Theophylline

Theophylline belongs to the pharmacological class Methylxanthines. Theophylline appears to have a bronchodilatory effect.

Theophylline had been approved for relieving the symptoms as well as for the treatment and maintenance of episodes of Bradycardia, asthma, Chronic Obstructive Pulmonary Disease, dipyridamole- or regadenoson-induced adverse reactions during nuclear cardiac stress testing, reversal, reversible airflow obstruction, acute symptoms, reversible airflow obstruction, chronic conditions, etc.

Theophylline is completely absorbed after oral administration.The apparent volume of distribution of Theophylline is found to be 0.3 to 0.7 L/kg.Theophylline is said to undergo hepatic metabolism via the cytochrome P450 system. In adults, theophylline and its metabolites undergo renal excretion.

The common side effects associated with Theophylline are an increase in urine volume, lightheadedness, headache, nausea, diarrhea, Persistent vomiting, chest pain or discomfort, dizziness, fainting, fast, slow, or irregular heartbeat, pounding or rapid pulse, etc.

Theophylline is available in the form of Oral and Intravenous formulations.

Theophylline is available in the U.S., Canada, E.U., India, Australia, and Japan.

Theophylline belongs to the pharmacological class Methyl Xanthines.

Theophylline has been found to relax the smooth muscle of the bronchial airways and the pulmonary blood vessels as well as reduces airway responsiveness to methacholine,histamine, adenosine, and allergen. Theophylline is said to competitively inhibit type III and type IV phosphodiesterase (PDE), which is the enzyme that is responsible for breaking down cyclic AMP in smooth muscle cells and possibly resulting in bronchodilation. Theophylline is also said to bind to the adenosine A2B receptor and blocks adenosine-mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase in order to prevent the transcription of inflammatory genes that are required for the acetylation of histones for transcription to begin.

Theophylline had been approved for relieving symptoms and also for the maintenance and treatment of episodes of Bradycardia, asthma, Chronic Obstructive Pulmonary Disease, dipyridamole- or regadenoson-induced adverse reactions during nuclear cardiac stress testing, reversal, reversible airflow obstruction, acute symptoms, reversible airflow obstruction, chronic conditions, etc.

The half-life of administered Theophylline, varies from 3 to 12.8 hours (mean 7.5 hours) in adults and from 1.5 to 7.8 hours (mean 3.4 hours) in children.

The onset of action of Theophylline is 30 minutes. The duration of action of Theophylline is 4-6 hours.

Theophylline can be used in the treatment of:

• Bradycardia
• Asthma
• Chronic Obstructive Pulmonary Disease
• Dipyridamole- or regadenoson-induced adverse reactions during nuclear cardiac stress testing, reversal
• Reversible airflow obstruction, acute symptoms
• Reversible airflow obstruction, chronic conditions

Theophylline is approved for use in the following clinical indications:

• Bradycardia
• Asthma
• Chronic Obstructive Pulmonary Disease
• Dipyridamole- or regadenoson-induced adverse reactions during nuclear cardiac stress testing, reversal
• Reversible airflow obstruction, acute symptoms
• Reversible airflow obstruction, chronic conditions

Oral

Capsule, extended-release (24 hours): 100 mg,200 mg,300 mg,400 mg

Tablet, extended-release (12 hours): 100 mg,200 mg,300 mg,450 mg

Tablet, extended-release (24 hours): 400 mg,600 mg

Oral elixir: 80 mg/15mL

I.V.

Intravenous solution: 400 mg/250mL D5W ,400 mg/500mL D5W ,800 mg/500mL D5W

225 mg; or 105 mg/5 mL; or 100 mg; or 200 mg; or 25 mg/mL; or 250 mg; or 500 mg

Systemic intravenous

• Dosage Adjustments in Hepatic Impairment Patients:

Oral: Use with caution and monitor serum theophylline concentrations frequently.

I.V Initial: 0.2 mg/kg/hour; maximum total daily dose: 400 mg/day unless serum theophylline concentrations indicate the need for a larger dose. Use with caution and monitor serum theophylline concentrations frequently.

• Dosage Adjustments in Pediatric Patients:

Doses should be individualized as per the steady-state serum concentrations; theophylline pharmacokinetics had age-dependent factors which might alter required doses, particularly in pediatric patients.

Infants 4 to 6 weeks: IV: 1.9 mg/kg/dose every 12 hours.

Infants 6 to 52 weeks: Continuous IV infusion: Dose (mg/kg/hour) = [(0.008 × age in weeks) + 0.21] divided by 0.8.

Maintaining health and cessation of smoking are a must.

Caffeine should be limited to use or avoided as it might lead to the risk of nervousness, rapid heartbeat, nausea, palpitations, etc.

Patients with an underlying liver disorder or liver dysfunction must avoid drinking alcohol.

A diet containing food with highly refined and high-energy-dense foods, glycemic index, red and processed meat, saturated and trans fat food, added sugar, salt, preservatives, low fiber, low antioxidants, and vitamins needs to be restricted.

The dietary restrictions need to be individualized as per the patient's requirements.

Theophylline may be contraindicated under the following conditions:

• Theophylline Injection is said to be contraindicated in patients who are hypersensitive to xanthines or to ethylenediamine.
• Theophylline Injection is also found to be contraindicated in patients who have coronary artery disease where myocardial stimulation may prove harmful.
• Theophylline Injection is also contraindicated in patients suffering from bronchiolitis (bronchopneumonia).

The treating physician should be closely monitoring the patients and keep pharmacovigilance as follows:

Theophylline toxicity: Potentially fatal and severe theophylline toxicity might occur if reduced theophylline clearance occurs. Theophylline clearance might be decreased in patients suffering from acute heart failure, pulmonary edema, cor pulmonale, fever i.e.≥102°F for ≥24 hours or lesser temperature elevations for longer periods, sepsis with multiorgan failure, hepatic disease, acute hepatitis, cirrhosis, hypothyroidism shock, infants <1 year, neonates (term and premature), infants <3 Months of age with decreased renal function, elderly >60 years, and patients following cessation of smoking. The benefits should be considered versus the risks and the need for more intensive monitoring in these patients; reduced dosing may be required. If a patient develops symptoms or signs of theophylline toxicity, such as nausea or persistent or repetitive vomiting, a serum theophylline level should be measured immediately, and the subsequent doses should be withheld.

Disease-related concerns:

• Cardiovascular disease: In patients with cardiac arrhythmias (excluding bradyarrhythmias)theophylline should be used with caution, use might exacerbate arrhythmias.

• Cystic fibrosis: In patients with cystic fibrosis, Theophylline should be used cautiously; increased theophylline clearance might occur.

• Hepatic impairment: In patients with hepatic impairment, Theophylline should be used cautiously. The risk of severe and potentially fatal theophylline toxicity is found to be increased. Theophylline clearance is reported to be decreased by≥50% in these patients. It is advised to frequently monitor serum theophylline concentrations.

• Hyperthyroidism: Use with caution in patients suffering from hyperthyroidism; increased theophylline clearance might occur.

• Peptic ulcer disease: Use with caution in patients suffering from active peptic ulcer disease; use might exacerbate a peptic ulcer.

• Seizure disorder: Use with caution in patients suffering from seizure disorders; use might exacerbate seizure disorder.

Avoid alcohol usage while on Theophylline medication, as alcohol can worsen the effects of any other underlying disease condition, including conditions such as blurred vision, dizziness, etc.

Theophylline, as theophylline, is found to be distributed into breast milk and might occasionally induce irritability or other signs of toxicity in the breastfed infants of mothers who are undergoing Theophylline therapy. The concentration of theophylline in breast milk is found to be 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 about 10 - 20 mg of theophylline on a daily basis. Serious adverse effects in the infant are less likely to occur unless the mother has toxic serum theophylline concentrations.

Pregnancy Category C:

Teratogenic Effects

There are found to be no adequate and well-controlled studies on pregnant women. In animal studies, maternal doses of theophylline which is less than 1 to 2 times the recommended oral dose in humans has been reported to cause fetal harm, including fetal malformations. Theophylline should be used during pregnancy only when the potential benefits outweighs the potential risk to the fetus.Post-marketing adverse event and population-based studies and reporting of theophylline which was used during human pregnancy had not demonstrated an increase in risk of major congenital anomalies. However, most studies did not have sufficient subjects to detect a less than 2-fold increase in risk for congenital anomalies. Post-marketing data had been reported voluntarily and these do not always seem to reliably estimate the frequency of particular adverse outcomes. In animal reproduction studies, theophylline had produced teratogenic effects when pregnant rats,mice, and rabbits were dosed during the organogenesis period.

In mice, a single intraperitoneal dose of theophylline at and above 100 mg/kg which is approximately equal to the maximum recommended oral dose for adults on a mg/m2 basis, had resulted in the produced a cleft palate as well as digital abnormalities. Subcutaneous hematoma, open eyelids,Micromelia, micrognathia, club foot, and embryolethality had been observed at doses which is approximately two times the maximum recommended oral dose for adults on the basis of a mg/m2.

In rats which were dosed from conception through organogenesis, an oral dose of 150 mg/kg/day of theophylline which is approximately 2 times the maximum recommended oral dose for adults on the basis of mg/m2 had produced digital abnormalities. Embryolethality occurred at a subcutaneous dose of 200 mg/kg/day which is approximately four times the maximum recommended oral dose for adults on the basis of a mg/m2 . In rabbits which were dosed intravenously throughout organogenesis with 60 mg/kg/day which is approximately two times the maximum recommended oral dose for adults on a mg/m2 basis, had caused cleft palate and was found to be embryolethal. This dose was found to be maternally toxic as one doe died and clinical signs of toxicity had also occurred in others. Doses at and above 15 mg/kg/day which is said to be less than the maximum recommended oral dose for adults on a mg/m2 basis, had caused increased incidence of skeletal variations.

There has been found to be no sufficient evidence on the scientific basis traceable regarding the use and safety of Theophylline in concurrent use with any particular food.

The adverse reactions related to Theophylline can be categorized as:

Common

• Insomnia
• Tremor
• Nausea
• Vomiting
• Diarrhea
• Headache
• Sweating
• Feeling restless or irritable.

The clinically relevant drug interactions of Theophylline is briefly summarized here:

The following drugs might inhibit theophylline metabolism and decrease Theophylline

clearance thereby resulting in increased serum levels and the potential for increased toxicity: alcohol, high dose allopurinol (> 600 mg/day), cimetidine, oestrogen containing oral contraceptives, diltiazem, thyroid hormones, beta-blockers,disulfuram, recombinant alpha-interferon, methotrexate, mexiletine, propranolol, tacrine, thiabendazole,ticlopidine, verapamil, and macrolide antibiotics and quinolones which including erythromycin, clarithromycin, ciprofloxacin and enoxacin.

The following drugs may interact with Theophylline:

Adenosine Theophylline might antagonize the cardiovascular effects of adenosine.

Halothane Concurrent use of Theophylline and halothane might result in ventricular arrythmias.

Ketamine Concurrent use of Theophylline and ketamine might result in a lowered seizure threshold.

Lithium Concurrent use of Theophylline and lithium might result in an increased excretion of lithium, and hence resulting in a reduction in the therapeutic effect of lithium. Adjustment of the lithium dosage might be required.

Beta-agonists Concurrent use of Theophylline and beta-agonists might produce increased cardiotoxic effects. Also, Theophylline might potentiate the hypoglycaemia which might be associated with administration of beta-agonists.

Beta-blocking agents (including ophthalmic agents) Concurrent use of the Theophylline with beta-blockers might result in an inhibition of the bronchodilatory effects of Theophylline.

Benzodiazepines Concurrent use of Theophylline and benzodiazepines might result in a reversal or reduction of the sedative effects of benzodiazepines.

Cardiac glycosides Version: Theophylline might enhance the sensitivity of the myocardium to as well as the toxic potential of cardiac glycosides.

Ephedrine and other sympathomimetic amines The Concurrent use of Theophylline and sympathomimetic amines might result in increased nausea, nervousness or insomnia.

Neuromuscular blocking agents, non-depolarizing Theophylline, might antagonize the neuromuscular blocking effects of these agents.

Xanthines The concurrent use of Theophylline and other xanthine containing medications might result in additive toxicity and should be avoided.

The common side effects of Theophylline include the following:

• Vomiting
• Increased urination (transient)
• Exfoliative dermatitis
• Skeletal muscle tremors
• Central nervous system excitement
• Headache
• Insomnia
• Irritability
• Restlessness
• Seizure
• Diarrhea
• Nausea
• Fast heart rate, flutter
• High calcium levels (hypercalcemia)
• Difficulty urinating (elderly males with prostatism)

Pregnancy Category C:

Teratogenic Effects

There are found to be no adequate and well-controlled studies on pregnant women. In animal studies, maternal doses of theophylline which is less 1 to 2 times the recommended oral dose in humans has been reported to caused fetal harm, including fetal malformations. Theophylline should be used during pregnancy only when the potential benefits outweighs the potential risk to the fetus.Post-marketing adverse event and population-based studies and reporting of theophylline which was used during human pregnancy had not demonstrated an increase in risk of major congenital anomalies. However, most studies did not have sufficient subjects to detect a less than 2-fold increase in risk for congenital anomalies. Post-marketing data had been reported voluntarily and these do not always seem to reliably estimate the frequency of particular adverse outcomes. In animal reproduction studies, theophylline had produced teratogenic effects when pregnant rats,mice, and rabbits were dosed during the organogenesis period.

In mice, a single intraperitoneal dose of theophylline at and above 100 mg/kg which is approximately equal to the maximum recommended oral dose for adults on a mg/m2 basis, had resulted in the produced a cleft palate as well as digital abnormalities. Subcutaneous hematoma, open eyelids,Micromelia, micrognathia, club foot, and embryolethality had been observed at doses which is approximately two times the maximum recommended oral dose for adults on a mg/m2 basis.

In rats which were dosed from conception through organogenesis, an oral dose of 150 mg/kg/day of theophylline which is approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis had produced digital abnormalities. Embryolethality occurred at a subcutaneous dose of 200 mg/kg/day which is approximately 4 times the maximum recommended oral dose for adults on a mg/m2 basis. In rabbits which were dosed intravenously throughout organogenesis with 60 mg/kg/day which is approximately two times the maximum recommended oral dose for adults on a mg/m2 basis, had caused cleft palate and was found to be embryolethal. This dose was found to be maternally toxic as one doe died and the clinical signs of toxicity had also occurred in others. Doses at and above 15 mg/kg/day which is said to be less than the maximum recommended oral dose for adults on a mg/m2 basis, had caused increased the incidence of skeletal variations.

Physicians should be vigilant and knowledgeable about the treatment pertaining to the treatment and identification of overdosage of Theophylline.

There are 2 common presentations: 1)acute overdose, which is said to be an infusion of excessive loading dose or the excessive maintenance infusion rate of theophylline for less than 24 hours, and 2) chronic overdosage,which is excessive maintenance infusion rate for greater than 24 hours.

The most common causes of chronic Theophylline overdose includes the clinician prescribing of an excessive dose or a normal dose of Theophylline in the presence of factors which are known to decrease the rate of the clearance of theophylline as well as increasing the dose of Theophylline in response to an exacerbation of symptoms without measuring first the serum theophylline concentration to determine whether a dose increase is safe.

Pharmacodynamics

Theophylline, is said to be an xanthine derivative chemically similar to theobromine and caffeine, which is used to treat asthma and bronchospasm. Theophylline is said to have 2 distinct actions in the airways of patients with reversible obstruction i.e. asthmatic; smooth muscle relaxation i.e., bronchodilation as well as suppression of the response of the airways to stimuli which are the non-bronchodilator prophylactic effects.

Pharmacokinetics

• Absorption

Theophylline is said to be rapidly and completely absorbed after oral administration in solution or in the immediate-release solid oral dosage form.

• Distribution

Once theophylline is found to enter the systemic circulation, and about 40% is bound to plasma protein, primarily albumin. The Unbound theophylline is distributed throughout body water, but is distributed poorly into body fat. The apparent volume of distribution of theophylline is found to be approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theophylline is found to pass freely across the placenta, into the breast milk as well as into the cerebrospinal fluid (CSF). Saliva theophylline concentrations which approximate unbound serum concentrations, but they are not reliable for routine or therapeutic monitoring unless some special techniques are being used. An increase in the volume of distribution of drug theophylline, which is primarily due to reduction in plasma protein binding, occurs in the premature neonates, in the patients with hepatic cirrhosis, in episodes of uncorrected acidemia, and the older patients and in women during the third trimester of pregnancy. In such cases, the patient might show signs of toxicity at total i.e.bound + unbound serum concentrations of drug theophylline in the therapeutic range which is 10-20 mcg/mL due to the elevated concentrations of the unbound pharmacologically active drug. Similarly, a patient with a decreased theophylline binding might have a subtherapeutic total drug concentration while the pharmacologically active unbound concentration is said to be in the therapeutic range. If only the total serum theophylline concentration is to be measured, this might lead to an unnecessary and potentially dangerous dose increase of theophylline. In the patients with reduced protein binding, the measurement of unbound serum theophylline concentration is said to provide a more reliable means of dosage adjustment than the measurement of total serum theophylline concentration. Generally, it is advised that the concentrations of unbound theophylline should be maintained in the range of 6-12 mcg/mL.

• Metabolism

The main route of metabolism of theophylline is Hepatic. Biotransformation occurs through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is found to be further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose was converted to N-methylated to caffeine. Caffeine and 3-methylxanthine are found to be the only theophylline metabolites with pharmacologic activity.

• Excretion

In neonates, it has been found that approximately 50% of the theophylline dose had been excreted unchanged in the urine. Beyond the first 3 months of life, approximately 10% of theophylline dose had been excreted unchanged in the urine. The remainder had been excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) as well as 3-methylxanthine (15-20%). Since little theophylline was excreted in the unchanged form in the urine and since active metabolites of theophylline such as caffeine, 3-methylxanthine were not found to accumulate to clinically significant levels even in the face of end-stage renal disease, therefore no dosage adjustment for renal insufficiency is foudn to be necessary in adults as well as in the pediatric patients more than three months of age. In contrast, the large fraction of the theophylline dose had been excreted in the urine in the unchanged form as theophylline and caffeine in neonates requires careful attention by reducing frequency of dosing and frequent monitoring of serum theophylline concentrations in neonates with the reduced renal function.

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