DRUGS & SUPPLEMENTS
Novo-Theophyl SR uses
Novo-Theophyl SR® (theophylline, anhydrous) Tablets in a controlled-release system allows a 24-hour dosing interval for appropriate patients.
Novo-Theophyl SR is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous Novo-Theophyl SR 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 Novo-Theophyl SR is C7H8N4O2 with a molecular weight of 180.17.
Each controlled-release tablet for oral administration, contains 400 or 600 mg of anhydrous Novo-Theophyl SR.
Inactive Ingredients: cetostearyl alcohol, hydroxyethyl cellulose, magnesium stearate, povidone and talc.
Mechanism of Action
Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR 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).
Novo-Theophyl SR 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 Novo-Theophyl SR concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Novo-Theophyl SR concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Novo-Theophyl SR concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Novo-Theophyl SR 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: Novo-Theophyl SR is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Novo-Theophyl SR does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.
The pharmacokinetics of Novo-Theophyl SR 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 Novo-Theophyl SR. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Novo-Theophyl SR 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 Novo-Theophyl SR clearance (see PRECAUTIONS, Laboratory Tests ).
Note: In addition to the factors listed above, Novo-Theophyl SR 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 Novo-Theophyl SR.
Novo-Theophyl SR® administered in the fed state is completely absorbed after oral administration.
In a single-dose crossover study, two 400 mg Novo-Theophyl SR 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 Novo-Theophyl SR 400 mg Tablets were administered to 17 fed adult asthmatics produced similar Novo-Theophyl SR 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.
A single-dose study in 15 normal fasting male volunteers whose Novo-Theophyl SR inherent mean elimination half-life was verified by a liquid Novo-Theophyl SR product to be 6.9±2.5 (SD) hours were administered two or three 400 mg Novo-Theophyl SR® Tablets. The relative bioavailability of Novo-Theophyl SR given in the fasting state in comparison to an immediate-release product was 59%. Peak serum Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR 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:
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 Novo-Theophyl SR® 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 Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR with Novo-Theophyl SR Tablets even when they are administered with a high fat, high calorie meal.
Similar studies were conducted with the 600 mg Novo-Theophyl SR Tablet. A single-dose study in 24 subjects with an established Novo-Theophyl SR clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Novo-Theophyl SR Tablet and one and one-half 400 mg Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR® Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Novo-Theophyl SR 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR Tablets. All subjects had previously established Novo-Theophyl SR 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 Novo-Theophyl SR Tablet regimens. Steady-state results were:
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 Novo-Theophyl SR Tablets whether dosed in the morning or evening.
Once Novo-Theophyl SR enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Novo-Theophyl SR distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Novo-Theophyl SR is approximately 0.45 L/kg based on ideal body weight. Novo-Theophyl SR passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva Novo-Theophyl SR 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 Novo-Theophyl SR, 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 Novo-Theophyl SR in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased Novo-Theophyl SR binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum Novo-Theophyl SR concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum Novo-Theophyl SR concentration provides a more reliable means of dosage adjustment than measurement of total serum Novo-Theophyl SR concentration. Generally, concentrations of unbound Novo-Theophyl SR should be maintained in the range of 6-12 mcg/mL.
Following oral dosing, Novo-Theophyl SR 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 Novo-Theophyl SR dose is N-methylated to caffeine. Novo-Theophyl SR 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 Novo-Theophyl SR metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Novo-Theophyl SR 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 Novo-Theophyl SR concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Novo-Theophyl SR concentration and thus, exert a pharmacologic effect.
Both the N-demethylation and hydroxylation pathways of Novo-Theophyl SR biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of Novo-Theophyl SR metabolism, non-linearity of elimination may begin in some patients at serum Novo-Theophyl SR concentrations <10 mcg/mL. Since this non-linearity results in more than proportional changes in serum Novo-Theophyl SR 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 Novo-Theophyl SR concentrations (see DOSAGE AND ADMINISTRATION, Table VI ). Accurate prediction of dose-dependency of Novo-Theophyl SR metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady-state serum Novo-Theophyl SR concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum Novo-Theophyl SR concentration in response to dosage changes.
In neonates, approximately 50% of the Novo-Theophyl SR dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Novo-Theophyl SR 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 Novo-Theophyl SR is excreted unchanged in the urine and since active metabolites of Novo-Theophyl SR (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 Novo-Theophyl SR dose excreted in the urine as unchanged Novo-Theophyl SR and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Novo-Theophyl SR concentrations in neonates with reduced renal function (See WARNINGS ).
|Drug||Type of Interaction||Effect**|
|*Refer to PRECAUTIONS, Drug Interactions for further information regarding table.|
|**Average effect on steady-state Novo-Theophyl SR concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum Novo-Theophyl SR concentration than the value listed.|
|Adenosine||Novo-Theophyl SR 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 Novo-Theophyl SR clearance for up to 24 hours.||30% increase|
|Allopurinol||Decreases Novo-Theophyl SR clearance at allopurinol doses ≥600 mg/day.||25% increase|
|Aminoglutethimide||Increases Novo-Theophyl SR clearance by induction of microsomal enzyme activity.||25% decrease|
|Carbamazepine||Similar to aminoglutethimide.||30% decrease|
|Cimetidine||Decreases Novo-Theophyl SR 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 Novo-Theophyl SR blocks adenosine receptors.||Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of Novo-Theophyl SR without reduction of diazepam dose may result in respiratory depression.|
|Disulfiram||Decreases Novo-Theophyl SR 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 Novo-Theophyl SR clearance by inhibiting cytochrome P450 3A3.||35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.|
|Estrogen||Estrogen containing oral contraceptives decrease Novo-Theophyl SR clearance in a dose-dependent fashion. The effect of progesterone on Novo-Theophyl SR 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, Novo-Theophyl SR increases release of endogenous catecholamines.||Increased risk of ventricular arrhythmias.|
|Interferon, human recombinant alpha-A||Decreases Novo-Theophyl SR clearance.||100% increase|
|Isoproterenol (IV)||Increases Novo-Theophyl SR clearance.||20% decrease|
|Ketamine||Pharmacologic||May lower Novo-Theophyl SR seizure threshold.|
|Lithium||Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR clearance.||25% decrease|
|Pancuronium||Novo-Theophyl SR 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 Novo-Theophyl SR clearance.||30% increase|
|Phenobarbital (PB)||Similar to aminoglutethimide.||25% decrease after two weeks of concurrent PB.|
|Phenytoin||Phenytoin increases Novo-Theophyl SR clearance by increasing microsomal enzyme activity. Novo-Theophyl SR decreases phenytoin absorption.||Serum Novo-Theophyl SR and phenytoin concentrations decrease about 40%.|
|Propafenone||Decreases Novo-Theophyl SR clearance and pharmacologic interaction.||40% increase. Beta-2 blocking effect may decrease efficacy of Novo-Theophyl SR.|
|Propranolol||Similar to cimetidine and pharmacologic interaction.||100% increase. Beta-2 blocking effect may decrease efficacy of Novo-Theophyl SR.|
|Rifampin||Increases Novo-Theophyl SR clearance by increasing cytochrome P450 1A2 and 3A3 activity.||20-40% decrease|
|St. John’s Wort (Hypericum Perforatum)||Decrease in Novo-Theophyl SR plasma concentrations.||Higher doses of Novo-Theophyl SR may be required to achieve desired effect. Stopping St. John’s Wort may result in Novo-Theophyl SR toxicity.|
|Sulfinpyrazone||Increases Novo-Theophyl SR clearance by increasing demethylation and hydroxylation. Decreases renal clearance of Novo-Theophyl SR.||20% decrease|
|Tacrine||Similar to cimetidine, also increases renal clearance of Novo-Theophyl SR.||90% increase|
|Thiabendazole||Decreases Novo-Theophyl SR clearance.||190% increase|
|Ticlopidine||Decreases Novo-Theophyl SR 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|
|hydrocortisone||Novo-Theophyl SR absorption)|
The bioavailability of Novo-Theophyl SR® Tablets (theophylline, anhydrous) has been studied with co-administration of food. In three single-dose studies, subjects given Novo-Theophyl SR 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 Novo-Theophyl SR assays in clinical use are immunoassays which are specific for Novo-Theophyl SR. 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 Novo-Theophyl SR 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.
Novo-Theophyl SR 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, Novo-Theophyl SR, 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, Novo-Theophyl SR 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, Novo-Theophyl SR 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. Novo-Theophyl SR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Novo-Theophyl SR is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of Novo-Theophyl SR 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 Novo-Theophyl SR per day is likely to receive 10-20 mg of Novo-Theophyl SR per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Novo-Theophyl SR concentrations.
Novo-Theophyl SR is safe and effective for the approved indications in pediatric patients. The maintenance dose of Novo-Theophyl SR must be selected with caution in pediatric patients since the rate of Novo-Theophyl SR clearance is highly variable across the pediatric age range.
Elderly patients are at a significantly greater risk of experiencing serious toxicity from Novo-Theophyl SR than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of Novo-Theophyl SR is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Novo-Theophyl SR 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 Novo-Theophyl SR concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Novo-Theophyl SR after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum Novo-Theophyl SR concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Novo-Theophyl SR Concentrations, and DOSAGE AND ADMINISTRATION ). The maximum daily dose of Novo-Theophyl SR 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 Novo-Theophyl SR concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Novo-Theophyl SR doses greater than 400 mg/d should be prescribed with caution in elderly patients. Novo-Theophyl SR 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 Novo-Theophyl SR are generally mild when peak serum Novo-Theophyl SR concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum Novo-Theophyl SR concentrations exceed 20 mcg/mL, however, Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR therapy and the potential therapeutic benefit of alternative treatment.
Other adverse reactions that have been reported at serum Novo-Theophyl SR 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 Novo-Theophyl SR concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Novo-Theophyl SR concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum Novo-Theophyl SR concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Novo-Theophyl SR concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Novo-Theophyl SR concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum Novo-Theophyl SR concentrations in three emergency departments. Differences in the incidence of manifestations of Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR clearance. The most common causes of chronic Novo-Theophyl SR 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 Novo-Theophyl SR clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Novo-Theophyl SR concentration to determine whether a dose increase is safe.
Severe toxicity from Novo-Theophyl SR overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of Novo-Theophyl SR was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum Novo-Theophyl SR 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 Novo-Theophyl SR concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum Novo-Theophyl SR concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from Novo-Theophyl SR is seen principally at serum concentrations >30 mcg/mL.
Several studies have described the clinical manifestations of Novo-Theophyl SR 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 Novo-Theophyl SR concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Novo-Theophyl SR concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum Novo-Theophyl SR 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 Novo-Theophyl SR concentration compared to patients without the underlying disease.
The frequency of various reported manifestations of Novo-Theophyl SR overdose according to the mode of overdose are listed in Table IV.
Other manifestations of Novo-Theophyl SR 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 Novo-Theophyl SR concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from Novo-Theophyl SR 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 Novo-Theophyl SR Overdose or Serum Novo-Theophyl SR Concentrations >30 mcg/mL (Note: Serum Novo-Theophyl SR concentrations may continue to increase after presentation of the patient for medical care.)
Increasing the rate of Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of Novo-Theophyl SR from the tissue compartment. Peritoneal dialysis is ineffective for Novo-Theophyl SR removal; exchange transfusions in neonates have been minimally effective.
Novo-Theophyl SR® 400 or 600 mg Tablets can be taken once a day in the morning or evening. It is recommended that Novo-Theophyl SR be taken with meals. Patients should be advised that if they choose to take Novo-Theophyl SR 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.
Novo-Theophyl SR® Tablets are not to be chewed or crushed because it may lead to a rapid release of Novo-Theophyl SR with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Novo-Theophyl SR 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 Novo-Theophyl SR.
Stabilized patients, 12 years of age or older, who are taking an immediate-release or controlled-release Novo-Theophyl SR product may be transferred to once-daily administration of 400 mg or 600 mg Novo-Theophyl SR Tablets on a mg-for-mg basis.
It must be recognized that the peak and trough serum Novo-Theophyl SR levels produced by the once-daily dosing may vary from those produced by the previous product and/or regimen.
The steady-state peak serum Novo-Theophyl SR concentration is a function of the dose, the dosing interval, and the rate of Novo-Theophyl SR absorption and clearance in the individual patient. Because of marked individual differences in the rate of Novo-Theophyl SR clearance, the dose required to achieve a peak serum Novo-Theophyl SR concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Novo-Theophyl SR 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 Novo-Theophyl SR dose that will provide both safe and effective serum concentrations for all patients. Administration of the median Novo-Theophyl SR dose required to achieve a therapeutic serum Novo-Theophyl SR concentration in a given population may result in either sub-therapeutic or potentially toxic serum Novo-Theophyl SR 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 Novo-Theophyl SR 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 Novo-Theophyl SR must be individualized on the basis of peak serum Novo-Theophyl SR 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 Novo-Theophyl SR concentrations to reach the new steady-state. Dosage adjustment should be guided by serum Novo-Theophyl SR 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 Novo-Theophyl SR concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum Novo-Theophyl SR concentrations should be monitored at frequent intervals, e.g., every 24 hours.
Novo-Theophyl SR distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.
Table V contains Novo-Theophyl SR dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for Novo-Theophyl SR dosage adjustment based upon serum Novo-Theophyl SR 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 Novo-Theophyl SR concentration.
Table V. Dosing initiation and titration (as anhydrous Novo-Theophyl SR). *
|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 Novo-Theophyl SR 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 Novo-Theophyl SR concentration measurement is indicated whenever adverse effects are present physiologic abnormalities that can reduce Novo-Theophyl SR clearance occur (e.g. sustained fever), or a drug that interacts with Novo-Theophyl SR 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 Novo-Theophyl SR is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.|
Novo-Theophyl SR® (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.
Novo-Theophyl SR® (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
Novo-Theophyl SR Tablets
400 mg Tablets
Novo-Theophyl SR Tablets 400 mg Tablets NDC 677781-251-01
Novo-Theophyl SR Tablets
600 mg Tablets
Novo-Theophyl SR Tablets 600 mg Tablets NDC 677781-252-01
Depending on the reaction of the Novo-Theophyl SR after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Novo-Theophyl SR 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 Novo-Theophyl SR 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. Arunabha Ray, MD Pharmacology