mcg hr/mL, Cmax=10.9±1.7 mcg/mL, Tmax=11.8±2.2 hours. In the fasting arm, the pharmacokinetic parameters (normalized to 800 mg) were AUC=146.4±40.9 mcg hr/mL, Cmax=6.7±1.7 mcg/mL, Tmax=7.3±2.2 hours.
Thus, administration of single Phyloday doses to healthy normal volunteers, under prolonged fasted conditions (at least 10 hour overnight fast before dosing followed by an additional four (4) hour fast after dosing) results in decreased bioavailability. However, there was no failure of this delivery system leading to a sudden and unexpected release of a large quantity of Phyloday with Phyloday Tablets even when they are administered with a high fat, high calorie meal.
Similar studies were conducted with the 600 mg Phyloday Tablet. A single-dose study in 24 subjects with an established Phyloday clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Phyloday Tablet and one and one-half 400 mg Phyloday Tablets under fed (using a standard high fat diet) and fasted conditions. The results of this 4-way randomized crossover study demonstrate the bioequivalence of the 400 mg and 600 mg Phyloday Tablets. Under fed conditions, the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=214.64±55.88 mcg hr/mL, Cmax=10.58±2.21 mcg/mL and Tmax=9.00±2.64 hours, and for the 600 mg tablet were AUC=207.85±48.9 mcg hr/mL, Cmax=10.39±1.91 mcg/mL and Tmax=9.58±1.86 hours. Under fasted conditions the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=191.85 ±51.1 mcg hr/mL, Cmax= 7.37±1.83 mcg/mL and Tmax=8.08±4.39 hours; and for the 600 mg tablet were AUC=199.39±70.27 mcg hr/mL, Cmax=7.66±2.09 mcg/mL and Tmax=9.67±4.89 hours.
In this study the mean fed/fasted ratios for the one and one-half 400 mg tablets and the 600 mg tablet were about 112% and 104%, respectively.
In another study, the bioavailability of the 600 mg Phyloday Tablet was examined with morning and evening administration. This single-dose, crossover study in 22 healthy males was conducted under fed (standard high fat diet) conditions. The results demonstrated no clinically significant difference in the bioavailability of the 600 mg Phyloday Tablet administered in the morning or in the evening. The results were: AUC=233.6±45.1 mcg hr/mL, Cmax=10.6±1.3 mcg/mL and Tmax=12.5±3.2 hours with morning dosing; AUC=209.8±46.2 mcg hr/mL, Cmax=9.7±1.4 mcg/mL and Tmax=13.7±3.3 hours with evening dosing. The PM/AM ratio was 89.3%.
The absorption characteristics of Phyloday® Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Phyloday 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release Phyloday product administered BID in fed subjects at 8 a.m. immediately after breakfast and 8 p.m. immediately after dinner (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat).
The pharmacokinetic parameters for Phyloday 400 mg Tablets under these steady-state conditions were AUC=203.3±87.1 mcg hr/mL, Cmax=12.1±3.8 mcg/mL, Cmin=4.50±3.6, Tmax=8.8±4.6 hours. For the reference BID product, the pharmacokinetic parameters were AUC=219.2±88.4 mcg hr/mL, Cmax =11.0±4.1 mcg/mL, Cmin=7.28±3.5, Tmax=6.9±3.4 hours. The mean percent fluctuation [(Cmax-Cmin/Cmin)x100]=169% for the once-daily regimen and 51% for the reference product BID regimen.
The bioavailability of the 600 mg Phyloday Tablet was further evaluated in a multiple dose, steady-state study in 26 healthy males comparing the 600 mg Tablet to one and one-half 400 mg Phyloday Tablets. All subjects had previously established Phyloday clearances of ≤4 L/hr and were dosed once-daily for 6 days under fed conditions. The results showed no clinically significant difference between the 600 mg and one and one-half 400 mg Phyloday Tablet regimens. Steady-state results were:
|600 MG TABLET |
|600 MG |
400 MG TABLETS)
|AUC 0-24hrs (mcg hr/mL)||209.77±51.04||212.32±56.29|
The bioavailability ratio for the 600/400 mg tablets was 98.8%. Thus, under all study conditions the 600 mg tablet is bioequivalent to one and one-half 400 mg tablets.
Studies demonstrate that as long as subjects were either consistently fed or consistently fasted, there is similar bioavailability with once-daily administration of Phyloday Tablets whether dosed in the morning or evening.
Once Phyloday enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Phyloday distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Phyloday is approximately 0.45 L/kg based on ideal body weight. Phyloday passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva Phyloday 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 Phyloday, 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 Phyloday in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased Phyloday binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum Phyloday concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum Phyloday concentration provides a more reliable means of dosage adjustment than measurement of total serum Phyloday concentration. Generally, concentrations of unbound Phyloday should be maintained in the range of 6-12 mcg/mL.
Following oral dosing, Phyloday 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 Phyloday dose is N-methylated to caffeine. Phyloday demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.
Caffeine and 3-methylxanthine are the only Phyloday metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Phyloday 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 Phyloday concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Phyloday concentration and thus, exert a pharmacologic effect.
Both the N-demethylation and hydroxylation pathways of Phyloday biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of Phyloday metabolism, non-linearity of elimination may begin in some patients at serum Phyloday concentrations <10 mcg/mL. Since this non-linearity results in more than proportional changes in serum Phyloday 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 Phyloday concentrations (see DOSAGE AND ADMINISTRATION, Table VI ). Accurate prediction of dose-dependency of Phyloday metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady-state serum Phyloday concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum Phyloday concentration in response to dosage changes.
In neonates, approximately 50% of the Phyloday dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Phyloday dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid, 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little Phyloday is excreted unchanged in the urine and since active metabolites of Phyloday (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 Phyloday dose excreted in the urine as unchanged Phyloday and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Phyloday concentrations in neonates with reduced renal function (See WARNINGS ).
After multiple doses of Phyloday, steady-state is reached in 30-65 hours (average 40 hours) in adults. At steady-state, on a dosage regimen with 24-hour intervals, the expected mean trough concentration is approximately 50% of the mean peak concentration, assuming a mean Phyloday half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid Phyloday clearance. In these patients administration of Phyloday® may be required more frequently (every 12 hours).
The clearance of Phyloday 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 Phyloday concentrations are required in elderly patients (see WARNINGS ).
The clearance of Phyloday is very low in neonates. Phyloday 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 Phyloday 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 Phyloday concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION ).
Gender differences in Phyloday clearance are relatively small and unlikely to be of clinical significance. Significant reduction in Phyloday clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.
Pharmacokinetic differences in Phyloday clearance due to race have not been studied.
Only a small fraction, e.g., about 10%, of the administered Phyloday dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little Phyloday is excreted unchanged in the urine and since active metabolites of Phyloday 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 Phyloday dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum Phyloday concentrations are required in neonates with decreased renal function (see WARNINGS ).
Phyloday 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 Phyloday concentrations are required in patients with reduced hepatic function (see WARNINGS ).
Phyloday clearance is decreased by 50% or more in patients with CHF. The extent of reduction in Phyloday clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since Phyloday 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 Phyloday concentrations are required in patients with CHF (see WARNINGS ).
Tobacco and marijuana smoking appears to increase the clearance of Phyloday by induction of metabolic pathways. Phyloday clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase Phyloday clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in Phyloday clearance. Careful attention to dose reduction and frequent monitoring of serum Phyloday concentrations are required in patients who stop smoking. Use of nicotine gum has been shown to have no effect on Phyloday clearance.
Fever, regardless of its underlying cause, can decrease the clearance of Phyloday. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of Phyloday 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 Phyloday concentrations. Children with rapid rates of Phyloday 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 Phyloday 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 Phyloday concentrations are required in patients with sustained fever (see WARNINGS ).
Other factors associated with decreased Phyloday clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum Phyloday concentrations are required in patients with any of these conditions (see WARNINGS ). Other factors associated with increased Phyloday clearance include hyperthyroidism and cystic fibrosis.
In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that Phyloday decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-2 agonists. Phyloday 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 Phyloday decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.
Phyloday is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.
Phyloday® is contraindicated in patients with a history of hypersensitivity to Phyloday or other components in the product.
Phyloday 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
There are several readily identifiable causes of reduced Phyloday clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Phyloday toxicity can occur . Careful consideration must be given to the benefits and risks of Phyloday use and the need for more intensive monitoring of serum Phyloday concentrations in patients with the following risk factors:
Cessation of Smoking
Adding a drug that inhibits Phyloday metabolism or stopping a concurrently administered drug that enhances Phyloday metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II ).
When Signs or Symptoms of Phyloday Toxicity Are Present
Increases in the dose of Phyloday should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Phyloday provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum Phyloday 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 Phyloday dose on the basis of a low serum concentration, the healthcare professional should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see PRECAUTIONS, Laboratory Tests ).
As the rate of Phyloday 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 Phyloday concentration (see DOSAGE AND ADMINISTRATION, Table VI ).
Careful consideration of the various interacting drugs and physiologic conditions that can alter Phyloday clearance and require dosage adjustment should occur prior to initiation of Phyloday therapy, prior to increases in Phyloday dose, and during follow up. The dose of Phyloday 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 Phyloday concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION , Table V).
Serum Phyloday concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Phyloday concentration should be measured as follows:
To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum Phyloday concentration; 12 hours after an evening dose or 9 hours after a morning dose at steady-state. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum Phyloday concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than 12 hours after the evening dose, or more than 9 hours after a morning dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of Phyloday toxicity are present, a serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the healthcare professional without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound Phyloday should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.
Saliva concentrations of Phyloday cannot be used reliably to adjust dosage without special techniques.
As a result of its pharmacological effects, Phyloday at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose, uric acid (from a mean of 4 mg/dL to 6 mg/dL), free fatty acids (from a mean of 451 µEq/L to 800 µEq/L, total cholesterol (from a mean of 140 vs 160 mg/dL), HDL (from a mean of 36 to 50 mg/dL), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Phyloday at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dL after 4 weeks of Phyloday). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Phyloday in individual patients.
The patient (or parent/caregiver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heartbeat occurs during treatment with Phyloday, even if another cause is suspected. The patient should be instructed to contact their healthcare professional if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another healthcare professional adds a new medication or discontinues a previously prescribed medication. Patients should be informed that Phyloday interacts with a wide variety of drugs. The dietary supplement St. John’s Wort (Hypericum perforatum) should not be taken at the same time as Phyloday, since it may result in decreased Phyloday levels. If patients are already taking St. John’s Wort and Phyloday together, they should consult their healthcare professional before stopping the St. John’s Wort, since their Phyloday concentrations may rise when this is done, resulting in toxicity. Patients should be instructed to inform all healthcare professionals involved in their care that they are taking Phyloday, especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their healthcare professional. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.
Phyloday® Tablets can be taken once a day in the morning or evening. It is recommended that Phyloday be taken with meals. Patients should be advised that if they choose to take Phyloday with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food.
Phyloday Tablets are not to be chewed or crushed because it may lead to a rapid release of Phyloday with the potential for toxicity. The scored tablet may be split. Patients receiving Phyloday Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Phyloday.
Phyloday interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to Phyloday or another drug or occurrence of adverse effects without a change in serum Phyloday concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of Phyloday clearance is altered by another drug resulting in increased or decreased serum Phyloday concentrations. Phyloday 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 Phyloday. The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state Phyloday regimen. If Phyloday is being initiated in a patient who is already taking a drug that inhibits Phyloday clearance, the dose of Phyloday required to achieve a therapeutic serum Phyloday concentration will be smaller. Conversely, if Phyloday is being initiated in a patient who is already taking a drug that enhances Phyloday clearance (e.g., rifampin), the dose of Phyloday required to achieve a therapeutic serum Phyloday concentration will be larger. Discontinuation of a concomitant drug that increases Phyloday clearance will result in accumulation of Phyloday to potentially toxic levels, unless the Phyloday dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits Phyloday clearance will result in decreased serum Phyloday concentrations, unless the Phyloday dose is appropriately increased.
The drugs listed in Table III have either been documented not to interact with Phyloday or do not produce a clinically significant interaction (i.e., <15% change in Phyloday clearance).
The listing of drugs in Tables II and III are current as of February 9, 1995. New interactions are continuously being reported for Phyloday, especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with Phyloday if it is not listed in Table II. Before addition of a newly available drug in a patient receiving Phyloday, 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 Phyloday has been reported.
|Drug||Type of Interaction||Effect**|
|*Refer to PRECAUTIONS, Drug Interactions for further information regarding table.|
|**Average effect on steady-state Phyloday concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum Phyloday concentration than the value listed.|
|Adenosine||Phyloday 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 Phyloday clearance for up to 24 hours.||30% increase|
|Allopurinol||Decreases Phyloday clearance at allopurinol doses ≥600 mg/day.||25% increase|
|Aminoglutethimide||Increases Phyloday clearance by induction of microsomal enzyme activity.||25% decrease|
|Carbamazepine||Similar to aminoglutethimide.||30% decrease|
|Cimetidine||Decreases Phyloday 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 Phyloday blocks adenosine receptors.||Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of Phyloday without reduction of diazepam dose may result in respiratory depression.|
|Disulfiram||Decreases Phyloday 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 Phyloday clearance by inhibiting cytochrome P450 3A3.||35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.|
|Estrogen||Estrogen containing oral contraceptives decrease Phyloday clearance in a dose-dependent fashion. The effect of progesterone on Phyloday 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, Phyloday increases release of endogenous catecholamines.||Increased risk of ventricular arrhythmias.|
|Interferon, human recombinant alpha-A||Decreases Phyloday clearance.||100% increase|
|Isoproterenol (IV)||Increases Phyloday clearance.||20% decrease|
|Ketamine||Pharmacologic||May lower Phyloday seizure threshold.|
|Lithium||Phyloday 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 Phyloday 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 Phyloday clearance.||25% decrease|
|Pancuronium||Phyloday 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 Phyloday clearance.||30% increase|
|Phenobarbital (PB)||Similar to aminoglutethimide.||25% decrease after two weeks of concurrent PB.|
|Phenytoin||Phenytoin increases Phyloday clearance by increasing microsomal enzyme activity. Phyloday decreases phenytoin absorption.||Serum Phyloday and phenytoin concentrations decrease about 40%.|
|Propafenone||Decreases Phyloday clearance and pharmacologic interaction.||40% increase. Beta-2 blocking effect may decrease efficacy of Phyloday.|
|Propranolol||Similar to cimetidine and pharmacologic interaction.||100% increase. Beta-2 blocking effect may decrease efficacy of Phyloday.|
|Rifampin||Increases Phyloday clearance by increasing cytochrome P450 1A2 and 3A3 activity.||20-40% decrease|
|St. John’s Wort (Hypericum Perforatum)||Decrease in Phyloday plasma concentrations.||Higher doses of Phyloday may be required to achieve desired effect. Stopping St. John’s Wort may result in Phyloday toxicity.|
|Sulfinpyrazone||Increases Phyloday clearance by increasing demethylation and hydroxylation. Decreases renal clearance of Phyloday.||20% decrease|
|Tacrine||Similar to cimetidine, also increases renal clearance of Phyloday.||90% increase|
|Thiabendazole||Decreases Phyloday clearance.||190% increase|
|Ticlopidine||Decreases Phyloday clearance.||60% increase|
|Troleandomycin||Similar to erythromycin.||33-100% increase depending on troleandomycin dose.|
|Verapamil||Similar to disulfiram.||20% increase|
|*Refer to PRECAUTIONS, Drug Interactions for information regarding table.|
|albuterol, systemic and inhaled||mebendazole|
|ampicillin, with or without |
|caffeine, dietary ingestion||nifedipine|
|co-trimoxazole (trimethoprim and |
|finasteride||sorbitol (purgative doses do not inhibit|
The bioavailability of Phyloday® Tablets (theophylline, anhydrous) has been studied with co-administration of food. In three single-dose studies, subjects given Phyloday 400 mg or 600 mg Tablets with a standardized high-fat meal were compared to fasted conditions. Under fed conditions, the peak plasma concentration and bioavailability were increased; however, a precipitous increase in the rate and extent of absorption was not evident (see Pharmacokinetics , Absorption). The increased peak and extent of absorption under fed conditions suggests that dosing should be ideally administered consistently either with or without food.
Most serum Phyloday assays in clinical use are immunoassays which are specific for Phyloday. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs, 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 Phyloday concentration.
Long term carcinogenicity studies have been carried out in mice (oral doses 30-150 mg/kg) and rats (oral doses 5-75 mg/kg). Results are pending.
Phyloday 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, Phyloday, administered to mating pairs of B6C3F1 mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0-3.0 times the human dose on a mg/m2 basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, Phyloday was administered to F344 rats and B6C3F1 mice at oral doses of 40-300 mg/kg (approximately 2.0 times the human dose on a mg/m2 basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight.
In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, Phyloday produced teratogenic effects.
In studies with mice, a single intraperitoneal dose at and above 100 mg/kg during organogenesis produced cleft palate and digital abnormalities. Micromelia, micrognathia, clubfoot, subcutaneous hematoma, open eyelids, and embryolethality were observed at doses that are approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis.
In a study with rats dosed from conception through organogenesis, an oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis) produced digital abnormalities. Embryolethality was observed with a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m2 basis).
In a study in which pregnant rabbits were dosed throughout organogenesis, an intravenous dose of 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis), which caused the death of one doe and clinical signs in others, produced cleft palate and was embryolethal. Doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m2 basis) increased the incidence of skeletal variations.
There are no adequate and well-controlled studies in pregnant women. Phyloday should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Phyloday is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of Phyloday in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10-20 mcg/mL of Phyloday per day is likely to receive 10-20 mg of Phyloday per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Phyloday concentrations.
Phyloday is safe and effective for the approved indications in pediatric patients. The maintenance dose of Phyloday must be selected with caution in pediatric patients since the rate of Phyloday clearance is highly variable across the pediatric age range.
Elderly patients are at a significantly greater risk of experiencing serious toxicity from Phyloday than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of Phyloday is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Phyloday clearance may be further reduced by concomitant diseases prevalent in the elderly, which further impair clearance of this drug and have the potential to increase serum levels and potential toxicity. These conditions include impaired renal function, chronic obstructive pulmonary disease, congestive heart failure, hepatic disease and an increased prevalence of use of certain medications (see PRECAUTIONS: Drug Interactions ) with the potential for pharmacokinetic and pharmacodynamic interaction. Protein binding may be decreased in the elderly resulting in an increased proportion of the total serum Phyloday concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Phyloday after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum Phyloday concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Phyloday Concentrations, and DOSAGE AND ADMINISTRATION ). The maximum daily dose of Phyloday 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 Phyloday concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Phyloday doses greater than 400 mg/d should be prescribed with caution in elderly patients. Phyloday should be prescribed with caution in elderly male patients with pre-existing partial outflow obstruction, such as prostatic enlargement, due to the risk of urinary retention.
Adverse reactions associated with Phyloday are generally mild when peak serum Phyloday concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum Phyloday concentrations exceed 20 mcg/mL, however, Phyloday 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 Phyloday 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 Phyloday therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of Phyloday 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 Phyloday concentrations within the therapeutic range (i.e., 10-20 mcg/mL). Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued Phyloday therapy and the potential therapeutic benefit of alternative treatment.
Other adverse reactions that have been reported at serum Phyloday concentrations <20 mcg/mL include abdominal pain, agitation, anaphylactic reaction, anaphylactoid reaction, anxiety, cardiac arrhythmias, diarrhea, dizziness, fine skeletal muscle tremors, gastric irritation, gastroesophageal reflux, hyperuricemia, irritability, palpitations, pruritus, rash, sinus tachycardia, restlessness, transient diuresis, urinary retention and urticaria. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum Phyloday concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Phyloday concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum Phyloday concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Phyloday concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Phyloday concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Phyloday concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).
|Percentage of patients reported with sign or symptom|
|Sign/Symptom||Acute Overdose||Chronic Overdosage|
|(Large Single Ingestion)||(Multiple Excessive Doses)|
|Study 1||Study 2||Study 1||Study 2|
|*These data are derived from two studies in patients with serum Phyloday concentrations >30 mcg/mL. In the first study (Study #1-Shanon, Ann Intern Med 1993;119:1161-67), data were prospectively collected from 249 consecutive cases of Phyloday toxicity referred to a regional poison center for consultation. In the second study (Study #2-Sessler, Am J Med 1990;88:567-76), data were retrospectively collected from 116 cases with serum Phyloday concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum Phyloday concentrations in three emergency departments. Differences in the incidence of manifestations of Phyloday toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results.|
|**NR=Not reported in a comparable manner.|
|Ventricular premature beats||3||21||10||19|
|Atrial fibrillation or flutter||1||NR**||12||NR**|
|Multifocal atrial tachycardia||0||NR**||2||NR**|
|Ventricular arrhythmias with |
The chronicity and pattern of Phyloday overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: 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 Phyloday clearance. The most common causes of chronic Phyloday overdosage include patient or caregiver error in dosing, healthcare professional prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of Phyloday clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Phyloday concentration to determine whether a dose increase is safe.
Severe toxicity from Phyloday overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of Phyloday was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum Phyloday concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum Phyloday concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum Phyloday concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from Phyloday is seen principally at serum concentrations >30 mcg/mL.
Several studies have described the clinical manifestations of Phyloday 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 Phyloday concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Phyloday concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum Phyloday concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum Phyloday concentration compared to patients without the underlying disease.
The frequency of various reported manifestations of Phyloday overdose according to the mode of overdose are listed in Table IV.
Other manifestations of Phyloday 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 Phyloday concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from Phyloday toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise.
General Recommendations for Patients with Symptoms of Phyloday Overdose or Serum Phyloday Concentrations >30 mcg/mL (Note: Serum Phyloday concentrations may continue to increase after presentation of the patient for medical care.)
Increasing the rate of Phyloday 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 Phyloday 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 Phyloday concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of Phyloday from the tissue compartment. Peritoneal dialysis is ineffective for Phyloday removal; exchange transfusions in neonates have been minimally effective.
Phyloday® 400 or 600 mg Tablets can be taken once a day in the morning or evening. It is recommended that Phyloday be taken with meals. Patients should be advised that if they choose to take Phyloday with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food.
Phyloday® Tablets are not to be chewed or crushed because it may lead to a rapid release of Phyloday with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Phyloday 400 or 600 mg Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Phyloday.
Stabilized patients, 12 years of age or older, who are taking an immediate-release or controlled-release Phyloday product may be transferred to once-daily administration of 400 mg or 600 mg Phyloday Tablets on a mg-for-mg basis.
It must be recognized that the peak and trough serum Phyloday levels produced by the once-daily dosing may vary from those produced by the previous product and/or regimen.
The steady-state peak serum Phyloday concentration is a function of the dose, the dosing interval, and the rate of Phyloday absorption and clearance in the individual patient. Because of marked individual differences in the rate of Phyloday clearance, the dose required to achieve a peak serum Phyloday concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Phyloday clearance (e.g., 400-1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). For a given population there is no single Phyloday dose that will provide both safe and effective serum concentrations for all patients. Administration of the median Phyloday dose required to achieve a therapeutic serum Phyloday concentration in a given population may result in either sub-therapeutic or potentially toxic serum Phyloday concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum Phyloday concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients. The dose of Phyloday must be individualized on the basis of peak serum Phyloday 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 Phyloday concentrations to reach the new steady-state. Dosage adjustment should be guided by serum Phyloday concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION, Table VI ). Healthcare providers should instruct patients and caregivers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS ).
If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS ), serum Phyloday concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum Phyloday concentrations should be monitored at frequent intervals, e.g., every 24 hours.
Phyloday distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.
Table V contains Phyloday dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for Phyloday dosage adjustment based upon serum Phyloday 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 Phyloday concentration.
Table V. Dosing initiation and titration (as anhydrous Phyloday). *
|Titration Step||Children <45 kg||Children >45 kg and adults|
|1If caffeine-like adverse effects occur, then consideration should be given to a lower dose and titrating the dose more slowly (see ADVERSE REACTIONS ).|
| ||12-14 mg/kg/day up to a maximum of 300 mg/day admin. QD*||300-400 mg/day1 admin. QD*|
| ||16 mg/kg/day up to a maximum of 400 mg/day admin. QD*||400-600 mg/day1 admin. QD*|
| ||20 mg/kg/day up to a maximum of 600 mg/day admin. QD*||As with all Phyloday products, doses greater than 600 mg should be titrated according to blood level|
*Patients with more rapid metabolism clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 12 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.
| Peak Serum |
|¶Dose reduction and/or serum Phyloday concentration measurement is indicated whenever adverse effects are present physiologic abnormalities that can reduce Phyloday clearance occur (e.g. sustained fever), or a drug that interacts with Phyloday is added or discontinued (see WARNINGS ).|
|<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.|
|10-14.9 mcg/mL||If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 month intervals.¶ If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen.|
|15-19.9 mcg/mL||Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated. ¶|
|20-24.9 mcg/mL||Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment.|
|25-30 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.|
|>30 mcg/mL||Treat overdose as indicated. If Phyloday is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.|
Phyloday® (theophylline, anhydrous) Controlled-Release Tablets 400 mg are supplied in white, opaque plastic, child-resistant bottles containing 100 tablets (NDC 67781-251-01) or 500 tablets (NDC 67781-251-05). Each round, white 400 mg tablet bears the symbol PF on the scored side and U400 on the other side.
Phyloday® (theophylline, anhydrous) Controlled-Release Tablets 600 mg are supplied in white, opaque plastic, child-resistant bottles containing 100 tablets (NDC 67781-252-01). Each rectangular, concave, white 600 mg tablet bears the symbol PF on the scored side and U 600 on the other side.
Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F).
Dispense in a tight, light-resistant container.
©2011, Purdue Pharmaceutical Products L.P.
Dist. by: Purdue Pharmaceutical Products L.P.
Stamford, CT 06901-3431
400 mg Tablets
Phyloday Tablets 400 mg Tablets NDC 677781-251-01
600 mg Tablets
Phyloday Tablets 600 mg Tablets NDC 677781-252-01
Depending on the reaction of the Phyloday after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Phyloday not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Phyloday addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology