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Elixophylline

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Overview

What is Elixophylline?

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:

The molecular formula of anhydrous theophylline is CHNO with a molecular weight of 180.17.

ELIXOPHYLLIN Elixir is available as a liquid intended for oral administration, containing 80 mg of theophylline anhydrous and 20% alcohol in each 15 mL (tablespoonful).

ELIXOPHYLLIN Elixir also contains the following inactive ingredients: citric acid, FD&C Red #40, glycerin, saccharin sodium, imitation tutti frutti fruit flavor and purified water. ELIXOPHYLLIN Elixir has a pH of 3.0 - 4.0.



What does Elixophylline look like?



What are the available doses of Elixophylline?

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What should I talk to my health care provider before I take Elixophylline?

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How should I use Elixophylline?

Theophylline 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.


What interacts with Elixophylline?

ELIXOPHYLLIN Elixir is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.



What are the warnings of Elixophylline?

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:

Conditions That Reduce Theophylline Clearance:

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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 motoring of serum theophylline concentrations in patients with the following risk factors:

Age

Concurrent Diseases

Cessation of Smoking

Drug Interactions

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 beta-selective agonists and systemically administered corticosteroids 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 ).

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 ).


What are the precautions of Elixophylline?

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 ).

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; 1-2 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 two 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 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). 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.

          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 have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the “Effect” column of 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 have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e., <15% change in theophylline clearance).

          The listing of drugs in and 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*.
          * Refer to for further information regarding table.
          ** Average effect on steady state theophylline concentration or other clinical effect forpharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
          DrugType of InteractionEffect**
          AdenosineTheophylline blocksHigher doses of adenosine
          adenosine receptors.may be required to achieve
          desired effect.
          AlcoholA single large dose of alcohol30% increase
          (3 ml/kg of whiskey) decreases
          theophylline clearance for up
          to 24 hours
          AllopurinolDecreases theophylline clearance25% increase at allopurinol
          doses ≥600 mg/day.
          Amino glutethimideIncreases theophylline clearance25% decrease
          by induction of microsomal enzyme
          activity.
          CarbamazepineSimilar to aminoglutethimide30% decrease
          CimetidineDecreases theophylline clearance70% increase
          by inhibiting cytochrome P450 1A2.
          CiprofloxacinSimilar to cimetidine.40% increase
          ClarithromycinSimilar to erythromycin.25% increase
          DiazepamBenzodiazepines increase CNSLarger diazepam doses
          concentrations of adenosine, a potentmay be required to
          CNS depressant, while theophyllineproduce desired level of
          blocks adenosine receptors.sedation. Discontinuation
          of theophylline without
          reduction of diazepam
          dose may result in
          respiratory depression.
          DisulfiramDecreases theophylline clearance50% increase
          by inhibiting hydroxylation and
          demethylation.
          EnoxacinSimilar to cimetidine.300% increase
          EphedrineSynergistic CNS effects.Increased frequency of
          nausea, nervousness,
          and insomnia.
          ErythromycinErythromycin metabolite decreases35% increase.
          theophylline clearance by inhibitingErythromycin steady-state
          cytochrome P450 3A3serum concentrations
          decrease by a similar amount.
          EstrogenEstrogen containing oral contraceptives decrease theophylline30% increase
          clearance in a dose-dependent fashion.
          The effect of progesterone on theophylline
          clearance is unknown.
          FlurazepamSimilar to diazepam.Similar to diazepam.
          FluvoxamineSimilar to cimetidine.Similar to cimetidine.
          HalothaneHalothane sensitizes theIncreased risk of ventricular
          myocardium to catecholamines,arrhythmias
          theophylline increases release of
          endogenous catecholamines.
          Interferon, humanDecreases theophylline clearance.100% increase
          recombinant alpha-A
          Isoproterenol (IV)Increases theophylline clearance.20% decrease
          KetaminePharmacologicMay lower theophylline
          seizure threshold.
          LithiumTheophylline increases renalLithium dose required to
          lithium clearance.achieve a therapeutic
          serum concentration
          increased an average of
          60%.
          LorazepamSimilar to diazepam.Similar to diazepam.
          Methotrexate (MTX)Decreases theophylline clearance.20% increase after low dose
          MTX, higher dose MTX may
          have a greater effect.
          MexiletineSimilar to disulfiram.80% increase
          MidazolamSimilar to diazepam.Similar to diazepam.
          MoricizineIncreases theophylline clearance.25% decrease
          PancuroniumTheophylline may antagonizeLarger dose of pancuronium may be required to
          non-depolarizing neuromuscular
          blocking effects; possibly due toachieve neuromuscular
          phosphodiesterase inhibition.blockade.
          PentoxifyllineDecreases theophylline clearance.30% increase
          Phenobarbital (PB)Similar to aminoglutethimide.25% decrease after two
          weeks of concurrent PB.
          PhenytoinPhenytoin increases theophyllineSerum theophylline and
          clearance by increasing microsomalphenytoin concentrations
          enzyme activity. Theophylline decreases phenytoin absorption.decrease about 40%.
          PropafenoneDecreases theophylline clearance40% increase. Beta-2
          and pharmacologic interaction.blocking effect may
          decrease efficacy of theophylline.
          PropranololSimilar to cimetidine and100% increase. Beta-2
          pharmacologic interaction.blocking effect may
          decrease efficacy
          of theophylline.
          RifampinIncreases theophylline clearance20-40% decrease
          by increasing cytochrome P450 1A2
          and 3A3 activity.
          SulfinpyrazoneIncreases theophylline clearance by20% decrease
          increasing demethylation and hydroxyllation.
          Decreases renal clearance of
          theophylline.
          TacrineSimilar to cimetidine, also increases90% increase
          renal clearance of theophylline.
          ThiabendazoleDecreases theophylline clearance.190% increase
          TiclopidineDecreases theophylline clearance.60% increase
          TroleandomycinSimilar to erythromycin.33-100% increase depending
          on troleandomycin dose.
          VerapamilSimilar 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.*
          * Refer to for information regarding table.
          albuterol,lomefloxacin
             systemic and inhaledmebendazole
          amoxicillinmedroxyprogesterone
          ampicillin,methylprednisolone
             with or without sulbactammetronidazole
          atenololmetoprolol
          azithromycinnadolol
          Caffeine,nifedipine
             dietary ingestionnizatidine
          cefactornorfloxacin
          co-trimoxazoleofloxacin
             (trimethoprim andomeprazole
             sulfamethoxazole)prednisone, prednisolone
          diltiazemranitidine
          dirithromycinrifabutin
          enfluraneroxithromycin
          famotidinesorbitol
          felodipine   (purgative doses do not
          finasteride   inhibit theophylline
          hydrocortisone   absorption)
          isofluranesucralfate
          isoniazid terbutaline,systemic
          isradipineterfenadine
          influenza vaccinetetracycline
          ketoconazoletocainide


          The Effect of Other Drugs on Theophylline Serum Concentration Measurements:

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

          Carcinogenesis, Mutagenesis, and Impairment of Fertility:

          Long term carcinogenicity studies have been carried out in mice (oral doses 30-150 mg/kg) and rats (oral doses 5-75mg/kg). Results are pending.

          Theophylline has been studied in Ames salmonella, and 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:

          CATEGORY C:

          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 per 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 (See ). 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 , and ). Due to the immaturity of theophylline metabolic pathways in infants under the age of one year, particular attention to dosage selection and frequent monitoring of serum theophylline concentrations are required when theophylline is prescribed to pediatric patients in this age group.

          Geriatric Use:

          Elderly patients are at significantly greater risk of experiencing serious toxicity from theophylline than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. Theophylline clearance is reduced in patients greater than 60 years of age, resulting in increased serum theophylline concentrations in response to a given theophylline dose. Protein binding may be decreased in the elderly resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of theophylline after chronic overdosage than younger patients. For these reasons, the maximum daily dose of theophylline in patients greater than 60 years of age ordinarily should not exceed 400 mg/day unless the patient continues to be symptomatic and the peak steady state serum theophylline concentration is <10 mcg/mL (see ). Theophylline doses greater than 400 mg/d should be prescribed with caution in elderly patients.


          What are the side effects of Elixophylline?

          Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum theophylline concentrations exceed 20 mcg/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see ). The transient caffeine-like adverse reactions occur in about 50% of patients when theophylline therapy is initiated at doses higher than recommended initial doses (e.g., >300 mg/day in adults and >12 mg/kg/day in children beyond >1 year of age). During the initiation of theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of theophylline therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see ). In a small percentage of patients (<3% of children and <10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum theophylline concentrations within the therapeutic range (i.e., 10-20 mcg/mL). Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued theophylline therapy and the potential therapeutic benefit of alternative treatment.

          Other adverse reactions that have been reported at serum theophylline concentrations <20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum theophylline concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum theophylline concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum theophylline concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).

          Table IV. Manifestations of theophylline toxicity.* Percentage of patients reported with sign or symptom
          * These data are derived from two studies in patients with serum theophylline 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 theophylline 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 theophylline concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum theophylline concentrations in three emergency departments. Differences in the incidence of manifestations of theophylline 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.
          Acute OverdoseChronic Overdosage
          (Large Single Ingestion)(Multiple Excessive Doses)
          Sign/SymptomStudy 1Study 2Study 1Study 2
          (n=157)(n=14)(n=92)(n=102)
          AsymptomaticNR**0NR**6
          Gastrointestinal
             Vomiting73933061
             Abdominal PainNR**21NR**12
             DiarrheaNR**0NR**14
             HematemesisNR**0NR**2
          Metabolic / Other
             Hypokalemia85794443
             Hyperglycemia98NR**18NR**
             Acid/base disturbance342195
             RhabdomyolysisNR**7NR**0
          Cardiovascular
             Sinus tachycardia1008610062
             Other supraventricular   tachycardias2211214
             Ventricular premature beats3211019
             Atrial fibrillation or flutter1NR**12NR**
             Multifocal atrial tachycardia0NR**2NR**
             Ventricular arrhythmias with   hemodynamic instability714400
             Hypotension/shockNR**21NR**8
          Neurologic
             NervousnessNR**64NR**21
             Tremors38291614
             DisorientationNR**7NR**11
             Seizures514145
          Death321104



          What should I look out for while using Elixophylline?

          ELIXOPHYLLIN Elixir is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.


          What might happen if I take too much Elixophylline?


          How should I store and handle Elixophylline?

          ELIXOPHYLLIN Elixir is a clear red solution with a mixed fruit flavor. Each tablespoonful (15 mL) contains 80 mg theophylline anhydrous.ELIXOPHYLLIN Elixir is available in bottles of473 mL     NDC 0456-0644-16ELIXOPHYLLIN Elixir is a clear red solution with a mixed fruit flavor. Each tablespoonful (15 mL) contains 80 mg theophylline anhydrous.ELIXOPHYLLIN Elixir is available in bottles of473 mL     NDC 0456-0644-16ELIXOPHYLLIN Elixir is a clear red solution with a mixed fruit flavor. Each tablespoonful (15 mL) contains 80 mg theophylline anhydrous.ELIXOPHYLLIN Elixir is available in bottles of473 mL     NDC 0456-0644-16


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          Clinical Information

          Chemical Structure

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          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 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 theophylline 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).

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

          Serum Concentration-Effect Relationship:

          Bronchodilation occurs over the serum theophylline concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum theophylline concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum theophylline concentrations >20mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum theophylline concentrations between 10 and 15 mcg/mL will achieve most of the drug's potential therapeutic benefit while minimizing the risk of serious adverse events.

          Non-Clinical Toxicology
          ELIXOPHYLLIN Elixir is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

          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 have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the “Effect” column of 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 have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e., <15% change in theophylline clearance).

          The listing of drugs in and 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.

          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 ).

          Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum theophylline concentrations exceed 20 mcg/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see ). The transient caffeine-like adverse reactions occur in about 50% of patients when theophylline therapy is initiated at doses higher than recommended initial doses (e.g., >300 mg/day in adults and >12 mg/kg/day in children beyond >1 year of age). During the initiation of theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of theophylline therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see ). In a small percentage of patients (<3% of children and <10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum theophylline concentrations within the therapeutic range (i.e., 10-20 mcg/mL). Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued theophylline therapy and the potential therapeutic benefit of alternative treatment.

          Other adverse reactions that have been reported at serum theophylline concentrations <20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum theophylline concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum theophylline concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum theophylline concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).

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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).