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  • Theophylline Tablets: side effects, for dogs, overdose, levels

    For the use only of a Registered Medical Practitioner or a Hospital or a Laboratory.

    Rx

    D. A. R. NO. ’2CS-3122-37

    Controlled Release Tablets of Theophylline

    Theophyllin_-_Theophylline.svg

    Theophyllin_-_Theophylline.svg

    Theophylline ® 400/600

    CONTINUS® controlled release system

    Description

    Theophylline 400/600 CONTINUS* tablets for oral administration con­tain 400mg/600mg of theophylline B.P. in a controlled release system which allows a 24-hour dosing interval for appropriate patients. Each white tablet bears the symbol   (@) on one side and is marked ‘U/400′ or ‘U/600′ on the other side.

    Clinical Pharmacology

    Theophylline has two distinct actions: smooth muscle relaxation (e.g. bronchodilation) and suppression of the response of the airways to stimuli (i.e. non-bronchodilator prophylactic effects). Studies suggest that bronchodilation 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 tr of PDE III or antagonism of adenosine receptors. Theophylline in­creases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an ad-enosine-mediated channel.

    Serum Concentration-Effect Relationship: Theophylline is often thought of as a drug which has a particularly well-defined therapeutic range with concentration from 5-20 meg/ml giving an optimum compromise between efficacy and toxicity. At serum theophylline concentrations >20mcg/mL, both the frequency and severity of adverse reactions in­crease.

    The pharmacokinetics of theophylline vary widely among similar pa­tients and cannot be predicted by age, sex, body weight or other de­mographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology and co-administration of other drugs can significantly alter the pharmacokinetic characteristics of theophyl­line. Within-subject variability in metabolism has also been reported in some studies.

    It is, therefore, recommended that serum theophylline concentration be measured frequently in severely ill patients (at 24 hour intervals) and periodically (e.g. at 6-12 month intervals) in patients receiving long-term therapy.

    Indications

    For the treatment and prophylaxis of bronchospasm associated with asthma and chronic obstructive pulmonary disease.

    Dosage and Administration

    UNICONTIN3 400/600mg CONTINUS” tablets may be taken once a day in the morning or evening. It is recommended that UNICONTIN* CONTINUS* be taken with meals. Patients should be advised that if they choose to take UNICONTIN* CONTINUS® with food it should be taken consistently with food and if they take it in a fasted condition, it should routinely be taken fasted. It is important that the product when­ever dosed be dosed consistently with or without food. UNICONTIN* CONTINUS® tablets must be swallowed and NOT chewed. UNICONTIN* 600mg CONTINUS* tablets may be split. Infrequently, patients receiving UNICONTIN® CONTINUS® tablets may pass an in­tact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual theophylline. Safety and effective­ness in children under 12 years of age have not been established with UNICONTIN® CONTINUS® tablets.

    Dosing initiation and titration (as anhydrous theophylline) A. Patients Without Risk Factors For Impaired Clearance:

     

    Titration Step Children <45 kg (12-1 5 years) Children >45 kg and Adults (16-60years)

    1.

    Starting dosage 12-14mg/kg/day

    300mg/day administered OD

    300-400mg/day administered OD

    2

    After 3 days, if tolerated, increase dose to : 16mg/kg/day up to a maximum of 400mg/day administered OD 400-600mg/day administered OD

    3

    After 3 more days, if tolerated and if needed, increase dose to : 20mg/kg/day up to a maximum of 600mg/day administered OD As with all theophylline products doses > 600 mg should be titrated according to blood level.

     

    B.Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Se­rum Theophylline Concentrations:

    In children 12-15 years of age, the theophylline dose should not ex­ceed 16mg/kg/day up to a maximum of 400mg daily in the presence of risk factors for reduced theophylline clearance or if it is not feasible to monitor serum theophylline concentrations.

    In adolescents >16 years and adults, including the elderly, the theo­phylline dose should not exceed 400mg/day in the presence of risk factors for reduced theophylline clearance or if it is not feasible to monitor serum theophylline concentrations.

    Dosage adjustment based upon serum theophylline concentration

    Peak serum Concentration

    <9.9mcg/mL

    10-14.9mcg/mL

    15-19.9mcg/mL

    20-24.9mcg/mL

    25-30mcg/mL

    >30mcg/mL

    Dosage Adjustment

    If symptoms are not controlled and current dosage is tolerated, increase dose about 25%. Recheck serum concentration after three days for further dosage adjustment.

    If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 month intervals.* If symptoms are not controlled and current dosage is tolerated, consider adding additional medication(s) to treatment regimen.

    Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated.*

    Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment.

    Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. If symptomatic, consider whether overdose treatment is indicated.

    Treat overdose as indicated. If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.

    * Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur or a drug that interacts with theophylline is added or discontinued.

    Maintenance Therapy

    Careful clinical titration is important to assure patient acceptance and safety of the medication. Patients, when stabilised as established by serum theophylline concentration or respiratory function, usually remain controlled without further dosage adjustment. It should be borne in mind however that for reasons stated in the Warnings And Precautions section, dosage adjustments may be necessary. Serum theophylline levels should be measured periodically (at 6 to 12 month intervals) even in clinically controlled patients.

    The elderly as well as patients with congestive heart failure, cor

    pulmonale and/or liver disease may have unusually low dosage

    requirements and thus may experience toxicity even at the

    recommended dosage.

    Do not maintain any dose that is not tolerated.

    Contraindications

    Patients with a history of hypersensitivity to theophylline or other

    components in the product; porphyria; concomitant administration with

    ephedrine in children.

    Warnings & Precautions

    Serum levels above 20mcg/mL are rarely found after appropriate administration of the recommended doses. However, in individuals in whom theophylline plasma clearance is reduced for any reason, even conventional doses may result in increased serum levels and potential toxicity. Reduced theophylline clearance has been documented in the following readily identifiable groups : 1) patients with impaired liver function, 2) patients over 60 years of age, particularly males and those with chronic lung disease, 3) those with cardiac failure from any cause, 4) patients with acute febrile illness, 5) neonates and infants, 6) hypothyroidism, 7) shock, 8) sepsis with multi-organ failure, and 9) those patients taking certain drugs. Toxic accumulation may occur in above cases. Frequently, such patients have markedly prolonged theophylline serum levels following discontinuation of the drug. Reduction of dosage and laboratory monitoring are especially appropriate in the above individuals. Severe side effects (cramps, convulsions, supraventricular tachycardia) may appear at very high serum concentrations. Patients once titrated to an effective dose, should not be changed from theophylline tablets preparations to other slow or sustained release xanthine preparations without re-titration and clinical assessment. Serious side effects such as ventricular arrhythmias, convulsions or even death may appear as the first sign of toxicity without any previous warning. Whenever a patient receiving theophylline develops nausea and vomiting, particularly repetitive vomiting, or other signs and 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. Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the clinician may instruct the patient to resume the drug at a lower dosage.

    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 increase in theophylline dose, and during follow up. 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.

    On an average, theophylline half-life is shorter in cigarette and marijuana smokers than in non-smokers but smokers can have theophylline half-lives as long as non-smokers.

    Use with caution in patients with cardiac arrhythmias, peptic ulcer, hyperthyroidism, severe hypertension and chronic alcoholism. Avoid concomitant use with other xanthine-containing products. The hypokalaemia resulting from beta agonist therapy, steroids, diuretics and hypoxia may be potentiated by xanthines. Particular care is advised in patients suffering from severe asthma who require hospitalization. It is recommended that serum potassium levels are monitored in such situation. Alternative treatment is advised for patients with a history of seizure activity.

    The herbal remedy St. John’s Wort (Hypericum perforatum) should not be taken at the same time as this medicine. If the patient is already taking St. John’s Wort, consult doctor before stopping the St. John’s Wort preparations.

    Drug-Drug Interactions: The following drug interactions have been

    demonstrated with theophylline:

    Agents That Decrease Theophylline Plasma Levels

    Barbiturates

    Charcoal

    Hydantoins1

    Ketoconazole

    Rifampicin

    Smoking (cigarettes and marijuana)

    Sulfinpyrazone

    Sympathomimetics (B-agonists)

    Thioamines2

    Carbamazepine3

    IsoniazidS

    Loop diureticsS

    Isoprenaline

    Alcohol

    Agents That Increase Theophylline Plasma Levels

    Allopurinol

    Beta blockers (non-selective)

    Calcium channel blockers

    Cimetidine

    Oral contraceptives

    Corticosteroids

    Disulfiram

    Ephedrine

    Influenza virus vaccine

    Interferon

    Macrolides

    Mexiletine

    Quinolones

    Thiabendazole

    Thyroid hormones*

    Carbamazepine3

    Isoniazid3

    Loop diuretics3

    Fluvoxamine

    Fluconazole

    Methotrexate

    Nizatidine

    Oxypentifylline

    Propafenone

    1 Decreased hydantoin levels may also occur.

    2|ncreased theophylline clearance in hyperthyroid patients.

    3May increase or decrease theophylline levels.

    Halothane with theophylline has resulted in catecholamine-induced

    arrhythmias.

    Theophylline decreases plasma levels of Zafirlukast.

    Ketamine and theophylHne co-administration has resulted in extensor-type seizures.

    Lithium plasma levels may be reduced by theophylline. A dose-dependent reversal of neuromuscular blockade by theophylline may occur with nondepolarizing muscle relaxants. Probenecid may increase the pharmacologic effects of theophylline due to decreased theophylline renal excretion. Theophyllines may antagonize the sedative effects of propofol. Case reports suggest that theophylline plasma levels may be increased by ranitidine, possibly increasing pharmacologic and toxic effects. How­ever, several controlled studies indicate that an interaction does not occur. It appears that if this interaction occurs, it is rare. The incidence of theophylline adverse reactions may possibly be en­hanced by concurrent use of tetracyclines.

    Drug-Food Interactions: The absorption characteristics of UNICONTIN® CONTINUS® tablets (theophylline anhydrous) have been studied and are enhanced by co-administration with food.

    Pregnancy and Lactation: Category C- There are no adequate and well controlled studies in pregnant women and there are no teratoge-nicity studies in non-rodents. Embryotoxicity was observed in rats at a dose of 220mg/kg in the absence of maternal toxicity. Theophylline should not be administered during pregnancy unless considered es­sential by the physician. Theophylline is secreted in breast milk and may cause irritability or other signs of toxicity in nursing infants. Be­cause of the potential for serious adverse reactions in nursing infants from theophylline, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.

    Side Effects

    Side effects are usually associated with the serum concentration of theophylline.

     

    Serum theophylline concentration Adverse reactions
    < 20mcg/mL > 20mcg/mL nausea, vomiting, headache, insomnia, tachypnea, epigastric pain, palpitation, hypotension, irritability, persistent vomiting, cardiac arrhythmias, intractable seizures, tachycardia.

    Others: alopecia, hyperglycemia, inappropriate ADH syndrome, rash.

    In a small percentage of patients the caffeine-like adverse effects per­sists during maintenance therapy even at peak serum theophylline con­centration within the therapeutic range (10-20mcg/mL). Dosage reduc­tion may alleviate the adverse effects in these patients. However, per­sistent adverse effects should result in a revaluation of the need for continued theophylline therapy and the potential therapeutic benefit of alternative treatment.

    Overdose

    Overdose with theophylline may be manifested by symptoms such as vomiting, abdominal pain, acid/base disturbance, rhabdomyolysis, si­nus tachycardia, ventricular arrhythmias, nervousness and seizures.

    Treatment of overdosage

    Empty stomach contents. Monitor electrocardiogram and maintain fluid balance. Oral activated charcoal has been found to reduce high theo­phylline serum concentrations. In severe poisoning, employ charcoal-column haemoperfusion. Treat symptoms on appearance. The physi­cian should be aware that tablets in the intestine will continue to re­lease theophylline for a period of hours. In the event of hypokalemia, potassium chloride should be given by slow intravenous infusion. Re­peated measurement of plasma potassium should be made.

    PHARMACEUTICAL PARTICULARS Incompatibilities : None Reported Shelf Life : 36 months Special Precautions for Storage

    Store at or below 25°C, in a dry place, protected from light. Keep out of reach of children.

    Packaging

    UNICONTIN® 400    : UNICONTIN® 600  :

    •Box of 100 tablets (10 x 10′s blister strips). Box of 100 tablets (10 x 10′s blister strips).

    Published on September 26, 2013 · Filed under: Science and Medicine; Tagged as: , ,
    1 Comment

One Response to “Theophylline Tablets: side effects, for dogs, overdose, levels”

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