Adverse reactions : תופעות לוואי

Adverse Reactions
Adverse reactions are uncommon at serum theophylline levels below 20 micrograms/ml, although they may occasionally occur at a lower level.
At a serum level between 20-25 micrograms/ml, the adverse reactions usually experienced are nausea, vomiting, diarrhea, headache and insomnia.
At a level above 30 micrograms/ml, the adverse reactions that appear represent the symptoms of overdosage. These are, in addition to the above, hematemesis, reflex hyperexcitability, muscle twitching, clonic and tonic generalized convulsions, tachycardia, circulatory failure, life-threatening ventricular arrhythmia, tachypnea and albuminuria.
AMINOPHYLLINE                      4. 5. 2014, RH                   Page 4 of 16 
Immune system:
Hypersensitivity reactions (see also Skin and Appendages).

Cardiovascular System:
Tachycardia, palpitations, extrasystoles, increased pulse rate, flushing, hypotension, circulatory failure, atrial and ventricular arrhythmia, peripheral vasocontriction.

Central Nervous System:
Headache, nervousness, insomnia, confusion, hyperventilation, irritability, restlessness, vertigo/dizziness, reflex hyperexcitability, seizures, anxiety, tremor, lightheadedness, excitement. Higher doses may lead to maniacal behavior, delirium and convulsions

Metabolism and nutrition disorders:
Metabolic disturbances such as            hypokalaemia,    hypophosphataemia,     and hyponatraemia may occur.

Eye Disorders:
Visual disturbances.

Gastrointestinal System:
Nausea, vomiting, heartburn, epigastric pain, abdominal cramps, anorexia, diarrhea, gastroesophageal reflux, gastrointestinal bleeding, haematemesis.

Genitourinary:
Increased urination, albuminuria.

Respiratory System:
Tachypnea.
Skin and Appendages:
Ethylenediamine hypersensitivity induced dermatitis (hives, maculo-papular skin rash, erythema, pruritus, urticaria, exfoliative dermatitis, sloughing of skin).

General disorders and administration site conditions :
Intramuscular injections are painful, the pain lasting several hours.
Higher doses may result in hyperthermia and extreme thirst.

Other:
Fever.
Adverse reactions that may occur after too rapid intravenous administration: Chest pain, decrease in blood pressure, dizziness, fast breathing, flushing, headache, pounding heartbeat, reaction to solution or administration technique (chills, fever, pain, redness or swelling at site of injection).

Adverse reactions whose incidence is rare:
Allergic reaction to ethylenediamine in aminophylline (skin rash or hives) {see also above}.
Note: These may not occur for 12 to 24 hours after initial administration.

Precautions
(see Warnings)
Theophylline should not be administered concurrently with other xanthine medications (see Contraindications).

AMINOPHYLLINE                     4. 5. 2014, RH                   Page 5 of 16 

This drug should be used with caution in patients with severe cardiac disease, compromised cardiac or circulatory functions, angina pectoris, acute myocardial injury (since myocardial stimulation would be harmful), severe hypoxemia, hypertension, hyperthyroidism, hypothyroidism, sepsis, seizure disorder, acute myocardial injury, cor pulmonale, congestive heart failure, liver disease, glaucoma, diabetes mellitus, tachyarrhythmias, in the elderly (particularly males) and in neonates. In particular, great caution should be used in giving theophylline to patients with congestive heart failure. Frequently, such patients have markedly prolonged theophylline serum levels.
Theophylline should be used cautiously in patients with gastritis or with a history of peptic ulcer.
Mean half-life in smokers is shorter than in nonsmokers, therefore smokers may require larger doses of theophylline.
Therapeutic doses of xanthines have been shown to induce gastroesophageal reflux when the patient is asleep or recumbent, thereby increasing the potential for aspiration which can aggravate bronchospasm; infants less than 2 years of age and elderly, debilitated, and stuporous patients with feeble gag and cough reflexes are especially susceptible to this effect.
Aminophylline Injection may lower the seizure threshold and should be administered with caution in patients with seizure disorder unless the patient is receiving appropriate anticonvulsant therapy. Dose adjustment of any anticonvulsant medication may be required.
Intravenous aminophylline must be administered slowly and cautiously to prevent dangerous CNS or cardiovascular toxicity. Too rapid intravenous administration may result in the following symptoms: anxiety, headache, nausea and vomiting, severe hypotension, dizziness, faintness, lightheadedness, palpitations, syncope, precordial pain, flushing, profound bradycardia, premature ventricular contractions, cardiac arrest.
Intramuscular administration is not recommended as it causes intense local pain (lasting for several hours) and sloughing of tissue.
The coagulation time of the blood is shortened with aminophylline therapy.
During regular therapy serum potassium levels must be monitored. This is essential during combination therapy with beta2-agonists, corticosteroids or diuretics (which possess hypokalemic effect), or in the presence of hypoxia.

Monitoring Serum Theophylline Concentrations:
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 and prior to increases in theophylline dose

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:
1. Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.
2. Whenever signs or symptoms of theophylline toxicity are present.
3. Whenever there is a new illness, worsening of an existing concurrent illness or a change in the patient’s treatment regimen that may alter theophylline clearance (e.g., fever, hepatitis, or drugs listed in Table I are added or discontinued).


AMINOPHYLLINE                     4. 5. 2014, RH                   Page 6 of 16 
In patients who have received no theophylline in the previous 24 hours, a serum concentration should be measured 30 minutes after completion of the intravenous loading dose to determine whether the serum concentration is <10 mcg/mL indicating the need for an additional loading dose or >20 mcg/mL indicating the need to delay starting the constant I.V. infusion. Once the infusion is begun, a second measurement should be obtained after one expected half-life (e.g., approximately 4 hours in children 1 to 9 years and 8 hours in non-smoking adults. The second measurement should be compared to the first to determine the direction in which the serum concentration has changed. The infusion rate can then be adjusted before steady state is reached in an attempt to prevent an excessive or sub-therapeutic theophylline concentration from being achieved.
If a patient has received theophylline in the previous 24 hours, the serum concentration should be measured before administering an intravenous loading dose to make sure that it is safe to do so. If a loading dose is not indicated (i.e., the serum theophylline concentration is ≥10 mcg/mL), a second measurement should be obtained as above at the appropriate time after starting the intravenous infusion. If, on the other hand, a loading dose is indicated for guidance on selection of the appropriate loading dose), a second blood sample should be obtained after the loading dose and a third sample should be obtained one expected half-life after starting the constant infusion to determine the direction in which the serum concentration has changed.
Once the above procedures related to initiation of intravenous theophylline infusion have been completed, subsequent serum samples for determination of theophylline concentration should be obtained at 24-hour intervals for the duration of the infusion.
The theophylline infusion rate should be increased or decreased as appropriate based on the serum theophylline levels.

When signs or symptoms of theophylline toxicity are present, the intravenous infusion should be stopped and a serum sample for theophylline concentration 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.

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 I have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the “Effect” column of Table I 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.

AMINOPHYLLINE                      4. 5. 2014, RH                   Page 7 of 16 
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 II have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e.,< 15% change in theophylline clearance).
The listing of drugs in Tables I and II are not conclusive. New interactions are continuously being reported for theophylline, especially with new chemical entities.
The clinician should not assume that a drug does not interact with theophylline if it is not listed in Table I. 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 I. Clinically Significant Drug Interactions With Theophylline* 
Drug               Type of Interaction                           Effect** 
Adenosine         Theophylline blocks adenosine           Higher doses of adenosine may be receptors.                              required to achieve desired effect.

Alcohol           A single large dose of alcohol                    30% increase (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.

Allopurinol       Decreases theophylline clearance                  25% increase at allopurinol doses ≥ 600 mg/day.

Aminoglutethimid Increases theophylline clearance                   25% decrease e                by induction of microsomal enzyme activity.

Carbamazepine     Similar to aminoglutethimide.                     30% decrease 
Cimetidine        Decreases theophylline clearance                  70% increase by inhibiting cytochrome P450 1A2.

Ciprofloxacin     Similar to cimetidine.                            40% increase 
Clarithromycin    Similar to erythromycin.                          25% increase 
Diazepam          Benzodiazepines increase CNS          Larger diazepam doses may be concentrations of adenosine, a        required to produce desired level of potent CNS depressant, while          sedation. Discontinuation of theophylline blocks adenosine         theophylline without reduction of receptors.                            diazepam dose may result in respiratory depression.
AMINOPHYLLINE                       4. 5. 2014, RH                      Page 8 of 16 Table I. Clinically Significant Drug Interactions With Theophylline*-continued 
Disulfiram    Decreases theophylline clearance by inhibiting            50% increase hydroxylation and demethylation.

Enoxacin      Similar to cimetidine.                                    300% increase 
Ephedrine     Synergistic CNS effects.                           Increased frequency of nausea, nervousness, and insomnia.

Erythromycin Erythromycin metabolite decreases theophylline      35% increase. Erythromycin clearance by inhibiting cytochrome P450 3A3.        steady-state serum concentrations decrease by a similar amount.

Estrogen      Estrogen containing oral contraceptives decrease          30% increase theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.

Flurazepam    Similar to diazepam.                               Similar to diazepam.

Fluvoxamine   Similar to cimetidine.                           Similar to cimetidine.
The concomitant use of theophylline and fluvoxamine should usually be avoided. Where this is not possible, patients should have their theophylline     dose   halved    and    plasma theophylline should be monitored closely
Halothane     Halothane sensitizes the myocardium to             Increased risk of ventricular catecholamines, theophylline increases release     arrhythmias.
of endogenous catecholamines.

Interferon,   Decreases theophylline clearance.                         100% increase human recombinant alpha-A

Isoproterenol Increases theophylline clearance.                         20% decrease (I.V.)

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.

AMINOPHYLLINE                          4. 5. 2014, RH                  Page 9 of 16 

Methotrexate     Decreases theophylline      20% increase after low dose MTX, higher dose (MTX)            clearance.                  MTX may have a greater effect.

Mexiletine       Similar to disulfiram.                        80% increase 
Table I. Clinically Significant Drug Interactions With Theophylline*-continued 

Midazolam        Similar to diazepam.                               Similar to diazepam.
Moricizine       Increases theophylline clearance.                     25% decrease 
Pancuronium      Theophylline may antagonize                   Larger dose of pancuronium nondepolarizing neuromuscular blocking        may be required to achieve effects; possibly due to phosphodiesterase    neuromuscular blockade.
inhibition.

Pentoxifylline   Decreases theophylline clearance.                     30% increase 
Phenobarbital    Similar to aminoglutethimide.                 25% decrease after two weeks (PB)                                                           of concurrent Phenobarbital.

Phenytoin        Phenytoin increases theophylline clearance    Serum theophylline and by increasing microsomal enzyme activity.     phenytoin concentrations Theophylline decreases phenytoin              decrease about 40%.
absorption.

Propafenone      Decreases theophylline clearance and          40% increase. Beta-2 blocking pharmacologic interaction.                    effect may decrease efficacy of theophylline.

Propranolol      Similar to cimetidine and pharmacologic       100% increase. Beta-2 interaction.                                  blocking effect may decrease efficacy of theophylline.

Rifampin         Increases theophylline clearance by                20 - 40% decrease increasing cytochrome P450 1A2 and 3A3 activity.

Sulfinpyrazone   Increases theophylline clearance by                   20% decrease increasing demethylation and hydroxylation.
Decreases renal clearance of theophylline.

Tacrine          Similar to cimetidine, also increases renal           90% increase clearance of theophylline.

Thiabendazole    Decreases theophylline clearance.                    190% increase 
Ticlopidine      Decreases theophylline clearance.                     60% increase 
Troleandomycin Similar to erythromycin.                        33 - 100% increase depending on troleandomycin dose.

AMINOPHYLLINE                         4. 5. 2014, RH                   Page 10 of 16 

Verapamil                   Similar to disulfiram.                                20% increase 
* Refer to Drug Interactions for further information regarding table.
** Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Table II. Drugs That Have Been Documented Not To Interact With Theophylline Or Drugs That Produce No Clinically Significant Interaction With Theophylline*  albuterol,                                                lomefloxacin systemic and inhaled                                      mebendazole amoxicillin                                               medroxyprogesterone ampicillin,                                               methylprednisolone with or without sulbactam                                 metronidazole atenolol                                                  metoprolol azithromycin                                              nadolol caffeine,                                                 nifedipine dietary ingestion                                         nizatidine cefaclor                                                  norfloxacin co-trimoxazole                                            ofloxacin (trimethoprim and sulfamethoxazole)                       omeprazole diltiazem                                                 prednisone, prednisolone dirithromycin                                             ranitidine enflurane                                                 rifabutin famotidine                                                roxithromycin felodipine                                                sorbitol finasteride                                               (purgative doses do not inhibit hydrocortisone                                            theophylline absorption) isoflurane                                                sucralfate isradipine                                                terbutaline, systemic influenza vaccine                                         terfenadine ketoconazole                                              tetracycline tocainide
* Refer to Drug Interactions for information regarding table.


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.

Other Drug Interactions
Theophylline/Cigarette and Marijuana Smoking:   Cigarette and marijuana smoking induce hepatic metabolism of theophylline. Smokers may therefore require a 50%- 100% increase in dosage.
Theophylline/St. John’s Wort (Hypericum perforatum): Plasma concentration of theophylline can be reduced by concomitant use of the herbal remedy St John's Wort (Hypericum perforatum).


AMINOPHYLLINE                             4. 5. 2014, RH                        Page 11 of 16 
Theophylline/Nicotine Chewing Gum/Other Smoking Deterrents/Cessation of Tobacco Smoking: Smoking cessation may increase the therapeutic effects of the xanthines (except dyphylline) by decreasing metabolism, thereby increasing their serum concentrations; however, after cessation of smoking, normalization of theophylline's pharmacokinetics may not occur for 3 months to 2 years, dosage adjustments may be necessary.
Theophylline/ Digitalis: Theophylline may enhance the sensitivity to and toxicity of digitalis.
Theophylline/ Oral Anticoagulants: Higher than usual doses may increase the effect of oral anticoagulants.
Theophylline/ Reserpine: Administration of theophylline with reserpine can cause tachycardia.
Theophylline/Fluconazole/Zafirlukast: These drugs may increase plasma theophylline concentrations.
Theophylline/Ritonavir: Plasma theophylline concentrations may be decreased.

Other Drug Interactions
Drugs that may decrease aminophylline clearance resulting in increased plasma theophylline concentrations and the potential for increased toxicity.

Quinolone antibiotics
Fluconazole
Isonaizid
Oral contraceptives
Zafirlukast
Thyroid hormones

Drugs that may decrease plasma theophylline concentrations
Ritonavir
Other Interactions
Xanthines: Concurrent use of other xanthine derivatives, including theophylline and pentoxifylline are contraindicated due to the risk of toxicity.

Benzodiazepines: Theophylline may reduce the effects of benzodiazepines.

Quinolones: Increased risk of convulsions.
General anaesthetics: Increased risk of convulsions with ketamine; increased risk of arrhythmias with halothane.

Pancuronium: Resistance to neuromuscular block with pancuronium has been reported in patients receiving aminophylline.

Sympathomimetics: Aminophylline may exhibit synergistic toxicity with ephedrine and other sympathomimetics and concurrent use may dispose the patient to cardiac arrhythmias.

β2-adrenergic agonists: Increased risk of cardiac arrhythmias

β-blockers: Antagonism of bronchodilator effects.
Cardiac glycosides: The direct stimulatory effect of aminophylline on the myocardium may enhance the sensitivity and toxic potential of the cardiac glycosides.


AMINOPHYLLINE                    4. 5. 2014, RH                 Page 12 of 16 
Adenosine: The anti-arrhythmic effect of adenosine is antagonised by theophylline.

Leukotriene antagonists: In clinical trials co-administration with theophylline resulted in decreased plasma levels of zafirlukast, by approximately 30%, but with no effect on plasma theophylline levels. However, during post-marketing surveillance, there have been rare cases of patients experiencing increased theophylline levels when co- administered zafirlukast.

Doxapram: Increased CNS stimulation.

Hypokalaemia:
The hypokalaemic effects of β2-adrenergic agonists may be potentiated by concomitant treatment with aminophylline.
There is an increased risk of hypokalaemia when theophylline derivatives are given with corticosteroids or diuretics


Drug/Food Interactions
Theophylline elimination is increased by a low carbohydrate, high protein diet and charcoal boiled foods. Conversely, the elimination is decreased by a high carbohydrate low protein diet.

Diagnostic Interference
When spectrophotometric methods are used, plasma theophylline concentrations may be falsely increased by coffee, tea, cola beverages, chocolate and paracetamol.
When high pressure liquid chromatography (HPLC) method is used, plasma theophylline concentrations may be falsely increased by caffeine, some cephalosporins and sulfa medications.
Theophylline/Dipyridamole-Assisted Myocardial Perfusion Studies: The theophylline bronchodilators, reverse the effects of dipyridamole on myocardial blood flow, thereby interfering with the test results. Therefore dipyridamole-assisted myocardial perfusion studies should not be performed if therapy with aminophylline, oxtriphylline, or theophylline cannot be withheld for 36 hours prior to the test.

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.

Serum levels should be monitored periodically to determine the theophylline level associated with observed clinical response and as the method of predicting toxicity.

For such measurements, the serum sample should be obtained at the time of peak concentration, 1 or 2 hours after administration for immediate release products. It is important that the patient will not have missed or taken additional doses during the previous 48 hours and that dosing intervals will have been reasonably equally spaced.


AMINOPHYLLINE                     4. 5. 2014, RH                  Page 13 of 16 
Dosage adjustment based on serum theophylline measurements when these instructions have not been followed may result in recommendations that present risk of toxicity to the patient.

Uric acid serum determinations:
Aminophylline produces false-positive elevations of serum uric acid as measured by the Bittner or colorimetric methods, but not by the uricase method.

Dosage and Administration
Parenteral drug products should be inspected visually for particulate matter and discoloration, prior to administration, whenever solution and container permit.
Aminophylline Injection should be administered by the intravenous route.

Aminophylline Injection should always be well diluted and warmed to room temperature.

Acute Symptoms of Bronchospasm Requiring Rapid Attainment of Theophylline Serum Levels for Bronchodilation.
Status asthmaticus should be considered a medical emergency and defined as that degree of bronchospasm which is not rapidly responsive to usual doses of conventional bronchodilators. Optimal therapy for such patients frequently requires both additional medication, parenterally administered, and close monitoring, preferably in an intensive care setting.

Loading Dose
Adults: In patients not currently receiving theophylline products, a loading dose of 6 mg aminophylline/kg body weight should be infused at a rate not exceeding 25 mg/minute. The loading dose should be reduced in patients receiving any theophylline-containing product. Each 0.6 mg aminophylline/kg body weight will result in approximately 1 microgram/ml increase in serum theophylline concentration.

Children: Doses are proportionally smaller and should be determined according to the child's weight.

Maintenance Infusions
The maintenance infusion rates recommended for continuous intravenous infusion of aminophylline are set out in the table below.
Monitoring of serum theophylline concentrations is recommended to accurately maintain therapeutic concentrations and as a guide to dosage adjustments.

Aminophylline Maintenance Infusion Rates (mg/kg body weight/hr)

Patient Group                    First 12 hours   Beyond 12 hours Children 6 months- 9 years                   1.2             1.0

Children 9-16 years and young adult smokers                               1.0            0.8

Otherwise-healthy nonsmoking adults                          0.7            0.5
Older patients and patients with cor pulmonale                    0.6            0.3 
Patients with congestive heart failure or liver disease                 0.5          0.1-0.2 
AMINOPHYLLINE                            4. 5. 2014, RH                 Page 14 of 16