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Theophylline, anhydrous

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Overview

What is Theophylline Extended Release?

Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous theophylline has the chemical name 1H-Purine-2,6-dione,3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula:

This product allows a 12-hour dosing interval for a majority of patients and a 24-hour dosing interval for selected patients (see section for description of appropriate patient populations).

Each extended-release tablet for oral administration contains either 100 mg, 200 mg, 300 mg or 450 mg of anhydrous theophylline. Tablets also contain as inactive ingredients: hypromellose, anhydrous lactose, magnesium stearate and povidone.



What does Theophylline Extended Release look like?



What are the available doses of Theophylline Extended Release?

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What should I talk to my health care provider before I take Theophylline Extended Release?

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How should I use Theophylline Extended Release?

Theophylline extended-release tablets are indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

Taking theophylline extended-release tablets immediately after a high-fat content meal may result in a somewhat higher C and delayed T, and somewhat greater extent of absorption. However, the differences are usually not great and this product may normally be administered without regard to meals (see , , ).

Theophylline extended-release tablets are recommended for chronic or long-term management and prevention of symptoms, and not for use in treating acute symptoms of asthma and reversible bronchospasm.


What interacts with Theophylline Extended Release?

Theophylline extended-release tablets are contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.



What are the warnings of Theophylline Extended Release?

Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.

Concurrent Illness: Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

          Active peptic ulcer disease

          Seizure disorders

          Cardiac arrhythmias (not including bradyarrhythmias).

Conditions that Reduce Theophylline Clearance: There are several readily identifiable causes of reduced theophylline clearance. . Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline concentrations in patients with the following risk factors:

Age: Neonates (term and premature), children 60 years).

Concurrent Diseases: Acute pulmonary edema, congestive heart failure, cor-pulmonale, fever (≥ 102° for 24 hours or more; or lesser temperature elevations for longer periods), reduced renal function in infants
Cessation of Smoking.

Drug Interactions: Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin). (See , , Table II.)

When Signs or Symptoms of Theophylline Toxicity Are Present:

Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately

Dosage Increases: Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered cortico-steroids in this circumstance and increases the risk of adverse effects. A steady-state serum theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the theophylline dose on the basis of a low serum concentration, the clinician should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see , Laboratory Tests).

As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum theophylline concentration (see , Table VI).


What are the precautions of Theophylline Extended Release?

General









          Careful consideration of the various interacting drugs and physiologic conditions that can alter theophylline clearance and require dosage adjustment should occur prior to initiation of theophylline therapy, prior to increases in theophylline dose, and during follow up (see ). The dose of theophylline selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of a week or longer with the final dose guided by monitoring serum theophylline concentrations and the patient’s clinical response (see , Table V).

          Monitoring Serum Theophylline Concentrations: Serum theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum theophylline concentration should be measured as follows:

          To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum theophylline concentration: 6-7 hours after a dose at steady-state. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum theophylline concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than seven hours after the dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of theophylline toxicity are present, the serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the clinician without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

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

          Effects on Laboratory Tests: As a result of its pharmacological effects, theophylline at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dL to 6 mg/dL), free fatty acids (from a mean of 451 µεq/L to 800 µεq/L, total cholesterol (from a mean of 140 vs 160 mg/dL), HDL (from a mean of 36 to 50 mg/dL), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Theophylline at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dl after 4 weeks of theophylline). The clinical importance of these changes should be weighed against the potential therapeutic benefit of theophylline in individual patients.

          Information for Patients

          The patient (or parent/care giver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heart beat occurs during treatment with theophylline, even if another cause is suspected. The patient should be instructed to contact their clinician if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another clinician adds a new medication or discontinues a previously prescribed medication. Patients should be instructed to inform all clinicians involved in their care that they are taking theophylline, especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their clinician. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.

          Theophylline extended-release tablets should not be chewed or crushed. When dosing on a once daily (q24h) basis, tablets should be taken whole and not split.

          Drug Interactions

          Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased or decreased serum theophylline concentrations. Theophylline only rarely alters the pharmacokinetics of other drugs.

          The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger. Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased.

          The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e.,
          The listing of drugs in Tables II and III are current as of February 9, 1995. New interactions are continuously being reported for theophylline, especially with new chemical entities. . Before addition of a newly available drug in a patient receiving theophylline, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and theophylline has been reported.

          Table II. Clinically significant drug interactions with theophylline.
               
           Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
           Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours 
           Allopurinol   25% increase
           Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity.  25% decrease
           Carbamazepine Similar to aminoglutethimide. 30% decrease
           Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
           Ciprofloxacin Similar to cimetidine. 40% increase
           Clarithromycin Similar to erythromycin. 25% increase
           Diazepam Benzodiazepines increase CNS concentratrions of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
           Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
           Enoxacin Similar to cimetidine. 300% increase
           Ephedrine Synergistic CNS effects Increased frequency of nausea, nervousness, and insomnia.
           Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
           Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance in unknown.  30% increase
           Flurazepam Similar to diazepam. Similar to diazepam.
           Fluvoxamine Similar to cimetidine. Similar to cimetidine.
           Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. 
           Interferon, human recombinant alpha-A Decreases theophylline clearance.  100% increase
           Isoproterenol (IV) Increase theophylline clearance. 20% increase
           Ketamine Pharmacologic May lower theophylline seizure threshold.
           Lithium  Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
           Lorazepam Similar to diazepam. Similar to diazepam.
           Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect.
           Mexiletine Similar to disulfiram. 80% increase
           Midazolam Similar to diazepam. Similar to diazepam.
           Moricizine Increases theophylline clearance. 25% increase
           Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects;possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
           Pentoxifylline Decreases theophylline clearance. 30% increase
           Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
           Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity.  Serum theophylline and phenytoin concentrations decrease about 40%.
           Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
           Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase Beta-2 blocking effect may decrease efficacy of theophylline.
           Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20-40% decrease
           Sulfinpyrazone Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.  20% increase
           Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase
           Thiabendazole Decreases theophylline clearance. 190% increase
           Ticlopidine Decreases theophylline clearance. 60% increase
           Troleandomycin  Similar to erythromycin. 33-100% increase depending on troleandomycin dose.
           Verapamil Similar to disulfiram. 20% increase
          Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.
           albuterol,  famotidine nizatidine
            systemic and inhaled  felodipine norfloxacin
           amoxicillin finasteride ofloxacin
           ampicillin,  hydrocortisone omeprazole
            with or without  isoflurane  prednisone, prednisolone
            sulbactam  isoniazid ranitidine
           atenolol isradipine rifabutin
           azithromycin influenza vaccine  roxithromycin
           caffeine,  ketoconazole sorbitol
            dietary digestion  lomefloxacin (purgative doses do not
           cefaclor mebendazole  inhibit theophylline
           co-trimoxazole  medroxyprogesterone absorption)
           (trimethoprim and  methylprednisolone  sucralfate
            sulfamethoxazole)  metronidazole terbutaline, systemic
           diltiazem metoprolol terfenadine
           dirithromycin nadolol  tetracycline
           enflurane  nifedipine tocainide


          Taking theophylline extended-release tablets immediately after ingesting a high fat content meal (45 g fat, 55 g carbohydrates, 28 g protein, 789 calories) may result in a somewhat higher Cmax and delayed T, and a somewhat greater extent of absorption when compared to taking it in the fasting state. The influence of the type and amount of other foods, as well as the time interval between drug and food, has not been studied.

          The Effect of Other Drugs on Theophylline Serum Concentration Measurements: Most serum theophylline assays in clinical use are immunoassays which are specific for theophylline. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs (e.g., cefazolin, cephalothin), however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum theophylline concentration.

          Carcinogenesis, Mutagenesis, Impairment of Fertility

          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.

          Theophylline has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.

          In a 14 week continuous breeding study, theophylline, administered to mating pairs of B6C3F1 mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0-3.0 times the human dose on a mg/m2 basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, theophylline was administered to F344 rats and B6C3F1 mice at oral doses of 40-300 mg/kg (approximately 2.0 times the human dose on a mg/m2 basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight.

          Pregnancy

          There are no adequate and well-controlled studies in pregnant women. Additionally, there are no teratogenicity studies in non-rodents (e.g., rabbits). Theophylline was not shown to be teratogenic in CD-1 mice at oral doses up to 400 mg/kg, approximately 2.0 times the human dose on a mg/m basis or in CD-1 rats at oral doses up to 260 mg/kg, approximately 3.0 times the recommended human dose on a mg/m basis. At a dose of 220 mg/kg, embryotoxicity was observed in rats in the absence of maternal toxicity.

          Nursing Mothers

          Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of theophylline in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10-20 mcg/mL of theophylline a day is likely to receive 10-20 mg of theophylline per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum theophylline concentrations.

          Pediatric Use

          Theophylline is safe and effective for the approved indications in pediatric patients. The maintenance dose of theophylline must be selected with caution in pediatric patients since the rate of theophylline clearance is highly variable across the age range of neonates to adolescents (see , Table I, , and , Table V).

          Geriatric Use

          Elderly patients are at significantly greater risk of experiencing serious toxicity from theophylline than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. Theophylline clearance is reduced in patients greater than 60 years of age, resulting in increased serum theophylline concentrations in response to a given theophylline dose. Protein binding may be decreased in the elderly resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of theophylline after chronic overdosage than younger patients. For these reasons, the maximum daily dose of theophylline in patients greater than 60 years of age ordinarily should not exceed 400 mg/day unless the patient continues to be symptomatic and the peak steady-state serum theophylline concentration is

          What are the side effects of Theophylline Extended Release?

          Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are 300 mg/day in adults and >12 mg/kg/day in children beyond 1 year of age). During the initiation of theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of theophylline therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see , Table V). In a small percentage of patients (
          Other adverse reactions that have been reported at serum theophylline concentrations

          Table IV. Manifestations of theophylline toxicity.           Percentage of patients reported with sign or symptom
              
              NR               0 
            Hematemesis  NR               0  NR                2
            Rhabdomyolysis  NR               7  NR               0
            Hypotension/shock  NR               21   NR               8
              3                  21  10                 4



          What should I look out for while using Theophylline Extended Release?

          Theophylline extended-release tablets are contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

          Concurrent Illness: Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

                    Active peptic ulcer disease

                    Seizure disorders

                    Cardiac arrhythmias (not including bradyarrhythmias).

          Conditions that Reduce Theophylline Clearance: There are several readily identifiable causes of reduced theophylline clearance. . Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline concentrations in patients with the following risk factors:

          Age: Neonates (term and premature), children 60 years).

          Concurrent Diseases: Acute pulmonary edema, congestive heart failure, cor-pulmonale, fever (≥ 102° for 24 hours or more; or lesser temperature elevations for longer periods), reduced renal function in infants
          Cessation of Smoking.

          Drug Interactions: Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin). (See , , Table II.)

          When Signs or Symptoms of Theophylline Toxicity Are Present:

          Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately

          Dosage Increases: Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered cortico-steroids in this circumstance and increases the risk of adverse effects. A steady-state serum theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the theophylline dose on the basis of a low serum concentration, the clinician should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see , Laboratory Tests).

          As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum theophylline concentration (see , Table VI).


          What might happen if I take too much Theophylline Extended Release?


          How should I store and handle Theophylline Extended Release?

          Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Keep out of reach of children.Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Keep out of reach of children.Theophylline Extended-release Tablets:300 mg - White, capsule-shaped, bisected tablets in blisterpacks of 30.                Debossed: PLIVA 459Theophylline Extended-release Tablets:300 mg - White, capsule-shaped, bisected tablets in blisterpacks of 30.                Debossed: PLIVA 459


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          Clinical Information

          Chemical Structure

          No Image found
          Clinical Pharmacology

          Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE lll and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE lll or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE lll (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).

          Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.

          Non-Clinical Toxicology
          Theophylline extended-release tablets are contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

          Concurrent Illness: Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

                    Active peptic ulcer disease

                    Seizure disorders

                    Cardiac arrhythmias (not including bradyarrhythmias).

          Conditions that Reduce Theophylline Clearance: There are several readily identifiable causes of reduced theophylline clearance. . Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline concentrations in patients with the following risk factors:

          Age: Neonates (term and premature), children 60 years).

          Concurrent Diseases: Acute pulmonary edema, congestive heart failure, cor-pulmonale, fever (≥ 102° for 24 hours or more; or lesser temperature elevations for longer periods), reduced renal function in infants
          Cessation of Smoking.

          Drug Interactions: Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin). (See , , Table II.)

          When Signs or Symptoms of Theophylline Toxicity Are Present:

          Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately

          Dosage Increases: Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered cortico-steroids in this circumstance and increases the risk of adverse effects. A steady-state serum theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the theophylline dose on the basis of a low serum concentration, the clinician should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see , Laboratory Tests).

          As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum theophylline concentration (see , Table VI).

          Careful consideration of the various interacting drugs and physiologic conditions that can alter theophylline clearance and require dosage adjustment should occur prior to initiation of theophylline therapy, prior to increases in theophylline dose, and during follow up (see ). The dose of theophylline selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of a week or longer with the final dose guided by monitoring serum theophylline concentrations and the patient’s clinical response (see , Table V).

          Monitoring Serum Theophylline Concentrations: Serum theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum theophylline concentration should be measured as follows:

          To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum theophylline concentration: 6-7 hours after a dose at steady-state. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum theophylline concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than seven hours after the dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of theophylline toxicity are present, the serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the clinician without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

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

          Effects on Laboratory Tests: As a result of its pharmacological effects, theophylline at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dL to 6 mg/dL), free fatty acids (from a mean of 451 µεq/L to 800 µεq/L, total cholesterol (from a mean of 140 vs 160 mg/dL), HDL (from a mean of 36 to 50 mg/dL), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Theophylline at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dl after 4 weeks of theophylline). The clinical importance of these changes should be weighed against the potential therapeutic benefit of theophylline in individual patients.

          Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are 300 mg/day in adults and >12 mg/kg/day in children beyond 1 year of age). During the initiation of theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of theophylline therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see , Table V). In a small percentage of patients (
          Other adverse reactions that have been reported at serum theophylline concentrations
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          Reference

          This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
          "https://dailymed.nlm.nih.gov/dailymed/"

          While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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          Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72
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          Interactions

          Interactions

          A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).